Article

Key clinical point: Nailfold capillaroscopy (NC) outcomes could not conclusively differentiate psoriasis from psoriatic arthritis (PsA).

Major finding: In addition to altered morphology, the density of capillaries at the nailfold was significantly lower in patients with psoriasis (standardized group difference [SMD] −0.91; P  =  .0058; area under curve [AUC] 0.740) and PsA (SMD −1.22; P  =  .0432; AUC, 0.806) compared with control individuals; however, no NC outcomes conclusively differentiated between psoriasis and PsA.

Study details: Findings are from a systematic review and meta-analysis of 22 studies investigating NC as a diagnostic tool for psoriasis or  PsA.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Lazar LT et al. Nailfold capillaroscopy as diagnostic test in patients with psoriasis and psoriatic arthritis: A systematic review. Microvasc Res. 2023;147:104476 (Jan 16). Doi: 10.1016/j.mvr.2023.104476

Key clinical point: Nailfold capillaroscopy (NC) outcomes could not conclusively differentiate psoriasis from psoriatic arthritis (PsA).

Major finding: In addition to altered morphology, the density of capillaries at the nailfold was significantly lower in patients with psoriasis (standardized group difference [SMD] −0.91; P  =  .0058; area under curve [AUC] 0.740) and PsA (SMD −1.22; P  =  .0432; AUC, 0.806) compared with control individuals; however, no NC outcomes conclusively differentiated between psoriasis and PsA.

Study details: Findings are from a systematic review and meta-analysis of 22 studies investigating NC as a diagnostic tool for psoriasis or  PsA.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Lazar LT et al. Nailfold capillaroscopy as diagnostic test in patients with psoriasis and psoriatic arthritis: A systematic review. Microvasc Res. 2023;147:104476 (Jan 16). Doi: 10.1016/j.mvr.2023.104476

Key clinical point: Nailfold capillaroscopy (NC) outcomes could not conclusively differentiate psoriasis from psoriatic arthritis (PsA).

Major finding: In addition to altered morphology, the density of capillaries at the nailfold was significantly lower in patients with psoriasis (standardized group difference [SMD] −0.91; P  =  .0058; area under curve [AUC] 0.740) and PsA (SMD −1.22; P  =  .0432; AUC, 0.806) compared with control individuals; however, no NC outcomes conclusively differentiated between psoriasis and PsA.

Study details: Findings are from a systematic review and meta-analysis of 22 studies investigating NC as a diagnostic tool for psoriasis or  PsA.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Lazar LT et al. Nailfold capillaroscopy as diagnostic test in patients with psoriasis and psoriatic arthritis: A systematic review. Microvasc Res. 2023;147:104476 (Jan 16). Doi: 10.1016/j.mvr.2023.104476

Key clinical point: Regular assessment of bone mineral density and initiation of primary prevention should be considered in patients with psoriatic arthritis (PsA) as they are predisposed to falls and fractures because of reduced bone density, particularly those with late-onset psoriasis involving scalp.

Major finding: Patients with PsA were at a significantly higher risk for osteopenia or osteoporosis (odds ratio [OR] 21.9; CI 7.1-67.7) and prevalent fractures (OR 3.42; P  =  .002) compared with control individuals, with scalp involvement (P  =  .0049) and late onset of psoriasis (P  =  .029) being significantly associated with greater number of prevalent fractures.

Study details: Findings are from an observational cohort study including 61 patients with PsA and 69 age-matched control individuals.

Disclosures: This study did not report the source of funding. The authors reported no conflicts of interest.

Source: Halasi A et al. Psoriatic arthritis and its special features predispose not only for osteoporosis but also for fractures and falls. J Dermatol. 2023 (Jan 17). Doi: 10.1111/1346-8138.16710

Key clinical point: Regular assessment of bone mineral density and initiation of primary prevention should be considered in patients with psoriatic arthritis (PsA) as they are predisposed to falls and fractures because of reduced bone density, particularly those with late-onset psoriasis involving scalp.

Major finding: Patients with PsA were at a significantly higher risk for osteopenia or osteoporosis (odds ratio [OR] 21.9; CI 7.1-67.7) and prevalent fractures (OR 3.42; P  =  .002) compared with control individuals, with scalp involvement (P  =  .0049) and late onset of psoriasis (P  =  .029) being significantly associated with greater number of prevalent fractures.

Study details: Findings are from an observational cohort study including 61 patients with PsA and 69 age-matched control individuals.

Disclosures: This study did not report the source of funding. The authors reported no conflicts of interest.

Source: Halasi A et al. Psoriatic arthritis and its special features predispose not only for osteoporosis but also for fractures and falls. J Dermatol. 2023 (Jan 17). Doi: 10.1111/1346-8138.16710

Key clinical point: Regular assessment of bone mineral density and initiation of primary prevention should be considered in patients with psoriatic arthritis (PsA) as they are predisposed to falls and fractures because of reduced bone density, particularly those with late-onset psoriasis involving scalp.

Major finding: Patients with PsA were at a significantly higher risk for osteopenia or osteoporosis (odds ratio [OR] 21.9; CI 7.1-67.7) and prevalent fractures (OR 3.42; P  =  .002) compared with control individuals, with scalp involvement (P  =  .0049) and late onset of psoriasis (P  =  .029) being significantly associated with greater number of prevalent fractures.

Study details: Findings are from an observational cohort study including 61 patients with PsA and 69 age-matched control individuals.

Disclosures: This study did not report the source of funding. The authors reported no conflicts of interest.

Source: Halasi A et al. Psoriatic arthritis and its special features predispose not only for osteoporosis but also for fractures and falls. J Dermatol. 2023 (Jan 17). Doi: 10.1111/1346-8138.16710

Key clinical point: A dose of 100 mg guselkumab every 4 or 8 weeks (Q4W/Q8W) demonstrated a favorable and consistent safety profile for up to 2 years in both tumor necrosis factor-α inhibitor (TNFi)-naive and TNFi-experienced patients with active psoriatic arthritis (PsA).

Major finding: In TNFi-naive vs TNFi-experienced patients receiving guselkumab, adverse events rates were consistent through 24 weeks (220.8/100 person-years [PY] vs 251.6/100 PY) and remained low through 2 years (139.69/100 PY vs 174.0/100 PY).

Study details: This pooled safety analysis of four phase 2/3 trials included 1554 TNFi-naive and TNFi-experienced patients with active PsA who were randomly assigned to receive 100 mg guselkumab Q4W or Q8W for ≤2 years or placebo with a crossover at week 24 to guselkumab Q4W or Q8W.

Disclosures: The four trials were funded by Janssen Research & Development, LLC. Seven authors declared being current or former employees of Janssen or owning stock or stock options in Johnson & Johnson. Several authors reported ties with Janssen and other sources.

Source: Rahman P et al. Safety of guselkumab with and without prior TNF-α inhibitor treatment: Pooled results across four studies in patients with psoriatic arthritis. J Rheumatol. 2023 (Jan 15). Doi: 10.3899/jrheum.220928

Key clinical point: A dose of 100 mg guselkumab every 4 or 8 weeks (Q4W/Q8W) demonstrated a favorable and consistent safety profile for up to 2 years in both tumor necrosis factor-α inhibitor (TNFi)-naive and TNFi-experienced patients with active psoriatic arthritis (PsA).

Major finding: In TNFi-naive vs TNFi-experienced patients receiving guselkumab, adverse events rates were consistent through 24 weeks (220.8/100 person-years [PY] vs 251.6/100 PY) and remained low through 2 years (139.69/100 PY vs 174.0/100 PY).

Study details: This pooled safety analysis of four phase 2/3 trials included 1554 TNFi-naive and TNFi-experienced patients with active PsA who were randomly assigned to receive 100 mg guselkumab Q4W or Q8W for ≤2 years or placebo with a crossover at week 24 to guselkumab Q4W or Q8W.

Disclosures: The four trials were funded by Janssen Research & Development, LLC. Seven authors declared being current or former employees of Janssen or owning stock or stock options in Johnson & Johnson. Several authors reported ties with Janssen and other sources.

Source: Rahman P et al. Safety of guselkumab with and without prior TNF-α inhibitor treatment: Pooled results across four studies in patients with psoriatic arthritis. J Rheumatol. 2023 (Jan 15). Doi: 10.3899/jrheum.220928

Key clinical point: A dose of 100 mg guselkumab every 4 or 8 weeks (Q4W/Q8W) demonstrated a favorable and consistent safety profile for up to 2 years in both tumor necrosis factor-α inhibitor (TNFi)-naive and TNFi-experienced patients with active psoriatic arthritis (PsA).

Major finding: In TNFi-naive vs TNFi-experienced patients receiving guselkumab, adverse events rates were consistent through 24 weeks (220.8/100 person-years [PY] vs 251.6/100 PY) and remained low through 2 years (139.69/100 PY vs 174.0/100 PY).

Study details: This pooled safety analysis of four phase 2/3 trials included 1554 TNFi-naive and TNFi-experienced patients with active PsA who were randomly assigned to receive 100 mg guselkumab Q4W or Q8W for ≤2 years or placebo with a crossover at week 24 to guselkumab Q4W or Q8W.

Disclosures: The four trials were funded by Janssen Research & Development, LLC. Seven authors declared being current or former employees of Janssen or owning stock or stock options in Johnson & Johnson. Several authors reported ties with Janssen and other sources.

Source: Rahman P et al. Safety of guselkumab with and without prior TNF-α inhibitor treatment: Pooled results across four studies in patients with psoriatic arthritis. J Rheumatol. 2023 (Jan 15). Doi: 10.3899/jrheum.220928

PEMAZYRE® (pemigatinib) is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s)¹. 

PEMAZYRE can cause serious adverse reactions including Ocular Toxicity (Retinal Pigment Epithelial Detachment [RPED] and Dry Eye), Hyperphosphatemia and Soft Tissue Mineralization, and Embryo-Fetal Toxicity. See Additional Important Safety Information Below¹.

Cholangiocarcinoma, or CCA, is a rare cancer formed in the bile duct. It is difficult to diagnose due to generalized symptoms patients often experience². As with any serious disease, the initial diagnosis can be an incredibly overwhelming experience for patients and their families. For people living with CCA specifically, the diagnosis process can be very long and arduous, which often means a patient’s condition can reach an advanced stage where the prognosis is poor by the time he or she is diagnosed³.

Scientific advancements, such as biomarker testing, or genomic analysis of a patient’s tissue, have made it possible to better understand a person’s specific cancer. Understanding patients’ tumors at the molecular level may help health care professionals individualize a treatment plan that is specific to each patient. 

As the genomic profile of CCA has become clearer, actionable alterations in the DNA that are amenable to treatment with either existing agents or those in development have come into focus. Certain actionable genomic alterations have been identified in up to 2/3 of patients with the intrahepatic subtype of CCA, although this percentage may vary in actual practice⁴. Specifically, research has found that fibroblast growth factor receptor 2 (FGFR2) alterations, which play an important role in the development of cancers like CCA, especially the intrahepatic subtype, is on the rise³. This has prompted recognition of comprehensive genomic testing. Due to the rapid advances in precision medicine for CCA, the NCCN guidelines recommend the use of biomarker testing for advanced CCA⁵. 

The First Targeted Treatment Option for CCA

Though an incredibly useful tool, there is a need for further education about the importance of early biomarker testing amongst the medical community. In one large community-based hospital in California, the implementation of a precision medicine program allowed oncologists and pathologists to standardize all tumor biomarker testing, resulting in an increase in testing⁵. However, there is still much improvement needed. What’s more, scientific advancements in recent years have opened the door to targeted treatment options including Pemazyre® (pemigatinib). Pemazyre was approved by the U.S. Food and Drug Administration (FDA) under accelerated approval in 2020 as the first targeted treatment for adults with previously treated, unresectable locally advanced or metastatic CCA with a FGFR2 fusion or other rearrangement as detected by an FDA-approved test.

“The FDA approval of Pemazyre was and continues to be an encouraging milestone for the CCA community, as patients historically had limited options after first-line chemotherapy or surgery, after which relapse rates were high,” said Dr. Sahai.

Pemazyre works by helping to stop the activity of the abnormal FGFR2 protein, which may help reduce the size of CCA tumors or cause them to disappear. Pemazyre’s approval was based on the results of the multicenter, open-label, single arm FIGHT-202 study in 146 previously treated patients with locally advanced or metastatic CCA1. 

• The efficacy population consisted of 107 patients with disease that had progressed on or after at least 1 prior therapy and who had an FGFR2 fusion or non-fusion rearrangement, as determined by a clinical trial assay (FoundationOne® CDx) performed at a central laboratory.
• The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR). The study found an ORR of 36%, and median DoR of 9.1 months. 
• The most common adverse reactions (incidence ≥20%) in all patients were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin.

Meet Fred, Battling CCA

Meet Fred – a man living with CCA. After noticing an unusual amount of blood following what he thought was a normal kidney stone, Fred contacted his doctor right away. Unfortunately, it was not clear from his initial symptoms what the problem was. A computed tomography (CT or CAT) scan revealed Fred did indeed have a kidney stone, but it also showed a large mass had formed on his liver, leading to more testing. After several tests, Fred was diagnosed with CCA. Because of the nonspecific symptoms he had been experiencing, his cancer unfortunately had time to grow. Upon advice from his doctor, Fred met with a CCA specialist who quickly ordered biomarker testing, revealing that he had FGFR2-driven CCA. With a molecular understanding of Fred’s specific CCA, his health care team was able to prescribe him Pemazyre. 

“I’m grateful I was able to start receiving treatment for my condition following chemotherapy and continue to see improvements in my condition,” noted Fred. “Though I fight side effects such as great fatigue, dry eye, dry skin, and fingernail discoloration, these innovations in science that lead to treatments like Pemazyre are what continue to give my family and I hope.”

Through his own experience, Fred has become an advocate for encouraging others living with CCA to educate themselves about the disease and the importance of early biomarker testing. “My advice is to be your own health advocate. Take charge of how your diagnosis and treatment plan is formed with your doctor, and don’t be afraid to speak openly with your doctor about the tools, like biomarker testing, that are available,” said Fred. “I feel fortunate that my health care team initiated biomarker testing quickly after my diagnosis, which enabled me to find an appropriate treatment option for my specific condition. I know that’s not always the case for my fellow CCA warriors, so I urge those in the community to take charge of their health conversations.” 

Leverage The Leading Tools at Hand 

Fred’s story, like that of so many other CCA patients, was a long and winding road to an accurate diagnosis; however, once he was diagnosed, biomarker testing allowed for Fred’s health care team to fully understand his condition, which led to a tailored treatment plan with Pemazyre. While the regular use of biomarker testing is on the rise, it’s critical that health care providers continue to institute early biomarker testing as standard practice, as it may provide the opportunity to quickly and accurately determine the best path forward for their patients. 

For more information about treatment with Pemazyre, visit Pemzayre.com and Full Prescribing Information.  

###

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

PEMAZYRE^® is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

Ocular Toxicity
Retinal Pigment Epithelial Detachment (RPED): PEMAZYRE can cause RPED, which may cause symptoms such as blurred vision, visual floaters, or photopsia. Clinical trials of PEMAZYRE did not conduct routine monitoring including optical coherence tomography (OCT) to detect asymptomatic RPED; therefore, the incidence of asymptomatic RPED with PEMAZYRE is unknown.

Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, RPED occurred in 11% of patients, including Grade 3-4 RPED in 1.3%. The median time to first onset of RPED was 56 days. RPED led to dose interruption of PEMAZYRE in 3.1% of patients, and dose reduction and permanent discontinuation in 1.3% and in 0.2% of patients, respectively. RPED resolved or improved to Grade 1 levels in 76% of patients who required dosage modification of PEMAZYRE for RPED.

Perform a comprehensive ophthalmological examination including OCT prior to initiation of PEMAZYRE and every 2 months for the first 6 months and every 3 months thereafter during treatment. For onset of visual symptoms, refer patients for ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of PEMAZYRE. Modify the dose or permanently discontinue PEMAZYRE as recommended in the prescribing information for PEMAZYRE. 

Dry Eye:  Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, dry eye occurred in 31% of patients, including Grade 3-4 in 1.6% of patients. Treat patients with ocular demulcents as needed.

Hyperphosphatemia and Soft Tissue Mineralization
PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Increases in phosphate levels are a pharmacodynamic effect of PEMAZYRE. Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, hyperphosphatemia was reported in 93% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was 8 days (range 1-169). Phosphate lowering therapy was required in 33% of patients receiving PEMAZYRE.

Monitor for hyperphosphatemia and initiate a low phosphate diet when serum phosphate level is >5.5 mg/dL. For serum phosphate levels >7 mg/dL, initiate phosphate lowering therapy and withhold, reduce the dose, or permanently discontinue PEMAZYRE based on duration and severity of hyperphosphatemia as recommended in the prescribing information.

Embryo-Fetal Toxicity
Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm when administered to a pregnant woman. Oral administration of pemigatinib to pregnant rats during the period of organogenesis caused fetal malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 13.5 mg.

Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.

Adverse Reactions:  Cholangiocarcinoma
Serious adverse reactions occurred in 45% of patients receiving PEMAZYRE (n=146). Serious adverse reactions in ≥2% of patients who received PEMAZYRE included abdominal pain, pyrexia, cholangitis, pleural effusion, acute kidney injury, cholangitis infective, failure to thrive, hypercalcemia, hyponatremia, small intestinal obstruction, and urinary tract infection. Fatal adverse reactions occurred in 4.1% of patients, including failure to thrive, bile duct obstruction, cholangitis, sepsis, and pleural effusion.

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received PEMAZYRE. Adverse reactions requiring permanent discontinuation in ≥1% of patients included intestinal obstruction and acute kidney injury.

Dosage interruptions due to an adverse reaction occurred in 43% of patients who received PEMAZYRE.  Adverse reactions requiring dosage interruption in ≥1% of patients included stomatitis, palmar-plantar erythrodysesthesia syndrome, arthralgia, fatigue, abdominal pain, AST increased, asthenia, pyrexia, ALT increased, cholangitis, small intestinal obstruction, alkaline phosphatase increased, diarrhea, hyperbilirubinemia, electrocardiogram QT prolonged, decreased appetite, dehydration, hypercalcemia, hyperphosphatemia, hypophosphatemia, back pain, pain in extremity, syncope, acute kidney injury, onychomadesis, and hypotension.

Dose reductions due to an adverse reaction occurred in 14% of patients who received PEMAZYRE.  Adverse reactions requiring dosage reductions in ≥1% of patients who received PEMAZYRE included stomatitis, arthralgia, palmar-plantar erythrodysesthesia syndrome, asthenia, and onychomadesis.

Clinically relevant adverse reactions occurring in ≤10% of patients included fractures (2.1%). In all patients treated with pemigatinib, 0.5% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N = 635]). Soft tissue mineralization, including cutaneous calcification, calcinosis, and non-uremic calciphylaxis associated with hyperphosphatemia were observed with PEMAZYRE treatment.

Within the first 21-day cycle of PEMAZYRE dosing, serum creatinine increased (mean increase of 0.2 mg/dL) and reached steady state by Day 8, and then decreased during the 7 days off therapy. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

In cholangiocarcinoma (n=146) the most common adverse reactions (incidence ≥20%) were hyperphosphatemia (60%), alopecia (49%), diarrhea (47%), nail toxicity (43%), fatigue (42%), dysgeusia (40%), nausea (40%), constipation (35%), stomatitis (35%), dry eye (35%), dry mouth (34%), decreased appetite (33%), vomiting (27%), arthralgia (25%), abdominal pain (23%), hypophosphatemia (23%), back pain (20%), and dry skin (20%).

Drug Interactions
Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. Reduce the dose of PEMAZYRE if concomitant use with a strong or moderate CYP3A inhibitor cannot be avoided. Avoid concomitant use of strong and moderate CYP3A inducers with PEMAZYRE.  
Special Populations
Advise lactating women not to breastfeed during treatment with PEMAZYRE and for 1 week after the last dose.

Reduce the recommended dose of PEMAZYRE for patients with severe renal impairment as described in the prescribing information.

Reduce the recommended dose of PEMAZYRE for patients with severe hepatic impairment as described in the prescribing information. 

Please see Full Prescribing Information for PEMAZYRE.

Incyte and the Incyte logo are registered trademarks of Incyte.
PEMAZYRE  and the PEMAZYRE logo are registered trademarks of Incyte.
All other trademarks are the property of their respective owners.
© 2022, Incyte. MAT-PEM-00414  10/22

^{References:
1.    Pemazyre. Prescribing Information. Incyte Corporation. Accessed August 22, 2022.https://www.pemazyre.com/pdf/prescribing-information.pdf.
2.    Signs and Symptoms of Bile Duct Cancer. American Cancer Society. Updated January 27, 2021. Accessed June 16, 2022. https://www.cancer.org/cancer/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html.
3.    Banales JM, Cardinale V, Carpino G, et al. Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the study of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2016;13(5):261-280.
4.    Ross JS, Wang K, Gay L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncol. 2014;19(3):235-242. 
5.    Cho M, Gholami S, Gui D, et al. Optimizing the diagnosis and biomarker testing for patients with intrahepatic cholangiocarcinoma: a multidisciplinary approach. National Library of Medicine. 2022;13(1).} 
 

PEMAZYRE® (pemigatinib) is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s)¹. 

PEMAZYRE can cause serious adverse reactions including Ocular Toxicity (Retinal Pigment Epithelial Detachment [RPED] and Dry Eye), Hyperphosphatemia and Soft Tissue Mineralization, and Embryo-Fetal Toxicity. See Additional Important Safety Information Below¹.

Cholangiocarcinoma, or CCA, is a rare cancer formed in the bile duct. It is difficult to diagnose due to generalized symptoms patients often experience². As with any serious disease, the initial diagnosis can be an incredibly overwhelming experience for patients and their families. For people living with CCA specifically, the diagnosis process can be very long and arduous, which often means a patient’s condition can reach an advanced stage where the prognosis is poor by the time he or she is diagnosed³.

Scientific advancements, such as biomarker testing, or genomic analysis of a patient’s tissue, have made it possible to better understand a person’s specific cancer. Understanding patients’ tumors at the molecular level may help health care professionals individualize a treatment plan that is specific to each patient. 

As the genomic profile of CCA has become clearer, actionable alterations in the DNA that are amenable to treatment with either existing agents or those in development have come into focus. Certain actionable genomic alterations have been identified in up to 2/3 of patients with the intrahepatic subtype of CCA, although this percentage may vary in actual practice⁴. Specifically, research has found that fibroblast growth factor receptor 2 (FGFR2) alterations, which play an important role in the development of cancers like CCA, especially the intrahepatic subtype, is on the rise³. This has prompted recognition of comprehensive genomic testing. Due to the rapid advances in precision medicine for CCA, the NCCN guidelines recommend the use of biomarker testing for advanced CCA⁵. 

The First Targeted Treatment Option for CCA

Though an incredibly useful tool, there is a need for further education about the importance of early biomarker testing amongst the medical community. In one large community-based hospital in California, the implementation of a precision medicine program allowed oncologists and pathologists to standardize all tumor biomarker testing, resulting in an increase in testing⁵. However, there is still much improvement needed. What’s more, scientific advancements in recent years have opened the door to targeted treatment options including Pemazyre® (pemigatinib). Pemazyre was approved by the U.S. Food and Drug Administration (FDA) under accelerated approval in 2020 as the first targeted treatment for adults with previously treated, unresectable locally advanced or metastatic CCA with a FGFR2 fusion or other rearrangement as detected by an FDA-approved test.

“The FDA approval of Pemazyre was and continues to be an encouraging milestone for the CCA community, as patients historically had limited options after first-line chemotherapy or surgery, after which relapse rates were high,” said Dr. Sahai.

Pemazyre works by helping to stop the activity of the abnormal FGFR2 protein, which may help reduce the size of CCA tumors or cause them to disappear. Pemazyre’s approval was based on the results of the multicenter, open-label, single arm FIGHT-202 study in 146 previously treated patients with locally advanced or metastatic CCA1. 

• The efficacy population consisted of 107 patients with disease that had progressed on or after at least 1 prior therapy and who had an FGFR2 fusion or non-fusion rearrangement, as determined by a clinical trial assay (FoundationOne® CDx) performed at a central laboratory.
• The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR). The study found an ORR of 36%, and median DoR of 9.1 months. 
• The most common adverse reactions (incidence ≥20%) in all patients were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin.

Meet Fred, Battling CCA

Meet Fred – a man living with CCA. After noticing an unusual amount of blood following what he thought was a normal kidney stone, Fred contacted his doctor right away. Unfortunately, it was not clear from his initial symptoms what the problem was. A computed tomography (CT or CAT) scan revealed Fred did indeed have a kidney stone, but it also showed a large mass had formed on his liver, leading to more testing. After several tests, Fred was diagnosed with CCA. Because of the nonspecific symptoms he had been experiencing, his cancer unfortunately had time to grow. Upon advice from his doctor, Fred met with a CCA specialist who quickly ordered biomarker testing, revealing that he had FGFR2-driven CCA. With a molecular understanding of Fred’s specific CCA, his health care team was able to prescribe him Pemazyre. 

“I’m grateful I was able to start receiving treatment for my condition following chemotherapy and continue to see improvements in my condition,” noted Fred. “Though I fight side effects such as great fatigue, dry eye, dry skin, and fingernail discoloration, these innovations in science that lead to treatments like Pemazyre are what continue to give my family and I hope.”

Through his own experience, Fred has become an advocate for encouraging others living with CCA to educate themselves about the disease and the importance of early biomarker testing. “My advice is to be your own health advocate. Take charge of how your diagnosis and treatment plan is formed with your doctor, and don’t be afraid to speak openly with your doctor about the tools, like biomarker testing, that are available,” said Fred. “I feel fortunate that my health care team initiated biomarker testing quickly after my diagnosis, which enabled me to find an appropriate treatment option for my specific condition. I know that’s not always the case for my fellow CCA warriors, so I urge those in the community to take charge of their health conversations.” 

Leverage The Leading Tools at Hand 

Fred’s story, like that of so many other CCA patients, was a long and winding road to an accurate diagnosis; however, once he was diagnosed, biomarker testing allowed for Fred’s health care team to fully understand his condition, which led to a tailored treatment plan with Pemazyre. While the regular use of biomarker testing is on the rise, it’s critical that health care providers continue to institute early biomarker testing as standard practice, as it may provide the opportunity to quickly and accurately determine the best path forward for their patients. 

For more information about treatment with Pemazyre, visit Pemzayre.com and Full Prescribing Information.  

###

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

PEMAZYRE^® is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

Ocular Toxicity
Retinal Pigment Epithelial Detachment (RPED): PEMAZYRE can cause RPED, which may cause symptoms such as blurred vision, visual floaters, or photopsia. Clinical trials of PEMAZYRE did not conduct routine monitoring including optical coherence tomography (OCT) to detect asymptomatic RPED; therefore, the incidence of asymptomatic RPED with PEMAZYRE is unknown.

Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, RPED occurred in 11% of patients, including Grade 3-4 RPED in 1.3%. The median time to first onset of RPED was 56 days. RPED led to dose interruption of PEMAZYRE in 3.1% of patients, and dose reduction and permanent discontinuation in 1.3% and in 0.2% of patients, respectively. RPED resolved or improved to Grade 1 levels in 76% of patients who required dosage modification of PEMAZYRE for RPED.

Perform a comprehensive ophthalmological examination including OCT prior to initiation of PEMAZYRE and every 2 months for the first 6 months and every 3 months thereafter during treatment. For onset of visual symptoms, refer patients for ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of PEMAZYRE. Modify the dose or permanently discontinue PEMAZYRE as recommended in the prescribing information for PEMAZYRE. 

Dry Eye:  Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, dry eye occurred in 31% of patients, including Grade 3-4 in 1.6% of patients. Treat patients with ocular demulcents as needed.

Hyperphosphatemia and Soft Tissue Mineralization
PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Increases in phosphate levels are a pharmacodynamic effect of PEMAZYRE. Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, hyperphosphatemia was reported in 93% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was 8 days (range 1-169). Phosphate lowering therapy was required in 33% of patients receiving PEMAZYRE.

Monitor for hyperphosphatemia and initiate a low phosphate diet when serum phosphate level is >5.5 mg/dL. For serum phosphate levels >7 mg/dL, initiate phosphate lowering therapy and withhold, reduce the dose, or permanently discontinue PEMAZYRE based on duration and severity of hyperphosphatemia as recommended in the prescribing information.

Embryo-Fetal Toxicity
Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm when administered to a pregnant woman. Oral administration of pemigatinib to pregnant rats during the period of organogenesis caused fetal malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 13.5 mg.

Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.

Adverse Reactions:  Cholangiocarcinoma
Serious adverse reactions occurred in 45% of patients receiving PEMAZYRE (n=146). Serious adverse reactions in ≥2% of patients who received PEMAZYRE included abdominal pain, pyrexia, cholangitis, pleural effusion, acute kidney injury, cholangitis infective, failure to thrive, hypercalcemia, hyponatremia, small intestinal obstruction, and urinary tract infection. Fatal adverse reactions occurred in 4.1% of patients, including failure to thrive, bile duct obstruction, cholangitis, sepsis, and pleural effusion.

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received PEMAZYRE. Adverse reactions requiring permanent discontinuation in ≥1% of patients included intestinal obstruction and acute kidney injury.

Dosage interruptions due to an adverse reaction occurred in 43% of patients who received PEMAZYRE.  Adverse reactions requiring dosage interruption in ≥1% of patients included stomatitis, palmar-plantar erythrodysesthesia syndrome, arthralgia, fatigue, abdominal pain, AST increased, asthenia, pyrexia, ALT increased, cholangitis, small intestinal obstruction, alkaline phosphatase increased, diarrhea, hyperbilirubinemia, electrocardiogram QT prolonged, decreased appetite, dehydration, hypercalcemia, hyperphosphatemia, hypophosphatemia, back pain, pain in extremity, syncope, acute kidney injury, onychomadesis, and hypotension.

Dose reductions due to an adverse reaction occurred in 14% of patients who received PEMAZYRE.  Adverse reactions requiring dosage reductions in ≥1% of patients who received PEMAZYRE included stomatitis, arthralgia, palmar-plantar erythrodysesthesia syndrome, asthenia, and onychomadesis.

Clinically relevant adverse reactions occurring in ≤10% of patients included fractures (2.1%). In all patients treated with pemigatinib, 0.5% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N = 635]). Soft tissue mineralization, including cutaneous calcification, calcinosis, and non-uremic calciphylaxis associated with hyperphosphatemia were observed with PEMAZYRE treatment.

Within the first 21-day cycle of PEMAZYRE dosing, serum creatinine increased (mean increase of 0.2 mg/dL) and reached steady state by Day 8, and then decreased during the 7 days off therapy. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

In cholangiocarcinoma (n=146) the most common adverse reactions (incidence ≥20%) were hyperphosphatemia (60%), alopecia (49%), diarrhea (47%), nail toxicity (43%), fatigue (42%), dysgeusia (40%), nausea (40%), constipation (35%), stomatitis (35%), dry eye (35%), dry mouth (34%), decreased appetite (33%), vomiting (27%), arthralgia (25%), abdominal pain (23%), hypophosphatemia (23%), back pain (20%), and dry skin (20%).

Drug Interactions
Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. Reduce the dose of PEMAZYRE if concomitant use with a strong or moderate CYP3A inhibitor cannot be avoided. Avoid concomitant use of strong and moderate CYP3A inducers with PEMAZYRE.  
Special Populations
Advise lactating women not to breastfeed during treatment with PEMAZYRE and for 1 week after the last dose.

Reduce the recommended dose of PEMAZYRE for patients with severe renal impairment as described in the prescribing information.

Reduce the recommended dose of PEMAZYRE for patients with severe hepatic impairment as described in the prescribing information. 

Please see Full Prescribing Information for PEMAZYRE.

Incyte and the Incyte logo are registered trademarks of Incyte.
PEMAZYRE  and the PEMAZYRE logo are registered trademarks of Incyte.
All other trademarks are the property of their respective owners.
© 2022, Incyte. MAT-PEM-00414  10/22

^{References:
1.    Pemazyre. Prescribing Information. Incyte Corporation. Accessed August 22, 2022.https://www.pemazyre.com/pdf/prescribing-information.pdf.
2.    Signs and Symptoms of Bile Duct Cancer. American Cancer Society. Updated January 27, 2021. Accessed June 16, 2022. https://www.cancer.org/cancer/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html.
3.    Banales JM, Cardinale V, Carpino G, et al. Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the study of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2016;13(5):261-280.
4.    Ross JS, Wang K, Gay L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncol. 2014;19(3):235-242. 
5.    Cho M, Gholami S, Gui D, et al. Optimizing the diagnosis and biomarker testing for patients with intrahepatic cholangiocarcinoma: a multidisciplinary approach. National Library of Medicine. 2022;13(1).} 
 

PEMAZYRE® (pemigatinib) is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s)¹. 

PEMAZYRE can cause serious adverse reactions including Ocular Toxicity (Retinal Pigment Epithelial Detachment [RPED] and Dry Eye), Hyperphosphatemia and Soft Tissue Mineralization, and Embryo-Fetal Toxicity. See Additional Important Safety Information Below¹.

Cholangiocarcinoma, or CCA, is a rare cancer formed in the bile duct. It is difficult to diagnose due to generalized symptoms patients often experience². As with any serious disease, the initial diagnosis can be an incredibly overwhelming experience for patients and their families. For people living with CCA specifically, the diagnosis process can be very long and arduous, which often means a patient’s condition can reach an advanced stage where the prognosis is poor by the time he or she is diagnosed³.

Scientific advancements, such as biomarker testing, or genomic analysis of a patient’s tissue, have made it possible to better understand a person’s specific cancer. Understanding patients’ tumors at the molecular level may help health care professionals individualize a treatment plan that is specific to each patient. 

As the genomic profile of CCA has become clearer, actionable alterations in the DNA that are amenable to treatment with either existing agents or those in development have come into focus. Certain actionable genomic alterations have been identified in up to 2/3 of patients with the intrahepatic subtype of CCA, although this percentage may vary in actual practice⁴. Specifically, research has found that fibroblast growth factor receptor 2 (FGFR2) alterations, which play an important role in the development of cancers like CCA, especially the intrahepatic subtype, is on the rise³. This has prompted recognition of comprehensive genomic testing. Due to the rapid advances in precision medicine for CCA, the NCCN guidelines recommend the use of biomarker testing for advanced CCA⁵. 

The First Targeted Treatment Option for CCA

Though an incredibly useful tool, there is a need for further education about the importance of early biomarker testing amongst the medical community. In one large community-based hospital in California, the implementation of a precision medicine program allowed oncologists and pathologists to standardize all tumor biomarker testing, resulting in an increase in testing⁵. However, there is still much improvement needed. What’s more, scientific advancements in recent years have opened the door to targeted treatment options including Pemazyre® (pemigatinib). Pemazyre was approved by the U.S. Food and Drug Administration (FDA) under accelerated approval in 2020 as the first targeted treatment for adults with previously treated, unresectable locally advanced or metastatic CCA with a FGFR2 fusion or other rearrangement as detected by an FDA-approved test.

“The FDA approval of Pemazyre was and continues to be an encouraging milestone for the CCA community, as patients historically had limited options after first-line chemotherapy or surgery, after which relapse rates were high,” said Dr. Sahai.

Pemazyre works by helping to stop the activity of the abnormal FGFR2 protein, which may help reduce the size of CCA tumors or cause them to disappear. Pemazyre’s approval was based on the results of the multicenter, open-label, single arm FIGHT-202 study in 146 previously treated patients with locally advanced or metastatic CCA1. 

• The efficacy population consisted of 107 patients with disease that had progressed on or after at least 1 prior therapy and who had an FGFR2 fusion or non-fusion rearrangement, as determined by a clinical trial assay (FoundationOne® CDx) performed at a central laboratory.
• The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR). The study found an ORR of 36%, and median DoR of 9.1 months. 
• The most common adverse reactions (incidence ≥20%) in all patients were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin.

Meet Fred, Battling CCA

Meet Fred – a man living with CCA. After noticing an unusual amount of blood following what he thought was a normal kidney stone, Fred contacted his doctor right away. Unfortunately, it was not clear from his initial symptoms what the problem was. A computed tomography (CT or CAT) scan revealed Fred did indeed have a kidney stone, but it also showed a large mass had formed on his liver, leading to more testing. After several tests, Fred was diagnosed with CCA. Because of the nonspecific symptoms he had been experiencing, his cancer unfortunately had time to grow. Upon advice from his doctor, Fred met with a CCA specialist who quickly ordered biomarker testing, revealing that he had FGFR2-driven CCA. With a molecular understanding of Fred’s specific CCA, his health care team was able to prescribe him Pemazyre. 

“I’m grateful I was able to start receiving treatment for my condition following chemotherapy and continue to see improvements in my condition,” noted Fred. “Though I fight side effects such as great fatigue, dry eye, dry skin, and fingernail discoloration, these innovations in science that lead to treatments like Pemazyre are what continue to give my family and I hope.”

Through his own experience, Fred has become an advocate for encouraging others living with CCA to educate themselves about the disease and the importance of early biomarker testing. “My advice is to be your own health advocate. Take charge of how your diagnosis and treatment plan is formed with your doctor, and don’t be afraid to speak openly with your doctor about the tools, like biomarker testing, that are available,” said Fred. “I feel fortunate that my health care team initiated biomarker testing quickly after my diagnosis, which enabled me to find an appropriate treatment option for my specific condition. I know that’s not always the case for my fellow CCA warriors, so I urge those in the community to take charge of their health conversations.” 

Leverage The Leading Tools at Hand 

Fred’s story, like that of so many other CCA patients, was a long and winding road to an accurate diagnosis; however, once he was diagnosed, biomarker testing allowed for Fred’s health care team to fully understand his condition, which led to a tailored treatment plan with Pemazyre. While the regular use of biomarker testing is on the rise, it’s critical that health care providers continue to institute early biomarker testing as standard practice, as it may provide the opportunity to quickly and accurately determine the best path forward for their patients. 

For more information about treatment with Pemazyre, visit Pemzayre.com and Full Prescribing Information.  

###

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

PEMAZYRE^® is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

Ocular Toxicity
Retinal Pigment Epithelial Detachment (RPED): PEMAZYRE can cause RPED, which may cause symptoms such as blurred vision, visual floaters, or photopsia. Clinical trials of PEMAZYRE did not conduct routine monitoring including optical coherence tomography (OCT) to detect asymptomatic RPED; therefore, the incidence of asymptomatic RPED with PEMAZYRE is unknown.

Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, RPED occurred in 11% of patients, including Grade 3-4 RPED in 1.3%. The median time to first onset of RPED was 56 days. RPED led to dose interruption of PEMAZYRE in 3.1% of patients, and dose reduction and permanent discontinuation in 1.3% and in 0.2% of patients, respectively. RPED resolved or improved to Grade 1 levels in 76% of patients who required dosage modification of PEMAZYRE for RPED.

Perform a comprehensive ophthalmological examination including OCT prior to initiation of PEMAZYRE and every 2 months for the first 6 months and every 3 months thereafter during treatment. For onset of visual symptoms, refer patients for ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of PEMAZYRE. Modify the dose or permanently discontinue PEMAZYRE as recommended in the prescribing information for PEMAZYRE. 

Dry Eye:  Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, dry eye occurred in 31% of patients, including Grade 3-4 in 1.6% of patients. Treat patients with ocular demulcents as needed.

Hyperphosphatemia and Soft Tissue Mineralization
PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Increases in phosphate levels are a pharmacodynamic effect of PEMAZYRE. Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, hyperphosphatemia was reported in 93% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was 8 days (range 1-169). Phosphate lowering therapy was required in 33% of patients receiving PEMAZYRE.

Monitor for hyperphosphatemia and initiate a low phosphate diet when serum phosphate level is >5.5 mg/dL. For serum phosphate levels >7 mg/dL, initiate phosphate lowering therapy and withhold, reduce the dose, or permanently discontinue PEMAZYRE based on duration and severity of hyperphosphatemia as recommended in the prescribing information.

Embryo-Fetal Toxicity
Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm when administered to a pregnant woman. Oral administration of pemigatinib to pregnant rats during the period of organogenesis caused fetal malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 13.5 mg.

Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.

Adverse Reactions:  Cholangiocarcinoma
Serious adverse reactions occurred in 45% of patients receiving PEMAZYRE (n=146). Serious adverse reactions in ≥2% of patients who received PEMAZYRE included abdominal pain, pyrexia, cholangitis, pleural effusion, acute kidney injury, cholangitis infective, failure to thrive, hypercalcemia, hyponatremia, small intestinal obstruction, and urinary tract infection. Fatal adverse reactions occurred in 4.1% of patients, including failure to thrive, bile duct obstruction, cholangitis, sepsis, and pleural effusion.

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received PEMAZYRE. Adverse reactions requiring permanent discontinuation in ≥1% of patients included intestinal obstruction and acute kidney injury.

Dosage interruptions due to an adverse reaction occurred in 43% of patients who received PEMAZYRE.  Adverse reactions requiring dosage interruption in ≥1% of patients included stomatitis, palmar-plantar erythrodysesthesia syndrome, arthralgia, fatigue, abdominal pain, AST increased, asthenia, pyrexia, ALT increased, cholangitis, small intestinal obstruction, alkaline phosphatase increased, diarrhea, hyperbilirubinemia, electrocardiogram QT prolonged, decreased appetite, dehydration, hypercalcemia, hyperphosphatemia, hypophosphatemia, back pain, pain in extremity, syncope, acute kidney injury, onychomadesis, and hypotension.

Dose reductions due to an adverse reaction occurred in 14% of patients who received PEMAZYRE.  Adverse reactions requiring dosage reductions in ≥1% of patients who received PEMAZYRE included stomatitis, arthralgia, palmar-plantar erythrodysesthesia syndrome, asthenia, and onychomadesis.

Clinically relevant adverse reactions occurring in ≤10% of patients included fractures (2.1%). In all patients treated with pemigatinib, 0.5% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N = 635]). Soft tissue mineralization, including cutaneous calcification, calcinosis, and non-uremic calciphylaxis associated with hyperphosphatemia were observed with PEMAZYRE treatment.

Within the first 21-day cycle of PEMAZYRE dosing, serum creatinine increased (mean increase of 0.2 mg/dL) and reached steady state by Day 8, and then decreased during the 7 days off therapy. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

In cholangiocarcinoma (n=146) the most common adverse reactions (incidence ≥20%) were hyperphosphatemia (60%), alopecia (49%), diarrhea (47%), nail toxicity (43%), fatigue (42%), dysgeusia (40%), nausea (40%), constipation (35%), stomatitis (35%), dry eye (35%), dry mouth (34%), decreased appetite (33%), vomiting (27%), arthralgia (25%), abdominal pain (23%), hypophosphatemia (23%), back pain (20%), and dry skin (20%).

Drug Interactions
Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. Reduce the dose of PEMAZYRE if concomitant use with a strong or moderate CYP3A inhibitor cannot be avoided. Avoid concomitant use of strong and moderate CYP3A inducers with PEMAZYRE.  
Special Populations
Advise lactating women not to breastfeed during treatment with PEMAZYRE and for 1 week after the last dose.

Reduce the recommended dose of PEMAZYRE for patients with severe renal impairment as described in the prescribing information.

Reduce the recommended dose of PEMAZYRE for patients with severe hepatic impairment as described in the prescribing information. 

Please see Full Prescribing Information for PEMAZYRE.

Incyte and the Incyte logo are registered trademarks of Incyte.
PEMAZYRE  and the PEMAZYRE logo are registered trademarks of Incyte.
All other trademarks are the property of their respective owners.
© 2022, Incyte. MAT-PEM-00414  10/22

^{References:
1.    Pemazyre. Prescribing Information. Incyte Corporation. Accessed August 22, 2022.https://www.pemazyre.com/pdf/prescribing-information.pdf.
2.    Signs and Symptoms of Bile Duct Cancer. American Cancer Society. Updated January 27, 2021. Accessed June 16, 2022. https://www.cancer.org/cancer/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html.
3.    Banales JM, Cardinale V, Carpino G, et al. Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the study of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2016;13(5):261-280.
4.    Ross JS, Wang K, Gay L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncol. 2014;19(3):235-242. 
5.    Cho M, Gholami S, Gui D, et al. Optimizing the diagnosis and biomarker testing for patients with intrahepatic cholangiocarcinoma: a multidisciplinary approach. National Library of Medicine. 2022;13(1).} 
 

Multiple sclerosis (MS) is one of the most common causes of neurological disability in young adults, occurring more frequently in women than men. The development of anti-cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) in recent years has significantly changed the way we treat MS. Compared to older standards of care, such as chemotherapy and immunosuppressive drugs, anti-CD20 mAbs have been shown to be more effective in treating MS with fewer side effects. 

Data have shown that B cells play a crucial role in the pathogenesis of MS via antigen-driven autoantibody responses and the cross-regulation of T-helper cells. CD20 is a protein that is expressed on the surface of B cells. Since B cells express the surface molecule CD20 at all points of differentiation, they provide a specific target for mAbs and are used to treat certain types of cancer and autoimmune disorders, including MS.

In people living with MS, the immune system mistakenly attacks the myelin sheath, a protective layer that surrounds nerve fibers in the central nervous system. This attack can cause inflammation and damage to the myelin sheath, leading to the development of various symptoms such as muscle weakness, vision problems, and issues with coordination and balance.

Anti-CD20 antibodies work by targeting and destroying B cells, which play a role in the immune system's attack on the myelin sheath. By targeting and destroying these cells, anti-CD20 antibodies may help to reduce the inflammation and damage to the myelin sheath and improve symptoms of MS.

There are several anti-CD20 mAbs used for the treatment of MS, including ocrelizumab, ofatumumab, ublituximab, and rituximab. Each drug has a unique mechanism of action and safety profile and distinct monitoring requirements. These therapies have been shown to deplete circulating B cells significantly for a certain amount of time, and they may be used in combination with other medications to treat MS. 

Ocrelizumab, a humanized anti-CD20 mAb administered by intravenous (IV) infusion, was approved in March 2017 by the US Food and Drug Administration (FDA) and is the first proven treatment to reduce disability progression in both primary progressive MS and relapsing MS. Interestingly, ocrelizumab binds to a CD20 epitope that overlaps partially with the epitope to which rituximab binds.

Ofatumumab is the first fully human anti-CD20 mAb and was approved by the FDA in August 2020 for treating relapsing forms of MS. The approval was on the basis of data from the phase 3 ASCLEPIOS I and II trials, which compared ofatumumab with teriflunomide, an oral agent that reduces the activity of proliferating T lymphocytes and B lymphocytes, mitigating the overall inflammatory response in MS. Subcutaneous ofatumumab demonstrated better efficacy than oral teriflunomide in reducing the annualized relapse rate in patients with MS. 

Ublituximab was recently approved by the FDA for treatment of relapsing forms of MS, including relapsing-remitting MS and active secondary progressive MS. Ublituximab works much like other anti-CD20 antibodies; however, it has been glycoengineered so that certain altered sugar molecules attached to the antibody increase its effectiveness. 

Rituximab is a chimeric monoclonal B-cell–depleting anti-CD20 antibody that has also showed promise as an escalation and as a first-line therapy for MS. The FDA has not approved it for this specific use yet, so its use is considered “off label.” A 2017 study showed that ofatumumab was more effective at depleting B cells than high doses of IV rituximab. 

It is important to note that anti-CD20 antibodies are not a cure for MS, and although they show promise for some patients, these agents do not work for everyone. The progress, severity, and specific symptoms of MS in any individual cannot yet be predicted; however, advances in research and treatment are leading to better understanding and moving us closer to curing this unpredictable, debilitating disease.

Multiple sclerosis (MS) is one of the most common causes of neurological disability in young adults, occurring more frequently in women than men. The development of anti-cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) in recent years has significantly changed the way we treat MS. Compared to older standards of care, such as chemotherapy and immunosuppressive drugs, anti-CD20 mAbs have been shown to be more effective in treating MS with fewer side effects. 

Data have shown that B cells play a crucial role in the pathogenesis of MS via antigen-driven autoantibody responses and the cross-regulation of T-helper cells. CD20 is a protein that is expressed on the surface of B cells. Since B cells express the surface molecule CD20 at all points of differentiation, they provide a specific target for mAbs and are used to treat certain types of cancer and autoimmune disorders, including MS.

In people living with MS, the immune system mistakenly attacks the myelin sheath, a protective layer that surrounds nerve fibers in the central nervous system. This attack can cause inflammation and damage to the myelin sheath, leading to the development of various symptoms such as muscle weakness, vision problems, and issues with coordination and balance.

Anti-CD20 antibodies work by targeting and destroying B cells, which play a role in the immune system's attack on the myelin sheath. By targeting and destroying these cells, anti-CD20 antibodies may help to reduce the inflammation and damage to the myelin sheath and improve symptoms of MS.

There are several anti-CD20 mAbs used for the treatment of MS, including ocrelizumab, ofatumumab, ublituximab, and rituximab. Each drug has a unique mechanism of action and safety profile and distinct monitoring requirements. These therapies have been shown to deplete circulating B cells significantly for a certain amount of time, and they may be used in combination with other medications to treat MS. 

Ocrelizumab, a humanized anti-CD20 mAb administered by intravenous (IV) infusion, was approved in March 2017 by the US Food and Drug Administration (FDA) and is the first proven treatment to reduce disability progression in both primary progressive MS and relapsing MS. Interestingly, ocrelizumab binds to a CD20 epitope that overlaps partially with the epitope to which rituximab binds.

Ofatumumab is the first fully human anti-CD20 mAb and was approved by the FDA in August 2020 for treating relapsing forms of MS. The approval was on the basis of data from the phase 3 ASCLEPIOS I and II trials, which compared ofatumumab with teriflunomide, an oral agent that reduces the activity of proliferating T lymphocytes and B lymphocytes, mitigating the overall inflammatory response in MS. Subcutaneous ofatumumab demonstrated better efficacy than oral teriflunomide in reducing the annualized relapse rate in patients with MS. 

Ublituximab was recently approved by the FDA for treatment of relapsing forms of MS, including relapsing-remitting MS and active secondary progressive MS. Ublituximab works much like other anti-CD20 antibodies; however, it has been glycoengineered so that certain altered sugar molecules attached to the antibody increase its effectiveness. 

Rituximab is a chimeric monoclonal B-cell–depleting anti-CD20 antibody that has also showed promise as an escalation and as a first-line therapy for MS. The FDA has not approved it for this specific use yet, so its use is considered “off label.” A 2017 study showed that ofatumumab was more effective at depleting B cells than high doses of IV rituximab. 

It is important to note that anti-CD20 antibodies are not a cure for MS, and although they show promise for some patients, these agents do not work for everyone. The progress, severity, and specific symptoms of MS in any individual cannot yet be predicted; however, advances in research and treatment are leading to better understanding and moving us closer to curing this unpredictable, debilitating disease.

Multiple sclerosis (MS) is one of the most common causes of neurological disability in young adults, occurring more frequently in women than men. The development of anti-cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) in recent years has significantly changed the way we treat MS. Compared to older standards of care, such as chemotherapy and immunosuppressive drugs, anti-CD20 mAbs have been shown to be more effective in treating MS with fewer side effects. 

Data have shown that B cells play a crucial role in the pathogenesis of MS via antigen-driven autoantibody responses and the cross-regulation of T-helper cells. CD20 is a protein that is expressed on the surface of B cells. Since B cells express the surface molecule CD20 at all points of differentiation, they provide a specific target for mAbs and are used to treat certain types of cancer and autoimmune disorders, including MS.

In people living with MS, the immune system mistakenly attacks the myelin sheath, a protective layer that surrounds nerve fibers in the central nervous system. This attack can cause inflammation and damage to the myelin sheath, leading to the development of various symptoms such as muscle weakness, vision problems, and issues with coordination and balance.

Anti-CD20 antibodies work by targeting and destroying B cells, which play a role in the immune system's attack on the myelin sheath. By targeting and destroying these cells, anti-CD20 antibodies may help to reduce the inflammation and damage to the myelin sheath and improve symptoms of MS.

There are several anti-CD20 mAbs used for the treatment of MS, including ocrelizumab, ofatumumab, ublituximab, and rituximab. Each drug has a unique mechanism of action and safety profile and distinct monitoring requirements. These therapies have been shown to deplete circulating B cells significantly for a certain amount of time, and they may be used in combination with other medications to treat MS. 

Ocrelizumab, a humanized anti-CD20 mAb administered by intravenous (IV) infusion, was approved in March 2017 by the US Food and Drug Administration (FDA) and is the first proven treatment to reduce disability progression in both primary progressive MS and relapsing MS. Interestingly, ocrelizumab binds to a CD20 epitope that overlaps partially with the epitope to which rituximab binds.

Ofatumumab is the first fully human anti-CD20 mAb and was approved by the FDA in August 2020 for treating relapsing forms of MS. The approval was on the basis of data from the phase 3 ASCLEPIOS I and II trials, which compared ofatumumab with teriflunomide, an oral agent that reduces the activity of proliferating T lymphocytes and B lymphocytes, mitigating the overall inflammatory response in MS. Subcutaneous ofatumumab demonstrated better efficacy than oral teriflunomide in reducing the annualized relapse rate in patients with MS. 

Ublituximab was recently approved by the FDA for treatment of relapsing forms of MS, including relapsing-remitting MS and active secondary progressive MS. Ublituximab works much like other anti-CD20 antibodies; however, it has been glycoengineered so that certain altered sugar molecules attached to the antibody increase its effectiveness. 

Rituximab is a chimeric monoclonal B-cell–depleting anti-CD20 antibody that has also showed promise as an escalation and as a first-line therapy for MS. The FDA has not approved it for this specific use yet, so its use is considered “off label.” A 2017 study showed that ofatumumab was more effective at depleting B cells than high doses of IV rituximab. 

It is important to note that anti-CD20 antibodies are not a cure for MS, and although they show promise for some patients, these agents do not work for everyone. The progress, severity, and specific symptoms of MS in any individual cannot yet be predicted; however, advances in research and treatment are leading to better understanding and moving us closer to curing this unpredictable, debilitating disease.

Migraine is a condition that particularly affects the population of reproductive-aged women. A significant amount of the literature discusses the effect of estrogen as a migraine trigger and specifically migraine with aura as a vascular risk factor. One topic that is not discussed in the literature is whether migraine could be a risk for miscarriage, also known as spontaneous abortion. The National Institutes of Health (NIH)-funded study by Crowe and colleagues looks at this risk, especially as it relates to the frequency of migraine, the use of acute migraine medications, and caffeine intake.

This was a broad study, including nearly 2000 patients with migraine, and was a continuation of a prior ongoing NIH-funded epidemiologic study. The initial study enrolled nearly 8000 participants, all of whom were women aged 21-45 years, were in a pregnancy planning stage, and were followed for up to 12 months or until a reported pregnancy. Questionnaires were given preconception, as well as early in pregnancy (defined as 8-9 weeks' gestation), and late in pregnancy (defined as 32 weeks' gestation).

During this study 19% of pregnancies ended in spontaneous abortion. A history of migraine preconception was not associated with spontaneous abortion risk on the basis of hazard ratios. There was a slight risk in those taking some migraine medication daily, either prophylactic or analgesic. Frequency of migraine itself was not noted as a risk for spontaneous abortion.

It is necessary that this important study be followed by further investigations looking at specific medication classes and their potential risk for spontaneous abortion. Migraine itself does not appear to be a risk for miscarriage; however, there remains the possibility that some preventive or acute medications may elevate this risk. At the current moment, there is not enough information to draw a conclusion. All clinicians who treat people with migraine, particularly women who are in their reproductive years, should continue to have conversations regarding pregnancy planning and the adjustment of both preventive and acute medications prior to conception.

Neck pain is a common comorbidity of both chronic and acute migraine, and botulinum toxin is a US Food and Drug Administration–approved treatment both for chronic migraine and certain painful neck conditions, including cervical dystonia. Migraine itself can be a disabling condition; when migraine is combined with other painful comorbidities the likelihood of disability becomes increased significantly. The standard PREEMPT protocol for botulinum toxin injection in chronic migraine of 155 units includes a number of injections in the trapezius and cervical paraspinal muscles. Many clinicians will give additional injections into these muscles and other areas around the neck, specifically targeting areas of neck and shoulder spasm and tenderness. Onan and colleagues investigated the quality of life and disability scores of patients who received these additional injections.

This was an open study, in which participants were given an additional 30 units of botulinum toxin into the general neck areas in a follow-the-pain protocol. The authors, used as a primary outcome, the reduction in the Migraine Disability Assessment (MIDAS) and Neck Disability Index (NDI) scores at 4 weeks and 3 months. The secondary outcome was the Headache Impact Test (HIT-6) score. An objective assessment of neck mobility or a quantification of trigger points were not calculated.

All scores, both the primary and secondary outcomes, were significantly decreased, and quality of life was also noted to be significantly improved with these additional injections. Most clinicians receive a 200-unit vial of botulinum toxin for each of their chronic migraine protocol injections. There is a growing body of evidence to argue that the additional units of botulinum toxin significantly improve outcomes, both regarding headache and neck pain. This study argues for delivering these additional injections of botulinum toxin, especially when neck pain is more prominent.

Much has been written about diet triggers and migraine recently. There has been some evidence for specific diet changes, ie, the addition of foods or nutrients that can be helpful or preventive for migraine. There is some evidence for the addition of omega-3 fatty acids. Huang and He investigated the effect of a high fiber diet on migraine frequency and severity.

This was a cross-sectional study involving data collected from the NIH/Centers for Disease Control and Prevention–sponsored National Health and Nutrition Examination Survey trial from 1999 to 2004. In the studied population, severe headache and migraine was present in approximately 20%, and dietary fiber intake was delineated on the basis of whether it was more than or less than 100 g/d. This study assessed dietary intake of fiber, via a 24-hour dietary recall that was conducted by trained interviewers during two interviews conducted over the course of 2 years.

A total of 12,000 participants were included in the study. There was a significant decrease in migraine severity between those with a higher and lower dietary fiber intake. The incidence of severe headache or migraine, as defined by frequency and severity, decreased in participants who had a dietary fiber intake > 100 g/d. The authors found that for every 10 g/d increase in dietary fiber intake, the prevalence of severe headache or migraine decreased by approximately 11%.

Although much has been written about the association between diet and migraine, most of the literature focuses on the avoidance of specific dietary triggers. A different consideration now exists, one that will likely increase compliance with dietary recommendations. Specifically, people treating patients with migraine can make recommendations regarding dietary changes that focus on adding specific healthy foods or other changes that can actually be associated with improving migraine frequency long-term. Recommending healthy fats, such as omega-3 fatty acids, and high fiber should be done for nearly all patients with migraine.

Migraine is a condition that particularly affects the population of reproductive-aged women. A significant amount of the literature discusses the effect of estrogen as a migraine trigger and specifically migraine with aura as a vascular risk factor. One topic that is not discussed in the literature is whether migraine could be a risk for miscarriage, also known as spontaneous abortion. The National Institutes of Health (NIH)-funded study by Crowe and colleagues looks at this risk, especially as it relates to the frequency of migraine, the use of acute migraine medications, and caffeine intake.

This was a broad study, including nearly 2000 patients with migraine, and was a continuation of a prior ongoing NIH-funded epidemiologic study. The initial study enrolled nearly 8000 participants, all of whom were women aged 21-45 years, were in a pregnancy planning stage, and were followed for up to 12 months or until a reported pregnancy. Questionnaires were given preconception, as well as early in pregnancy (defined as 8-9 weeks' gestation), and late in pregnancy (defined as 32 weeks' gestation).

During this study 19% of pregnancies ended in spontaneous abortion. A history of migraine preconception was not associated with spontaneous abortion risk on the basis of hazard ratios. There was a slight risk in those taking some migraine medication daily, either prophylactic or analgesic. Frequency of migraine itself was not noted as a risk for spontaneous abortion.

It is necessary that this important study be followed by further investigations looking at specific medication classes and their potential risk for spontaneous abortion. Migraine itself does not appear to be a risk for miscarriage; however, there remains the possibility that some preventive or acute medications may elevate this risk. At the current moment, there is not enough information to draw a conclusion. All clinicians who treat people with migraine, particularly women who are in their reproductive years, should continue to have conversations regarding pregnancy planning and the adjustment of both preventive and acute medications prior to conception.

Neck pain is a common comorbidity of both chronic and acute migraine, and botulinum toxin is a US Food and Drug Administration–approved treatment both for chronic migraine and certain painful neck conditions, including cervical dystonia. Migraine itself can be a disabling condition; when migraine is combined with other painful comorbidities the likelihood of disability becomes increased significantly. The standard PREEMPT protocol for botulinum toxin injection in chronic migraine of 155 units includes a number of injections in the trapezius and cervical paraspinal muscles. Many clinicians will give additional injections into these muscles and other areas around the neck, specifically targeting areas of neck and shoulder spasm and tenderness. Onan and colleagues investigated the quality of life and disability scores of patients who received these additional injections.

This was an open study, in which participants were given an additional 30 units of botulinum toxin into the general neck areas in a follow-the-pain protocol. The authors, used as a primary outcome, the reduction in the Migraine Disability Assessment (MIDAS) and Neck Disability Index (NDI) scores at 4 weeks and 3 months. The secondary outcome was the Headache Impact Test (HIT-6) score. An objective assessment of neck mobility or a quantification of trigger points were not calculated.

All scores, both the primary and secondary outcomes, were significantly decreased, and quality of life was also noted to be significantly improved with these additional injections. Most clinicians receive a 200-unit vial of botulinum toxin for each of their chronic migraine protocol injections. There is a growing body of evidence to argue that the additional units of botulinum toxin significantly improve outcomes, both regarding headache and neck pain. This study argues for delivering these additional injections of botulinum toxin, especially when neck pain is more prominent.

Much has been written about diet triggers and migraine recently. There has been some evidence for specific diet changes, ie, the addition of foods or nutrients that can be helpful or preventive for migraine. There is some evidence for the addition of omega-3 fatty acids. Huang and He investigated the effect of a high fiber diet on migraine frequency and severity.

This was a cross-sectional study involving data collected from the NIH/Centers for Disease Control and Prevention–sponsored National Health and Nutrition Examination Survey trial from 1999 to 2004. In the studied population, severe headache and migraine was present in approximately 20%, and dietary fiber intake was delineated on the basis of whether it was more than or less than 100 g/d. This study assessed dietary intake of fiber, via a 24-hour dietary recall that was conducted by trained interviewers during two interviews conducted over the course of 2 years.

A total of 12,000 participants were included in the study. There was a significant decrease in migraine severity between those with a higher and lower dietary fiber intake. The incidence of severe headache or migraine, as defined by frequency and severity, decreased in participants who had a dietary fiber intake > 100 g/d. The authors found that for every 10 g/d increase in dietary fiber intake, the prevalence of severe headache or migraine decreased by approximately 11%.

Although much has been written about the association between diet and migraine, most of the literature focuses on the avoidance of specific dietary triggers. A different consideration now exists, one that will likely increase compliance with dietary recommendations. Specifically, people treating patients with migraine can make recommendations regarding dietary changes that focus on adding specific healthy foods or other changes that can actually be associated with improving migraine frequency long-term. Recommending healthy fats, such as omega-3 fatty acids, and high fiber should be done for nearly all patients with migraine.

Migraine is a condition that particularly affects the population of reproductive-aged women. A significant amount of the literature discusses the effect of estrogen as a migraine trigger and specifically migraine with aura as a vascular risk factor. One topic that is not discussed in the literature is whether migraine could be a risk for miscarriage, also known as spontaneous abortion. The National Institutes of Health (NIH)-funded study by Crowe and colleagues looks at this risk, especially as it relates to the frequency of migraine, the use of acute migraine medications, and caffeine intake.

This was a broad study, including nearly 2000 patients with migraine, and was a continuation of a prior ongoing NIH-funded epidemiologic study. The initial study enrolled nearly 8000 participants, all of whom were women aged 21-45 years, were in a pregnancy planning stage, and were followed for up to 12 months or until a reported pregnancy. Questionnaires were given preconception, as well as early in pregnancy (defined as 8-9 weeks' gestation), and late in pregnancy (defined as 32 weeks' gestation).

During this study 19% of pregnancies ended in spontaneous abortion. A history of migraine preconception was not associated with spontaneous abortion risk on the basis of hazard ratios. There was a slight risk in those taking some migraine medication daily, either prophylactic or analgesic. Frequency of migraine itself was not noted as a risk for spontaneous abortion.

It is necessary that this important study be followed by further investigations looking at specific medication classes and their potential risk for spontaneous abortion. Migraine itself does not appear to be a risk for miscarriage; however, there remains the possibility that some preventive or acute medications may elevate this risk. At the current moment, there is not enough information to draw a conclusion. All clinicians who treat people with migraine, particularly women who are in their reproductive years, should continue to have conversations regarding pregnancy planning and the adjustment of both preventive and acute medications prior to conception.

Neck pain is a common comorbidity of both chronic and acute migraine, and botulinum toxin is a US Food and Drug Administration–approved treatment both for chronic migraine and certain painful neck conditions, including cervical dystonia. Migraine itself can be a disabling condition; when migraine is combined with other painful comorbidities the likelihood of disability becomes increased significantly. The standard PREEMPT protocol for botulinum toxin injection in chronic migraine of 155 units includes a number of injections in the trapezius and cervical paraspinal muscles. Many clinicians will give additional injections into these muscles and other areas around the neck, specifically targeting areas of neck and shoulder spasm and tenderness. Onan and colleagues investigated the quality of life and disability scores of patients who received these additional injections.

This was an open study, in which participants were given an additional 30 units of botulinum toxin into the general neck areas in a follow-the-pain protocol. The authors, used as a primary outcome, the reduction in the Migraine Disability Assessment (MIDAS) and Neck Disability Index (NDI) scores at 4 weeks and 3 months. The secondary outcome was the Headache Impact Test (HIT-6) score. An objective assessment of neck mobility or a quantification of trigger points were not calculated.

All scores, both the primary and secondary outcomes, were significantly decreased, and quality of life was also noted to be significantly improved with these additional injections. Most clinicians receive a 200-unit vial of botulinum toxin for each of their chronic migraine protocol injections. There is a growing body of evidence to argue that the additional units of botulinum toxin significantly improve outcomes, both regarding headache and neck pain. This study argues for delivering these additional injections of botulinum toxin, especially when neck pain is more prominent.

Much has been written about diet triggers and migraine recently. There has been some evidence for specific diet changes, ie, the addition of foods or nutrients that can be helpful or preventive for migraine. There is some evidence for the addition of omega-3 fatty acids. Huang and He investigated the effect of a high fiber diet on migraine frequency and severity.

This was a cross-sectional study involving data collected from the NIH/Centers for Disease Control and Prevention–sponsored National Health and Nutrition Examination Survey trial from 1999 to 2004. In the studied population, severe headache and migraine was present in approximately 20%, and dietary fiber intake was delineated on the basis of whether it was more than or less than 100 g/d. This study assessed dietary intake of fiber, via a 24-hour dietary recall that was conducted by trained interviewers during two interviews conducted over the course of 2 years.

A total of 12,000 participants were included in the study. There was a significant decrease in migraine severity between those with a higher and lower dietary fiber intake. The incidence of severe headache or migraine, as defined by frequency and severity, decreased in participants who had a dietary fiber intake > 100 g/d. The authors found that for every 10 g/d increase in dietary fiber intake, the prevalence of severe headache or migraine decreased by approximately 11%.

Although much has been written about the association between diet and migraine, most of the literature focuses on the avoidance of specific dietary triggers. A different consideration now exists, one that will likely increase compliance with dietary recommendations. Specifically, people treating patients with migraine can make recommendations regarding dietary changes that focus on adding specific healthy foods or other changes that can actually be associated with improving migraine frequency long-term. Recommending healthy fats, such as omega-3 fatty acids, and high fiber should be done for nearly all patients with migraine.

HMG-CoA reductase inhibitors (statins) have been shown to effectively reduce low-density lipoprotein cholesterol (LDL-C) as well as morbidity and mortality in patients who have either atherosclerotic cardiovascular disease (ASCVD) or risk factors for ASCVD.^1-12 However, research shows that up to 20% of patients are unable to tolerate statin therapy due to muscle-related adverse events (AEs).¹³ This presents a substantial clinical challenge, as current management strategies for patients with statin-associated muscle symptoms, such as intermittent administration of statins and ezetimibe, seldom achieve the > 50% LDL-C reduction recommended by the 2018 American Heart Association/American College of Cardiology Clinical Practice Guidelines.¹⁴ Additionally, statin-intolerant patients who have antihyperlipidemic medication lowered or discontinued are at an increased risk of future cardiovascular events.¹⁵ Observational data also show that about 70% of adult patients (primarily with genetic lipid disorders such as heterozygous familial hypercholesterolemia) do not achieve an LDL-C level < 100 mg/dL despite treatment with maximum doses of statins with or without ezetimibe.^16,17

PCSK9 inhibitors (PCSK9i) have robust efficacy data to support use in patients who do not meet their LDL-C goal despite maximally tolerated lipid therapy.¹⁴ However, long-term safety data for PCSK9i are not as robust as its efficacy data. Specifically, safety data relating to muscle-related AEs, which are the most widely recognized AE associated with statins, have only been reported in a few clinical trials with varying incidence rates, levels of significance, and relatively small study populations. Furthermore, the real-world prevalence of muscle-related PCSK9i AEs is unknown. Clinical guidance for management strategies for muscle-related AEs associated with PCSK9i is largely lacking. For this study, muscle-related AEs were defined as any new or unusual muscle soreness, weakness, cramping, aches, and stiffness that persists, is generally bilateral, and typically affects the large muscles. It is important to note, that muscle-related AEs associated with statins, ezetimibe, and PCSK9i can be attributed to the nocebo effect.

According to the prescribing information for alirocumab and evolocumab, myalgia, muscle spasms, and musculoskeletal pain each occurred in < 5% of the study populations.^18,19 From these data, muscle-related PCSK9i AEs are thought to be relatively rare, based on the ODYSSEY-OUTCOME and FOURIER trials, which did not enroll statin-intolerant patients.^20,21 However, currently available safety data from 3 small, randomized clinical trials specifically in statin-intolerant patients taking a PCSK9i suggest that muscle-related AEs occur at a rate of 12.2% to 32.5% and discontinuation rates varied from 0% to 15.9%.^22-25 As the incidence rates of muscle-related AEs in the prescribing information and clinical trials varied widely, this study will provide quantitative data on the percentage of patients that developed muscle-related PCSK9i AEs in a veteran population to help shed light on a topic that is not well studied.

Methods

This was a single-center, retrospective chart review of patients prescribed a PCSK9i between December 1, 2017, and September 1, 2021, and were managed in a pharmacy-led patient aligned care team (PACT) clinic at the Wilkes-Barre US Department of Veterans Affairs (VA) Medical Center (WBVAMC) in Pennsylvania. This study was approved by the Coatesville VA Medical Center Institutional Review Board, which oversees research conducted at WBVAMC. Veterans aged ≥ 18 years were included in the study. Patients were excluded if they had a history of serious hypersensitivity reaction to a PCSK9i or rhabdomyolysis or did not meet the VA criteria for use.²⁶

The primary outcome was the percentage of patients who developed a muscle-related AE while on a PCSK9i in a PACT clinic. Data were further analyzed based on patients who (1) tolerated a full PCSK9i dose; (2) tolerated alternative PCSK9i following initial intolerance; (3) required a PCSK9i dose reduction, or (4) discontinued PCSK9i. A secondary outcome was the percentage of statin- and/or ezetimibe-intolerant patients in these 4 groups. Another secondary outcome was the management strategies taken for patients who were on a reduced (monthly) dose of PCSK9i who did not reach their LDL-C goal. Management strategies that were assessed included restarting weekly statin, restarting weekly ezetimibe, increasing the dose of the same PCSK9i administered monthly, and switching to an alternative PCSK9i.

Data were collected using the VA Computerized Patient Record System (CPRS) and stored in a secure, locked spreadsheet. Baseline patient demographic characteristics collected included age (at PCSK9i start); sex; race; and PCSK9i name, dose, and frequency. We recorded when a patient switched PCSK9i, whether or not it was due to a muscle-related AE, and the name of the original PCSK9i. Also collected were lipid therapy intolerances prior to PCSK9i initiation (ie, intolerance to statin, ezetimibe, or both).

Patients were considered statin intolerant due to a muscle-related AE in accordance with the VA PCSK9i Criteria for Use, which requires trial of at least 3 statins, one of which was trialed at the lowest dosage approved by the US Food and Drug Administration (FDA) and resulted in intolerable skeletal muscle AEs that worsened during treatment and resolved when the statin was stopped. For our study purposes, patients taking alternative day dosing of statins due to muscle-related AEs (ie, 2- or 3-times weekly dosing) were not considered statin intolerant; however, patients taking once-weekly statin dosing were considered statin intolerant. Patients were considered ezetimibe intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when ezetimibe was stopped. Patients were considered PCSK9i intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when the PCSK9i was stopped. Patients with non–muscle-related intolerances to statins, ezetimibe, and PCSK9i were not considered statin, ezetimibe, and PCSK9i intolerant.

Alirocumab was initiated at 75 mg subcutaneous (SQ) once every 2 weeks or evolocumab 140 mg SQ once every 2 weeks in our study. The protocol allowed for a dose reduction of alirocumab 75 mg SQ once monthly if a patient experienced AEs, but this dose reduction strategy was not used for any patients on evolocumab in this study. Of note, alirocumab 75 mg SQ once monthly is not an FDA-approved dosing strategy. However, it is similar in concept to the alternative statin dosing (ie, alternate day dosing, once-weekly dosing) and may avoid the need to discontinue PCSK9i therapy altogether.

A review of the CPRS also documented whether a muscle-related AE occurred while the patient was on a PCSK9i (if yes, the specific AE was recorded), the result of PCSK9i therapy (tolerated full dose, required a dose reduction, switched medication, or discontinued), and management strategies taken for patients who did not meet their LDL-C goal while on a reduced (monthly) PCSK9i dose. Prior lipid therapy intolerances, PCSK9i-related AEs, results of PCSK9i therapy, and management strategies for patients who did not meet LDL-C goal while on a reduced PCSK9i dose were obtained by reviewing the PACT pharmacist’s clinic notes and assessment, along with clinic notes and medication history listed within the CPRS.

Statistical Analysis

Descriptive statistics were used for the demographic characteristics of study patients. The primary outcome was calculated as a binary measure (yes/no) of whether the patient developed a muscle-related AE while on a PCSK9i. The secondary outcome of statin, ezetimibe, or statin and ezetimibe intolerances in subgroups also was calculated as a binary measure.

Results

For the study, 156 charts were reviewed and 137 patients were included (Figure).

For the secondary results, 4 patients (2.9%) tolerated an alternate PCSK9i (evolocumab 140 mg SQ every 2 weeks) after initial intolerance to PCSK9i, 16 (11.7%) required a dose reduction, and 6 (4.4%) discontinued PCSK9i due to a muscle-related AE.

Discussion

This retrospective study found 17.5% of patients experienced muscle-related PCSK9i AEs. These occurred at a higher rate than reported in the prescribing information (< 5%) and were similar to the incidence rates reported in the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE clinical trials (12.0%-32.5%), which is what we hypothesized.^18,19,22-25 It is important to note that the incidence rates of muscle-related AEs reported in the prescribing information for alirocumab and evolocumab were based on trials that did not include statin- and/or ezetimibe-intolerant patients; whereas many patients in our study and patients in the clinical trials were statin and/or ezetimibe intolerant.

Additionally, a new study by Donald and colleagues found an incidence rate of 32% to 36% for muscle-related PCSK9i AEs.²⁷ Collectively, the data from clinical trials and our study indicate that patients with prior intolerances to statin and/or ezetimibe appear to have a higher likelihood of developing a muscle-related PCSK9i intolerance. In our study, 23 of 24 patients who developed a muscle-related PCSK9i AE had a prior history of statin and/or ezetimibe intolerances. This should alert clinicians prescribing PCSK9i in patients with a history of statin and/or ezetimibe intolerance to counsel their patients on the possibility of muscle-related PCSK9i AEs and management strategies. However, it is important to note that there was a substantial number of patients in our study who were statin and/or ezetimibe intolerant due to a prior muscle-related AE who tolerated the full dose of PCSK9i.

To our knowledge, this was the first trial to evaluate muscle-related PCSK9i AEs in a veteran population. Additionally, our study appears to be the first to use 2 PCSK9i dosing strategies that are not FDA approved: Dose reduction for patients who experienced a muscle-related AE on alirocumab 75 mg SQ every 2 weeks and dose escalation for patients who did not meet their LDL-C goal on alirocumab 75 mg SQ monthly following an initial intolerance to 2-week dosing. The dose-reduction strategy allowed patients who experienced a muscle-related AE to alirocumab 75 mg to reduce administration from every 2 weeks to monthly.

This strategy was only performed with alirocumab, the preferred PCSK9i at WBVAMC, but the same dose-reduction strategy can theoretically be used with evolocumab as well. Reduced monthly dosing of alirocumab allowed patients with a prior intolerance to remain on a lower dosage without discontinuation. This is important because as noted by Myers and colleagues, individuals without access to PCSK9i were found to have a significantly higher incidence ratio of cardiovascular events compared with those taking PCSK9i.¹⁵ Also of note, > 30% of patients on the reduced monthly dose of alirocumab still met their LDL-C goal. Therefore, using this dose-reduction strategy (instead of patients discontinuing therapy altogether due to a muscle-related intolerance) can lessen the risk of major adverse cardiovascular events (MACE) as well as mitigate muscle-related AEs that occurred while on 2-week PCSK9i dosing regimens. While we acknowledge that this reduced monthly dose of either alirocumab or evolocumab is not FDA approved, it is similar to alternative statin dosing that also is not FDA approved but may minimize the need to discontinue PCSK9i therapy. It would be beneficial if these dosing strategies were investigated by future research.

The dose-escalation strategy for patients who did not meet their LDL-C goal while on the reduced, monthly dose of alirocumab also was unique. Alirocumab was increased from 75 mg SQ once monthly to 150 mg SQ once monthly. Interestingly, we found that through the end of the chart review period, all patients tolerated the increase well, despite having an initial muscle-related AE to alirocumab 75 mg every 2 weeks, which is the same total monthly dosage. This approach is similar to that of once-weekly statin dosing or a drug holiday and may be explained by the long half-life of PCSK9i. Regardless of the mechanism, this finding suggests that an increased monthly dose of PCSK9i is a potential alternative for patients who cannot tolerate the FDA-approved dose. However, the ability for patients to achieve goal LDL-C on the monthly dosage requires future study.

Limitations

The results of this study should be considered with the following limitations. First, this was a retrospective chart review performed over a prespecified period. Any muscle-related AEs or LDL-C lowering effects from PCSK9i that occurred outside the review period were not captured. Our study was small and only included 137 patients, though it was similar in size to the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE trials.^22-24 Additionally, the study was primarily composed of White men and may not be representative of other populations. Some muscle-related PCSK9i AEs may be attributed to the nocebo. Last, our study did not capture patients on a PCSK9i who were not followed in the PACT clinic.

Conclusions

We found that muscle-related PCSK9i AEs occurred at a similar rate as those reported in previous clinical trials and exceeded the incidence rate reported in the prescribing information for alirocumab and evolocumab. It appears that patients who have a prior muscle-related intolerance to a statin and/or ezetimibe had a higher likelihood of developing a muscle-related PCSK9i AE. In our study, only 1 patient developed a muscle-related PCSK9i AE who did not have a prior history of muscle-related intolerance to either a statin or ezetimibe. However, in our study, a substantial percentage of patients with statin and/or ezetimibe intolerances tolerated the full PCSK9i dose well, proving that PCSK9i are still a reasonable alternative for patients with prior intolerances to statins and/or ezetimibe.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the US Department of Veterans Affairs Medical Center, Wilkes-Barre, Pennsylvania.

HMG-CoA reductase inhibitors (statins) have been shown to effectively reduce low-density lipoprotein cholesterol (LDL-C) as well as morbidity and mortality in patients who have either atherosclerotic cardiovascular disease (ASCVD) or risk factors for ASCVD.^1-12 However, research shows that up to 20% of patients are unable to tolerate statin therapy due to muscle-related adverse events (AEs).¹³ This presents a substantial clinical challenge, as current management strategies for patients with statin-associated muscle symptoms, such as intermittent administration of statins and ezetimibe, seldom achieve the > 50% LDL-C reduction recommended by the 2018 American Heart Association/American College of Cardiology Clinical Practice Guidelines.¹⁴ Additionally, statin-intolerant patients who have antihyperlipidemic medication lowered or discontinued are at an increased risk of future cardiovascular events.¹⁵ Observational data also show that about 70% of adult patients (primarily with genetic lipid disorders such as heterozygous familial hypercholesterolemia) do not achieve an LDL-C level < 100 mg/dL despite treatment with maximum doses of statins with or without ezetimibe.^16,17

PCSK9 inhibitors (PCSK9i) have robust efficacy data to support use in patients who do not meet their LDL-C goal despite maximally tolerated lipid therapy.¹⁴ However, long-term safety data for PCSK9i are not as robust as its efficacy data. Specifically, safety data relating to muscle-related AEs, which are the most widely recognized AE associated with statins, have only been reported in a few clinical trials with varying incidence rates, levels of significance, and relatively small study populations. Furthermore, the real-world prevalence of muscle-related PCSK9i AEs is unknown. Clinical guidance for management strategies for muscle-related AEs associated with PCSK9i is largely lacking. For this study, muscle-related AEs were defined as any new or unusual muscle soreness, weakness, cramping, aches, and stiffness that persists, is generally bilateral, and typically affects the large muscles. It is important to note, that muscle-related AEs associated with statins, ezetimibe, and PCSK9i can be attributed to the nocebo effect.

According to the prescribing information for alirocumab and evolocumab, myalgia, muscle spasms, and musculoskeletal pain each occurred in < 5% of the study populations.^18,19 From these data, muscle-related PCSK9i AEs are thought to be relatively rare, based on the ODYSSEY-OUTCOME and FOURIER trials, which did not enroll statin-intolerant patients.^20,21 However, currently available safety data from 3 small, randomized clinical trials specifically in statin-intolerant patients taking a PCSK9i suggest that muscle-related AEs occur at a rate of 12.2% to 32.5% and discontinuation rates varied from 0% to 15.9%.^22-25 As the incidence rates of muscle-related AEs in the prescribing information and clinical trials varied widely, this study will provide quantitative data on the percentage of patients that developed muscle-related PCSK9i AEs in a veteran population to help shed light on a topic that is not well studied.

Methods

This was a single-center, retrospective chart review of patients prescribed a PCSK9i between December 1, 2017, and September 1, 2021, and were managed in a pharmacy-led patient aligned care team (PACT) clinic at the Wilkes-Barre US Department of Veterans Affairs (VA) Medical Center (WBVAMC) in Pennsylvania. This study was approved by the Coatesville VA Medical Center Institutional Review Board, which oversees research conducted at WBVAMC. Veterans aged ≥ 18 years were included in the study. Patients were excluded if they had a history of serious hypersensitivity reaction to a PCSK9i or rhabdomyolysis or did not meet the VA criteria for use.²⁶

The primary outcome was the percentage of patients who developed a muscle-related AE while on a PCSK9i in a PACT clinic. Data were further analyzed based on patients who (1) tolerated a full PCSK9i dose; (2) tolerated alternative PCSK9i following initial intolerance; (3) required a PCSK9i dose reduction, or (4) discontinued PCSK9i. A secondary outcome was the percentage of statin- and/or ezetimibe-intolerant patients in these 4 groups. Another secondary outcome was the management strategies taken for patients who were on a reduced (monthly) dose of PCSK9i who did not reach their LDL-C goal. Management strategies that were assessed included restarting weekly statin, restarting weekly ezetimibe, increasing the dose of the same PCSK9i administered monthly, and switching to an alternative PCSK9i.

Data were collected using the VA Computerized Patient Record System (CPRS) and stored in a secure, locked spreadsheet. Baseline patient demographic characteristics collected included age (at PCSK9i start); sex; race; and PCSK9i name, dose, and frequency. We recorded when a patient switched PCSK9i, whether or not it was due to a muscle-related AE, and the name of the original PCSK9i. Also collected were lipid therapy intolerances prior to PCSK9i initiation (ie, intolerance to statin, ezetimibe, or both).

Patients were considered statin intolerant due to a muscle-related AE in accordance with the VA PCSK9i Criteria for Use, which requires trial of at least 3 statins, one of which was trialed at the lowest dosage approved by the US Food and Drug Administration (FDA) and resulted in intolerable skeletal muscle AEs that worsened during treatment and resolved when the statin was stopped. For our study purposes, patients taking alternative day dosing of statins due to muscle-related AEs (ie, 2- or 3-times weekly dosing) were not considered statin intolerant; however, patients taking once-weekly statin dosing were considered statin intolerant. Patients were considered ezetimibe intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when ezetimibe was stopped. Patients were considered PCSK9i intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when the PCSK9i was stopped. Patients with non–muscle-related intolerances to statins, ezetimibe, and PCSK9i were not considered statin, ezetimibe, and PCSK9i intolerant.

Alirocumab was initiated at 75 mg subcutaneous (SQ) once every 2 weeks or evolocumab 140 mg SQ once every 2 weeks in our study. The protocol allowed for a dose reduction of alirocumab 75 mg SQ once monthly if a patient experienced AEs, but this dose reduction strategy was not used for any patients on evolocumab in this study. Of note, alirocumab 75 mg SQ once monthly is not an FDA-approved dosing strategy. However, it is similar in concept to the alternative statin dosing (ie, alternate day dosing, once-weekly dosing) and may avoid the need to discontinue PCSK9i therapy altogether.

A review of the CPRS also documented whether a muscle-related AE occurred while the patient was on a PCSK9i (if yes, the specific AE was recorded), the result of PCSK9i therapy (tolerated full dose, required a dose reduction, switched medication, or discontinued), and management strategies taken for patients who did not meet their LDL-C goal while on a reduced (monthly) PCSK9i dose. Prior lipid therapy intolerances, PCSK9i-related AEs, results of PCSK9i therapy, and management strategies for patients who did not meet LDL-C goal while on a reduced PCSK9i dose were obtained by reviewing the PACT pharmacist’s clinic notes and assessment, along with clinic notes and medication history listed within the CPRS.

Statistical Analysis

Descriptive statistics were used for the demographic characteristics of study patients. The primary outcome was calculated as a binary measure (yes/no) of whether the patient developed a muscle-related AE while on a PCSK9i. The secondary outcome of statin, ezetimibe, or statin and ezetimibe intolerances in subgroups also was calculated as a binary measure.

Results

For the study, 156 charts were reviewed and 137 patients were included (Figure).

For the secondary results, 4 patients (2.9%) tolerated an alternate PCSK9i (evolocumab 140 mg SQ every 2 weeks) after initial intolerance to PCSK9i, 16 (11.7%) required a dose reduction, and 6 (4.4%) discontinued PCSK9i due to a muscle-related AE.

Discussion

This retrospective study found 17.5% of patients experienced muscle-related PCSK9i AEs. These occurred at a higher rate than reported in the prescribing information (< 5%) and were similar to the incidence rates reported in the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE clinical trials (12.0%-32.5%), which is what we hypothesized.^18,19,22-25 It is important to note that the incidence rates of muscle-related AEs reported in the prescribing information for alirocumab and evolocumab were based on trials that did not include statin- and/or ezetimibe-intolerant patients; whereas many patients in our study and patients in the clinical trials were statin and/or ezetimibe intolerant.

Additionally, a new study by Donald and colleagues found an incidence rate of 32% to 36% for muscle-related PCSK9i AEs.²⁷ Collectively, the data from clinical trials and our study indicate that patients with prior intolerances to statin and/or ezetimibe appear to have a higher likelihood of developing a muscle-related PCSK9i intolerance. In our study, 23 of 24 patients who developed a muscle-related PCSK9i AE had a prior history of statin and/or ezetimibe intolerances. This should alert clinicians prescribing PCSK9i in patients with a history of statin and/or ezetimibe intolerance to counsel their patients on the possibility of muscle-related PCSK9i AEs and management strategies. However, it is important to note that there was a substantial number of patients in our study who were statin and/or ezetimibe intolerant due to a prior muscle-related AE who tolerated the full dose of PCSK9i.

To our knowledge, this was the first trial to evaluate muscle-related PCSK9i AEs in a veteran population. Additionally, our study appears to be the first to use 2 PCSK9i dosing strategies that are not FDA approved: Dose reduction for patients who experienced a muscle-related AE on alirocumab 75 mg SQ every 2 weeks and dose escalation for patients who did not meet their LDL-C goal on alirocumab 75 mg SQ monthly following an initial intolerance to 2-week dosing. The dose-reduction strategy allowed patients who experienced a muscle-related AE to alirocumab 75 mg to reduce administration from every 2 weeks to monthly.

This strategy was only performed with alirocumab, the preferred PCSK9i at WBVAMC, but the same dose-reduction strategy can theoretically be used with evolocumab as well. Reduced monthly dosing of alirocumab allowed patients with a prior intolerance to remain on a lower dosage without discontinuation. This is important because as noted by Myers and colleagues, individuals without access to PCSK9i were found to have a significantly higher incidence ratio of cardiovascular events compared with those taking PCSK9i.¹⁵ Also of note, > 30% of patients on the reduced monthly dose of alirocumab still met their LDL-C goal. Therefore, using this dose-reduction strategy (instead of patients discontinuing therapy altogether due to a muscle-related intolerance) can lessen the risk of major adverse cardiovascular events (MACE) as well as mitigate muscle-related AEs that occurred while on 2-week PCSK9i dosing regimens. While we acknowledge that this reduced monthly dose of either alirocumab or evolocumab is not FDA approved, it is similar to alternative statin dosing that also is not FDA approved but may minimize the need to discontinue PCSK9i therapy. It would be beneficial if these dosing strategies were investigated by future research.

The dose-escalation strategy for patients who did not meet their LDL-C goal while on the reduced, monthly dose of alirocumab also was unique. Alirocumab was increased from 75 mg SQ once monthly to 150 mg SQ once monthly. Interestingly, we found that through the end of the chart review period, all patients tolerated the increase well, despite having an initial muscle-related AE to alirocumab 75 mg every 2 weeks, which is the same total monthly dosage. This approach is similar to that of once-weekly statin dosing or a drug holiday and may be explained by the long half-life of PCSK9i. Regardless of the mechanism, this finding suggests that an increased monthly dose of PCSK9i is a potential alternative for patients who cannot tolerate the FDA-approved dose. However, the ability for patients to achieve goal LDL-C on the monthly dosage requires future study.

Limitations

The results of this study should be considered with the following limitations. First, this was a retrospective chart review performed over a prespecified period. Any muscle-related AEs or LDL-C lowering effects from PCSK9i that occurred outside the review period were not captured. Our study was small and only included 137 patients, though it was similar in size to the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE trials.^22-24 Additionally, the study was primarily composed of White men and may not be representative of other populations. Some muscle-related PCSK9i AEs may be attributed to the nocebo. Last, our study did not capture patients on a PCSK9i who were not followed in the PACT clinic.

Conclusions

We found that muscle-related PCSK9i AEs occurred at a similar rate as those reported in previous clinical trials and exceeded the incidence rate reported in the prescribing information for alirocumab and evolocumab. It appears that patients who have a prior muscle-related intolerance to a statin and/or ezetimibe had a higher likelihood of developing a muscle-related PCSK9i AE. In our study, only 1 patient developed a muscle-related PCSK9i AE who did not have a prior history of muscle-related intolerance to either a statin or ezetimibe. However, in our study, a substantial percentage of patients with statin and/or ezetimibe intolerances tolerated the full PCSK9i dose well, proving that PCSK9i are still a reasonable alternative for patients with prior intolerances to statins and/or ezetimibe.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the US Department of Veterans Affairs Medical Center, Wilkes-Barre, Pennsylvania.

HMG-CoA reductase inhibitors (statins) have been shown to effectively reduce low-density lipoprotein cholesterol (LDL-C) as well as morbidity and mortality in patients who have either atherosclerotic cardiovascular disease (ASCVD) or risk factors for ASCVD.^1-12 However, research shows that up to 20% of patients are unable to tolerate statin therapy due to muscle-related adverse events (AEs).¹³ This presents a substantial clinical challenge, as current management strategies for patients with statin-associated muscle symptoms, such as intermittent administration of statins and ezetimibe, seldom achieve the > 50% LDL-C reduction recommended by the 2018 American Heart Association/American College of Cardiology Clinical Practice Guidelines.¹⁴ Additionally, statin-intolerant patients who have antihyperlipidemic medication lowered or discontinued are at an increased risk of future cardiovascular events.¹⁵ Observational data also show that about 70% of adult patients (primarily with genetic lipid disorders such as heterozygous familial hypercholesterolemia) do not achieve an LDL-C level < 100 mg/dL despite treatment with maximum doses of statins with or without ezetimibe.^16,17

PCSK9 inhibitors (PCSK9i) have robust efficacy data to support use in patients who do not meet their LDL-C goal despite maximally tolerated lipid therapy.¹⁴ However, long-term safety data for PCSK9i are not as robust as its efficacy data. Specifically, safety data relating to muscle-related AEs, which are the most widely recognized AE associated with statins, have only been reported in a few clinical trials with varying incidence rates, levels of significance, and relatively small study populations. Furthermore, the real-world prevalence of muscle-related PCSK9i AEs is unknown. Clinical guidance for management strategies for muscle-related AEs associated with PCSK9i is largely lacking. For this study, muscle-related AEs were defined as any new or unusual muscle soreness, weakness, cramping, aches, and stiffness that persists, is generally bilateral, and typically affects the large muscles. It is important to note, that muscle-related AEs associated with statins, ezetimibe, and PCSK9i can be attributed to the nocebo effect.

According to the prescribing information for alirocumab and evolocumab, myalgia, muscle spasms, and musculoskeletal pain each occurred in < 5% of the study populations.^18,19 From these data, muscle-related PCSK9i AEs are thought to be relatively rare, based on the ODYSSEY-OUTCOME and FOURIER trials, which did not enroll statin-intolerant patients.^20,21 However, currently available safety data from 3 small, randomized clinical trials specifically in statin-intolerant patients taking a PCSK9i suggest that muscle-related AEs occur at a rate of 12.2% to 32.5% and discontinuation rates varied from 0% to 15.9%.^22-25 As the incidence rates of muscle-related AEs in the prescribing information and clinical trials varied widely, this study will provide quantitative data on the percentage of patients that developed muscle-related PCSK9i AEs in a veteran population to help shed light on a topic that is not well studied.

Methods

This was a single-center, retrospective chart review of patients prescribed a PCSK9i between December 1, 2017, and September 1, 2021, and were managed in a pharmacy-led patient aligned care team (PACT) clinic at the Wilkes-Barre US Department of Veterans Affairs (VA) Medical Center (WBVAMC) in Pennsylvania. This study was approved by the Coatesville VA Medical Center Institutional Review Board, which oversees research conducted at WBVAMC. Veterans aged ≥ 18 years were included in the study. Patients were excluded if they had a history of serious hypersensitivity reaction to a PCSK9i or rhabdomyolysis or did not meet the VA criteria for use.²⁶

The primary outcome was the percentage of patients who developed a muscle-related AE while on a PCSK9i in a PACT clinic. Data were further analyzed based on patients who (1) tolerated a full PCSK9i dose; (2) tolerated alternative PCSK9i following initial intolerance; (3) required a PCSK9i dose reduction, or (4) discontinued PCSK9i. A secondary outcome was the percentage of statin- and/or ezetimibe-intolerant patients in these 4 groups. Another secondary outcome was the management strategies taken for patients who were on a reduced (monthly) dose of PCSK9i who did not reach their LDL-C goal. Management strategies that were assessed included restarting weekly statin, restarting weekly ezetimibe, increasing the dose of the same PCSK9i administered monthly, and switching to an alternative PCSK9i.

Data were collected using the VA Computerized Patient Record System (CPRS) and stored in a secure, locked spreadsheet. Baseline patient demographic characteristics collected included age (at PCSK9i start); sex; race; and PCSK9i name, dose, and frequency. We recorded when a patient switched PCSK9i, whether or not it was due to a muscle-related AE, and the name of the original PCSK9i. Also collected were lipid therapy intolerances prior to PCSK9i initiation (ie, intolerance to statin, ezetimibe, or both).

Patients were considered statin intolerant due to a muscle-related AE in accordance with the VA PCSK9i Criteria for Use, which requires trial of at least 3 statins, one of which was trialed at the lowest dosage approved by the US Food and Drug Administration (FDA) and resulted in intolerable skeletal muscle AEs that worsened during treatment and resolved when the statin was stopped. For our study purposes, patients taking alternative day dosing of statins due to muscle-related AEs (ie, 2- or 3-times weekly dosing) were not considered statin intolerant; however, patients taking once-weekly statin dosing were considered statin intolerant. Patients were considered ezetimibe intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when ezetimibe was stopped. Patients were considered PCSK9i intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when the PCSK9i was stopped. Patients with non–muscle-related intolerances to statins, ezetimibe, and PCSK9i were not considered statin, ezetimibe, and PCSK9i intolerant.

Alirocumab was initiated at 75 mg subcutaneous (SQ) once every 2 weeks or evolocumab 140 mg SQ once every 2 weeks in our study. The protocol allowed for a dose reduction of alirocumab 75 mg SQ once monthly if a patient experienced AEs, but this dose reduction strategy was not used for any patients on evolocumab in this study. Of note, alirocumab 75 mg SQ once monthly is not an FDA-approved dosing strategy. However, it is similar in concept to the alternative statin dosing (ie, alternate day dosing, once-weekly dosing) and may avoid the need to discontinue PCSK9i therapy altogether.

A review of the CPRS also documented whether a muscle-related AE occurred while the patient was on a PCSK9i (if yes, the specific AE was recorded), the result of PCSK9i therapy (tolerated full dose, required a dose reduction, switched medication, or discontinued), and management strategies taken for patients who did not meet their LDL-C goal while on a reduced (monthly) PCSK9i dose. Prior lipid therapy intolerances, PCSK9i-related AEs, results of PCSK9i therapy, and management strategies for patients who did not meet LDL-C goal while on a reduced PCSK9i dose were obtained by reviewing the PACT pharmacist’s clinic notes and assessment, along with clinic notes and medication history listed within the CPRS.

Statistical Analysis

Descriptive statistics were used for the demographic characteristics of study patients. The primary outcome was calculated as a binary measure (yes/no) of whether the patient developed a muscle-related AE while on a PCSK9i. The secondary outcome of statin, ezetimibe, or statin and ezetimibe intolerances in subgroups also was calculated as a binary measure.

Results

For the study, 156 charts were reviewed and 137 patients were included (Figure).

For the secondary results, 4 patients (2.9%) tolerated an alternate PCSK9i (evolocumab 140 mg SQ every 2 weeks) after initial intolerance to PCSK9i, 16 (11.7%) required a dose reduction, and 6 (4.4%) discontinued PCSK9i due to a muscle-related AE.

Discussion

This retrospective study found 17.5% of patients experienced muscle-related PCSK9i AEs. These occurred at a higher rate than reported in the prescribing information (< 5%) and were similar to the incidence rates reported in the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE clinical trials (12.0%-32.5%), which is what we hypothesized.^18,19,22-25 It is important to note that the incidence rates of muscle-related AEs reported in the prescribing information for alirocumab and evolocumab were based on trials that did not include statin- and/or ezetimibe-intolerant patients; whereas many patients in our study and patients in the clinical trials were statin and/or ezetimibe intolerant.

Additionally, a new study by Donald and colleagues found an incidence rate of 32% to 36% for muscle-related PCSK9i AEs.²⁷ Collectively, the data from clinical trials and our study indicate that patients with prior intolerances to statin and/or ezetimibe appear to have a higher likelihood of developing a muscle-related PCSK9i intolerance. In our study, 23 of 24 patients who developed a muscle-related PCSK9i AE had a prior history of statin and/or ezetimibe intolerances. This should alert clinicians prescribing PCSK9i in patients with a history of statin and/or ezetimibe intolerance to counsel their patients on the possibility of muscle-related PCSK9i AEs and management strategies. However, it is important to note that there was a substantial number of patients in our study who were statin and/or ezetimibe intolerant due to a prior muscle-related AE who tolerated the full dose of PCSK9i.

To our knowledge, this was the first trial to evaluate muscle-related PCSK9i AEs in a veteran population. Additionally, our study appears to be the first to use 2 PCSK9i dosing strategies that are not FDA approved: Dose reduction for patients who experienced a muscle-related AE on alirocumab 75 mg SQ every 2 weeks and dose escalation for patients who did not meet their LDL-C goal on alirocumab 75 mg SQ monthly following an initial intolerance to 2-week dosing. The dose-reduction strategy allowed patients who experienced a muscle-related AE to alirocumab 75 mg to reduce administration from every 2 weeks to monthly.

This strategy was only performed with alirocumab, the preferred PCSK9i at WBVAMC, but the same dose-reduction strategy can theoretically be used with evolocumab as well. Reduced monthly dosing of alirocumab allowed patients with a prior intolerance to remain on a lower dosage without discontinuation. This is important because as noted by Myers and colleagues, individuals without access to PCSK9i were found to have a significantly higher incidence ratio of cardiovascular events compared with those taking PCSK9i.¹⁵ Also of note, > 30% of patients on the reduced monthly dose of alirocumab still met their LDL-C goal. Therefore, using this dose-reduction strategy (instead of patients discontinuing therapy altogether due to a muscle-related intolerance) can lessen the risk of major adverse cardiovascular events (MACE) as well as mitigate muscle-related AEs that occurred while on 2-week PCSK9i dosing regimens. While we acknowledge that this reduced monthly dose of either alirocumab or evolocumab is not FDA approved, it is similar to alternative statin dosing that also is not FDA approved but may minimize the need to discontinue PCSK9i therapy. It would be beneficial if these dosing strategies were investigated by future research.

The dose-escalation strategy for patients who did not meet their LDL-C goal while on the reduced, monthly dose of alirocumab also was unique. Alirocumab was increased from 75 mg SQ once monthly to 150 mg SQ once monthly. Interestingly, we found that through the end of the chart review period, all patients tolerated the increase well, despite having an initial muscle-related AE to alirocumab 75 mg every 2 weeks, which is the same total monthly dosage. This approach is similar to that of once-weekly statin dosing or a drug holiday and may be explained by the long half-life of PCSK9i. Regardless of the mechanism, this finding suggests that an increased monthly dose of PCSK9i is a potential alternative for patients who cannot tolerate the FDA-approved dose. However, the ability for patients to achieve goal LDL-C on the monthly dosage requires future study.

Limitations

The results of this study should be considered with the following limitations. First, this was a retrospective chart review performed over a prespecified period. Any muscle-related AEs or LDL-C lowering effects from PCSK9i that occurred outside the review period were not captured. Our study was small and only included 137 patients, though it was similar in size to the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE trials.^22-24 Additionally, the study was primarily composed of White men and may not be representative of other populations. Some muscle-related PCSK9i AEs may be attributed to the nocebo. Last, our study did not capture patients on a PCSK9i who were not followed in the PACT clinic.

Conclusions

We found that muscle-related PCSK9i AEs occurred at a similar rate as those reported in previous clinical trials and exceeded the incidence rate reported in the prescribing information for alirocumab and evolocumab. It appears that patients who have a prior muscle-related intolerance to a statin and/or ezetimibe had a higher likelihood of developing a muscle-related PCSK9i AE. In our study, only 1 patient developed a muscle-related PCSK9i AE who did not have a prior history of muscle-related intolerance to either a statin or ezetimibe. However, in our study, a substantial percentage of patients with statin and/or ezetimibe intolerances tolerated the full PCSK9i dose well, proving that PCSK9i are still a reasonable alternative for patients with prior intolerances to statins and/or ezetimibe.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the US Department of Veterans Affairs Medical Center, Wilkes-Barre, Pennsylvania.

Growing up I can remember my father telling stories of service members in the medical battalion he commanded in World War II (WWII) who after the war with his encouragement and their GI Bill educational benefits went to school to become doctors, nurses, and dentists. They were among the 2,300,000 veterans who attended US colleges and universities through the Servicemen’s Readjustment Act passed in 1944. The American Legion navigated the bill through the twists and turns of congressional support, and it was one of their leaders who invented the catchy GI Bill shorthand.²

As with most political legislation, there were mixed motives driving passage of the act, and like many policies in America, the primary impetus was economic. While the war was raging overseas, at home the US Department of Labor predicted that by the war’s end, 16 million service members would be jobless. Apprehensive about the prospect of yet another financial depression, in 1943 a White House agency recommended that the federal government fund education and training for the individuals who had served during the war.²

While troops stormed the beaches of Normandy, wartime President Franklin D. Roosevelt (FDR) signed the bill that delivered not only educational and training opportunities for service members and veterans, but also funded home loans and US Department of Veterans Affairs (VA) hospitals. The bill was practical in that it provided not only tuition, but also books, supplies, a living stipend, and counseling for the students. The bill technically expired in 1956, but a series of extensions and expansions has been true to the original intention to offer those who served their nation in the military a better life as citizens.

Articles describing the impact of the GI Bill use terms like life changing and transformative.^3,4 Our contemporary culture makes it difficult to imagine how out of reach a college education was for the generation that fought WWII. Universities were primarily for the rich and connected, the powerful and privileged. Were it not for the upward social mobility the GI Bill propelled, the American dream would not have become a reality for many farmers, small town merchants, and factory workers. The GI Bill though could not by itself ensure equity. The systemic racism endemic in the United States and among the elected representatives who debated the bill resulted in many Black service members especially in the South being denied entrance to institutions of higher learning.⁵ Despite this invidious discrimination, the bill was a profound effort to help many other service members to successfully reintegrate into the society they had preserved and defended.⁴

“With the signing of this bill, a well-rounded program of special veterans’ benefits is nearly completed,” FDR said, capturing its noble intent: “It gives emphatic notice to the men and women in our armed forces that the American people do not intend to let them down.”⁶

Regrettably, we have not kept FDR’s pledge. Now unscrupulous businesses are preying on the aspirations of military personnel and veterans for an education and thwarting their ability to seek gainful employment. For more than a decade, respected news media have reported that for-profit universities were exploiting service members trying to improve their lives through obtaining a college education via the GI Bill.⁷ The sad irony is that what enabled the exploitation to occur was a major expansion of the benefits under the Post-9/11 GI Bill. This version granted educational funding to any individual who had served on active duty for 90 days or more after September 10, 2001.⁸ Federal law prohibits for-profit educational institutions from receiving more than 90% of their total revenue from federal student aid. A loophole in the law enabled these institutions to categorize GI Bill funding as private not government dollars. Bad old American greed drove these for-profit colleges and universities to aggressively recruit veterans who trusted in the good faith of the academic institutions. Once the GI Bill monies were exhausted, veterans had already invested so much time and energy in a degree or certificate, the schools could persuade them to take out student loans with the promise of job placement assistance that never materialized. They took advantage of the veterans’ hopes to fatten their own bottom line in the face of declining enrolments.⁹ Journalists, government, think tank reports, and even a documentary described the tragic stories of service members left unemployed with immense debt and degrees that to many of them were now worthless.¹⁰

After years of reporters exposing the scam and politically thwarted efforts to stop it, Congress and President Biden closed what was known as the 90/10 loophole. This ended the weaponization of education it had promoted. In October 2022, the US Department of Education announced its final rule to prohibit the widespread educational fraud that had betrayed so many veterans and service members, which Secretary Dennis McDonough described as “abuse.”¹¹Some readers may wonder why I have devoted an editorial to a topic that seems somewhat distant from the health care that is the primary domain of Federal Practitioner. It happens that education is in closer proximity to health for our patients than many of us might have realized. A 2018 Military Medicine study found that veterans who took advantage of the educational opportunities of the GI Bill had better health and reduced smoking, among other benefits.¹² This connection between health and education should serve as a source of pride for all of us in federal practice as we are part of organizations that affirm the holistic concept of health that embraces not just medicine but education, housing, and other services essential for comprehensive well-being.

Growing up I can remember my father telling stories of service members in the medical battalion he commanded in World War II (WWII) who after the war with his encouragement and their GI Bill educational benefits went to school to become doctors, nurses, and dentists. They were among the 2,300,000 veterans who attended US colleges and universities through the Servicemen’s Readjustment Act passed in 1944. The American Legion navigated the bill through the twists and turns of congressional support, and it was one of their leaders who invented the catchy GI Bill shorthand.²

As with most political legislation, there were mixed motives driving passage of the act, and like many policies in America, the primary impetus was economic. While the war was raging overseas, at home the US Department of Labor predicted that by the war’s end, 16 million service members would be jobless. Apprehensive about the prospect of yet another financial depression, in 1943 a White House agency recommended that the federal government fund education and training for the individuals who had served during the war.²

While troops stormed the beaches of Normandy, wartime President Franklin D. Roosevelt (FDR) signed the bill that delivered not only educational and training opportunities for service members and veterans, but also funded home loans and US Department of Veterans Affairs (VA) hospitals. The bill was practical in that it provided not only tuition, but also books, supplies, a living stipend, and counseling for the students. The bill technically expired in 1956, but a series of extensions and expansions has been true to the original intention to offer those who served their nation in the military a better life as citizens.

Articles describing the impact of the GI Bill use terms like life changing and transformative.^3,4 Our contemporary culture makes it difficult to imagine how out of reach a college education was for the generation that fought WWII. Universities were primarily for the rich and connected, the powerful and privileged. Were it not for the upward social mobility the GI Bill propelled, the American dream would not have become a reality for many farmers, small town merchants, and factory workers. The GI Bill though could not by itself ensure equity. The systemic racism endemic in the United States and among the elected representatives who debated the bill resulted in many Black service members especially in the South being denied entrance to institutions of higher learning.⁵ Despite this invidious discrimination, the bill was a profound effort to help many other service members to successfully reintegrate into the society they had preserved and defended.⁴

“With the signing of this bill, a well-rounded program of special veterans’ benefits is nearly completed,” FDR said, capturing its noble intent: “It gives emphatic notice to the men and women in our armed forces that the American people do not intend to let them down.”⁶

Regrettably, we have not kept FDR’s pledge. Now unscrupulous businesses are preying on the aspirations of military personnel and veterans for an education and thwarting their ability to seek gainful employment. For more than a decade, respected news media have reported that for-profit universities were exploiting service members trying to improve their lives through obtaining a college education via the GI Bill.⁷ The sad irony is that what enabled the exploitation to occur was a major expansion of the benefits under the Post-9/11 GI Bill. This version granted educational funding to any individual who had served on active duty for 90 days or more after September 10, 2001.⁸ Federal law prohibits for-profit educational institutions from receiving more than 90% of their total revenue from federal student aid. A loophole in the law enabled these institutions to categorize GI Bill funding as private not government dollars. Bad old American greed drove these for-profit colleges and universities to aggressively recruit veterans who trusted in the good faith of the academic institutions. Once the GI Bill monies were exhausted, veterans had already invested so much time and energy in a degree or certificate, the schools could persuade them to take out student loans with the promise of job placement assistance that never materialized. They took advantage of the veterans’ hopes to fatten their own bottom line in the face of declining enrolments.⁹ Journalists, government, think tank reports, and even a documentary described the tragic stories of service members left unemployed with immense debt and degrees that to many of them were now worthless.¹⁰

After years of reporters exposing the scam and politically thwarted efforts to stop it, Congress and President Biden closed what was known as the 90/10 loophole. This ended the weaponization of education it had promoted. In October 2022, the US Department of Education announced its final rule to prohibit the widespread educational fraud that had betrayed so many veterans and service members, which Secretary Dennis McDonough described as “abuse.”¹¹Some readers may wonder why I have devoted an editorial to a topic that seems somewhat distant from the health care that is the primary domain of Federal Practitioner. It happens that education is in closer proximity to health for our patients than many of us might have realized. A 2018 Military Medicine study found that veterans who took advantage of the educational opportunities of the GI Bill had better health and reduced smoking, among other benefits.¹² This connection between health and education should serve as a source of pride for all of us in federal practice as we are part of organizations that affirm the holistic concept of health that embraces not just medicine but education, housing, and other services essential for comprehensive well-being.

Growing up I can remember my father telling stories of service members in the medical battalion he commanded in World War II (WWII) who after the war with his encouragement and their GI Bill educational benefits went to school to become doctors, nurses, and dentists. They were among the 2,300,000 veterans who attended US colleges and universities through the Servicemen’s Readjustment Act passed in 1944. The American Legion navigated the bill through the twists and turns of congressional support, and it was one of their leaders who invented the catchy GI Bill shorthand.²

As with most political legislation, there were mixed motives driving passage of the act, and like many policies in America, the primary impetus was economic. While the war was raging overseas, at home the US Department of Labor predicted that by the war’s end, 16 million service members would be jobless. Apprehensive about the prospect of yet another financial depression, in 1943 a White House agency recommended that the federal government fund education and training for the individuals who had served during the war.²

While troops stormed the beaches of Normandy, wartime President Franklin D. Roosevelt (FDR) signed the bill that delivered not only educational and training opportunities for service members and veterans, but also funded home loans and US Department of Veterans Affairs (VA) hospitals. The bill was practical in that it provided not only tuition, but also books, supplies, a living stipend, and counseling for the students. The bill technically expired in 1956, but a series of extensions and expansions has been true to the original intention to offer those who served their nation in the military a better life as citizens.

Articles describing the impact of the GI Bill use terms like life changing and transformative.^3,4 Our contemporary culture makes it difficult to imagine how out of reach a college education was for the generation that fought WWII. Universities were primarily for the rich and connected, the powerful and privileged. Were it not for the upward social mobility the GI Bill propelled, the American dream would not have become a reality for many farmers, small town merchants, and factory workers. The GI Bill though could not by itself ensure equity. The systemic racism endemic in the United States and among the elected representatives who debated the bill resulted in many Black service members especially in the South being denied entrance to institutions of higher learning.⁵ Despite this invidious discrimination, the bill was a profound effort to help many other service members to successfully reintegrate into the society they had preserved and defended.⁴

“With the signing of this bill, a well-rounded program of special veterans’ benefits is nearly completed,” FDR said, capturing its noble intent: “It gives emphatic notice to the men and women in our armed forces that the American people do not intend to let them down.”⁶

Regrettably, we have not kept FDR’s pledge. Now unscrupulous businesses are preying on the aspirations of military personnel and veterans for an education and thwarting their ability to seek gainful employment. For more than a decade, respected news media have reported that for-profit universities were exploiting service members trying to improve their lives through obtaining a college education via the GI Bill.⁷ The sad irony is that what enabled the exploitation to occur was a major expansion of the benefits under the Post-9/11 GI Bill. This version granted educational funding to any individual who had served on active duty for 90 days or more after September 10, 2001.⁸ Federal law prohibits for-profit educational institutions from receiving more than 90% of their total revenue from federal student aid. A loophole in the law enabled these institutions to categorize GI Bill funding as private not government dollars. Bad old American greed drove these for-profit colleges and universities to aggressively recruit veterans who trusted in the good faith of the academic institutions. Once the GI Bill monies were exhausted, veterans had already invested so much time and energy in a degree or certificate, the schools could persuade them to take out student loans with the promise of job placement assistance that never materialized. They took advantage of the veterans’ hopes to fatten their own bottom line in the face of declining enrolments.⁹ Journalists, government, think tank reports, and even a documentary described the tragic stories of service members left unemployed with immense debt and degrees that to many of them were now worthless.¹⁰

After years of reporters exposing the scam and politically thwarted efforts to stop it, Congress and President Biden closed what was known as the 90/10 loophole. This ended the weaponization of education it had promoted. In October 2022, the US Department of Education announced its final rule to prohibit the widespread educational fraud that had betrayed so many veterans and service members, which Secretary Dennis McDonough described as “abuse.”¹¹Some readers may wonder why I have devoted an editorial to a topic that seems somewhat distant from the health care that is the primary domain of Federal Practitioner. It happens that education is in closer proximity to health for our patients than many of us might have realized. A 2018 Military Medicine study found that veterans who took advantage of the educational opportunities of the GI Bill had better health and reduced smoking, among other benefits.¹² This connection between health and education should serve as a source of pride for all of us in federal practice as we are part of organizations that affirm the holistic concept of health that embraces not just medicine but education, housing, and other services essential for comprehensive well-being.

Veterans who interact with the criminal justice system (ie, justice-involved veterans) have heightened rates of mental health and psychosocial needs, including posttraumatic stress disorder (PTSD), substance use disorder, depression, suicidal ideation and attempt, and homelessness.^1,2 Alongside these criminogenic risk factors, recidivism is common among justice-involved veterans: About 70% of incarcerated veterans disclosed at least one prior incarceration.³

To address the complex interplay of psychosocial factors, mental health concerns, and justice involvement among veterans, veterans treatment courts (VTCs) emerged as an alternative to incarceration.⁴ VTC participation often consists of integrated treatment and rehabilitative services (eg, vocational training, health care), ongoing monitoring for substance use, graduated responses to address treatment adherence, and ongoing communication with the judge and legal counsel.⁴

A primary aim of these courts is to address psychosocial needs believed to underlie criminal behavior, thus reducing risk of recidivism and promoting successful recovery and community integration for eligible veterans. To do so, VTCs collaborate with community-based and/or US Department of Veterans Affairs services, such as the Veterans Justice Outreach program (VJO). VJO specialists identify and refer justice-involved veterans to Veterans Health Administration (VHA) and community care and serve as a liaison between VTC staff and VHA health care professionals (HCPs).⁵

VTC outcome studies highlight the importance of not only diverting veterans to problem-solving courts, but also ensuring their optimal participation. Successful graduates of VTC programs demonstrate significant improvements in mental health symptoms, life satisfaction, and social support, as well as lower rates of law enforcement interactions.^6,7 However, less is known about supporting those veterans who have difficulty engaging in VTCs and either discontinue participation or require lengthier periods of participation to meet court graduation requirements.⁸ One possibility to improve engagement among these veterans is to enhance court practices to best meet their needs.

In addition to delivering treatment, VHA mental health professionals may serve a critical interdisciplinary role by lending expertise to support VTC practices. For example, equipping court professionals with clinical knowledge and skills related to motivation may strengthen the staff’s interactions with participants, enabling them to address barriers as they arise and to facilitate veterans’ treatment adherence. Additionally, responsiveness to the impact of trauma exposure, which is common among this population, may prove important as related symptoms can affect veterans’ engagement, receptivity, and behavior in court settings. Indeed, prior examinations of justice-involved veterans have found trauma exposure rates ranging from 60% to 90% and PTSD rates ranging from 27% to 40%.^1,2 Notably, involvement with the justice system (eg, incarceration) may itself further increase risk of trauma exposure (eg, experiencing a physical or sexual assault in prison) or exacerbate existing PTSD.⁹ Nonetheless, whereas many drug courts and domestic violence courts have been established, problem-solving courts with a specialized focus on trauma exposure remain rare, suggesting a potential gap in court training.

VHA HCPs have the potential to facilitate justice-involved veterans’ successful court and treatment participation by coordinating with VJO specialists to provide training and consultation to the courts. Supporting efforts to effectively and responsively address criminogenic risk (eg, mental health) in VTC settings may in turn reduce the likelihood of recidivism.¹⁰ Given the elevated rates of trauma exposure among justice-involved veterans and the relative lack of trauma-focused VTCs, we developed a trauma-informed training for VTC professionals that centered on related clinical presentations of justice-involved veterans and frequently occurring challenges in the context of court participation.

Program Development

This educational program aimed to (1) provide psychoeducation on trauma exposure, PTSD, and existing evidence-based treatments; (2) present clinical considerations for justice-involved veterans related to trauma exposure and/or PTSD; and (3) introduce skills to facilitate effective communication and trauma-informed care practices among professionals working with veterans in a treatment court.

Prior to piloting the program, we conducted a needs assessment with VTC professionals and identified relevant theoretical constructs and brief interventions for inclusion in the training. Additionally, given the dearth of prior research on mental health education for VTCs, the team consulted with the developers of PTSD 101, a VHA workshop for veterans’ families that promotes psychoeducation, support, and effective communication.¹¹ Doing so informed approaches to delivering education to nonclinical audiences that interact with veterans with histories of trauma exposure. As this was a program development project, it was determined to be exempt from institutional review board review.

Needs Assessment

In the initial stages of development, local VJO specialists identified regional VTCs and facilitated introductions to these courts. Two of the 3 Rocky Mountain region VTCs that were contacted expressed interest in receiving trauma-informed training. Based on preliminary interest, the facilitators conducted a needs assessment with VJO and VTC staff from these 2 courts to capture requests for specific content and past experiences with other mental health trainings.

Guided by the focus group model, the needs assessments took place during three 1-hour meetings with VJO specialists and a 1-hour meeting with VJO specialists, VTC professionals, and community-based clinical partners.¹² Additionally, attending a VTC graduation and court session allowed for observations of court practices and interactions with veterans. A total of 13 professionals (judges, court coordinators, case managers, peer mentors, VJO specialists, and clinicians who specialize in substance use disorder and intimate partner violence) participated in the needs assessments.

The most critical need identified by court professionals was a focus on how to apply knowledge about trauma and PTSD to interactions with justice-involved veterans. This was reportedly absent from prior training sessions the courts had received. Both Rocky Mountain region VTCs expressed a strong interest in and openness to adapting practices based on research and practice recommendations. Additional requests that emerged included a refresher on psychoeducation related to trauma and how to address the personal impact of working with this population (eg, compassion fatigue).

Training Components

Based on the needs identified by VTC professionals and informed by consultation with the developers of PTSD 101,

Fostering court familiarity with cognitive processing therapy and prolonged exposure may bolster veteran engagement in treatment through regular reinforcement of skills and concepts introduced in therapy. This may prove particularly salient given the limited engagement with mental health treatment and elevated dropout rates from PTSD treatment among the general veteran population.^15,16

Exercises and metaphors were used to illustrate concepts in multiple ways. For example, training attendees engaged in a “stop, drop, and roll” thought exercise in which they were asked to brainstorm behavioral reactions to catching on fire. This exercise illustrated the tendency for individuals to revert to common yet unhelpful attempts at problem solving (eg, running due to panic, which would exacerbate the fire), particularly in crisis and without prior education regarding adaptive ways to respond. Attendee-generated examples, such as running, were used to demonstrate the importance of practicing and reinforcing skill development prior to a crisis, to ensure proficiency and optimal response. Additionally, in prompting consideration of one’s response tendencies, this exercise may engender empathy and understanding for veterans.

Skills training. Efforts to promote veteran engagement in court, facilitate motivation and readiness for change, and address barriers that arise (eg, distress associated with court appearances) may support successful and timely graduation. As such, skills training constituted the largest component of the training and drew from observations of court practices and the VTCs’ identified challenges. Consistent with the project’s aims and reported needs of the court, skills that target common presentations following trauma exposure (eg, avoidance, hypervigilance) were prioritized for this pilot training. Strategies included brief interventions from dialectical behavior therapy, acceptance and commitment therapy, and motivational interviewing to strengthen the support provided by staff to veterans and address their needs (Table 2).

Training attendees also participated in exercises to reiterate skills. For example, attendees completed an ambivalence matrix using an audience-identified common behavior that is difficult to change (eg, heavy alcohol use as a coping mechanism for distress).

Attendees engaged in an exercise that involved identifying unhelpful thoughts and behaviors, targets for validation, and veteran strengths from a hypothetical case vignette. This vignette involved a VTC participant who initially engaged effectively but began to demonstrate difficulty appropriately engaging in court and mental health treatment as well as challenging interactions with VTC staff (eg, raised voice during court sessions, not respecting communication boundaries).

Pilot Test

Based on scheduling parameters communicated by court coordinators, the pilot training was designed as a presentation during times reserved for court staffing meetings. To accommodate court preferences due to the COVID-19 pandemic, one 90-minute training was conducted virtually in March 2022, and the other training was conducted in person in April 2022 for 2 hours. The trainings were facilitated by 2 VHA clinical psychologists and included the judge, court coordinator, VJO specialist, peer mentors, case managers, probation/parole officers, and community-based HCPs who partner with the court (eg, social workers, psychologists). About 12 to 15 professionals attended each training session.

Feedback

Feedback was solicited from attendees via an anonymous online survey. Seven participants completed the survey; the response rate of about 20% was consistent with those observed for other surveys of court professionals.²⁰ Many attendees also provided feedback directly to the facilitators. Feedback highlighted that the skills-based components not only were perceived as most helpful but also notably distinguished this training. “What set this training apart from other training events was the practical applications,” one attendee noted. “It was not just information or education, both instructors did an incredible job of explaining exactly how we could apply the knowledge they were sharing. They did this in such a way that it was easy to understand and apply.”

Specific skills were consistently identified as helpful, including managing intense emotions, addressing ambivalence, and approaching sanctions and rewards. Additionally, employing a less formal approach to the training, with relatable overviews of concepts and immediate responsiveness to requests for expansion on a topic, was perceived as a unique benefit: Another attendee appreciated that “It was beneficial to sit around a table with a less formal presentation and be able to ask questions.” This approach seemed particularly well suited for the program’s cross-disciplinary audience. Attendees reported that they valued the relatively limited focus on DSM-5 criteria. Attendees emphasized that education specific to veterans on evidence-based PTSD treatments, psychoeducation, and avoidance was very helpful. Respondents also recommended that the training be lengthened to a daylong workshop to accommodate greater opportunity to practice skills and consultation.

The consultation portion of the training provided insight into additional areas of importance to incorporate into future iterations. Identified needs included appropriate and realistic boundary setting (eg, addressing disruptions in the courtroom), suggestions for improving and expanding homework assigned by the court, and ways to address concerns about PTSD treatment shared by veterans in court (eg, attributing substance use relapses to the intensiveness of trauma-focused treatment vs lack of familiarity with alternate coping skills). Additionally, the VTC professionals’ desire to support mental health professionals’ work with veterans was clearly evident, highlighting the bidirectional value of interdisciplinary collaboration between VHA mental health professionals and VTC professionals.

Discussion

A trauma-informed training was developed and delivered to 2 VTCs in the Rocky Mountain region with the goal of providing relevant psychoeducation and introducing skills to bolster court practices that address veteran needs. Psychoeducational components of the training that were particularly well received and prompted significant participant engagement included discussions and examples of avoidance, levels of validation, language to facilitate motivation and address barriers, mechanisms underlying treatment, and potential functions underlying limited veteran treatment engagement. Distress tolerance, approaches to sanctions and rewards, and use of ambivalence matrices to guide motivation were identified as particularly helpful skills.

The pilot phase of this trauma-informed training provided valuable insights into developing mental health trainings for VTCs. Specifically, VTCs may benefit from the expertise of VHA HCPs and are particularly interested in learning brief skills to improve their practices. The usefulness of such trainings may be bolstered by efforts to form relationships with the court to identify their perceived needs and employing an iterative process that is responsive to feedback both during and after the training. Last, each stage of this project was strengthened by collaboration with VJO specialists, highlighting the importance of future collaboration between VJO and VHA mental health clinics to further support justice-involved veterans. For example, VJO specialists were instrumental in identifying training needs related to veterans’ clinical presentations in court, facilitating introductions to local VTCs, and helping to address barriers to piloting, like scheduling.

Modifications and Future Directions

The insights gained through the process of training design, delivery, and feedback inform future development of this training. Based on the feedback received, subsequent versions of the training may be expanded into a half- or full-day workshop to allow for adequate time for skills training and feedback, as well as consultation. Doing so will enable facilitators to further foster attendees’ familiarity with and confidence in their ability to use these skills. Furthermore, the consultation portion of this training revealed areas that may benefit from greater attention, including how to address challenging interactions in court (eg, addressing gender dynamics between court professionals and participants) and better support veterans who are having difficulty engaging in mental health treatment (eg, courts’ observation of high rates of dropout around the third or fourth session of evidence-based treatment for PTSD). Last, all attendees who responded to the survey expressed interest in a brief resource guide based on the training, emphasizing the need for ready access to key skills and concepts to support the use of strategies learned.

An additional future aim of this project is to conduct a more thorough evaluation of the needs and outcomes related to this trauma-informed training for VTC professionals. With the rapid growth of VTCs nationwide, relatively little examination of court processes and practices has occurred, and there is a lack of research on the development or effectiveness of mental health trainings provided to VTCs.²¹ Therefore, we intend to conduct larger scale qualitative interviews with court personnel and VJO specialists to obtain a clearer understanding of the needs related to skills-based training and gaps in psychoeducation. These comprehensive needs assessments may also capture common comorbidities that were not incorporated into the pilot training (eg, substance use disorders) but may be important training targets for court professionals. This information will be used to inform subsequent expansion and adaptation of the training into a longer workshop. Program evaluation will be conducted via survey-based feedback on perceived usefulness of the workshop and self-report of confidence in and use of strategies to improve court practices. Furthermore, efforts to obtain veteran outcome data, such as treatment engagement and successful participation in VTC, may be pursued.

Limitations

This training development and pilot project provided valuable foundational information regarding a largely unexamined component of treatment courts—the benefit of skills-based trainings to facilitate court practices related to justice-involved veterans. However, it is worth noting that survey responses were limited; thus, the feedback received may not reflect all attendees’ perceptions. Additionally, because both training sessions were conducted solely with 2 courts in the Rocky Mountain area, feedback may be limited to the needs of this geographic region.

Conclusions

A trauma-informed training was developed for VTCs to facilitate relevant understanding of justice-involved veterans’ needs and presentations in court, introduce skills to address challenges that arise (eg, motivation, emotional dysregulation), and provide interdisciplinary support to court professionals. This training was an important step toward fostering strong collaborations between VHA HCPs and community-based veterans courts, and feedback received during development and following implementation highlighted the perceived need for a skills-based approach to such trainings. Further program development and evaluation can strengthen this training and provide a foundation for dissemination to a broader scope of VTCs, with the goal of reducing recidivism risk among justice-involved veterans by promoting effective engagement in problem-solving court.

Veterans who interact with the criminal justice system (ie, justice-involved veterans) have heightened rates of mental health and psychosocial needs, including posttraumatic stress disorder (PTSD), substance use disorder, depression, suicidal ideation and attempt, and homelessness.^1,2 Alongside these criminogenic risk factors, recidivism is common among justice-involved veterans: About 70% of incarcerated veterans disclosed at least one prior incarceration.³

To address the complex interplay of psychosocial factors, mental health concerns, and justice involvement among veterans, veterans treatment courts (VTCs) emerged as an alternative to incarceration.⁴ VTC participation often consists of integrated treatment and rehabilitative services (eg, vocational training, health care), ongoing monitoring for substance use, graduated responses to address treatment adherence, and ongoing communication with the judge and legal counsel.⁴

A primary aim of these courts is to address psychosocial needs believed to underlie criminal behavior, thus reducing risk of recidivism and promoting successful recovery and community integration for eligible veterans. To do so, VTCs collaborate with community-based and/or US Department of Veterans Affairs services, such as the Veterans Justice Outreach program (VJO). VJO specialists identify and refer justice-involved veterans to Veterans Health Administration (VHA) and community care and serve as a liaison between VTC staff and VHA health care professionals (HCPs).⁵

VTC outcome studies highlight the importance of not only diverting veterans to problem-solving courts, but also ensuring their optimal participation. Successful graduates of VTC programs demonstrate significant improvements in mental health symptoms, life satisfaction, and social support, as well as lower rates of law enforcement interactions.^6,7 However, less is known about supporting those veterans who have difficulty engaging in VTCs and either discontinue participation or require lengthier periods of participation to meet court graduation requirements.⁸ One possibility to improve engagement among these veterans is to enhance court practices to best meet their needs.

In addition to delivering treatment, VHA mental health professionals may serve a critical interdisciplinary role by lending expertise to support VTC practices. For example, equipping court professionals with clinical knowledge and skills related to motivation may strengthen the staff’s interactions with participants, enabling them to address barriers as they arise and to facilitate veterans’ treatment adherence. Additionally, responsiveness to the impact of trauma exposure, which is common among this population, may prove important as related symptoms can affect veterans’ engagement, receptivity, and behavior in court settings. Indeed, prior examinations of justice-involved veterans have found trauma exposure rates ranging from 60% to 90% and PTSD rates ranging from 27% to 40%.^1,2 Notably, involvement with the justice system (eg, incarceration) may itself further increase risk of trauma exposure (eg, experiencing a physical or sexual assault in prison) or exacerbate existing PTSD.⁹ Nonetheless, whereas many drug courts and domestic violence courts have been established, problem-solving courts with a specialized focus on trauma exposure remain rare, suggesting a potential gap in court training.

VHA HCPs have the potential to facilitate justice-involved veterans’ successful court and treatment participation by coordinating with VJO specialists to provide training and consultation to the courts. Supporting efforts to effectively and responsively address criminogenic risk (eg, mental health) in VTC settings may in turn reduce the likelihood of recidivism.¹⁰ Given the elevated rates of trauma exposure among justice-involved veterans and the relative lack of trauma-focused VTCs, we developed a trauma-informed training for VTC professionals that centered on related clinical presentations of justice-involved veterans and frequently occurring challenges in the context of court participation.

Program Development

This educational program aimed to (1) provide psychoeducation on trauma exposure, PTSD, and existing evidence-based treatments; (2) present clinical considerations for justice-involved veterans related to trauma exposure and/or PTSD; and (3) introduce skills to facilitate effective communication and trauma-informed care practices among professionals working with veterans in a treatment court.

Prior to piloting the program, we conducted a needs assessment with VTC professionals and identified relevant theoretical constructs and brief interventions for inclusion in the training. Additionally, given the dearth of prior research on mental health education for VTCs, the team consulted with the developers of PTSD 101, a VHA workshop for veterans’ families that promotes psychoeducation, support, and effective communication.¹¹ Doing so informed approaches to delivering education to nonclinical audiences that interact with veterans with histories of trauma exposure. As this was a program development project, it was determined to be exempt from institutional review board review.

Needs Assessment

In the initial stages of development, local VJO specialists identified regional VTCs and facilitated introductions to these courts. Two of the 3 Rocky Mountain region VTCs that were contacted expressed interest in receiving trauma-informed training. Based on preliminary interest, the facilitators conducted a needs assessment with VJO and VTC staff from these 2 courts to capture requests for specific content and past experiences with other mental health trainings.

Guided by the focus group model, the needs assessments took place during three 1-hour meetings with VJO specialists and a 1-hour meeting with VJO specialists, VTC professionals, and community-based clinical partners.¹² Additionally, attending a VTC graduation and court session allowed for observations of court practices and interactions with veterans. A total of 13 professionals (judges, court coordinators, case managers, peer mentors, VJO specialists, and clinicians who specialize in substance use disorder and intimate partner violence) participated in the needs assessments.

The most critical need identified by court professionals was a focus on how to apply knowledge about trauma and PTSD to interactions with justice-involved veterans. This was reportedly absent from prior training sessions the courts had received. Both Rocky Mountain region VTCs expressed a strong interest in and openness to adapting practices based on research and practice recommendations. Additional requests that emerged included a refresher on psychoeducation related to trauma and how to address the personal impact of working with this population (eg, compassion fatigue).

Training Components

Based on the needs identified by VTC professionals and informed by consultation with the developers of PTSD 101,

Fostering court familiarity with cognitive processing therapy and prolonged exposure may bolster veteran engagement in treatment through regular reinforcement of skills and concepts introduced in therapy. This may prove particularly salient given the limited engagement with mental health treatment and elevated dropout rates from PTSD treatment among the general veteran population.^15,16

Exercises and metaphors were used to illustrate concepts in multiple ways. For example, training attendees engaged in a “stop, drop, and roll” thought exercise in which they were asked to brainstorm behavioral reactions to catching on fire. This exercise illustrated the tendency for individuals to revert to common yet unhelpful attempts at problem solving (eg, running due to panic, which would exacerbate the fire), particularly in crisis and without prior education regarding adaptive ways to respond. Attendee-generated examples, such as running, were used to demonstrate the importance of practicing and reinforcing skill development prior to a crisis, to ensure proficiency and optimal response. Additionally, in prompting consideration of one’s response tendencies, this exercise may engender empathy and understanding for veterans.

Skills training. Efforts to promote veteran engagement in court, facilitate motivation and readiness for change, and address barriers that arise (eg, distress associated with court appearances) may support successful and timely graduation. As such, skills training constituted the largest component of the training and drew from observations of court practices and the VTCs’ identified challenges. Consistent with the project’s aims and reported needs of the court, skills that target common presentations following trauma exposure (eg, avoidance, hypervigilance) were prioritized for this pilot training. Strategies included brief interventions from dialectical behavior therapy, acceptance and commitment therapy, and motivational interviewing to strengthen the support provided by staff to veterans and address their needs (Table 2).

Training attendees also participated in exercises to reiterate skills. For example, attendees completed an ambivalence matrix using an audience-identified common behavior that is difficult to change (eg, heavy alcohol use as a coping mechanism for distress).

Attendees engaged in an exercise that involved identifying unhelpful thoughts and behaviors, targets for validation, and veteran strengths from a hypothetical case vignette. This vignette involved a VTC participant who initially engaged effectively but began to demonstrate difficulty appropriately engaging in court and mental health treatment as well as challenging interactions with VTC staff (eg, raised voice during court sessions, not respecting communication boundaries).

Pilot Test

Based on scheduling parameters communicated by court coordinators, the pilot training was designed as a presentation during times reserved for court staffing meetings. To accommodate court preferences due to the COVID-19 pandemic, one 90-minute training was conducted virtually in March 2022, and the other training was conducted in person in April 2022 for 2 hours. The trainings were facilitated by 2 VHA clinical psychologists and included the judge, court coordinator, VJO specialist, peer mentors, case managers, probation/parole officers, and community-based HCPs who partner with the court (eg, social workers, psychologists). About 12 to 15 professionals attended each training session.

Feedback

Feedback was solicited from attendees via an anonymous online survey. Seven participants completed the survey; the response rate of about 20% was consistent with those observed for other surveys of court professionals.²⁰ Many attendees also provided feedback directly to the facilitators. Feedback highlighted that the skills-based components not only were perceived as most helpful but also notably distinguished this training. “What set this training apart from other training events was the practical applications,” one attendee noted. “It was not just information or education, both instructors did an incredible job of explaining exactly how we could apply the knowledge they were sharing. They did this in such a way that it was easy to understand and apply.”

Specific skills were consistently identified as helpful, including managing intense emotions, addressing ambivalence, and approaching sanctions and rewards. Additionally, employing a less formal approach to the training, with relatable overviews of concepts and immediate responsiveness to requests for expansion on a topic, was perceived as a unique benefit: Another attendee appreciated that “It was beneficial to sit around a table with a less formal presentation and be able to ask questions.” This approach seemed particularly well suited for the program’s cross-disciplinary audience. Attendees reported that they valued the relatively limited focus on DSM-5 criteria. Attendees emphasized that education specific to veterans on evidence-based PTSD treatments, psychoeducation, and avoidance was very helpful. Respondents also recommended that the training be lengthened to a daylong workshop to accommodate greater opportunity to practice skills and consultation.

The consultation portion of the training provided insight into additional areas of importance to incorporate into future iterations. Identified needs included appropriate and realistic boundary setting (eg, addressing disruptions in the courtroom), suggestions for improving and expanding homework assigned by the court, and ways to address concerns about PTSD treatment shared by veterans in court (eg, attributing substance use relapses to the intensiveness of trauma-focused treatment vs lack of familiarity with alternate coping skills). Additionally, the VTC professionals’ desire to support mental health professionals’ work with veterans was clearly evident, highlighting the bidirectional value of interdisciplinary collaboration between VHA mental health professionals and VTC professionals.

Discussion

A trauma-informed training was developed and delivered to 2 VTCs in the Rocky Mountain region with the goal of providing relevant psychoeducation and introducing skills to bolster court practices that address veteran needs. Psychoeducational components of the training that were particularly well received and prompted significant participant engagement included discussions and examples of avoidance, levels of validation, language to facilitate motivation and address barriers, mechanisms underlying treatment, and potential functions underlying limited veteran treatment engagement. Distress tolerance, approaches to sanctions and rewards, and use of ambivalence matrices to guide motivation were identified as particularly helpful skills.

The pilot phase of this trauma-informed training provided valuable insights into developing mental health trainings for VTCs. Specifically, VTCs may benefit from the expertise of VHA HCPs and are particularly interested in learning brief skills to improve their practices. The usefulness of such trainings may be bolstered by efforts to form relationships with the court to identify their perceived needs and employing an iterative process that is responsive to feedback both during and after the training. Last, each stage of this project was strengthened by collaboration with VJO specialists, highlighting the importance of future collaboration between VJO and VHA mental health clinics to further support justice-involved veterans. For example, VJO specialists were instrumental in identifying training needs related to veterans’ clinical presentations in court, facilitating introductions to local VTCs, and helping to address barriers to piloting, like scheduling.

Modifications and Future Directions

The insights gained through the process of training design, delivery, and feedback inform future development of this training. Based on the feedback received, subsequent versions of the training may be expanded into a half- or full-day workshop to allow for adequate time for skills training and feedback, as well as consultation. Doing so will enable facilitators to further foster attendees’ familiarity with and confidence in their ability to use these skills. Furthermore, the consultation portion of this training revealed areas that may benefit from greater attention, including how to address challenging interactions in court (eg, addressing gender dynamics between court professionals and participants) and better support veterans who are having difficulty engaging in mental health treatment (eg, courts’ observation of high rates of dropout around the third or fourth session of evidence-based treatment for PTSD). Last, all attendees who responded to the survey expressed interest in a brief resource guide based on the training, emphasizing the need for ready access to key skills and concepts to support the use of strategies learned.

An additional future aim of this project is to conduct a more thorough evaluation of the needs and outcomes related to this trauma-informed training for VTC professionals. With the rapid growth of VTCs nationwide, relatively little examination of court processes and practices has occurred, and there is a lack of research on the development or effectiveness of mental health trainings provided to VTCs.²¹ Therefore, we intend to conduct larger scale qualitative interviews with court personnel and VJO specialists to obtain a clearer understanding of the needs related to skills-based training and gaps in psychoeducation. These comprehensive needs assessments may also capture common comorbidities that were not incorporated into the pilot training (eg, substance use disorders) but may be important training targets for court professionals. This information will be used to inform subsequent expansion and adaptation of the training into a longer workshop. Program evaluation will be conducted via survey-based feedback on perceived usefulness of the workshop and self-report of confidence in and use of strategies to improve court practices. Furthermore, efforts to obtain veteran outcome data, such as treatment engagement and successful participation in VTC, may be pursued.

Limitations

This training development and pilot project provided valuable foundational information regarding a largely unexamined component of treatment courts—the benefit of skills-based trainings to facilitate court practices related to justice-involved veterans. However, it is worth noting that survey responses were limited; thus, the feedback received may not reflect all attendees’ perceptions. Additionally, because both training sessions were conducted solely with 2 courts in the Rocky Mountain area, feedback may be limited to the needs of this geographic region.

Conclusions

A trauma-informed training was developed for VTCs to facilitate relevant understanding of justice-involved veterans’ needs and presentations in court, introduce skills to address challenges that arise (eg, motivation, emotional dysregulation), and provide interdisciplinary support to court professionals. This training was an important step toward fostering strong collaborations between VHA HCPs and community-based veterans courts, and feedback received during development and following implementation highlighted the perceived need for a skills-based approach to such trainings. Further program development and evaluation can strengthen this training and provide a foundation for dissemination to a broader scope of VTCs, with the goal of reducing recidivism risk among justice-involved veterans by promoting effective engagement in problem-solving court.

Veterans who interact with the criminal justice system (ie, justice-involved veterans) have heightened rates of mental health and psychosocial needs, including posttraumatic stress disorder (PTSD), substance use disorder, depression, suicidal ideation and attempt, and homelessness.^1,2 Alongside these criminogenic risk factors, recidivism is common among justice-involved veterans: About 70% of incarcerated veterans disclosed at least one prior incarceration.³

To address the complex interplay of psychosocial factors, mental health concerns, and justice involvement among veterans, veterans treatment courts (VTCs) emerged as an alternative to incarceration.⁴ VTC participation often consists of integrated treatment and rehabilitative services (eg, vocational training, health care), ongoing monitoring for substance use, graduated responses to address treatment adherence, and ongoing communication with the judge and legal counsel.⁴

A primary aim of these courts is to address psychosocial needs believed to underlie criminal behavior, thus reducing risk of recidivism and promoting successful recovery and community integration for eligible veterans. To do so, VTCs collaborate with community-based and/or US Department of Veterans Affairs services, such as the Veterans Justice Outreach program (VJO). VJO specialists identify and refer justice-involved veterans to Veterans Health Administration (VHA) and community care and serve as a liaison between VTC staff and VHA health care professionals (HCPs).⁵

VTC outcome studies highlight the importance of not only diverting veterans to problem-solving courts, but also ensuring their optimal participation. Successful graduates of VTC programs demonstrate significant improvements in mental health symptoms, life satisfaction, and social support, as well as lower rates of law enforcement interactions.^6,7 However, less is known about supporting those veterans who have difficulty engaging in VTCs and either discontinue participation or require lengthier periods of participation to meet court graduation requirements.⁸ One possibility to improve engagement among these veterans is to enhance court practices to best meet their needs.

In addition to delivering treatment, VHA mental health professionals may serve a critical interdisciplinary role by lending expertise to support VTC practices. For example, equipping court professionals with clinical knowledge and skills related to motivation may strengthen the staff’s interactions with participants, enabling them to address barriers as they arise and to facilitate veterans’ treatment adherence. Additionally, responsiveness to the impact of trauma exposure, which is common among this population, may prove important as related symptoms can affect veterans’ engagement, receptivity, and behavior in court settings. Indeed, prior examinations of justice-involved veterans have found trauma exposure rates ranging from 60% to 90% and PTSD rates ranging from 27% to 40%.^1,2 Notably, involvement with the justice system (eg, incarceration) may itself further increase risk of trauma exposure (eg, experiencing a physical or sexual assault in prison) or exacerbate existing PTSD.⁹ Nonetheless, whereas many drug courts and domestic violence courts have been established, problem-solving courts with a specialized focus on trauma exposure remain rare, suggesting a potential gap in court training.

VHA HCPs have the potential to facilitate justice-involved veterans’ successful court and treatment participation by coordinating with VJO specialists to provide training and consultation to the courts. Supporting efforts to effectively and responsively address criminogenic risk (eg, mental health) in VTC settings may in turn reduce the likelihood of recidivism.¹⁰ Given the elevated rates of trauma exposure among justice-involved veterans and the relative lack of trauma-focused VTCs, we developed a trauma-informed training for VTC professionals that centered on related clinical presentations of justice-involved veterans and frequently occurring challenges in the context of court participation.

Program Development

This educational program aimed to (1) provide psychoeducation on trauma exposure, PTSD, and existing evidence-based treatments; (2) present clinical considerations for justice-involved veterans related to trauma exposure and/or PTSD; and (3) introduce skills to facilitate effective communication and trauma-informed care practices among professionals working with veterans in a treatment court.

Prior to piloting the program, we conducted a needs assessment with VTC professionals and identified relevant theoretical constructs and brief interventions for inclusion in the training. Additionally, given the dearth of prior research on mental health education for VTCs, the team consulted with the developers of PTSD 101, a VHA workshop for veterans’ families that promotes psychoeducation, support, and effective communication.¹¹ Doing so informed approaches to delivering education to nonclinical audiences that interact with veterans with histories of trauma exposure. As this was a program development project, it was determined to be exempt from institutional review board review.

Needs Assessment

In the initial stages of development, local VJO specialists identified regional VTCs and facilitated introductions to these courts. Two of the 3 Rocky Mountain region VTCs that were contacted expressed interest in receiving trauma-informed training. Based on preliminary interest, the facilitators conducted a needs assessment with VJO and VTC staff from these 2 courts to capture requests for specific content and past experiences with other mental health trainings.

Guided by the focus group model, the needs assessments took place during three 1-hour meetings with VJO specialists and a 1-hour meeting with VJO specialists, VTC professionals, and community-based clinical partners.¹² Additionally, attending a VTC graduation and court session allowed for observations of court practices and interactions with veterans. A total of 13 professionals (judges, court coordinators, case managers, peer mentors, VJO specialists, and clinicians who specialize in substance use disorder and intimate partner violence) participated in the needs assessments.

The most critical need identified by court professionals was a focus on how to apply knowledge about trauma and PTSD to interactions with justice-involved veterans. This was reportedly absent from prior training sessions the courts had received. Both Rocky Mountain region VTCs expressed a strong interest in and openness to adapting practices based on research and practice recommendations. Additional requests that emerged included a refresher on psychoeducation related to trauma and how to address the personal impact of working with this population (eg, compassion fatigue).

Training Components

Based on the needs identified by VTC professionals and informed by consultation with the developers of PTSD 101,

Fostering court familiarity with cognitive processing therapy and prolonged exposure may bolster veteran engagement in treatment through regular reinforcement of skills and concepts introduced in therapy. This may prove particularly salient given the limited engagement with mental health treatment and elevated dropout rates from PTSD treatment among the general veteran population.^15,16

Exercises and metaphors were used to illustrate concepts in multiple ways. For example, training attendees engaged in a “stop, drop, and roll” thought exercise in which they were asked to brainstorm behavioral reactions to catching on fire. This exercise illustrated the tendency for individuals to revert to common yet unhelpful attempts at problem solving (eg, running due to panic, which would exacerbate the fire), particularly in crisis and without prior education regarding adaptive ways to respond. Attendee-generated examples, such as running, were used to demonstrate the importance of practicing and reinforcing skill development prior to a crisis, to ensure proficiency and optimal response. Additionally, in prompting consideration of one’s response tendencies, this exercise may engender empathy and understanding for veterans.

Skills training. Efforts to promote veteran engagement in court, facilitate motivation and readiness for change, and address barriers that arise (eg, distress associated with court appearances) may support successful and timely graduation. As such, skills training constituted the largest component of the training and drew from observations of court practices and the VTCs’ identified challenges. Consistent with the project’s aims and reported needs of the court, skills that target common presentations following trauma exposure (eg, avoidance, hypervigilance) were prioritized for this pilot training. Strategies included brief interventions from dialectical behavior therapy, acceptance and commitment therapy, and motivational interviewing to strengthen the support provided by staff to veterans and address their needs (Table 2).

Training attendees also participated in exercises to reiterate skills. For example, attendees completed an ambivalence matrix using an audience-identified common behavior that is difficult to change (eg, heavy alcohol use as a coping mechanism for distress).

Attendees engaged in an exercise that involved identifying unhelpful thoughts and behaviors, targets for validation, and veteran strengths from a hypothetical case vignette. This vignette involved a VTC participant who initially engaged effectively but began to demonstrate difficulty appropriately engaging in court and mental health treatment as well as challenging interactions with VTC staff (eg, raised voice during court sessions, not respecting communication boundaries).

Pilot Test

Based on scheduling parameters communicated by court coordinators, the pilot training was designed as a presentation during times reserved for court staffing meetings. To accommodate court preferences due to the COVID-19 pandemic, one 90-minute training was conducted virtually in March 2022, and the other training was conducted in person in April 2022 for 2 hours. The trainings were facilitated by 2 VHA clinical psychologists and included the judge, court coordinator, VJO specialist, peer mentors, case managers, probation/parole officers, and community-based HCPs who partner with the court (eg, social workers, psychologists). About 12 to 15 professionals attended each training session.

Feedback

Feedback was solicited from attendees via an anonymous online survey. Seven participants completed the survey; the response rate of about 20% was consistent with those observed for other surveys of court professionals.²⁰ Many attendees also provided feedback directly to the facilitators. Feedback highlighted that the skills-based components not only were perceived as most helpful but also notably distinguished this training. “What set this training apart from other training events was the practical applications,” one attendee noted. “It was not just information or education, both instructors did an incredible job of explaining exactly how we could apply the knowledge they were sharing. They did this in such a way that it was easy to understand and apply.”

Specific skills were consistently identified as helpful, including managing intense emotions, addressing ambivalence, and approaching sanctions and rewards. Additionally, employing a less formal approach to the training, with relatable overviews of concepts and immediate responsiveness to requests for expansion on a topic, was perceived as a unique benefit: Another attendee appreciated that “It was beneficial to sit around a table with a less formal presentation and be able to ask questions.” This approach seemed particularly well suited for the program’s cross-disciplinary audience. Attendees reported that they valued the relatively limited focus on DSM-5 criteria. Attendees emphasized that education specific to veterans on evidence-based PTSD treatments, psychoeducation, and avoidance was very helpful. Respondents also recommended that the training be lengthened to a daylong workshop to accommodate greater opportunity to practice skills and consultation.

The consultation portion of the training provided insight into additional areas of importance to incorporate into future iterations. Identified needs included appropriate and realistic boundary setting (eg, addressing disruptions in the courtroom), suggestions for improving and expanding homework assigned by the court, and ways to address concerns about PTSD treatment shared by veterans in court (eg, attributing substance use relapses to the intensiveness of trauma-focused treatment vs lack of familiarity with alternate coping skills). Additionally, the VTC professionals’ desire to support mental health professionals’ work with veterans was clearly evident, highlighting the bidirectional value of interdisciplinary collaboration between VHA mental health professionals and VTC professionals.

Discussion

A trauma-informed training was developed and delivered to 2 VTCs in the Rocky Mountain region with the goal of providing relevant psychoeducation and introducing skills to bolster court practices that address veteran needs. Psychoeducational components of the training that were particularly well received and prompted significant participant engagement included discussions and examples of avoidance, levels of validation, language to facilitate motivation and address barriers, mechanisms underlying treatment, and potential functions underlying limited veteran treatment engagement. Distress tolerance, approaches to sanctions and rewards, and use of ambivalence matrices to guide motivation were identified as particularly helpful skills.

The pilot phase of this trauma-informed training provided valuable insights into developing mental health trainings for VTCs. Specifically, VTCs may benefit from the expertise of VHA HCPs and are particularly interested in learning brief skills to improve their practices. The usefulness of such trainings may be bolstered by efforts to form relationships with the court to identify their perceived needs and employing an iterative process that is responsive to feedback both during and after the training. Last, each stage of this project was strengthened by collaboration with VJO specialists, highlighting the importance of future collaboration between VJO and VHA mental health clinics to further support justice-involved veterans. For example, VJO specialists were instrumental in identifying training needs related to veterans’ clinical presentations in court, facilitating introductions to local VTCs, and helping to address barriers to piloting, like scheduling.

Modifications and Future Directions

The insights gained through the process of training design, delivery, and feedback inform future development of this training. Based on the feedback received, subsequent versions of the training may be expanded into a half- or full-day workshop to allow for adequate time for skills training and feedback, as well as consultation. Doing so will enable facilitators to further foster attendees’ familiarity with and confidence in their ability to use these skills. Furthermore, the consultation portion of this training revealed areas that may benefit from greater attention, including how to address challenging interactions in court (eg, addressing gender dynamics between court professionals and participants) and better support veterans who are having difficulty engaging in mental health treatment (eg, courts’ observation of high rates of dropout around the third or fourth session of evidence-based treatment for PTSD). Last, all attendees who responded to the survey expressed interest in a brief resource guide based on the training, emphasizing the need for ready access to key skills and concepts to support the use of strategies learned.

An additional future aim of this project is to conduct a more thorough evaluation of the needs and outcomes related to this trauma-informed training for VTC professionals. With the rapid growth of VTCs nationwide, relatively little examination of court processes and practices has occurred, and there is a lack of research on the development or effectiveness of mental health trainings provided to VTCs.²¹ Therefore, we intend to conduct larger scale qualitative interviews with court personnel and VJO specialists to obtain a clearer understanding of the needs related to skills-based training and gaps in psychoeducation. These comprehensive needs assessments may also capture common comorbidities that were not incorporated into the pilot training (eg, substance use disorders) but may be important training targets for court professionals. This information will be used to inform subsequent expansion and adaptation of the training into a longer workshop. Program evaluation will be conducted via survey-based feedback on perceived usefulness of the workshop and self-report of confidence in and use of strategies to improve court practices. Furthermore, efforts to obtain veteran outcome data, such as treatment engagement and successful participation in VTC, may be pursued.

Limitations

This training development and pilot project provided valuable foundational information regarding a largely unexamined component of treatment courts—the benefit of skills-based trainings to facilitate court practices related to justice-involved veterans. However, it is worth noting that survey responses were limited; thus, the feedback received may not reflect all attendees’ perceptions. Additionally, because both training sessions were conducted solely with 2 courts in the Rocky Mountain area, feedback may be limited to the needs of this geographic region.

Conclusions

A trauma-informed training was developed for VTCs to facilitate relevant understanding of justice-involved veterans’ needs and presentations in court, introduce skills to address challenges that arise (eg, motivation, emotional dysregulation), and provide interdisciplinary support to court professionals. This training was an important step toward fostering strong collaborations between VHA HCPs and community-based veterans courts, and feedback received during development and following implementation highlighted the perceived need for a skills-based approach to such trainings. Further program development and evaluation can strengthen this training and provide a foundation for dissemination to a broader scope of VTCs, with the goal of reducing recidivism risk among justice-involved veterans by promoting effective engagement in problem-solving court.

Aspirin is an antiplatelet agent that binds irreversibly to COX-1 and COX-2 enzymes, which results in decreased prostaglandin and thromboxane A2 production and inhibition of platelet aggregation. Aspirin often is used for its antipyretic, analgesic, and antiplatelet properties. Its use in cardiovascular disease (CVD) has been studied extensively over the past few decades, and recent data are changing the framework for aspirin use in primary prevention of atherosclerotic cardiovascular disease (ASCVD). Primary prevention refers to efforts to prevent the incidence of cardiovascular events, whereas secondary prevention refers to efforts to prevent a cardiovascular event after one has occurred.¹ This differentiation is important as it guides the course of treatment.

Three trials published in 2018 evaluated aspirin use in primary prevention of ASCVD. The ASCEND trial evaluated aspirin use for primary prevention of ASCVD in patients with diabetes mellitus (DM). This study concluded that although aspirin prevented serious vascular events in patients with DM, the benefit observed was largely counteracted by the bleeding hazard.² The ARRIVE trial evaluated aspirin use for primary prevention in patients with a moderate CVD risk. The study concluded that aspirin use in patients at moderate risk of CVD could not be assessed due to the low incidence rate of CVD; however, the study concluded that aspirin did not reduce the incidence of cardiovascular events for patients at low CVD risk and that aspirin caused more mild gastrointestinal bleeds compared with placebo.³ The ASPREE trial evaluated aspirin use for primary prevention in patients aged > 70 years to determine whether its use prolonged a healthy lifespan. This trial concluded that patients who received daily aspirin were at a higher risk of major hemorrhage and that aspirin did not diminish CVD risk compared with placebo.⁴

These studies led to a paradigm shift in therapy to reevaluate aspirin use for primary prevention. Current indications for aspirin include secondary prevention of ASCVD (ie, myocardial infarction [MI], coronary artery bypass graft, transient ischemic attack [TIA], and stroke), venous thromboembolism prophylaxis in the setting of orthopedic surgery, or valvular disease with replacement and analgesia. It is important to note that certain clinical circumstances may warrant aspirin use for primary prevention of ASCVD on a patient-specific basis, and this decision should be made using a risk/benefit analysis with the patient.

In April 2022, the US Preventive Services Task Force (USPSTF) recommended against using low-dose aspirin for primary prevention of ASCVD in individuals aged ≥ 60 years. The USPSTF noted that for patients who have a ≥ 10%, 10-year CVD risk, the decision to initiate aspirin should be based on a risk/benefit discussion and may be beneficial in certain patient populations.⁵A 2019 National Heart, Lung, and Blood Institute survey found that 29 million Americans used aspirin for primary prevention of ASCVD, and 6.6 million of these Americans used aspirin for primary prevention without the recommendation of a health care professional (HCP). Almost half of these individuals were aged > 70 years and, therefore, at an increased risk for bleeding.⁶ With the recent studies and changes in guidelines highlighting a higher risk rather than benefit with the use of aspirin for primary prevention, the current use of aspirin for primary prevention in the United States needs to be readdressed.

HCPs should assess the appropriateness of aspirin use in their patients to ensure that the risks of aspirin do not outweigh the benefits. Pharmacists can play a vital role in the assessment of aspirin for primary prevention during patient visits and make recommendations to primary care practitioners to deprescribe aspirin when appropriate.

Methods

The objective of this study was to evaluate the appropriateness of aspirin therapy in patient aligned care team (PACT) clinics at the Captain James A. Lovell Federal Health Care Center (FHCC) in North Chicago, Illinois. The PACT clinics are a category of clinics that include all the primary care clinics at FHCC.

The primary outcome of this study was to determine the percentage of patients inappropriately on aspirin therapy. To assess the inappropriate use of aspirin, relevant history of ASCVD was collected. Patients were divided into 3 groups: those with a history of ASCVD, those with no risk factors or history of ASCVD, and those with risk factors and no history of ASCVD. Patients were then categorized for their indication for aspirin use, which included either primary or secondary prevention of ASCVD. Patients were categorized into the primary prevention group if they had no history of ASCVD, whereas patients with a history of ASCVD were placed into the secondary prevention group.

ASCVD was defined as patients with acute coronary syndrome (ACS), history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral artery disease (PAD), including aortic aneurysm (all with an atherosclerotic origin). Possible ASCVD risk was defined as patients with DM with a major risk factor (family history of premature ASCVD, hypertension, dyslipidemia, smoking, chronic kidney disease [CKD]/albuminuria) or patients diagnosed with coronary artery disease without an event. The percentage of patients followed by a PACT pharmacist, the number of pharmacist follow-up visits during the study period, and the date of the first 81-mg aspirin pharmacy order that was filled at FHCC were also collected.

The secondary outcome of this study focused on patients who were using aspirin for primary prevention and assessed potential reasons that may warrant deprescribing aspirin therapy. One reason for deprescribing is that aspirin may not be indicated for some patients, including those with DM without cardiovascular complications, patients aged > 70 years, and/or patients with CKD (defined as estimated glomerular filtration rate < 60 mL/min). Another reason for deprescribing is contraindication, which included patients with coagulopathy, thrombocytopenia (defined as platelet count < 150,000 mL), a history of gastrointestinal bleeding, peptic ulcer disease or other major bleeds, and/or consistent use of medications that increase bleeding risk (such as nonsteroidal anti-inflammatory agents, steroids, or anticoagulants) for > 14 days.

The safety outcome of this study assessed bleeding events while on aspirin therapy. All patients were categorized depending on if they had a major, minor, or no bleeding event while on aspirin therapy. Hemorrhagic stroke, symptomatic intracranial bleeding, bleeds located in other critical sites or organs (intracranial, intraspinal, intraocular, retroperitoneal, intra‐articular or pericardial), bleeds causing hemodynamic instability requiring vasopressors, bleeds causing a > 2 g/dL hemoglobin drop since initiation of aspirin therapy, severe extracranial bleeding requiring transfusion or hospitalization, fatal bleeding, or bleeds requiring > 2 units of red blood cell transfusion were considered major bleeding events. Minor bleeding events were any events that did not meet the criteria for major bleeding, including bruising, bleeding gums, epistaxis, hemorrhoidal bleeds, and bleeding that did not require intervention or treatment.⁷

Patients were included if they were aged > 18 years, had an active prescription for 81-mg aspirin tablet on September 30, 2021, and were seen in FHCC PACT clinics or at affiliated community-based outpatient centers. Other doses of aspirin were excluded as the 81-mg dose is the standard dose for primary prevention of ASCVD in the United States. US Department of Defense patients, home-based primary care patients, and community living center patients were excluded in this study. Patients with an aspirin prescription from a non–US Department of Veterans Affairs (VA) facility and patients on aspirin for reasons other than cardiovascular protection (such as pain, fever, etc) also were excluded from this study.

Data were collected from the FHCC electronic health record. A list was generated to include all active prescriptions for aspirin filled at FHCC as of September 30, 2021. Data were reviewed before this date to capture primary and secondary outcomes. No information was gathered from the chart after that date. This project was approved by the Edward Hines, Jr. VA Hospital Institutional Review Board. The primary and secondary outcomes were reported using descriptive statistics.

Results

This study reviewed 140 patient records and 105 patients met inclusion criteria.

For the primary endpoint, 53 patients (50%) were on aspirin for secondary prevention and 52 (50%) were on aspirin for primary prevention. Of the 105 patients included in the study, 31 (30%) had a possible ASCVD risk and were taking aspirin for primary prevention, while 21 (20%) had no ASCVD and were taking aspirin for primary prevention. Of the 52 patients on aspirin for primary prevention, 31 patients (60%) had a possible risk for ASCVD. Of the 52 patients in the primary prevention group, 15 (29%) were followed by a pharmacist, and the average number of follow-up appointments was 4.

The secondary endpoint focused on patients taking aspirin for primary prevention and the factors that may warrant deprescribing aspirin. Of the 52 patients on aspirin for primary prevention, 25 patients were aged > 70 years, 15 patients were concurrently taking medications that may increase bleeding risk,

Discussion

The majority of patients in this study were on aspirin appropriately. Indications deemed appropriate for aspirin therapy include secondary prevention and primary prevention with a possible ASCVD risk. About 20% of the total patient population in this study was taking aspirin for primary prevention with no ASCVD risk. For these patients, the risk of bleeding likely outweighs the benefits of aspirin therapy as patients are at low risk for ASCVD; therefore, aspirin therapy is likely inappropriate in this patient population. These patients may be unnecessarily at an increased risk for bleeding and may benefit from deprescribing aspirin. For the safety of patients, HCPs should be continuously assessing the appropriateness of aspirin for primary prevention and deprescribing when necessary.

About one-third of the patients using aspirin for primary prevention were followed by a pharmacist. Pharmacists can play a key role in deprescribing aspirin for primary prevention when aspirin use is deemed inappropriate. About 30% of the total patient population in this study was on aspirin for primary prevention with possible ASCVD risk. This patient population may benefit from aspirin therapy as they are at a higher risk for ASCVD. For these patients, a risk/benefit discussion is necessary to determine the appropriateness of aspirin for primary prevention. This risk/benefit discussion should be a continuous conversation between patients and HCPs as different factors such as age and changes in comorbid conditions and medications may increase bleeding risk.

The secondary endpoint focused on patients taking aspirin for primary prevention and the factors that may warrant deprescribing aspirin. The most common factors seen in this study included patients who were aged > 70 years, patients who were concurrently taking medications that may increase bleeding risk, and patients with CKD. All of these factors increase bleeding risk, making the risks potentially outweigh the benefits of aspirin for primary prevention. These factors should be the primary focus when assessing patients on aspirin for primary prevention to promote deprescribing aspirin if deemed appropriate as they were the most prevalent in this study.

The safety endpoints focused on bleeding events as a whole as well as the bleeding events seen in the primary prevention group. There were 2 major bleeding events and 20 minor bleeding events in the primary prevention group. The number of bleeding events both major and minor further shows the need for a continuous risk/benefit discussion between patients and HCPs on continued aspirin use for primary prevention. The bleeding risk with aspirin is prevalent. HCPs should continue to assess for factors that increase the bleeding risk that may warrant deprescribing aspirin to prevent future bleeding events in this patient population.

Strengths and Limitations

As there have been recent updates to guidelines on the use of aspirin for primary prevention, a strength of this study is that it evaluates a topic that is relevant in health care. Another strength of this study is that it focuses on specific patient factors that HCPs can assess when determining whether aspirin for primary prevention is appropriate in their patients. These specific patient factors can also be used as a guide to help HCPs deprescribe aspirin for primary prevention when appropriate.

One of the limitations of this study is that bleeding events that occurred outside of the FHCC were unable to be assessed unless the HCP specifically commented on the bleeding event in the chart. This could potentially underestimate the bleeding events seen in this study. Another limitation is that the bleeding risk for patients who were not on aspirin was not assessed. There was no comparison group to ascertain whether the bleeding risk was higher in the aspirin group compared with a no aspirin group. However, many of the major clinical trials saw an increased risk of bleeding in the aspirin group compared with placebo.

Conclusions

Aspirin therapy for secondary prevention remains an important part of treatment. Aspirin therapy for primary prevention may be appropriate for patients with a possible ASCVD risk. The therapy may be inappropriate in cases where patients have an increased bleeding risk and low or no ASCVD risk. It is important to continuously assess the need for aspirin therapy for patients in the setting of primary prevention. Common factors seen in this study to warrant deprescribing aspirin for primary prevention include patients aged > 70 years, concurrent use of medications that increase bleeding risk, and patients with CKD. By assessing ASCVD risk as well as bleeding risk and having a risk/benefit discussion between the HCP and patient, aspirin used for primary prevention can be appropriately deprescribed when the risks of bleeding outweigh the benefits.

Acknowledgments

The authors thank the Captain James A. Lovell Federal Health Care Center research committee (Hong-Yen Vi, PharmD, BCPS; Shaiza Khan, PharmD, BCPS; Yinka Alaka, BPharm, PharmD; Jennifer Kwon, PharmD, BCOP) and coinvestigator Aeman Choudhury, PharmD, BCPS, BCACP.

Aspirin is an antiplatelet agent that binds irreversibly to COX-1 and COX-2 enzymes, which results in decreased prostaglandin and thromboxane A2 production and inhibition of platelet aggregation. Aspirin often is used for its antipyretic, analgesic, and antiplatelet properties. Its use in cardiovascular disease (CVD) has been studied extensively over the past few decades, and recent data are changing the framework for aspirin use in primary prevention of atherosclerotic cardiovascular disease (ASCVD). Primary prevention refers to efforts to prevent the incidence of cardiovascular events, whereas secondary prevention refers to efforts to prevent a cardiovascular event after one has occurred.¹ This differentiation is important as it guides the course of treatment.

Three trials published in 2018 evaluated aspirin use in primary prevention of ASCVD. The ASCEND trial evaluated aspirin use for primary prevention of ASCVD in patients with diabetes mellitus (DM). This study concluded that although aspirin prevented serious vascular events in patients with DM, the benefit observed was largely counteracted by the bleeding hazard.² The ARRIVE trial evaluated aspirin use for primary prevention in patients with a moderate CVD risk. The study concluded that aspirin use in patients at moderate risk of CVD could not be assessed due to the low incidence rate of CVD; however, the study concluded that aspirin did not reduce the incidence of cardiovascular events for patients at low CVD risk and that aspirin caused more mild gastrointestinal bleeds compared with placebo.³ The ASPREE trial evaluated aspirin use for primary prevention in patients aged > 70 years to determine whether its use prolonged a healthy lifespan. This trial concluded that patients who received daily aspirin were at a higher risk of major hemorrhage and that aspirin did not diminish CVD risk compared with placebo.⁴

These studies led to a paradigm shift in therapy to reevaluate aspirin use for primary prevention. Current indications for aspirin include secondary prevention of ASCVD (ie, myocardial infarction [MI], coronary artery bypass graft, transient ischemic attack [TIA], and stroke), venous thromboembolism prophylaxis in the setting of orthopedic surgery, or valvular disease with replacement and analgesia. It is important to note that certain clinical circumstances may warrant aspirin use for primary prevention of ASCVD on a patient-specific basis, and this decision should be made using a risk/benefit analysis with the patient.

In April 2022, the US Preventive Services Task Force (USPSTF) recommended against using low-dose aspirin for primary prevention of ASCVD in individuals aged ≥ 60 years. The USPSTF noted that for patients who have a ≥ 10%, 10-year CVD risk, the decision to initiate aspirin should be based on a risk/benefit discussion and may be beneficial in certain patient populations.⁵A 2019 National Heart, Lung, and Blood Institute survey found that 29 million Americans used aspirin for primary prevention of ASCVD, and 6.6 million of these Americans used aspirin for primary prevention without the recommendation of a health care professional (HCP). Almost half of these individuals were aged > 70 years and, therefore, at an increased risk for bleeding.⁶ With the recent studies and changes in guidelines highlighting a higher risk rather than benefit with the use of aspirin for primary prevention, the current use of aspirin for primary prevention in the United States needs to be readdressed.

HCPs should assess the appropriateness of aspirin use in their patients to ensure that the risks of aspirin do not outweigh the benefits. Pharmacists can play a vital role in the assessment of aspirin for primary prevention during patient visits and make recommendations to primary care practitioners to deprescribe aspirin when appropriate.

Methods

The objective of this study was to evaluate the appropriateness of aspirin therapy in patient aligned care team (PACT) clinics at the Captain James A. Lovell Federal Health Care Center (FHCC) in North Chicago, Illinois. The PACT clinics are a category of clinics that include all the primary care clinics at FHCC.

The primary outcome of this study was to determine the percentage of patients inappropriately on aspirin therapy. To assess the inappropriate use of aspirin, relevant history of ASCVD was collected. Patients were divided into 3 groups: those with a history of ASCVD, those with no risk factors or history of ASCVD, and those with risk factors and no history of ASCVD. Patients were then categorized for their indication for aspirin use, which included either primary or secondary prevention of ASCVD. Patients were categorized into the primary prevention group if they had no history of ASCVD, whereas patients with a history of ASCVD were placed into the secondary prevention group.

ASCVD was defined as patients with acute coronary syndrome (ACS), history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral artery disease (PAD), including aortic aneurysm (all with an atherosclerotic origin). Possible ASCVD risk was defined as patients with DM with a major risk factor (family history of premature ASCVD, hypertension, dyslipidemia, smoking, chronic kidney disease [CKD]/albuminuria) or patients diagnosed with coronary artery disease without an event. The percentage of patients followed by a PACT pharmacist, the number of pharmacist follow-up visits during the study period, and the date of the first 81-mg aspirin pharmacy order that was filled at FHCC were also collected.

The secondary outcome of this study focused on patients who were using aspirin for primary prevention and assessed potential reasons that may warrant deprescribing aspirin therapy. One reason for deprescribing is that aspirin may not be indicated for some patients, including those with DM without cardiovascular complications, patients aged > 70 years, and/or patients with CKD (defined as estimated glomerular filtration rate < 60 mL/min). Another reason for deprescribing is contraindication, which included patients with coagulopathy, thrombocytopenia (defined as platelet count < 150,000 mL), a history of gastrointestinal bleeding, peptic ulcer disease or other major bleeds, and/or consistent use of medications that increase bleeding risk (such as nonsteroidal anti-inflammatory agents, steroids, or anticoagulants) for > 14 days.

The safety outcome of this study assessed bleeding events while on aspirin therapy. All patients were categorized depending on if they had a major, minor, or no bleeding event while on aspirin therapy. Hemorrhagic stroke, symptomatic intracranial bleeding, bleeds located in other critical sites or organs (intracranial, intraspinal, intraocular, retroperitoneal, intra‐articular or pericardial), bleeds causing hemodynamic instability requiring vasopressors, bleeds causing a > 2 g/dL hemoglobin drop since initiation of aspirin therapy, severe extracranial bleeding requiring transfusion or hospitalization, fatal bleeding, or bleeds requiring > 2 units of red blood cell transfusion were considered major bleeding events. Minor bleeding events were any events that did not meet the criteria for major bleeding, including bruising, bleeding gums, epistaxis, hemorrhoidal bleeds, and bleeding that did not require intervention or treatment.⁷

Patients were included if they were aged > 18 years, had an active prescription for 81-mg aspirin tablet on September 30, 2021, and were seen in FHCC PACT clinics or at affiliated community-based outpatient centers. Other doses of aspirin were excluded as the 81-mg dose is the standard dose for primary prevention of ASCVD in the United States. US Department of Defense patients, home-based primary care patients, and community living center patients were excluded in this study. Patients with an aspirin prescription from a non–US Department of Veterans Affairs (VA) facility and patients on aspirin for reasons other than cardiovascular protection (such as pain, fever, etc) also were excluded from this study.

Data were collected from the FHCC electronic health record. A list was generated to include all active prescriptions for aspirin filled at FHCC as of September 30, 2021. Data were reviewed before this date to capture primary and secondary outcomes. No information was gathered from the chart after that date. This project was approved by the Edward Hines, Jr. VA Hospital Institutional Review Board. The primary and secondary outcomes were reported using descriptive statistics.

Results

This study reviewed 140 patient records and 105 patients met inclusion criteria.

For the primary endpoint, 53 patients (50%) were on aspirin for secondary prevention and 52 (50%) were on aspirin for primary prevention. Of the 105 patients included in the study, 31 (30%) had a possible ASCVD risk and were taking aspirin for primary prevention, while 21 (20%) had no ASCVD and were taking aspirin for primary prevention. Of the 52 patients on aspirin for primary prevention, 31 patients (60%) had a possible risk for ASCVD. Of the 52 patients in the primary prevention group, 15 (29%) were followed by a pharmacist, and the average number of follow-up appointments was 4.

The secondary endpoint focused on patients taking aspirin for primary prevention and the factors that may warrant deprescribing aspirin. Of the 52 patients on aspirin for primary prevention, 25 patients were aged > 70 years, 15 patients were concurrently taking medications that may increase bleeding risk,

Discussion

The majority of patients in this study were on aspirin appropriately. Indications deemed appropriate for aspirin therapy include secondary prevention and primary prevention with a possible ASCVD risk. About 20% of the total patient population in this study was taking aspirin for primary prevention with no ASCVD risk. For these patients, the risk of bleeding likely outweighs the benefits of aspirin therapy as patients are at low risk for ASCVD; therefore, aspirin therapy is likely inappropriate in this patient population. These patients may be unnecessarily at an increased risk for bleeding and may benefit from deprescribing aspirin. For the safety of patients, HCPs should be continuously assessing the appropriateness of aspirin for primary prevention and deprescribing when necessary.

About one-third of the patients using aspirin for primary prevention were followed by a pharmacist. Pharmacists can play a key role in deprescribing aspirin for primary prevention when aspirin use is deemed inappropriate. About 30% of the total patient population in this study was on aspirin for primary prevention with possible ASCVD risk. This patient population may benefit from aspirin therapy as they are at a higher risk for ASCVD. For these patients, a risk/benefit discussion is necessary to determine the appropriateness of aspirin for primary prevention. This risk/benefit discussion should be a continuous conversation between patients and HCPs as different factors such as age and changes in comorbid conditions and medications may increase bleeding risk.

The secondary endpoint focused on patients taking aspirin for primary prevention and the factors that may warrant deprescribing aspirin. The most common factors seen in this study included patients who were aged > 70 years, patients who were concurrently taking medications that may increase bleeding risk, and patients with CKD. All of these factors increase bleeding risk, making the risks potentially outweigh the benefits of aspirin for primary prevention. These factors should be the primary focus when assessing patients on aspirin for primary prevention to promote deprescribing aspirin if deemed appropriate as they were the most prevalent in this study.

The safety endpoints focused on bleeding events as a whole as well as the bleeding events seen in the primary prevention group. There were 2 major bleeding events and 20 minor bleeding events in the primary prevention group. The number of bleeding events both major and minor further shows the need for a continuous risk/benefit discussion between patients and HCPs on continued aspirin use for primary prevention. The bleeding risk with aspirin is prevalent. HCPs should continue to assess for factors that increase the bleeding risk that may warrant deprescribing aspirin to prevent future bleeding events in this patient population.

Strengths and Limitations

As there have been recent updates to guidelines on the use of aspirin for primary prevention, a strength of this study is that it evaluates a topic that is relevant in health care. Another strength of this study is that it focuses on specific patient factors that HCPs can assess when determining whether aspirin for primary prevention is appropriate in their patients. These specific patient factors can also be used as a guide to help HCPs deprescribe aspirin for primary prevention when appropriate.

One of the limitations of this study is that bleeding events that occurred outside of the FHCC were unable to be assessed unless the HCP specifically commented on the bleeding event in the chart. This could potentially underestimate the bleeding events seen in this study. Another limitation is that the bleeding risk for patients who were not on aspirin was not assessed. There was no comparison group to ascertain whether the bleeding risk was higher in the aspirin group compared with a no aspirin group. However, many of the major clinical trials saw an increased risk of bleeding in the aspirin group compared with placebo.

Conclusions

Aspirin therapy for secondary prevention remains an important part of treatment. Aspirin therapy for primary prevention may be appropriate for patients with a possible ASCVD risk. The therapy may be inappropriate in cases where patients have an increased bleeding risk and low or no ASCVD risk. It is important to continuously assess the need for aspirin therapy for patients in the setting of primary prevention. Common factors seen in this study to warrant deprescribing aspirin for primary prevention include patients aged > 70 years, concurrent use of medications that increase bleeding risk, and patients with CKD. By assessing ASCVD risk as well as bleeding risk and having a risk/benefit discussion between the HCP and patient, aspirin used for primary prevention can be appropriately deprescribed when the risks of bleeding outweigh the benefits.

Acknowledgments

The authors thank the Captain James A. Lovell Federal Health Care Center research committee (Hong-Yen Vi, PharmD, BCPS; Shaiza Khan, PharmD, BCPS; Yinka Alaka, BPharm, PharmD; Jennifer Kwon, PharmD, BCOP) and coinvestigator Aeman Choudhury, PharmD, BCPS, BCACP.

Aspirin is an antiplatelet agent that binds irreversibly to COX-1 and COX-2 enzymes, which results in decreased prostaglandin and thromboxane A2 production and inhibition of platelet aggregation. Aspirin often is used for its antipyretic, analgesic, and antiplatelet properties. Its use in cardiovascular disease (CVD) has been studied extensively over the past few decades, and recent data are changing the framework for aspirin use in primary prevention of atherosclerotic cardiovascular disease (ASCVD). Primary prevention refers to efforts to prevent the incidence of cardiovascular events, whereas secondary prevention refers to efforts to prevent a cardiovascular event after one has occurred.¹ This differentiation is important as it guides the course of treatment.

Three trials published in 2018 evaluated aspirin use in primary prevention of ASCVD. The ASCEND trial evaluated aspirin use for primary prevention of ASCVD in patients with diabetes mellitus (DM). This study concluded that although aspirin prevented serious vascular events in patients with DM, the benefit observed was largely counteracted by the bleeding hazard.² The ARRIVE trial evaluated aspirin use for primary prevention in patients with a moderate CVD risk. The study concluded that aspirin use in patients at moderate risk of CVD could not be assessed due to the low incidence rate of CVD; however, the study concluded that aspirin did not reduce the incidence of cardiovascular events for patients at low CVD risk and that aspirin caused more mild gastrointestinal bleeds compared with placebo.³ The ASPREE trial evaluated aspirin use for primary prevention in patients aged > 70 years to determine whether its use prolonged a healthy lifespan. This trial concluded that patients who received daily aspirin were at a higher risk of major hemorrhage and that aspirin did not diminish CVD risk compared with placebo.⁴

These studies led to a paradigm shift in therapy to reevaluate aspirin use for primary prevention. Current indications for aspirin include secondary prevention of ASCVD (ie, myocardial infarction [MI], coronary artery bypass graft, transient ischemic attack [TIA], and stroke), venous thromboembolism prophylaxis in the setting of orthopedic surgery, or valvular disease with replacement and analgesia. It is important to note that certain clinical circumstances may warrant aspirin use for primary prevention of ASCVD on a patient-specific basis, and this decision should be made using a risk/benefit analysis with the patient.

In April 2022, the US Preventive Services Task Force (USPSTF) recommended against using low-dose aspirin for primary prevention of ASCVD in individuals aged ≥ 60 years. The USPSTF noted that for patients who have a ≥ 10%, 10-year CVD risk, the decision to initiate aspirin should be based on a risk/benefit discussion and may be beneficial in certain patient populations.⁵A 2019 National Heart, Lung, and Blood Institute survey found that 29 million Americans used aspirin for primary prevention of ASCVD, and 6.6 million of these Americans used aspirin for primary prevention without the recommendation of a health care professional (HCP). Almost half of these individuals were aged > 70 years and, therefore, at an increased risk for bleeding.⁶ With the recent studies and changes in guidelines highlighting a higher risk rather than benefit with the use of aspirin for primary prevention, the current use of aspirin for primary prevention in the United States needs to be readdressed.

HCPs should assess the appropriateness of aspirin use in their patients to ensure that the risks of aspirin do not outweigh the benefits. Pharmacists can play a vital role in the assessment of aspirin for primary prevention during patient visits and make recommendations to primary care practitioners to deprescribe aspirin when appropriate.

Methods

The objective of this study was to evaluate the appropriateness of aspirin therapy in patient aligned care team (PACT) clinics at the Captain James A. Lovell Federal Health Care Center (FHCC) in North Chicago, Illinois. The PACT clinics are a category of clinics that include all the primary care clinics at FHCC.

The primary outcome of this study was to determine the percentage of patients inappropriately on aspirin therapy. To assess the inappropriate use of aspirin, relevant history of ASCVD was collected. Patients were divided into 3 groups: those with a history of ASCVD, those with no risk factors or history of ASCVD, and those with risk factors and no history of ASCVD. Patients were then categorized for their indication for aspirin use, which included either primary or secondary prevention of ASCVD. Patients were categorized into the primary prevention group if they had no history of ASCVD, whereas patients with a history of ASCVD were placed into the secondary prevention group.

ASCVD was defined as patients with acute coronary syndrome (ACS), history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral artery disease (PAD), including aortic aneurysm (all with an atherosclerotic origin). Possible ASCVD risk was defined as patients with DM with a major risk factor (family history of premature ASCVD, hypertension, dyslipidemia, smoking, chronic kidney disease [CKD]/albuminuria) or patients diagnosed with coronary artery disease without an event. The percentage of patients followed by a PACT pharmacist, the number of pharmacist follow-up visits during the study period, and the date of the first 81-mg aspirin pharmacy order that was filled at FHCC were also collected.

The secondary outcome of this study focused on patients who were using aspirin for primary prevention and assessed potential reasons that may warrant deprescribing aspirin therapy. One reason for deprescribing is that aspirin may not be indicated for some patients, including those with DM without cardiovascular complications, patients aged > 70 years, and/or patients with CKD (defined as estimated glomerular filtration rate < 60 mL/min). Another reason for deprescribing is contraindication, which included patients with coagulopathy, thrombocytopenia (defined as platelet count < 150,000 mL), a history of gastrointestinal bleeding, peptic ulcer disease or other major bleeds, and/or consistent use of medications that increase bleeding risk (such as nonsteroidal anti-inflammatory agents, steroids, or anticoagulants) for > 14 days.

The safety outcome of this study assessed bleeding events while on aspirin therapy. All patients were categorized depending on if they had a major, minor, or no bleeding event while on aspirin therapy. Hemorrhagic stroke, symptomatic intracranial bleeding, bleeds located in other critical sites or organs (intracranial, intraspinal, intraocular, retroperitoneal, intra‐articular or pericardial), bleeds causing hemodynamic instability requiring vasopressors, bleeds causing a > 2 g/dL hemoglobin drop since initiation of aspirin therapy, severe extracranial bleeding requiring transfusion or hospitalization, fatal bleeding, or bleeds requiring > 2 units of red blood cell transfusion were considered major bleeding events. Minor bleeding events were any events that did not meet the criteria for major bleeding, including bruising, bleeding gums, epistaxis, hemorrhoidal bleeds, and bleeding that did not require intervention or treatment.⁷

Patients were included if they were aged > 18 years, had an active prescription for 81-mg aspirin tablet on September 30, 2021, and were seen in FHCC PACT clinics or at affiliated community-based outpatient centers. Other doses of aspirin were excluded as the 81-mg dose is the standard dose for primary prevention of ASCVD in the United States. US Department of Defense patients, home-based primary care patients, and community living center patients were excluded in this study. Patients with an aspirin prescription from a non–US Department of Veterans Affairs (VA) facility and patients on aspirin for reasons other than cardiovascular protection (such as pain, fever, etc) also were excluded from this study.

Data were collected from the FHCC electronic health record. A list was generated to include all active prescriptions for aspirin filled at FHCC as of September 30, 2021. Data were reviewed before this date to capture primary and secondary outcomes. No information was gathered from the chart after that date. This project was approved by the Edward Hines, Jr. VA Hospital Institutional Review Board. The primary and secondary outcomes were reported using descriptive statistics.

Results

This study reviewed 140 patient records and 105 patients met inclusion criteria.

For the primary endpoint, 53 patients (50%) were on aspirin for secondary prevention and 52 (50%) were on aspirin for primary prevention. Of the 105 patients included in the study, 31 (30%) had a possible ASCVD risk and were taking aspirin for primary prevention, while 21 (20%) had no ASCVD and were taking aspirin for primary prevention. Of the 52 patients on aspirin for primary prevention, 31 patients (60%) had a possible risk for ASCVD. Of the 52 patients in the primary prevention group, 15 (29%) were followed by a pharmacist, and the average number of follow-up appointments was 4.

The secondary endpoint focused on patients taking aspirin for primary prevention and the factors that may warrant deprescribing aspirin. Of the 52 patients on aspirin for primary prevention, 25 patients were aged > 70 years, 15 patients were concurrently taking medications that may increase bleeding risk,

Discussion

The majority of patients in this study were on aspirin appropriately. Indications deemed appropriate for aspirin therapy include secondary prevention and primary prevention with a possible ASCVD risk. About 20% of the total patient population in this study was taking aspirin for primary prevention with no ASCVD risk. For these patients, the risk of bleeding likely outweighs the benefits of aspirin therapy as patients are at low risk for ASCVD; therefore, aspirin therapy is likely inappropriate in this patient population. These patients may be unnecessarily at an increased risk for bleeding and may benefit from deprescribing aspirin. For the safety of patients, HCPs should be continuously assessing the appropriateness of aspirin for primary prevention and deprescribing when necessary.

About one-third of the patients using aspirin for primary prevention were followed by a pharmacist. Pharmacists can play a key role in deprescribing aspirin for primary prevention when aspirin use is deemed inappropriate. About 30% of the total patient population in this study was on aspirin for primary prevention with possible ASCVD risk. This patient population may benefit from aspirin therapy as they are at a higher risk for ASCVD. For these patients, a risk/benefit discussion is necessary to determine the appropriateness of aspirin for primary prevention. This risk/benefit discussion should be a continuous conversation between patients and HCPs as different factors such as age and changes in comorbid conditions and medications may increase bleeding risk.

The secondary endpoint focused on patients taking aspirin for primary prevention and the factors that may warrant deprescribing aspirin. The most common factors seen in this study included patients who were aged > 70 years, patients who were concurrently taking medications that may increase bleeding risk, and patients with CKD. All of these factors increase bleeding risk, making the risks potentially outweigh the benefits of aspirin for primary prevention. These factors should be the primary focus when assessing patients on aspirin for primary prevention to promote deprescribing aspirin if deemed appropriate as they were the most prevalent in this study.

The safety endpoints focused on bleeding events as a whole as well as the bleeding events seen in the primary prevention group. There were 2 major bleeding events and 20 minor bleeding events in the primary prevention group. The number of bleeding events both major and minor further shows the need for a continuous risk/benefit discussion between patients and HCPs on continued aspirin use for primary prevention. The bleeding risk with aspirin is prevalent. HCPs should continue to assess for factors that increase the bleeding risk that may warrant deprescribing aspirin to prevent future bleeding events in this patient population.

Strengths and Limitations

As there have been recent updates to guidelines on the use of aspirin for primary prevention, a strength of this study is that it evaluates a topic that is relevant in health care. Another strength of this study is that it focuses on specific patient factors that HCPs can assess when determining whether aspirin for primary prevention is appropriate in their patients. These specific patient factors can also be used as a guide to help HCPs deprescribe aspirin for primary prevention when appropriate.

One of the limitations of this study is that bleeding events that occurred outside of the FHCC were unable to be assessed unless the HCP specifically commented on the bleeding event in the chart. This could potentially underestimate the bleeding events seen in this study. Another limitation is that the bleeding risk for patients who were not on aspirin was not assessed. There was no comparison group to ascertain whether the bleeding risk was higher in the aspirin group compared with a no aspirin group. However, many of the major clinical trials saw an increased risk of bleeding in the aspirin group compared with placebo.

Conclusions

Aspirin therapy for secondary prevention remains an important part of treatment. Aspirin therapy for primary prevention may be appropriate for patients with a possible ASCVD risk. The therapy may be inappropriate in cases where patients have an increased bleeding risk and low or no ASCVD risk. It is important to continuously assess the need for aspirin therapy for patients in the setting of primary prevention. Common factors seen in this study to warrant deprescribing aspirin for primary prevention include patients aged > 70 years, concurrent use of medications that increase bleeding risk, and patients with CKD. By assessing ASCVD risk as well as bleeding risk and having a risk/benefit discussion between the HCP and patient, aspirin used for primary prevention can be appropriately deprescribed when the risks of bleeding outweigh the benefits.

Acknowledgments

The authors thank the Captain James A. Lovell Federal Health Care Center research committee (Hong-Yen Vi, PharmD, BCPS; Shaiza Khan, PharmD, BCPS; Yinka Alaka, BPharm, PharmD; Jennifer Kwon, PharmD, BCOP) and coinvestigator Aeman Choudhury, PharmD, BCPS, BCACP.