In the era of COVID-19, health system pharmacy leaders are struggling to keep up with the scores of demands on their resources and time.

With coronavirus-related emergency department visits and hospitals admissions reminiscent of 2020, especially across the South and Southwest, pharmacy leaders are looking for effective and, in some cases, alternative solutions to help them just make it through a busy week.

503B outsourcing facilities are proving to be crucial partners to health-system and hospital pharmacies in helping to mitigate drug shortages and the impact on patients during the COVID-19 Delta variant surge this summer. The Drug Quality and Security Act, passed in 2013, has allowed 503B outsourcing facilities to compound certain nonsterile and sterile drug products in anticipation of need by providers

 and based on meeting certain standards required by the FDA. With massive demand spikes for critical care medications because of the Delta variant, 503B facilities can supplement hospitals when commercial manufacturers cannot supply.

“Compounding sterile products is a complex business,” said Brian Swift, PharmD, MBA, chief pharmacy officer, enterprise vice president, and associate dean of professional affairs at Jefferson College of Pharmacy at Thomas Jefferson University Hospitals in Philadelphia, Pennsylvania. “503B compounding facilities serve an integral role in how we think about and execute our pharmacy strategy, especially during the pandemic.”

What follows are the 5 reasons to consider a 503B compounding partner:

Many 503B facilities have invested significantly in their operations, creating both expertise and operational capacity to support hundreds of hospitals and physician practice sites across the country. These 503B organizations are highly automated and have redundant systems to generate the high-quality, reproducible products we have come to rely upon as providers. Their product offerings have become standardized over time, which has resulted in more cost-effective production at scale, which brings substantial benefits to a hospital’s pharmacy.

As COVID-19–driven demand surges continue, these same 503B facilities can leverage their scale and relationships with active pharmaceutical ingredient and finished-goods suppliers to generate the much-needed doses of critical medications, such as fentanyl, midazolam, and certain neuromuscular blockers that providers urgently need in the intensive care unit.

This “just in time” inventory approach can help augment drug volumes to get through periods of supply shortages when traditional drug manufacturers and distributors are unable to keep up.

Compounding drugs such as concentrated intrathecal narcotic bags or manipulating nonsterile, raw materials into a final, sterilized product takes money and time. 503Bs can alleviate the burdensome task of compounding high-risk medications and at a lower cost point than many hospitals can achieve. Working with a 503B facility on high-risk medications also minimizes the downstream risk to patients who require them.

With the strain on virtually all hospital staff members during the Delta surge, including pharmacy employees assisting with COVID-19 vaccinations and booster requests, 503B partners can quickly assist by off-loading routine compounded sterile product volume at their offsite location. We are seeing a particular shortage of well-trained pharmacy technicians, so moving some work off the hospital campus may make sense for pharmacy leaders. Most 503B facilities work closely with hospital leadership to coordinate delivery to various facilities as needed. This removes some of the predictable hospital pharmacy clean-room workload, freeing up staff members to focus on the most pressing tasks.

As Premier noted in early 2020, having a multifactorial approach to combat drug shortages, in and out of a pandemic, is essential to providing high-quality patient care.

 The entire US drug supply chain, and most notably hospitals, must become more resilient to weather this surge stage of the pandemic and drive health care transformation for the future.

503Bs can play an important role in enhancing pharmacy supply chain resiliency, but hospitals must choose their 503B facilities wisely. Leveraging multiple 503B partners, for instance, not only avoids putting all one’s eggs in one basket, but also helps competing vendors drive up quality while lowering costs. Diversity and strong 503B partner relationships ultimately benefit patients.

An important aspect when choosing to work with a 503B outsourcing facility is to have a robust vetting process to ensure the highest standards are achieved. For 503Bs failing to meet rigorous inspection or review, these facilities must either invest properly to comply with industry standards or exit the market; there is no third option. Health-system pharmacy leaders expect 503B partners to have the proper controls and procedures in place to produce the highest-quality end products.

Integrating a 503B facility into the pharmacy supply chain strategy has become a key component for hospitals during the global pandemic, and this trend will continue. A 503B’s ability to quickly provide vital medications can help address moment-in-time market imbalances, including spot, regional, and emergency-related shortages, and create added resiliency for the future. 

is vice president of field pharmacy services at Premier, Inc, in Charlotte, North Carolina.

1. Information for outsourcing facilities. FDA. Updated September 10, 2020. Accessed August 31, 2021. https://www.fda.gov/drugs/human-drug-compounding/information-outsourcing-facilities

2. Premier Inc. data shows drugs essential to providing care for COVID-19 patients quickly slipping into shortage. News release. Premier Inc. March 31, 2021. Accessed August 31, 2021. https://www.premierinc.com/newsroom/press-releases/premier-inc-data-shows-drugs-essentialto-providing-care-for-covid-19-patients-quickly-slipping-into-shortage

Articles

Integrating these facilities into the pharmacy supply chain strategy has become key for hospitals during the pandemic.

As COVID-19 Continues to Surge, Turn to 503Bs for Help

Rabies is an acute, fatal, progressive viral disease that claims nearly 60,000 lives a year.

Most deaths occur in Africa and Asia, with approximately 80% in rural areas. Human rabies is rare in the United States because of animal control programs and veterinary vaccination.

 Any mammal can be infected by the rabies virus and may become a carrier, but the most common wild reservoirs include bats, foxes, raccoons, and skunks. The most common domestic reservoirs include cats, cattle, and dogs.

 Contact with infected bats is the leading cause of human rabies in the United States. Worldwide, contact with infected dogs is the leading cause of human rabies death.

The rabies virus is transmitted via direct contact with infectious tissue or fluids of infected mammals. This includes nervous tissue, saliva, respiratory tract fluids, and tears. Direct contact implies broken skin or mucous membranes of the eyes, mouth, or nose.

 The incubation period is between 20 and 60 days but can span several years before the virus enters the central nervous system. The disease manifests as furious rabies, causing hyperactivity, hydrophobia, and sometimes aerophobia, or as paralytic rabies, causing paralysis starting at the site of transmission. Once clinical symptoms appear, survival is rare and associated with permanent disability and severe brain damage.

 Fortunately, vaccinations have nearly eliminated death from rabies.

Recommendations for Prophylaxis and Vaccinations

Per CDC guidelines, the United States population at large does not need vaccinations. Travelers to other countries, particularly Africa and Asia, should visit the CDC Poxvirus and Rabies Branch website (https://www.cdc.gov/rabies/resources/countries-risk.html) to evaluate their risk of rabies exposure and assess their need for postexposure prophylaxis (PEP).

 PEP consists of 1 dose of rabies immune globin and 4 doses of rabies vaccines on days 0,3, 7, and 14.

Travelers should consider preexposure prophylaxis (PrEP) vaccination if planned activities include encounters with domestic or wild animals, if staying longer than a month in an area where dog rabies is common, or if visiting remote areas where medical care may be delayed.

 The CDC categorizes risk into 3 categories: continuous, frequent, and infrequent. The degree of risk is determined by the extent of contact with the rabies virus, such as working in a research lab or in vaccine production (continuous risk), working with animals in endemic rabies areas (frequent risk), traveling to an endemic area, or working with animals in areas where rabies is not endemic (infrequent risk).

In addition to these categories, people who are more likely to encounter rabid animals include adventure travelers, campers, cave explorers, and visitors to rural areas. Consider immunizing children because they may not report bites or may receive more severe bites.

PrEP vaccination was recently updated for immunocompetent individuals 18 years and older to 2 doses on days 0 and 7 rather than 3 doses on days 0, 7, and 21 or 28. The Advisory Committee on Immunization Practices further recommended an intramuscular booster dose of rabies vaccines in lieu of a titer check for immunocompetent individuals 18 years and older with elevated and sustained risk of rabies exposures. This booster dose should be administered no sooner than day 21 and no later than 3 years after the 2-dose PrEP vaccinations.

Those considering PrEP vaccination do not need to delay for minor illness, such as colds. 

Consider delaying vaccination for those with AIDS/HIV, allergic reactions to the rabies vaccine in the past, cancer, or severe allergies, or individuals who are breastfeeding, pregnant, or taking immunocompromising medication. After rabies exposure, all patients should be vaccinated, regardless of any of the above conditions.

 Adverse effects of the vaccine are usually mild and may include dizziness, headache, muscle aches, pain, redness and swelling at the injection site, stomach pain, and upset stomach. Symptoms are self-limiting and resolve in a few days.

The same vaccine is used before and after exposure. The 2 rabies vaccines available in the United States are the human diploid cell vaccine (Imovax Rabies; Sanofi Pasteur SA) and the purified chick embryo cell vaccine (RabAvert; GlaxoSmithKline).

 Both are administered intramuscularly and contain inactivated rabies virus.

 In the event of a shortage or if one vaccine becomes unavailable, the vaccines are interchangeable. If a patient started a series with one vaccine, the other may be used to complete both a pre- and postexposure series.

PrEP is something to consider if traveling to areas with a high probability of encountering domestic or wild animals or if working in a high-risk field. PrEP vaccination does not eliminate the need for treatment after exposure, but it will simplify treatment and provide protection to those unable to seek higher-level care quickly. 

is a clinical pharmacist of infectious diseases at Olathe Health in Kansas City, Missouri.

is chief of hematology oncology pharmacy at Tripler Army Medical Center in Honolulu, Hawaii. 

1. Wallace RM, Petersen BW, Shlim DR. Travel-related infectious diseases - rabies. In: 

. Oxford University Press; 2019:169-392. Accessed August 13, 2021. 

https://wwwnc.cdc.gov/travel/yellowbook/2020/travel-related-infectious-diseases/rabies

2. Rabies and your pet. American Veterinary Medical Association. Accessed August 14, 2021. 

https://www.avma.org/resources/public-health/rabies-and-your-pet

3. What kind of animal did you come in contact with? CDC. June 11, 2019. Accessed August 13, 2021. https://www.cdc.gov/rabies/exposure/animals/index.html

4. Rabies. CDC. Updated September 25, 2020. Accessed August 13, 2021. 

5. Manning SE, Rupprecht CE, Fishbein D, et al; Advisory Committee on Immunization Practices Centers for Disease Control and Prevention (CDC). Human rabies prevention--United States, 2008: recommendations of the Advisory Committee on Immunization Practices. 

6. Rabies. World Health Organization. May 17, 2021. Accessed August 14, 2021. 

https://www.who.int/news-room/fact-sheets/detail/rabies

7. RabAvert. Prescribing information. GlaxoSmithKline; 2018. Accessed August 14, 2021. 

https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Package-Insert---RabAvert.pdf

8. Vaccines by disease. US Department of Health & Human Services. Updated April 29, 2021. Accessed August 14, 2021. 

9. Preexposure vaccinations. CDC. Updated April 22, 2011. Accessed August 14, 2021. 

https://www.cdc.gov/rabies/specific_groups/travelers/pre-exposure_vaccinations.html

10. ACIP recommendations. CDC. Updated July 13, 2021. Accessed August 14, 2021. 

https://www.cdc.gov/vaccines/acip/recommendations.html

11. Imovax Rabies. Prescribing information. Sanofi Pasteur SA; 2019. Accessed August 14, 2021. 

Infectious Diseases Focus

PrEP simplifies management of the virus by eliminating the need for immune globulin and decreasing the number of doses needed.

Hit Me With Your Best Shot: Rabies Pre-exposure Vaccination

Chronic lymphocytic leukemia (CLL) is an indolent B-cell malignancy. Approximately 195,000 people in the United States are living with CLL, and an estimated 21,250 new cases and 4320 deaths are predicted for 2021.

“Small lymphocytic lymphoma (SLL)” is used to describe patients with CLL with limited circulating CLL cells.

 The median age of diagnosis is 72 years, and it’s more common in men.

CLL has a heterogeneous presentation and clinical course.

 Treatment options have evolved from chemoimmunotherapy to the use of targeted small molecules that inhibit Bruton tyrosine kinase (BTK), PI3K, and BCL2.

 National Comprehensive Cancer Network guidelines recommend acalabrutinib (Calquence) plus or minus obinutuzumab (Gazyva), ibrutinib (Imbruvica), or venetoclax (Venclexta) plus obinutuzumab as preferred treatment regimens in the first-line setting and acalabrutinib, ibrutinib, or venetoclax plus rituximab (Rituxan) in the second-line or subsequent therapy setting.

BTK inhibitor therapy (acalabrutinib and ibrutinib) provides high response rates and durable remissions but requires continuous therapy.

 These drugs are generally tolerable, but toxicities developing with continuous therapy include bleeding, cardiac arrhythmias, diarrhea, hypertension, and infection.

 Adherence, cost, drug interactions, and resistance can also pose issues.

Venetoclax inhibits the antiapoptotic molecule BCL2, which is highly expressed in CLL cells. Because venetoclax is highly effective, it can cause tumor lysis syndrome. Venetoclax can also cause neutropenia and thrombocytopenia. Recently, 2 clinical trials investigated fixed-duration therapy with venetoclax and a CD20 monoclonal antibody.

The phase 3 MURANO trial randomized 389 patients with relapsed or refractory (R/R) CLL/SLL after at least 1 prior treatment to either bendamustine-rituximab (BR) for 6 months or venetoclax-rituximab for 2 years. The median age of patients was 65 years. After a median follow-up of 23.8 months, the primary end point of progression-free survival (PFS) was not reached in the venetoclax-rituximab arm and was 17 months in the BR arm.

 Grade 3/4 neutropenia and tumor lysis syndrome occurred in 57.7% and 3.1% of patients treated with venetoclax-rituximab, respectively. A longer follow-up showed continued durability of a fixed-duration regimen with a 4-year PFS of 4.6% in the BR arm and 57.3% in the venetoclax-rituximab arm.

The phase 3 CLL14 trial randomized 432 treatment-naive patients with CLL/SLL for 1 year to either chlorambucil (Leukeran)-obinutuzumab or venetoclax-obinutuzumab. The median age was 72 years. After a median follow-up of 28.1 months, the results favored venetoclax-obinutuzumab (HR, 0.35; P < .001 for PFS).

 Grade 3/4 neutropenia occurred in 52.8% of patients, with no cases of tumor lysis syndrome. At a median of 39.6 months, PFS continued to favor venetoclax-obinutuzumab (HR, 0.31; P < .0001).

The findings of the MURANO trial in R/R and the CLL14 trial in patients who are treatment naive for CLL/SLL showed that fixed-duration venetoclax with a CD20 monoclonal antibody is superior to chemoimmunotherapy (BR or chlorambucil-obinutuzumab) and offers a viable treatment option for patients that allows for treatment-free intervals.

The treatment landscape in CLL/SLL is quickly evolving and offers patients multiple options, including but not limited to continuous therapy with BTK inhibitors and fixed-duration therapy with venetoclax-based regimens. Fixed-duration, venetoclax-based combination therapy may be an option for patients who are resistant or do not tolerate BTK inhibitors or prefer fixed-duration therapy. In addition, fixed-duration venetoclax may limit treatment-related adverse effects, cost, and therapy resistance.

is a hematology/oncology clinical pharmacy specialist at the University of Rochester Medical Center in New York.

1. Chronic lymphocytic leukemia. National Comprehensive Cancer Network. 2021. Accessed August 19, 2021. https://www.nccn.org/patients/guidelines/content/PDF/cll-patient.pdf

2. Cancer stat facts: leukemia — chronic lymphocytic leukemia (CLL). National Cancer Institute. Accessed August 17, 2021. https://seer.cancer.gov/statfacts/html/clyl.html

3. Hallek M. Chronic lymphocytic leukemia: 2020 update on diagnosi s, risk stratifi cation and treatment. Am J Hematol. 2019;94(11):1266-1287. doi:10.1002/ajh.2559

4. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi:10.1182/blood-2017-09-806398

5. Burger JA. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020;383(5):460-473. doi:10.1056/NEJMra1908213

6. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223. doi:10.1056/NEJMoa1400376

7. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388

8. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2

9. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355

10. Lipsky A, Lamanna N. Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology Am Soc Hematol Educ Program. 2020;2020(1):336-345. doi:10.1182/hematology.2020000118

11. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120. doi:10.1056/NEJMoa1713976

12. Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. 2020;38(34):4042-4054. doi:10.1200/JCO.20.00948

13. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi:10.1056/NEJMoa1815281

14. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200. doi:10.1016/S1470-2045(20)30443-5

Patients now have multiple options, including continuous therapy with BTK inhibitors and fixed-duration therapy with venetoclax-based regimens.

Treatment Landscape Is Quickly Evolving for CLL/SLL

The Drug Quality and Security Act was signed into law on November 27, 2013, and included the Title 2 Drug Supply Chain and Security Act (DSCSA).

This legislation was introduced to enact a federal prescription drug safety standard to decrease contamination, counterfeiting, diversion, and otherwise harmful illicit activities. It also improves the detection and elimination of potentially unsafe drugs from the drug supply chain to protect US consumers.

DSCSA required that several key initiatives be implemented and maintained to ensure supply chain safety. These have included building an interoperable system for the handling of suspected counterfeit products and product serialization, tracing, and verification. Components of this regulation have been phased in over time, and manufacturers and suppliers have spent unspecified funds relabeling, retooling, and working on the supply chain with the ultimate goal of unit-level traceability by November 27, 2023.

DSCSA was broad in scope, encompassing prescription drugs in finished form for administration (capsules, tablets, and lyophilized powder for reconstitution). It does not cover, or exempts, several items that are difficult to monitor, including blood or blood components for transfusion; compounded, homeopathic, and imaging drugs; intravenous and OTC products; medical gases; and radioactive biologics and drugs.

Critical components of DSCSA that pharmacists need to know and continuously monitor include the following:

Supply chain participants have been required to electronically share product transaction history with the next member of the chain (interoperable data) until the member is providing the medication to the final user.

 This part often has included significant documentation if the pharmacies are transferring medication between 2 locations. This can now be done electronically. Also, DSCSA required that the transaction, history, information, and statement be provided upon a change of ownership between trading partners.

 Therefore, if pharmacies loan products between pharmacies under different ownership, they would be accountable to provide the statements to the entity where the product is loaned and maintain records for 6 years. Exceptions include distribution among hospitals under common control, intracompany distributions, and public health emergencies dispensed under a prescription.

For serialization, a unique serial number is added to each saleable unit of each prescription product, which has been linked to the information about the product’s batch number, expiration date, and origin. This process allows end-to-end tracing and gives businesses the ability to manage and track many transactions and large data sets between trading partners. The key for pharmacies is that these systems are interoperable.

This is a product for which there is reason to think that it appears unfit for distribution because it could result in serious adverse health consequences or death or it is potentially counterfeit, diverted, stolen, or the subject of a fraudulent transaction. In case of any of these events, the pharmacy will need policies and procedures in place and a segregated area to store the product until a resolution is found.

This is a statement in electronic or paper form, including the information for each prior transaction going back to the product manufacturer.

This includes the names and addresses of the businesses from which and to which ownership was transferred, dosage form, established or proprietary name of a product, lot size, National Drug Code container size, number of containers, product strength, and shipment and transaction dates.

This is a document or electronic statement showing that the entity transferring ownership in a transaction did not deliberately provide false transaction information, knowingly alter the transaction history, or intentionally ship an illegitimate or suspect product; had processes and systems in place to comply with verification requirements under the law; received the product from an individual authorized as required under DSCSA; and received transaction information and a statement from the prior owner of the product, as mandatory under the law.

In the event of a suspect product inquiry, supply chain companies must be able to produce relevant transaction documentation within 24 hours (dispensers have 48 hours). Businesses need a storage and retrieval system that quickly supports these queries. The verification process requires a system be put into place to allow for the quarantine and investigation of suspect products and a mechanism to notify the FDA and trading partners if an illegitimate product is found.

DSCSA was enacted and phased in over the past several years with the intent to help secure the pharmaceutical supply chain. Pharmacy health-system managers should continue to work with FDA-approved partners to analyze their data requirements, operations, and technology and to understand their responsibilities around tracking and tracing.

is vice president of operations support at CompleteRx Ltd in Houston, Texas.

is director of experiential learning, manager of clinical support services, and associate professor of pharmacy practice, administration, and research at Marshall University School of Pharmacy in Huntington, West Virginia.

Alberto Coustasse-Hencke, MD, DrPh, MBA, MPH, 

is a professor of health care management and administration at Marshall University Lewis College of Business in Huntington, West Virginia.

Pharmacy health-system managers should understand the key components of the drug quality and security act.

Law Helps Ensure Safety of the Supply Chain

The American College of Chest Physicians (CHEST) has been developing and publishing guidelines related to venous thromboembolism (VTE) management for more than 30 years.

These clinical practice recommendations guide clinicians and physicians through the prophylaxis and treatment of VTE by covering aspects from initial management through secondary prevention and risk reduction of postthrombotic syndrome.

CHEST's most recent publication, the 10th edition of the Antithrombotic Guideline, contains updated recommendations on 12 topics that were in the ninth edition and addresses 3 new topics.

 These new guidelines also contain 4 new guidance statements that did not appear in the ninth edition (2012) or first update (2016), and 8 statements have been substantially modified in recent years because of new evidence.

VTE is a common condition in which a blood clot forms in a vein, dislodges, and then travels in the blood.

 It is the third-leading vascular diagnosis after heart attack and stroke, affecting more than 900,000 Americans each year, and is associated with considerable morbidity and mortality.

Deep vein thrombosis (DVT) is the result of thrombus formation in a deep vein, most commonly in the lower extremities. Pulmonary embolism (PE) occurs when a thrombus dislodges from a vein and travels to the heart and then to a lung, completely or partially occluding the pulmonary artery or its branches.

The most common triggers for VTE are cancer, hip or leg fracture, hospitalization, immobilization, and surgery. In women, pregnancy and the use of hormones such as estrogen or oral contraceptives for menopause symptoms can also play a role.

Certain groups are at higher risk for clotting, including individuals older than 40 years, with risk doubling each subsequent decade; people with antiphospholipid antibody syndrome, cancer, polycythemia vera, or autoimmune disorders such as lupus; and those who are obese or overweight.

Genetic causes of excessive blood clotting are also important. Inherited traits such as antithrombin deficiency, factor V Leiden, or protein C or S deficiency can contribute to a hypercoagulable state.

The mainstay of therapy for VTE is anti-coagulation, provided there is no contraindication. Following initial anticoagulation, patients with DVT or PE usually continue anticoagulation for a period to prevent embolism, future recurrences, and thrombosis-related death.

In the CHEST guidelines, treatment recommendations are graded as strong (grade 1) and weak (grade 2) based on the level of high-quality (grade A), medium-quality (grade B), or low-quality (grade C) evidence.

The 13 strong recommendations in the 10th edition include the following:

In patients with acute DVT of the leg, guidelines recommend against the use of an inferior vena cava (IVC) filter in addition to anticoagulants.

In patients with acute isolated distal DVT of the leg managed with anticoagulation, the recommendation is to use the same anticoagulant regimen as for patients with acute proximal DVT.

In patients with cerebral venous sinus thrombosis, the recommendation is to use anticoagulation therapy for at least the treatment phase (first 3 months) over no anticoagulant therapy.

In patients with thrombosis and antiphospholipid syndrome being treated with anticoagulant therapy, adjusted-dose vitamin K antagonists are recommended over direct oral anticoagulant therapy.

Recommendations that are unchanged but now supported by better evidence include discouragement of IVC filter use in anticoagulated patients, discouragement of thrombolytic therapy in PE patients who are not hypotensive or deteriorating on anticoagulation, and encouragement of indefinite anticoagulant therapy after a first unprovoked PE.

New evidence also led to several changes, including the use of novel oral anticoagulants (NOACs). NOACs are recommended over vitamin K antagonists (VKAs) for the treatment of VTE in patients without cancer. Low-molecular-weight heparin is still the preferred long-term treatment for cancer and VTE, but it is no longer suggested to use VKAs over NOACs in these patients.

Clinicians often ask which NOAC is preferred, and these guidelines state that individual patients may favor selection of one NOAC over another in patients without or with cancer or may favor selection of a NOAC or VKA in patients with cancer. The guidelines did not express an overall preference for one NOAC over another or for either a NOAC or VKA in patients with cancer because indirect comparisons have not shown convincingly varying outcomes with different NOACs. NOACs have not been compared with VKA in a broad spectrum of patients with VTE and cancer, and there are no direct comparison trials of different NOACs.

Another notable change in the 10th edition is that, based on a new low-risk-of-bias study, graduated compression stockings are not routinely used to prevent postthrombotic syndrome.

VTE treatment and anticoagulation management are common in clinical practice. Pharmacists should be up-to-date with the recommendations and evidence around therapies and knowledgeable about the newest evidence related to VTE management. Although there is still uncertainty related to limited disease and special patient populations, the newest recommendations serve as a guide to therapy.

is the 340B compliance coordinator at Baptist Health in Jacksonville, Florida.

1. CHEST releases new guidelines for antithrombotic therapy in VTE disease. News release. American College of Chest Physicians. August 3, 2021. Accessed August 13, 2021. https://www.chestnet.org/Newsroom/Press-Releases/2021/08/CHEST-releases-new-guidelines-for-antithrombotic-therapy-for-VTE-disease

2. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.02

3. Stevens SM, Woller SC, Baumann Kreuzinger L, et al. Antithrombotic therapy for VTE disease: second update of the CHEST Guideline and Expert Panel Report – executive summary. Chest. Published online July 31, 2021. doi:10.1016/j.chest.2021.07.056

4. Data and statistics on venous thromboembolism. CDC. Updated February 7, 2020. Updated February 7, 2020. Accessed August 23, 2021. https://www.cdc.gov/ncbddd/dvt/data.html

5. Kearon C. Natural history of venous thromboembolism. Circulation. 2003;107(suppl 1):I22-130. doi:10.1161/01.CIR.0000078464.82671.78

6. Philippe HM. Overview of venous thromboembolism. Am J Manag Care. 2017;23 (suppl 20):S376-S382.

7. Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(suppl 1):I9-I16. doi:10.1161/01.CIR.0000078469.07362.E6

8. Schulman S, Kearon C, Kakkar AK, et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718. doi:10.1056/NEJMoa1113697

Clinical Care Focus

Pharmacists should stay knowledgeable about recommendations and evidence related to therapies.

Become Familiar with VTE Treatment and Anticoagulation Management

Post-Intensive Care Syndrome (PICS) comprises a series of ailments that patients experience upon discharge from the hospital following care for a critical illness.

These ailments may be a new occurrence or worsening of a cognitive, mental, or physical health issue. From pain to anxiety and depression to difficulty concentrating and remembering, the manifestation of PICS varies.

The overall population of critical care patients who experience PICS is unknown; however, with improved survival rates and increased ventilator users, many discharged patients experience at least 1 problem associated with PICS. These patients often have trouble returning to their pre-illness state, with some never fully recovering. Resolution of symptoms is dependent upon both the patient and the symptom, with time frames of a few weeks to several years.

PICS can appear in any patient, regardless of demographics or environment. Severity of symptoms also differs, although some risk factors have been defined. Remaining within the intensive care unit (ICU), especially while intubated and sedated, is a major risk factor for developing PICS, which can also result from dysregulated blood glucose, respiratory distress syndrome, prolonged delirium, and sepsis while in the hospital.

Unfortunately, PICS is not exclusive to the patient and can similarly be experienced by caregivers. The patient’s family can develop anxiety, depression, and post-traumatic stress disorder, and maintenance of their well-being is a crucial objective. PICS can, however, be prevented, or at least managed, through close monitoring and interventions. Caregivers, family, and the medical team, including pharmacists, can involve themselves in the patient’s critical care journey to improve the care and prognosis of PICS.

In terms of prevention, there are many factors to consider. Certain drugs used in the ICU have been found to be associated with PICS.

 Also, blood glucose levels are an important laboratory value to monitor in patients in the ICU because hyperglycemia has been found to be associated with increased morbidity and mortality.

Generally, insulin is used to manage blood glucose levels if they become elevated. The clinical guidelines recommend targeting a glucose goal of approximately 140 mg/dL to 180 mg/dL.

 If glucose levels go beyond the recommended target, that is an indication to optimize the insulin dose.

Medications for the treatment of delirium that are a concern in the development of PICS. Antipsychotics not only have weak evidence in the prevention and treatment of delirium but, when used in the ICU, they also can potentially precipitate effects of delirium or other adverse effects and increase the patient’s chances of developing PICS.

 The best way to prevent delirium is through early mobilization. Another concern is that antipsychotics and other medications initiated in the ICU are often continued erroneously during transitions of care.

In terms of comorbidities, pain and sedation are associated with an increased risk of developing PICS. When an individual is sedated for a long period of time, the likelihood of delirium increases, so light sedation using nonbenzodiazepines for the shortest amount of time is preferable. Also, in terms of pain management, nonopioid analgesics are preferred over opioid analgesics because opioids can also cause central nervous system depression and prolonged immobilization.

Monitoring these conditions closely is vital because any improvement in a patient’s status may warrant a dose reduction. Furthermore, pain should be monitored using validated pain scales, such as the Behavioral Pain Scale and the Critical-Care Pain Observation Tool. Monitoring pain helps improve patient experience and quality of life after discharge because individuals who recall pain in the ICU often develop chronic pain.

 Finally, in terms of monitoring sedation, the Richmond Agitation and Sedation Scale or another validated sedation assessment tool should be used.

Transitions of care (TOC) are an important aspect of prevention because medication errors during TOC are common.

 TOC can get complicated for a patient, especially if they are discharged with many different medications. Pharmacists can help by making sure that the medications prescribed to the patient are appropriate for the outpatient setting. Pharmacists can also screen for and discontinue any unnecessary medications to reduce the pill burden for patients. In addition, pharmacists can educate patients about the importance of medication adherence and how nonadherence can lead to the disease state worsening.

Patients who develop PICS are treated based on their symptoms. If their minds are affected, they can be started on medications and therapy. If their physical states are affected, they may initiate exercise and physical therapy. If quality of life is affected, occupational therapy is an option.

There are many avenues through which patients with PICS can heal, and PICS clinics are a promising way to start. These clinics are a developing idea in North America but are well established in Europe.

Traditionally, the clinics include multidisciplinary teams that support patients who have shown at least 1 risk factor for PICS. These teams often include nurses, occupational and physical therapists, physicians, and social workers, but pharmacists can also play a big role by reviewing medications and counseling on adherence and proper use. Through pharmacists’ efforts, therapies can be optimized and mistakes such as potential interactions or unnecessary medications that fell through the cracks during TOC can be corrected.

PICS clinics provide an invaluable opportunity to comfort and educate patients, continue care, and provide patients the opportunity to comment on and share their ICU and post-ICU experiences, empowering them in their care.

Patients requiring ICU care can experience impairments in normal bodily functions that make it difficult to perform self-care and participate in daily activities. This can have a detrimental effect on mental health and overall well-being, which can lead to a greater risk of hospitalization, institutionalization, and mortality.

It is critical to manage PICS with education, follow-up, and medication to lower the rate of these incidences and provide patients with a better quality of life once discharged from the ICU. Health care providers should participate in TOC to minimize the risks of medication error and discontinue unnecessary medications using proper guidelines and protocols. Health care providers should be aware of the risks of and treatments for PICS, not only to better serve patients, but also to help educate caregivers and family members so that they may continue to provide care outside the health care setting.

Winston Su, Olivia Wierciszewski, Kapil Rawal, 

 are PharmD candidates at the Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey in Piscataway.

Deepali Dixit, PharmD, BCPS, BCCCP, FCCM, 

is a clinical associate professor of pharmacy practice and administration at the Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey.

1. Fernandes A, Jaeger MS, Chudow M. Post-intensive care syndrome: a review of preventive strategies and follow-up care.

2019;76(2):119-122. doi:10.1093/ajhp/zxy009

2. Kosinski S, Mohammad RA, Pitcher M, et al. What is post-intensive care syndrome (PICS)? 

. 2020;201(8):15-16. doi:10.1164/rccm.2018P15

3. Viana MV, Moraes RB, Fabbrin AR, Santos MF, Gerchman F. Assessment and treatment of hyperglycemia in critically ill patients.

2014;26(1):71-76. doi:10.5935/0103-507x.20140011

4. Umpierrez GE, Pasquel FJ. Management of inpatient hyperglycemia and diabetes in older adults.

2017;40(4):509-517. doi:10.2337/dc16-0989

5. Agar MR, Lawlor PG, Quinn S, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. 

2017;177(1): 34-42. doi:10.1001/jamainternmed.2016.7491

6. Granja C, Lopes A, Moreira S, Dias C, Costa-Pereira A, Carneiro A; JMIP Study Group. Patients’ recollections of experiences in the intensive care unit may affect their quality of life.

7. Griffiths JA, Barber VS, Cuthbertson BH, Young JD. A national survey of intensive care follow-up clinics. 

 2006;61(10):950-955. doi:10.1111/j.1365-2044.2006.04792.x

8. Stollings JL, Bloom SL, Wang L, Ely EW, Jackson JC, Sevin CM. Critical care pharmacists and medication management in an ICU recovery center. 

2018;52(8):713-723. doi:10.1177/1060028018759343

Managing transitions of care is vital to discontinue use of unnecessary drugs and minimize medication errors.

Pharmacists Can Help Treat Post-Intensive Care Syndrome

Vaccinations are a huge success story in global health care and have helped eliminate smallpox and nearly eradicate polio. According to the CDC, immunization against deadly diseases saves 2 million to 3 million lives per year.

The COVID-19 vaccines are no different. Vaccine effectiveness studies provide a growing body of evidence that mRNA COVID-19 vaccines reduce the risk of contracting the virus, including severe disease, in fully vaccinated individuals by 90% or more.

 Yet vaccine hesitancy or outright opposition is prolonging the pandemic and landing many patients in intensive care units.

According to the results of a survey conducted in August 2021 by Morning Consult, a data intelligence company, 18% of Americans are opposed to getting vaccinated and 10% are hesitant.

Vaccinations are a huge success story in global health care and have helped eliminate smallpox and nearly eradicate polio. 

September 2021