Federal Practitioner

TOPLINE:

Among 1.3 million male veterans treated for prostate cancer, 11,327 (0.86%) developed breast cancer an average of 5.4 years after initial diagnosis. Younger age at prostate cancer diagnosis, metastatic disease, androgen deprivation therapy (ADT), radiation treatment, and prolonged use of certain cardiovascular disease (CVD) medications were associated with increased risk for breast cancer.

METHODOLOGY:

• Researchers used a retrospective cohort design in Veterans Health Administration (VHA) care, pulling data from the Veterans Affairs (VA) Prostate Cancer Data Core at the VA Corporate Data Warehouse.
• Participants included 1,314,492 male veterans with prostate cancer treated at VHA facilities from January 1, 2000, to March 12, 2024.
• Exposure definitions included prostate cancer treatments (ADT, anti-androgen treatment, radiation-brachytherapy, and platinum chemotherapy) and CVD medications (furosemide, spironolactone, digoxin) captured via inpatient/outpatient/fee-based pharmacy and Current Procedural Terminology codes.
• Analysis measured time from prostate cancer diagnosis to breast cancer diagnosis, death, or March 12, 2024, applying Cox proportional hazards and Fine-Gray competing risk methods, with a sensitivity analysis adding body mass index (BMI) after excluding 71,718 missing values.

TAKEAWAY:

• Metastatic prostate cancer at diagnosis more than doubled the risk for breast cancer compared to nonmetastatic disease (hazard ratio [HR], 2.03; 95% CI, 1.90-2.17; P < .0001; subdistribution hazard ratio [SHR], 1.68; 95% CI, 1.57-1.81; P < .0001).
• Younger age at prostate cancer diagnosis was associated with increased risk for breast cancer (HR, 0.97; 95% CI, 0.97-0.98; P < .0001; SHR, 0.957; 95% CI, 0.955-0.959; P < .0001), indicating that for each additional year of age at diagnosis, the risk decreased.
• Continuation of CVD medications after prostate cancer diagnosis was associated with increased risk for breast cancer: furosemide (HR, 1.51; 95% CI, 1.39-1.63; P < .0001; SHR, 1.21; 95% CI, 1.12-1.31; P < .0001), spironolactone (HR, 1.36; 95% CI, 1.15-1.61; P = .0004; SHR, 1.23; 95% CI, 1.04-1.47; P = .0174), and digoxin (HR, 1.49; 95% CI, 1.29-1.72; P < .0001; SHR, 1.26; 95% CI, 1.10-1.46; P = .0015).
• Radiation therapy and ADT were associated with increased risk for breast cancer (radiation: HR, 1.06; 95% CI, 1.02-1.11; P = .0088; SHR, 1.10; 95% CI, 1.05-1.15; P < .0001; ADT: HR, 1.24; 95% CI, 1.17-1.32; P < .0001; SHR, 1.28; 95% CI, 1.20-1.37; P < .0001), while abiraterone was associated with decreased risk (HR, 0.36; 95% CI, 0.31-0.42; P < .0001; SHR, 0.39; 95% CI, 0.34-0.45; P < .0001).

IN PRACTICE:

"While there is a lack of data, male veterans with previous prostate cancer are at an elevated risk of breast cancer (0.87%), than their civilian counterparts (0.14%),” the authors wrote. “To address the current gap in knowledge and data, this study leveraged an existing large cohort of male veterans with prostate cancer and examined factors associated with increased risk of male breast cancer."

SOURCE:

The study was led by Erum Z. Whyne, VA North Texas Health Care System in Dallas, and Haekyung Jeon-Slaughter, University of Texas Southwestern Medical Center in Dallas. It was published online in The Prostate.

LIMITATIONS:

Though the study findings are based on large, representative data from male veterans with previously diagnosed prostate cancer, the results might not be generalizable to the overall male breast cancer population. As a retrospective cohort study, results may be biased and causality is difficult to establish. The study did not examine other known risk factors for male breast cancer incidence, such as family history, BRCA2 mutations, and military environmental exposure due to lack of data. BMI had missingness of 5.46% (n = 71,718) and was not included as a covariate in the final model, though sensitivity analysis showed it was not significantly associated with increased risk for male breast cancer.

DISCLOSURES:

The research was supported using resources and facilities of the VA Informatics and Computing Infrastructure (VINCI), VA HSR RES 13-457. The VA North Texas Health Care System Institutional Review Board approved the study and waived informed consent. No conflicts of interest were disclosed by the authors.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE:

Among 1.3 million male veterans treated for prostate cancer, 11,327 (0.86%) developed breast cancer an average of 5.4 years after initial diagnosis. Younger age at prostate cancer diagnosis, metastatic disease, androgen deprivation therapy (ADT), radiation treatment, and prolonged use of certain cardiovascular disease (CVD) medications were associated with increased risk for breast cancer.

METHODOLOGY:

• Researchers used a retrospective cohort design in Veterans Health Administration (VHA) care, pulling data from the Veterans Affairs (VA) Prostate Cancer Data Core at the VA Corporate Data Warehouse.
• Participants included 1,314,492 male veterans with prostate cancer treated at VHA facilities from January 1, 2000, to March 12, 2024.
• Exposure definitions included prostate cancer treatments (ADT, anti-androgen treatment, radiation-brachytherapy, and platinum chemotherapy) and CVD medications (furosemide, spironolactone, digoxin) captured via inpatient/outpatient/fee-based pharmacy and Current Procedural Terminology codes.
• Analysis measured time from prostate cancer diagnosis to breast cancer diagnosis, death, or March 12, 2024, applying Cox proportional hazards and Fine-Gray competing risk methods, with a sensitivity analysis adding body mass index (BMI) after excluding 71,718 missing values.

TAKEAWAY:

• Metastatic prostate cancer at diagnosis more than doubled the risk for breast cancer compared to nonmetastatic disease (hazard ratio [HR], 2.03; 95% CI, 1.90-2.17; P < .0001; subdistribution hazard ratio [SHR], 1.68; 95% CI, 1.57-1.81; P < .0001).
• Younger age at prostate cancer diagnosis was associated with increased risk for breast cancer (HR, 0.97; 95% CI, 0.97-0.98; P < .0001; SHR, 0.957; 95% CI, 0.955-0.959; P < .0001), indicating that for each additional year of age at diagnosis, the risk decreased.
• Continuation of CVD medications after prostate cancer diagnosis was associated with increased risk for breast cancer: furosemide (HR, 1.51; 95% CI, 1.39-1.63; P < .0001; SHR, 1.21; 95% CI, 1.12-1.31; P < .0001), spironolactone (HR, 1.36; 95% CI, 1.15-1.61; P = .0004; SHR, 1.23; 95% CI, 1.04-1.47; P = .0174), and digoxin (HR, 1.49; 95% CI, 1.29-1.72; P < .0001; SHR, 1.26; 95% CI, 1.10-1.46; P = .0015).
• Radiation therapy and ADT were associated with increased risk for breast cancer (radiation: HR, 1.06; 95% CI, 1.02-1.11; P = .0088; SHR, 1.10; 95% CI, 1.05-1.15; P < .0001; ADT: HR, 1.24; 95% CI, 1.17-1.32; P < .0001; SHR, 1.28; 95% CI, 1.20-1.37; P < .0001), while abiraterone was associated with decreased risk (HR, 0.36; 95% CI, 0.31-0.42; P < .0001; SHR, 0.39; 95% CI, 0.34-0.45; P < .0001).

IN PRACTICE:

"While there is a lack of data, male veterans with previous prostate cancer are at an elevated risk of breast cancer (0.87%), than their civilian counterparts (0.14%),” the authors wrote. “To address the current gap in knowledge and data, this study leveraged an existing large cohort of male veterans with prostate cancer and examined factors associated with increased risk of male breast cancer."

SOURCE:

The study was led by Erum Z. Whyne, VA North Texas Health Care System in Dallas, and Haekyung Jeon-Slaughter, University of Texas Southwestern Medical Center in Dallas. It was published online in The Prostate.

LIMITATIONS:

Though the study findings are based on large, representative data from male veterans with previously diagnosed prostate cancer, the results might not be generalizable to the overall male breast cancer population. As a retrospective cohort study, results may be biased and causality is difficult to establish. The study did not examine other known risk factors for male breast cancer incidence, such as family history, BRCA2 mutations, and military environmental exposure due to lack of data. BMI had missingness of 5.46% (n = 71,718) and was not included as a covariate in the final model, though sensitivity analysis showed it was not significantly associated with increased risk for male breast cancer.

DISCLOSURES:

The research was supported using resources and facilities of the VA Informatics and Computing Infrastructure (VINCI), VA HSR RES 13-457. The VA North Texas Health Care System Institutional Review Board approved the study and waived informed consent. No conflicts of interest were disclosed by the authors.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE:

Among 1.3 million male veterans treated for prostate cancer, 11,327 (0.86%) developed breast cancer an average of 5.4 years after initial diagnosis. Younger age at prostate cancer diagnosis, metastatic disease, androgen deprivation therapy (ADT), radiation treatment, and prolonged use of certain cardiovascular disease (CVD) medications were associated with increased risk for breast cancer.

METHODOLOGY:

• Researchers used a retrospective cohort design in Veterans Health Administration (VHA) care, pulling data from the Veterans Affairs (VA) Prostate Cancer Data Core at the VA Corporate Data Warehouse.
• Participants included 1,314,492 male veterans with prostate cancer treated at VHA facilities from January 1, 2000, to March 12, 2024.
• Exposure definitions included prostate cancer treatments (ADT, anti-androgen treatment, radiation-brachytherapy, and platinum chemotherapy) and CVD medications (furosemide, spironolactone, digoxin) captured via inpatient/outpatient/fee-based pharmacy and Current Procedural Terminology codes.
• Analysis measured time from prostate cancer diagnosis to breast cancer diagnosis, death, or March 12, 2024, applying Cox proportional hazards and Fine-Gray competing risk methods, with a sensitivity analysis adding body mass index (BMI) after excluding 71,718 missing values.

TAKEAWAY:

• Metastatic prostate cancer at diagnosis more than doubled the risk for breast cancer compared to nonmetastatic disease (hazard ratio [HR], 2.03; 95% CI, 1.90-2.17; P < .0001; subdistribution hazard ratio [SHR], 1.68; 95% CI, 1.57-1.81; P < .0001).
• Younger age at prostate cancer diagnosis was associated with increased risk for breast cancer (HR, 0.97; 95% CI, 0.97-0.98; P < .0001; SHR, 0.957; 95% CI, 0.955-0.959; P < .0001), indicating that for each additional year of age at diagnosis, the risk decreased.
• Continuation of CVD medications after prostate cancer diagnosis was associated with increased risk for breast cancer: furosemide (HR, 1.51; 95% CI, 1.39-1.63; P < .0001; SHR, 1.21; 95% CI, 1.12-1.31; P < .0001), spironolactone (HR, 1.36; 95% CI, 1.15-1.61; P = .0004; SHR, 1.23; 95% CI, 1.04-1.47; P = .0174), and digoxin (HR, 1.49; 95% CI, 1.29-1.72; P < .0001; SHR, 1.26; 95% CI, 1.10-1.46; P = .0015).
• Radiation therapy and ADT were associated with increased risk for breast cancer (radiation: HR, 1.06; 95% CI, 1.02-1.11; P = .0088; SHR, 1.10; 95% CI, 1.05-1.15; P < .0001; ADT: HR, 1.24; 95% CI, 1.17-1.32; P < .0001; SHR, 1.28; 95% CI, 1.20-1.37; P < .0001), while abiraterone was associated with decreased risk (HR, 0.36; 95% CI, 0.31-0.42; P < .0001; SHR, 0.39; 95% CI, 0.34-0.45; P < .0001).

IN PRACTICE:

"While there is a lack of data, male veterans with previous prostate cancer are at an elevated risk of breast cancer (0.87%), than their civilian counterparts (0.14%),” the authors wrote. “To address the current gap in knowledge and data, this study leveraged an existing large cohort of male veterans with prostate cancer and examined factors associated with increased risk of male breast cancer."

SOURCE:

The study was led by Erum Z. Whyne, VA North Texas Health Care System in Dallas, and Haekyung Jeon-Slaughter, University of Texas Southwestern Medical Center in Dallas. It was published online in The Prostate.

LIMITATIONS:

Though the study findings are based on large, representative data from male veterans with previously diagnosed prostate cancer, the results might not be generalizable to the overall male breast cancer population. As a retrospective cohort study, results may be biased and causality is difficult to establish. The study did not examine other known risk factors for male breast cancer incidence, such as family history, BRCA2 mutations, and military environmental exposure due to lack of data. BMI had missingness of 5.46% (n = 71,718) and was not included as a covariate in the final model, though sensitivity analysis showed it was not significantly associated with increased risk for male breast cancer.

DISCLOSURES:

The research was supported using resources and facilities of the VA Informatics and Computing Infrastructure (VINCI), VA HSR RES 13-457. The VA North Texas Health Care System Institutional Review Board approved the study and waived informed consent. No conflicts of interest were disclosed by the authors.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disease that arises from loss-of-function mutations in the FLCN gene. FLCN encodes folliculin, which is presumed to function as a tumor suppressor, though its precise role is incompletely understood.^1,2 BHD is characterized by multiple pulmonary cysts leading to recurrent spontaneous pneumothoraces, cutaneous lesions—specifically fibrofolliculomas—and an increased risk of renal malignancies. Diagnosing BHD is challenging due to the variable presentation of the disease. Some patients may only have cystic lung diseases, while others may not have characteristic skin lesions.^3-5 It is important to maintain awareness of BHD, especially when the diagnosis dictates the need for genetic counseling.

Case Presentation

A male veteran in his 60s, who was a lifelong nonsmoker with a history of extensive bullous emphysema and recurrent pneumothoraces, presented to the Veterans Affairs Greater Los Angeles Healthcare System pulmonary clinic while transferring care from a separate institution.

According to the patient, the first pneumothorax episode occurred about 20 years before presentation, followed by a recurrence a few years later after he was diagnosed with emphysema. He underwent pleurodesis of the right lung during his service abroad. Another episode nearly a decade after the first pneumothorax necessitated pleurodesis of the left lung (Figure 1). The patient's family history revealed pulmonary cysts in 1 immediate family member but no history of renal tumors. Notably, his mother passed away at a young age due to tuberculosis.

On physical examination, numerous skin tags and acrochordons on the face were observed, which had been stable for > 30 years. Despite a slow decline in exercise capacity following pleurodesis, the patient could still walk multiple miles daily and climb 3 flights of stairs before needing to rest. Pulmonary function testing (PFT) showed a forced expiratory volume in 1 second (FEV₁)/forced vital capacity ratio of 0.84 with reduced FEV₁, total lung capacity (TLC), and diffusion capacity for carbon monoxide (DL_CO), indicating a mild restrictive ventilatory defect and reduced diffusing capacity.

Laboratory results revealed a normal α-1 antitrypsin level: 133 mg/dL (reference, 83-199 mg/dL), with a Pi*MS phenotype and undetectable antinuclear antibodies. The most recent chest computed tomography (CT) in 2019, displayed paraseptal and centrilobular emphysema, scattered blebs, and scarring consistent with prior pleurodesis procedures (Figure 2).

Genetic testing for the FLCN gene revealed heterozygous pathogenic mutation: c.1285del and p.His429Thrfs*39, which confirmed the diagnosis of BHD. A shave biopsy of a postauricular papular lesion confirmed a histologic pattern of fibrofolliculoma/trichodiscoma.

Follow-up and Outcomes

After confirmation of the BHD diagnosis, the patient was referred to genetic counseling and scheduled for annual magnetic resonance imaging (MRI) of the abdomen and pelvis to screen for renal malignancies. As the patient was able to establish care with a new long-term primary care practitioner in the outpatient setting, he continues regular follow-up visits in the pulmonary clinic with stable respiratory symptoms and no recurrent pneumothoraces thus far.

Discussion

Differential Diagnoses of Cystic Pulmonary Lesions

BHD is an important differential diagnosis to consider in the presentation of diffuse cystic lung diseases. Still, 2 other crucial considerations are pulmonary Langerhans cell histiocytosis (PLCH) and lymphangioleiomyomatosis (LAM), which occur at slightly higher frequencies than BHD.⁶

One of the first steps in radiographically evaluating cystic lung diseases is to characterize the cysts. The Fleischner Society defines true cysts as a “round parenchymal lucency or low-attenuating area with a well-defined interface with normal lung.”⁷ Mimics of cystic lesions may include cavitary lung lesions, thick-walled spaces within another area of mass, nodule, or consolidation. Another mimic is a pneumatocele, a pseudocyst that lacks epithelial lining and may be secondary to bacterial pneumonia, pneumocystis infections, trauma, or prior mechanical ventilation.⁸After characterizing true cysts, different patterns of cystic lesions can also be associated with specific diseases. Cysts in PLCH are commonly more uniform and round, whereas the cysts in LAM may be more irregularly shaped. ⁹ Cysts in BHD may be larger and predominantly located in basal and paramediastinal areas.⁴LAM is associated with tuberous sclerosis, which can also present with skin lesions (angiofibromas) and renal tumors (angiomyolipomas), thus creating a very similar picture to BHD. Therefore, tissue biopsies of skin lesions are essential as histopathology can identify characteristic fibrofolliculomas specific to BHD. While genetic testing would also strongly support the diagnosis of BHD, it is essential to note that negative genetic testing does not rule out BHD.⁴Lastly, lymphoid interstitial pneumonia (LIP) is another important consideration in the differential diagnosis of cystic lung diseases. LIP presents with not only perivascular cysts and centrilobular nodules but also diffuse ground-glass attenuation.¹⁰ In contrast to BHD, LIP is associated with autoimmune diseases such as Sjögren syndrome and infectious diseases such as HIV; thus, it may be differentiated from BHD by the presence of underlying disease processes and may warrant serologic testing for potential rheumatologic disorders.

Characteristics and Diagnostic Criteria


Cystic lung disease is the most common presentation of BHD. It presents in > 80% of cases and confers a 50-fold increase in the risk of spontaneous pneumothorax compared with the general population.^4,11 Recurrent pneumothoraces are observed in about 25% to 30% of patients with BHD, typically occurring between the third and fifth decades of life and at significantly decreased rates after 50 years of age.¹² A spontaneous pneumothorax might serve as the initial and perhaps the sole clinical presentation for some patients with BHD, but others may present with other respiratory symptoms such as cough and exertional dyspnea. PFT results may be normal or reveal a mild restrictive ventilatory defect and reduced DL_CO, as reported in a few cases.⁶ The management of pulmonary complications primarily revolves around reducing the risk of pneumothoraces, which includes precautions such as avoiding positive pressure ventilation and air travel. Early pleurodesis with the first occurrence of a spontaneous pneumothorax is considered in some cases.¹³

The distinctive dermatologic features associated with BHD include multiple white papules primarily found on the nose and face. Pathologically, these manifestations have a range of histologic distinctions, from fibrofolliculomas to benign hamartomas of the hair follicles and trichodiscomas.⁵ The diagnostic criteria outlined by Menko et al note that confirmation of BHD requires the presence of either ≥ 5 pathologically confirmed fibrofolliculomas or trichodiscomas, a documented pathogenic FLCN gene mutation, or the fulfillment of 2 minor criteria. These minor criteria include the presence of multiple lung cysts, early-onset renal cancer, or a first-degree relative with BHD.⁵

Recurrent Pneumothoraces Management

After the first episode of spontaneous pneumothorax, early pleurodesis is indicated as the risk of recurrence can be as high as 75%.^4,14 Specific pleurodesis modalities have shown promising results, such as total pleural covering with cellulose mesh. In a small retrospective review, cellulose mesh demonstrated a significant reduction in the recurrence rate of pneumothorax at 7.5 years for patients with BHD compared with partial covering.¹⁵ Apart from preventing further pneumothorax episodes in the affected lung, it is also important to highlight patient education and monitoring after initial pleurodesis, as the contralateral lung is also at risk. As demonstrated in this case, the patient had received pleurodesis of his right lung but experienced another pneumothorax of his contralateral lung a few years later.

Lastly, the patient was advised to avoid air travel altogether; however, current data may suggest that air travel may not be an absolute contraindication for patients with BHD. Although the literature on this topic is limited, a retrospective study by Johannesma et al involving 158 patients with BHD surveyed on pneumothorax occurrence after air travel indicated a calculated risk of 0.63% per flight. Notably, only 3 of 13 patients with BHD and recurrent pneumothoraces after travel had undergone pleurodesis in the past.¹⁶ Therefore, counseling patients on the potential risks of air travel and allowing essential flights while diligently monitoring for symptoms during and after travel may be a reasonable, patient-centered approach in contrast to a complete restriction on air travel.

Timing to Diagnosis

Diagnosing BHD is challenging and often delayed. In a 2022 study by Steinlein et al, the average delay in BHD diagnoses in their cohort was 9.3 years, with 4 patients also diagnosed with renal malignancy during the study period.¹⁷ The difficulty in diagnosis can be attributed to the heterogeneous presentation among affected family members, some of whom may exclusively exhibit pulmonary cystic lesions without dermatologic findings.

A lack of longitudinal care for this patient may have contributed to the diagnostic delay. The patient had pneumothorax events across separate care settings and locations, and due to employment-related relocations, he often re-established care at various health care systems. This case highlights the importance of continuity of care, especially in BHD, where monitoring for renal tumors is also essential to long-term management.^17,18

Renal Tumor Monitoring

Finally, once BHD is diagnosed, one of the most important considerations is to begin routine monitoring for renal malignancies. Current recommendations advise starting lifelong renal cancer screening, even as early as age 20 years, with annual MRIs, as renal ultrasound may not be sufficiently sensitive to detect smaller lesions.¹⁹ The screening interval can be extended to every 2 years for patients without a family history of renal tumors or suspicious renal lesions. If tumors are found, then nephron-sparing surgery is recommended, given the potential for the development of chronic renal insufficiency in patients with BHD.²⁰

Conclusions

BHD is a rare and complex syndrome in which early recognition and diagnosis play a pivotal role in preventing potentially severe complications such as renal malignancies. Suspicion of a genetic disorder, such as BHD, LAM, or PLCH, should arise in patients who experience spontaneous pneumothorax, especially in the presence of multiple cystic lesions or a family history of pneumothoraces. Early consideration of pleurodesis after the first spontaneous pneumothorax is advisable. The complex presentation of BHD contributes to the difficulty of diagnosis and may delay recognition, which can be exacerbated by variable continuity of care.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disease that arises from loss-of-function mutations in the FLCN gene. FLCN encodes folliculin, which is presumed to function as a tumor suppressor, though its precise role is incompletely understood.^1,2 BHD is characterized by multiple pulmonary cysts leading to recurrent spontaneous pneumothoraces, cutaneous lesions—specifically fibrofolliculomas—and an increased risk of renal malignancies. Diagnosing BHD is challenging due to the variable presentation of the disease. Some patients may only have cystic lung diseases, while others may not have characteristic skin lesions.^3-5 It is important to maintain awareness of BHD, especially when the diagnosis dictates the need for genetic counseling.

Case Presentation

A male veteran in his 60s, who was a lifelong nonsmoker with a history of extensive bullous emphysema and recurrent pneumothoraces, presented to the Veterans Affairs Greater Los Angeles Healthcare System pulmonary clinic while transferring care from a separate institution.

According to the patient, the first pneumothorax episode occurred about 20 years before presentation, followed by a recurrence a few years later after he was diagnosed with emphysema. He underwent pleurodesis of the right lung during his service abroad. Another episode nearly a decade after the first pneumothorax necessitated pleurodesis of the left lung (Figure 1). The patient's family history revealed pulmonary cysts in 1 immediate family member but no history of renal tumors. Notably, his mother passed away at a young age due to tuberculosis.

On physical examination, numerous skin tags and acrochordons on the face were observed, which had been stable for > 30 years. Despite a slow decline in exercise capacity following pleurodesis, the patient could still walk multiple miles daily and climb 3 flights of stairs before needing to rest. Pulmonary function testing (PFT) showed a forced expiratory volume in 1 second (FEV₁)/forced vital capacity ratio of 0.84 with reduced FEV₁, total lung capacity (TLC), and diffusion capacity for carbon monoxide (DL_CO), indicating a mild restrictive ventilatory defect and reduced diffusing capacity.

Laboratory results revealed a normal α-1 antitrypsin level: 133 mg/dL (reference, 83-199 mg/dL), with a Pi*MS phenotype and undetectable antinuclear antibodies. The most recent chest computed tomography (CT) in 2019, displayed paraseptal and centrilobular emphysema, scattered blebs, and scarring consistent with prior pleurodesis procedures (Figure 2).

Genetic testing for the FLCN gene revealed heterozygous pathogenic mutation: c.1285del and p.His429Thrfs*39, which confirmed the diagnosis of BHD. A shave biopsy of a postauricular papular lesion confirmed a histologic pattern of fibrofolliculoma/trichodiscoma.

Follow-up and Outcomes

After confirmation of the BHD diagnosis, the patient was referred to genetic counseling and scheduled for annual magnetic resonance imaging (MRI) of the abdomen and pelvis to screen for renal malignancies. As the patient was able to establish care with a new long-term primary care practitioner in the outpatient setting, he continues regular follow-up visits in the pulmonary clinic with stable respiratory symptoms and no recurrent pneumothoraces thus far.

Discussion

Differential Diagnoses of Cystic Pulmonary Lesions

BHD is an important differential diagnosis to consider in the presentation of diffuse cystic lung diseases. Still, 2 other crucial considerations are pulmonary Langerhans cell histiocytosis (PLCH) and lymphangioleiomyomatosis (LAM), which occur at slightly higher frequencies than BHD.⁶

One of the first steps in radiographically evaluating cystic lung diseases is to characterize the cysts. The Fleischner Society defines true cysts as a “round parenchymal lucency or low-attenuating area with a well-defined interface with normal lung.”⁷ Mimics of cystic lesions may include cavitary lung lesions, thick-walled spaces within another area of mass, nodule, or consolidation. Another mimic is a pneumatocele, a pseudocyst that lacks epithelial lining and may be secondary to bacterial pneumonia, pneumocystis infections, trauma, or prior mechanical ventilation.⁸After characterizing true cysts, different patterns of cystic lesions can also be associated with specific diseases. Cysts in PLCH are commonly more uniform and round, whereas the cysts in LAM may be more irregularly shaped. ⁹ Cysts in BHD may be larger and predominantly located in basal and paramediastinal areas.⁴LAM is associated with tuberous sclerosis, which can also present with skin lesions (angiofibromas) and renal tumors (angiomyolipomas), thus creating a very similar picture to BHD. Therefore, tissue biopsies of skin lesions are essential as histopathology can identify characteristic fibrofolliculomas specific to BHD. While genetic testing would also strongly support the diagnosis of BHD, it is essential to note that negative genetic testing does not rule out BHD.⁴Lastly, lymphoid interstitial pneumonia (LIP) is another important consideration in the differential diagnosis of cystic lung diseases. LIP presents with not only perivascular cysts and centrilobular nodules but also diffuse ground-glass attenuation.¹⁰ In contrast to BHD, LIP is associated with autoimmune diseases such as Sjögren syndrome and infectious diseases such as HIV; thus, it may be differentiated from BHD by the presence of underlying disease processes and may warrant serologic testing for potential rheumatologic disorders.

Characteristics and Diagnostic Criteria


Cystic lung disease is the most common presentation of BHD. It presents in > 80% of cases and confers a 50-fold increase in the risk of spontaneous pneumothorax compared with the general population.^4,11 Recurrent pneumothoraces are observed in about 25% to 30% of patients with BHD, typically occurring between the third and fifth decades of life and at significantly decreased rates after 50 years of age.¹² A spontaneous pneumothorax might serve as the initial and perhaps the sole clinical presentation for some patients with BHD, but others may present with other respiratory symptoms such as cough and exertional dyspnea. PFT results may be normal or reveal a mild restrictive ventilatory defect and reduced DL_CO, as reported in a few cases.⁶ The management of pulmonary complications primarily revolves around reducing the risk of pneumothoraces, which includes precautions such as avoiding positive pressure ventilation and air travel. Early pleurodesis with the first occurrence of a spontaneous pneumothorax is considered in some cases.¹³

The distinctive dermatologic features associated with BHD include multiple white papules primarily found on the nose and face. Pathologically, these manifestations have a range of histologic distinctions, from fibrofolliculomas to benign hamartomas of the hair follicles and trichodiscomas.⁵ The diagnostic criteria outlined by Menko et al note that confirmation of BHD requires the presence of either ≥ 5 pathologically confirmed fibrofolliculomas or trichodiscomas, a documented pathogenic FLCN gene mutation, or the fulfillment of 2 minor criteria. These minor criteria include the presence of multiple lung cysts, early-onset renal cancer, or a first-degree relative with BHD.⁵

Recurrent Pneumothoraces Management

After the first episode of spontaneous pneumothorax, early pleurodesis is indicated as the risk of recurrence can be as high as 75%.^4,14 Specific pleurodesis modalities have shown promising results, such as total pleural covering with cellulose mesh. In a small retrospective review, cellulose mesh demonstrated a significant reduction in the recurrence rate of pneumothorax at 7.5 years for patients with BHD compared with partial covering.¹⁵ Apart from preventing further pneumothorax episodes in the affected lung, it is also important to highlight patient education and monitoring after initial pleurodesis, as the contralateral lung is also at risk. As demonstrated in this case, the patient had received pleurodesis of his right lung but experienced another pneumothorax of his contralateral lung a few years later.

Lastly, the patient was advised to avoid air travel altogether; however, current data may suggest that air travel may not be an absolute contraindication for patients with BHD. Although the literature on this topic is limited, a retrospective study by Johannesma et al involving 158 patients with BHD surveyed on pneumothorax occurrence after air travel indicated a calculated risk of 0.63% per flight. Notably, only 3 of 13 patients with BHD and recurrent pneumothoraces after travel had undergone pleurodesis in the past.¹⁶ Therefore, counseling patients on the potential risks of air travel and allowing essential flights while diligently monitoring for symptoms during and after travel may be a reasonable, patient-centered approach in contrast to a complete restriction on air travel.

Timing to Diagnosis

Diagnosing BHD is challenging and often delayed. In a 2022 study by Steinlein et al, the average delay in BHD diagnoses in their cohort was 9.3 years, with 4 patients also diagnosed with renal malignancy during the study period.¹⁷ The difficulty in diagnosis can be attributed to the heterogeneous presentation among affected family members, some of whom may exclusively exhibit pulmonary cystic lesions without dermatologic findings.

A lack of longitudinal care for this patient may have contributed to the diagnostic delay. The patient had pneumothorax events across separate care settings and locations, and due to employment-related relocations, he often re-established care at various health care systems. This case highlights the importance of continuity of care, especially in BHD, where monitoring for renal tumors is also essential to long-term management.^17,18

Renal Tumor Monitoring

Finally, once BHD is diagnosed, one of the most important considerations is to begin routine monitoring for renal malignancies. Current recommendations advise starting lifelong renal cancer screening, even as early as age 20 years, with annual MRIs, as renal ultrasound may not be sufficiently sensitive to detect smaller lesions.¹⁹ The screening interval can be extended to every 2 years for patients without a family history of renal tumors or suspicious renal lesions. If tumors are found, then nephron-sparing surgery is recommended, given the potential for the development of chronic renal insufficiency in patients with BHD.²⁰

Conclusions

BHD is a rare and complex syndrome in which early recognition and diagnosis play a pivotal role in preventing potentially severe complications such as renal malignancies. Suspicion of a genetic disorder, such as BHD, LAM, or PLCH, should arise in patients who experience spontaneous pneumothorax, especially in the presence of multiple cystic lesions or a family history of pneumothoraces. Early consideration of pleurodesis after the first spontaneous pneumothorax is advisable. The complex presentation of BHD contributes to the difficulty of diagnosis and may delay recognition, which can be exacerbated by variable continuity of care.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disease that arises from loss-of-function mutations in the FLCN gene. FLCN encodes folliculin, which is presumed to function as a tumor suppressor, though its precise role is incompletely understood.^1,2 BHD is characterized by multiple pulmonary cysts leading to recurrent spontaneous pneumothoraces, cutaneous lesions—specifically fibrofolliculomas—and an increased risk of renal malignancies. Diagnosing BHD is challenging due to the variable presentation of the disease. Some patients may only have cystic lung diseases, while others may not have characteristic skin lesions.^3-5 It is important to maintain awareness of BHD, especially when the diagnosis dictates the need for genetic counseling.

Case Presentation

A male veteran in his 60s, who was a lifelong nonsmoker with a history of extensive bullous emphysema and recurrent pneumothoraces, presented to the Veterans Affairs Greater Los Angeles Healthcare System pulmonary clinic while transferring care from a separate institution.

According to the patient, the first pneumothorax episode occurred about 20 years before presentation, followed by a recurrence a few years later after he was diagnosed with emphysema. He underwent pleurodesis of the right lung during his service abroad. Another episode nearly a decade after the first pneumothorax necessitated pleurodesis of the left lung (Figure 1). The patient's family history revealed pulmonary cysts in 1 immediate family member but no history of renal tumors. Notably, his mother passed away at a young age due to tuberculosis.

On physical examination, numerous skin tags and acrochordons on the face were observed, which had been stable for > 30 years. Despite a slow decline in exercise capacity following pleurodesis, the patient could still walk multiple miles daily and climb 3 flights of stairs before needing to rest. Pulmonary function testing (PFT) showed a forced expiratory volume in 1 second (FEV₁)/forced vital capacity ratio of 0.84 with reduced FEV₁, total lung capacity (TLC), and diffusion capacity for carbon monoxide (DL_CO), indicating a mild restrictive ventilatory defect and reduced diffusing capacity.

Laboratory results revealed a normal α-1 antitrypsin level: 133 mg/dL (reference, 83-199 mg/dL), with a Pi*MS phenotype and undetectable antinuclear antibodies. The most recent chest computed tomography (CT) in 2019, displayed paraseptal and centrilobular emphysema, scattered blebs, and scarring consistent with prior pleurodesis procedures (Figure 2).

Genetic testing for the FLCN gene revealed heterozygous pathogenic mutation: c.1285del and p.His429Thrfs*39, which confirmed the diagnosis of BHD. A shave biopsy of a postauricular papular lesion confirmed a histologic pattern of fibrofolliculoma/trichodiscoma.

Follow-up and Outcomes

After confirmation of the BHD diagnosis, the patient was referred to genetic counseling and scheduled for annual magnetic resonance imaging (MRI) of the abdomen and pelvis to screen for renal malignancies. As the patient was able to establish care with a new long-term primary care practitioner in the outpatient setting, he continues regular follow-up visits in the pulmonary clinic with stable respiratory symptoms and no recurrent pneumothoraces thus far.

Discussion

Differential Diagnoses of Cystic Pulmonary Lesions

BHD is an important differential diagnosis to consider in the presentation of diffuse cystic lung diseases. Still, 2 other crucial considerations are pulmonary Langerhans cell histiocytosis (PLCH) and lymphangioleiomyomatosis (LAM), which occur at slightly higher frequencies than BHD.⁶

One of the first steps in radiographically evaluating cystic lung diseases is to characterize the cysts. The Fleischner Society defines true cysts as a “round parenchymal lucency or low-attenuating area with a well-defined interface with normal lung.”⁷ Mimics of cystic lesions may include cavitary lung lesions, thick-walled spaces within another area of mass, nodule, or consolidation. Another mimic is a pneumatocele, a pseudocyst that lacks epithelial lining and may be secondary to bacterial pneumonia, pneumocystis infections, trauma, or prior mechanical ventilation.⁸After characterizing true cysts, different patterns of cystic lesions can also be associated with specific diseases. Cysts in PLCH are commonly more uniform and round, whereas the cysts in LAM may be more irregularly shaped. ⁹ Cysts in BHD may be larger and predominantly located in basal and paramediastinal areas.⁴LAM is associated with tuberous sclerosis, which can also present with skin lesions (angiofibromas) and renal tumors (angiomyolipomas), thus creating a very similar picture to BHD. Therefore, tissue biopsies of skin lesions are essential as histopathology can identify characteristic fibrofolliculomas specific to BHD. While genetic testing would also strongly support the diagnosis of BHD, it is essential to note that negative genetic testing does not rule out BHD.⁴Lastly, lymphoid interstitial pneumonia (LIP) is another important consideration in the differential diagnosis of cystic lung diseases. LIP presents with not only perivascular cysts and centrilobular nodules but also diffuse ground-glass attenuation.¹⁰ In contrast to BHD, LIP is associated with autoimmune diseases such as Sjögren syndrome and infectious diseases such as HIV; thus, it may be differentiated from BHD by the presence of underlying disease processes and may warrant serologic testing for potential rheumatologic disorders.

Characteristics and Diagnostic Criteria


Cystic lung disease is the most common presentation of BHD. It presents in > 80% of cases and confers a 50-fold increase in the risk of spontaneous pneumothorax compared with the general population.^4,11 Recurrent pneumothoraces are observed in about 25% to 30% of patients with BHD, typically occurring between the third and fifth decades of life and at significantly decreased rates after 50 years of age.¹² A spontaneous pneumothorax might serve as the initial and perhaps the sole clinical presentation for some patients with BHD, but others may present with other respiratory symptoms such as cough and exertional dyspnea. PFT results may be normal or reveal a mild restrictive ventilatory defect and reduced DL_CO, as reported in a few cases.⁶ The management of pulmonary complications primarily revolves around reducing the risk of pneumothoraces, which includes precautions such as avoiding positive pressure ventilation and air travel. Early pleurodesis with the first occurrence of a spontaneous pneumothorax is considered in some cases.¹³

The distinctive dermatologic features associated with BHD include multiple white papules primarily found on the nose and face. Pathologically, these manifestations have a range of histologic distinctions, from fibrofolliculomas to benign hamartomas of the hair follicles and trichodiscomas.⁵ The diagnostic criteria outlined by Menko et al note that confirmation of BHD requires the presence of either ≥ 5 pathologically confirmed fibrofolliculomas or trichodiscomas, a documented pathogenic FLCN gene mutation, or the fulfillment of 2 minor criteria. These minor criteria include the presence of multiple lung cysts, early-onset renal cancer, or a first-degree relative with BHD.⁵

Recurrent Pneumothoraces Management

After the first episode of spontaneous pneumothorax, early pleurodesis is indicated as the risk of recurrence can be as high as 75%.^4,14 Specific pleurodesis modalities have shown promising results, such as total pleural covering with cellulose mesh. In a small retrospective review, cellulose mesh demonstrated a significant reduction in the recurrence rate of pneumothorax at 7.5 years for patients with BHD compared with partial covering.¹⁵ Apart from preventing further pneumothorax episodes in the affected lung, it is also important to highlight patient education and monitoring after initial pleurodesis, as the contralateral lung is also at risk. As demonstrated in this case, the patient had received pleurodesis of his right lung but experienced another pneumothorax of his contralateral lung a few years later.

Lastly, the patient was advised to avoid air travel altogether; however, current data may suggest that air travel may not be an absolute contraindication for patients with BHD. Although the literature on this topic is limited, a retrospective study by Johannesma et al involving 158 patients with BHD surveyed on pneumothorax occurrence after air travel indicated a calculated risk of 0.63% per flight. Notably, only 3 of 13 patients with BHD and recurrent pneumothoraces after travel had undergone pleurodesis in the past.¹⁶ Therefore, counseling patients on the potential risks of air travel and allowing essential flights while diligently monitoring for symptoms during and after travel may be a reasonable, patient-centered approach in contrast to a complete restriction on air travel.

Timing to Diagnosis

Diagnosing BHD is challenging and often delayed. In a 2022 study by Steinlein et al, the average delay in BHD diagnoses in their cohort was 9.3 years, with 4 patients also diagnosed with renal malignancy during the study period.¹⁷ The difficulty in diagnosis can be attributed to the heterogeneous presentation among affected family members, some of whom may exclusively exhibit pulmonary cystic lesions without dermatologic findings.

A lack of longitudinal care for this patient may have contributed to the diagnostic delay. The patient had pneumothorax events across separate care settings and locations, and due to employment-related relocations, he often re-established care at various health care systems. This case highlights the importance of continuity of care, especially in BHD, where monitoring for renal tumors is also essential to long-term management.^17,18

Renal Tumor Monitoring

Finally, once BHD is diagnosed, one of the most important considerations is to begin routine monitoring for renal malignancies. Current recommendations advise starting lifelong renal cancer screening, even as early as age 20 years, with annual MRIs, as renal ultrasound may not be sufficiently sensitive to detect smaller lesions.¹⁹ The screening interval can be extended to every 2 years for patients without a family history of renal tumors or suspicious renal lesions. If tumors are found, then nephron-sparing surgery is recommended, given the potential for the development of chronic renal insufficiency in patients with BHD.²⁰

Conclusions

BHD is a rare and complex syndrome in which early recognition and diagnosis play a pivotal role in preventing potentially severe complications such as renal malignancies. Suspicion of a genetic disorder, such as BHD, LAM, or PLCH, should arise in patients who experience spontaneous pneumothorax, especially in the presence of multiple cystic lesions or a family history of pneumothoraces. Early consideration of pleurodesis after the first spontaneous pneumothorax is advisable. The complex presentation of BHD contributes to the difficulty of diagnosis and may delay recognition, which can be exacerbated by variable continuity of care.

DIAGNOSIS

Senile gluteal dermatosis (SGD). SGD is a friction- related skin injury, also known as recliner butt, chronic tissue injury, or grandfather’s disease.^1-4 The hallmarks include blanchable erythematous plaques and/or purplish discoloration of the fleshy part of the buttocks or posterior thighs, with little to no change over months to years. Additional findings may include skin erosions, lichenification, and ridging. SGD is most commonly seen in older adults with impaired mobility who spend prolonged periods in a reclined position, particularly those who slide down in a chair, “scoot,” or drag the buttocks during transfers or repositioning.

The pathogenesis of SGD is thought to involve microischemia associated with prolonged sitting.⁴ Histopathologic findings are nonspecific and may include hyperkeratosis, psoriasiform epidermal hyperplasia, vascular dilatation or proliferation in the superficial dermis, and reactive lymphohistiocytic perivascular infiltrate.⁴ The condition is poorly recognized and is likely underreported. Treatment involves reducing frictional injury by avoiding the reclined position, minimizing sliding during transfers, and frequent repositioning. Petroleum-based ointments may be applied to reduce friction and protect the skin barrier. Heat-dissipating chair cushions can be used to offload pressure and improve the local microclimate. Friction-related skin injuries need to be differentiated from pressure injuries, in which pressure and shear are the driving forces, and lesions are located over bony prominences.

Unlike SGD, chronic lichen sclerosus typically occurs in the anogenital area, including the scrotum and vulva, and is typically intensely pruritic, with white, atrophic plaques.

A stage 2 pressure injury is characterized by an area of partial-thickness skin loss with exposed dermis, usually overlying a bony prominence. Although friction-related skin injuries may contain erosions, they are often maroon or purple and are not located over a bony prominence.

Deep tissue injury (DTI) is characterized by nonblanchable dark red or purple skin discoloration, with intact or nonintact skin. While friction injuries may mimic DTIs, they lack the characteristic anatomic location over a bony prominence and the predictable evolution pattern seen in DTIs.

Incontinence-associated dermatitis (IAD) results from prolonged exposure to urine and/or feces and presents with erythema, inflammation, and epidermal erosion. Although IAD can look similar or coincide with SGD, the affected area is typically red, not purple. Skin ridging and lichenification are also not seen in IAD cases.

Sedentary behavior is prevalent among older adults, with nearly 60% spending > 4 hours per day sitting.⁵ Prolonged sitting puts them at risk for friction-related skin injuries. Even though friction-related skin injuries are typically nonprogressive, these patients are also at risk for pressure injuries that are typically acquired in a sitting position (eg, ischial and sacrococcygeal). Therefore, it is imperative that clinicians not only address SGD but also implement a pressure injury prevention plan.

DIAGNOSIS

Senile gluteal dermatosis (SGD). SGD is a friction- related skin injury, also known as recliner butt, chronic tissue injury, or grandfather’s disease.^1-4 The hallmarks include blanchable erythematous plaques and/or purplish discoloration of the fleshy part of the buttocks or posterior thighs, with little to no change over months to years. Additional findings may include skin erosions, lichenification, and ridging. SGD is most commonly seen in older adults with impaired mobility who spend prolonged periods in a reclined position, particularly those who slide down in a chair, “scoot,” or drag the buttocks during transfers or repositioning.

The pathogenesis of SGD is thought to involve microischemia associated with prolonged sitting.⁴ Histopathologic findings are nonspecific and may include hyperkeratosis, psoriasiform epidermal hyperplasia, vascular dilatation or proliferation in the superficial dermis, and reactive lymphohistiocytic perivascular infiltrate.⁴ The condition is poorly recognized and is likely underreported. Treatment involves reducing frictional injury by avoiding the reclined position, minimizing sliding during transfers, and frequent repositioning. Petroleum-based ointments may be applied to reduce friction and protect the skin barrier. Heat-dissipating chair cushions can be used to offload pressure and improve the local microclimate. Friction-related skin injuries need to be differentiated from pressure injuries, in which pressure and shear are the driving forces, and lesions are located over bony prominences.

Unlike SGD, chronic lichen sclerosus typically occurs in the anogenital area, including the scrotum and vulva, and is typically intensely pruritic, with white, atrophic plaques.

A stage 2 pressure injury is characterized by an area of partial-thickness skin loss with exposed dermis, usually overlying a bony prominence. Although friction-related skin injuries may contain erosions, they are often maroon or purple and are not located over a bony prominence.

Deep tissue injury (DTI) is characterized by nonblanchable dark red or purple skin discoloration, with intact or nonintact skin. While friction injuries may mimic DTIs, they lack the characteristic anatomic location over a bony prominence and the predictable evolution pattern seen in DTIs.

Incontinence-associated dermatitis (IAD) results from prolonged exposure to urine and/or feces and presents with erythema, inflammation, and epidermal erosion. Although IAD can look similar or coincide with SGD, the affected area is typically red, not purple. Skin ridging and lichenification are also not seen in IAD cases.

Sedentary behavior is prevalent among older adults, with nearly 60% spending > 4 hours per day sitting.⁵ Prolonged sitting puts them at risk for friction-related skin injuries. Even though friction-related skin injuries are typically nonprogressive, these patients are also at risk for pressure injuries that are typically acquired in a sitting position (eg, ischial and sacrococcygeal). Therefore, it is imperative that clinicians not only address SGD but also implement a pressure injury prevention plan.

DIAGNOSIS

Senile gluteal dermatosis (SGD). SGD is a friction- related skin injury, also known as recliner butt, chronic tissue injury, or grandfather’s disease.^1-4 The hallmarks include blanchable erythematous plaques and/or purplish discoloration of the fleshy part of the buttocks or posterior thighs, with little to no change over months to years. Additional findings may include skin erosions, lichenification, and ridging. SGD is most commonly seen in older adults with impaired mobility who spend prolonged periods in a reclined position, particularly those who slide down in a chair, “scoot,” or drag the buttocks during transfers or repositioning.

The pathogenesis of SGD is thought to involve microischemia associated with prolonged sitting.⁴ Histopathologic findings are nonspecific and may include hyperkeratosis, psoriasiform epidermal hyperplasia, vascular dilatation or proliferation in the superficial dermis, and reactive lymphohistiocytic perivascular infiltrate.⁴ The condition is poorly recognized and is likely underreported. Treatment involves reducing frictional injury by avoiding the reclined position, minimizing sliding during transfers, and frequent repositioning. Petroleum-based ointments may be applied to reduce friction and protect the skin barrier. Heat-dissipating chair cushions can be used to offload pressure and improve the local microclimate. Friction-related skin injuries need to be differentiated from pressure injuries, in which pressure and shear are the driving forces, and lesions are located over bony prominences.

Unlike SGD, chronic lichen sclerosus typically occurs in the anogenital area, including the scrotum and vulva, and is typically intensely pruritic, with white, atrophic plaques.

A stage 2 pressure injury is characterized by an area of partial-thickness skin loss with exposed dermis, usually overlying a bony prominence. Although friction-related skin injuries may contain erosions, they are often maroon or purple and are not located over a bony prominence.

Deep tissue injury (DTI) is characterized by nonblanchable dark red or purple skin discoloration, with intact or nonintact skin. While friction injuries may mimic DTIs, they lack the characteristic anatomic location over a bony prominence and the predictable evolution pattern seen in DTIs.

Incontinence-associated dermatitis (IAD) results from prolonged exposure to urine and/or feces and presents with erythema, inflammation, and epidermal erosion. Although IAD can look similar or coincide with SGD, the affected area is typically red, not purple. Skin ridging and lichenification are also not seen in IAD cases.

Sedentary behavior is prevalent among older adults, with nearly 60% spending > 4 hours per day sitting.⁵ Prolonged sitting puts them at risk for friction-related skin injuries. Even though friction-related skin injuries are typically nonprogressive, these patients are also at risk for pressure injuries that are typically acquired in a sitting position (eg, ischial and sacrococcygeal). Therefore, it is imperative that clinicians not only address SGD but also implement a pressure injury prevention plan.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a key role in migraine pathophysiology by promoting the dilation of cerebral blood vessels and transmitting pain signals.¹ CGRP has generated interest for the prevention and acute treatment of migraine. Since 2018, 8 novel CGRP-targeting therapies have been approved by the US Food and Drug Administration (FDA) for the management of migraines.^2,3 For migraine prevention, there are 4 injectable monoclonal antibodies (mAbs) directed against the CGRP receptor (erenumab) or the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab). There are also 2 oral small-molecule CGRP receptor antagonists, termed gepants, that also are approved for migraine prevention (atogepant and rimegepant). Three gepants are approved for acute migraine treatment and are administered orally (rimegepant and ubrogepant) or intranasally (zavegepant) (Table 1).

CGRP-targeting therapies have received attention for their role in vasodilation within the cerebral, coronary, and renal vasculature.⁴ CGRP-mediated vasodilatory effects cause systemic regulation of blood pressure (BP) and play a protective role in hypertension.² Some studies, particularly with erenumab, have shown that the inhibitory role of the agent leads to an increase in BP, as well as gastrointestinal issues such as constipation.^2,5 The FDA recently updated monitoring recommendations for all CGRP-targeting therapies to include the potential for BP elevations and hypertension. Outside of this, there is no definitive evidence linking dual CGRP-targeted therapy to higher cardiovascular or gastrointestinal risks and prescribing information does not carry contraindications.⁶

In a 2021 consensus statement, the American Headache Society (AHS) recommended CGRP-targeting therapies for migraine prevention after inability to tolerate or inadequate response to an 8-week trial of ≥ 2 drug classes including antihypertensives, antiseizure medications, antidepressants, and onabotulinumtoxinA.⁷ For acute treatment, AHS recommended gepant use after contraindication to or inadequate response to ≥ 2 triptans. Guidance on combination CGRP-targeting therapies for both prevention and acute treatment was not provided.⁷ More recently, the AHS published a position statement noting substantial efficacy and safety data for CGRP-targeting therapies and suggested its consideration as a first-line option for migraine prevention, though use for acute treatment or combination CGRP-targeting therapies for both prevention and acute treatment were not addressed.⁸

The International Headache Society guidelines for the acute treatment of migraines recommend nonopioid analgesics as first-line therapy for mild migraine attacks. For moderate to severe attacks, triptans with or without a nonopioid analgesic were recommended as first-line therapy, prior to consideration of CGRP-targeted therapy.⁹ The increased use of this new drug class has also led to combination use of CGRP-targeting therapies for migraine prevention and acute treatment as seen in clinical practice and reflected by some case reports, case series, and small studies describing such use.^10-14 In light of the similar mechanism of action of these therapies and the physiologic role of CGRP, there have been calls for safety evaluation.¹⁵

To our knowledge, no studies have evaluated dual CGRP-targeting regimens for migraine in the veteran population. In 2023, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD) updated their clinical practice guidelines for the management of headache.³ For migraine prevention, the VA/DoD guidelines include a strong recommendation for the use of erenumab, fremanezumab, and galcanezumab; a weak recommendation for the use of atogepant; and a recommendation neither for nor against the use of rimegepant. For acute treatment, the guidelines assign a weak recommendation for the use of rimegepant and ubrogepant. Combination use was not addressed.³

Prior to the VA/DoD guidelines, the Veterans Health Administration restricted the dual use of CGRP-targeting therapies for both preventive and acute migraine treatment. However, the VA Pharmacy Benefit Management Service removed the restriction in the Criteria for Use documents, allowing broader access to these medications for veterans.^16-22 This change permits the use of CGRP-targeting drugs for both acute and preventive migraine treatment after initial data reflecting real-world case reports and open-label studies suggested possible efficacy without a clear safety concern.^11,12 This study aims to fill the gap in the literature by evaluating the safety, efficacy, and overall outcomes of combination CGRP-targeting treatment for migraine prevention and acute treatment in a veteran population.

Methods

This single-center, retrospective, medication use evaluation at the Ralph H. Johnson VA Medical Center (RHJVAMC) was reviewed by the RHJVAMC Research and Development Committee and Quality Improvement Program Evaluation Self Certification Tool, which both determined that institutional review board approval was not required because it was considered part of routine care and quality improvement. Computerized Patient Record System (CPRS) data were reviewed between April 1, 2023 (after the Criteria for Use for CGRP-targeting therapies was updated), through January 31, 2025. Patients were included if they had a confirmed diagnosis of migraine using the International Classification of Headache Disorders, 3rd edition criteria and had concomitant active prescriptions for both a preventive and acute treatment CGRP-targeting agent during the project period.²³ Only patients receiving care from the RHJVAMC neurology department were included.

The primary objective was to assess the safety of dual CGRP-targeting therapies for migraine treatment. Key safety endpoints included effects on liver function, kidney function, and BP. Safety outcomes were graded using Common Terminology Criteria for Adverse Events.²⁴ Changes in liver function were categorized as grade 1, 2, or 3 elevations: grade 1 (aspartate aminotransferase [AST]/alanine aminotransferase [ALT] up to 3x the upper limit of normal [ULN] or bilirubin > 1.5 x ULN); grade 2 (AST/ALT 3-6 x ULN or bilirubin 1.5-3 x ULN); and grade 3 (AST/ALT 5-10 x ULN or bilirubin 3-10 x ULN). Kidney function changes were assessed by serum creatinine levels using a similar grading system: Grade 1 (≤ 1.5 x ULN); grade 2 (1.5-3 x baseline of normal); and grade 3 (3-6 x ULN or baseline). Changes in BP were monitored from baseline to the time of the first neurology follow-up. Elevations were grouped into 2 categories, defined as BP ≥ 140 mm Hg systolic and/or 90 mm Hg diastolic (category 1) and ≥ 160 mm Hg systolic and/or 100 mm Hg diastolic (category 2). Neurology documentation was also reviewed in CPRS for individual patient-reported adverse effects (AEs). Safety endpoints were tracked for any occurrence during the project period.

The secondary objective was to describe the patient-reported efficacy of adding a gepant for acute migraine treatment to existing CGRP-targeting therapies for migraine prevention, in those patients who were stable for ≥ 12 weeks on the preventive therapy. Neurology documentation of headache characteristics, including headache severity as rated on a numerical pain score from 0 (no pain) to 10 (worst pain), and duration of headaches (in hours) were recorded during the project period. Changes in headache characteristics were tracked from baseline (ie, the neurology visit when the gepant was first requested) to the first neurology follow-up within 6 months of initiating gepant for acute treatment. If ranges were provided within documentation, a mean was calculated and used for data collection. Neurology documentation was also reviewed for any patient report of overall effectiveness with the added gepant, and categorized as symptoms improved, worsened, or did not change based on subjective report. Descriptive statistics were used for data analysis. A 1-sample Wilcoxon signed rank test was performed as an exploratory analysis for change in headache characteristics from baseline to first neurology follow-up within 6 months. Each individual CGRP regimen was counted as a unique data point to adequately describe changes associated with each new medication and/or dose adjustment. Therefore, patients could be included more than once to account for each distinct treatment regimen.

Results

From April 1, 2023, to January 31, 2025, 96 patients were identified with active prescriptions for dual CGRP-targeting therapies. Of the 96 patients, 89 were included in the final analysis; 1 patient lacked a migraine diagnosis and 6 did not have a concomitant dual CGRP-targeted regimen and were excluded. The mean age of patients was 46.8 years and 54 (61%) were female. The most common migraine diagnosis was chronic migraine in 68 patients (76%). Triptans, ibuprofen, and acetaminophen were the most commonly used acute treatment medications (Table 2).

Safety Assessment

Many of the 89 unique patients trialed > 1 regimen. Thus, for the safety analysis, we analyzed 149 patients on unique dual CGRP-targeting regimens (Table 3). Ubrogepant was used by 126 patients (84.6%) for acute treatment. For preventive therapy, 63 patients (42.3%) used erenumab injections and 55 (36.9%) used fremanezumab injections. Seven patients (4.7%) reported AEs (Table 4). Five of the 7 AEs were noted in the package inserts.^25-32 One patient taking both atogepant and ubrogepant reported brain fog that resolved after a dose reduction of atogepant to every other day dosing. A patient taking fremanezumab and rimegepant reported myalgia/joint pain after the first fremanezumab injection, which resolved after a few days and did not recur during the study period.

Nine of 149 patient regimens (6.0%) were associated with changes in liver function tests or serum creatinine, though all but 1 were grade 1 (1 patient had a grade 2 ALT elevation). Twenty-five patients (16.8%) experienced changes in BP, most of which were category 1 elevations. Four patients had systolic or diastolic BP ≥ 160 mm Hg or 100 mm Hg, respectively (Table 5).

Efficacy Assessment

Of the 149 unique dual CGRP regimens, 59 were eligible for the exploratory efficacy analysis. Data were excluded from the efficacy analysis if patients had not been on a stable CGRP preventive migraine regimen for ≥ 12 weeks prior to the addition of a gepant. Fourteen regimens were excluded due to a lack of clear documentation on efficacy, leaving 45 analyzed regimens. Of the 45 regimens, 34 were from unique patients. There was no median change in migraine intensity or duration found in the efficacy analysis (0.0, P = .18, and 0.0, P = .92, respectively). Ten patients on dual CGRP therapy reported that the addition of a gepant for acute treatment improved their symptoms, 20 reported that their symptoms were unchanged and/or worsened, and 29 lacked documentation.

Discussion

This study aimed to describe the safety and efficacy of concomitant CGRP regimens for migraine prevention and acute treatment. To our knowledge, this was the first descriptive study of these agents in a veteran population. The potential for increased AEs with concomitant use of CGRP antagonists is due to the similarities in the mechanism of action between the agents, which both target the same receptor/ligand pathway. Given CGRP activity in both the gastrointestinal and cardiovascular systems, the potential for related AEs is speculative. Patient-reported AEs occurred in 7 of 149 unique treatment regimens reviewed for an incidence rate < 5%. All AEs were nonserious and self-limiting.

Our findings are consistent with available research. A 2024 retrospective, exploratory real-world study evaluating the safety and tolerability of combining CGRP-targeting mAbs with gepants reported findings consistent with our results. This analysis included adult patients treated with ≥ 1 previous anti-CGRP mAb and found that 234 of 516 patients included received a combination of a gepant in addition to a CGRP-targeting mAb. Of these 234 patients, 1.3% reported nonserious AEs.³³ Similarly, in a multicenter, open-label, long-term safety study in adults experiencing multiple monthly migraine attacks, a subgroup of 13 participants taking a stable dose of an anti-CGRP mAb also took rimegepant 75 mg as needed for acute treatment for 12 weeks. These patients experienced no serious AEs or any AEs leading to discontinuation.¹⁴ A study evaluating the drug-drug interaction, safety, and tolerability of dual therapy (atogepant 60 mg daily and ubrogepant 100 mg every 3 days) in 26 patients found no serious AEs, including no significant changes from baseline in laboratory results, vital signs, or safety-related 12-lead electrocardiogram parameters.¹⁵The TANDEM real-world, open-label, prospective study demonstrated similar results. It evaluated the safety and tolerability of concomitant use of ubrogepant and atogepant in patients with episodic migraines and found no increase in AEs when comparing atogepant alone with combination therapy. Twenty-six patients (9.9%) discontinued treatment due to AEs. The most common treatment-related AEs were constipation, nausea, decreased appetite, and fatigue. Efficacy data were also noted to be an exploratory endpoint in the TANDEM study; however, results have not been published.¹²

Within this safety analysis, new onset gastrointestinal AEs, specifically nausea, only occurred in 1 patient. Hypertension occurred in 25 treatment regimens (16.8%) for 21 unique patients (4 BP elevations occurred in 1 patient on 4 different regimens). However, the retrospective nature of reporting may limit accurate assessment. A closer analysis determined that elevated BP readings correlated with elevated pain scores at the time of the readings, which could have factored into the BP elevations. However, ongoing monitoring is needed due to an increased risk of hypertension, particularly given recent FDA labeling updates for CGRP-targeting therapies including gepants. In light of this, and the overall low incidence of hypertension reported, no new safety concerns were identified.

Limitations

Efficacy data in this project were exploratory. This evaluation did not show a significant difference in migraine intensity or duration after adding a gepant for acute treatment. The study was not powered to detect a significant difference. Limited data exist assessing efficacy outcomes with dual CGRP-targeting treatment regimens. The COURAGE study assessed the real-world effectiveness of ubrogepant and CGRP mAbs with or without the addition of onabotulinumtoxinA. The final analysis of the ubrogepant and CGRP mAb arm included 245 total patients and assessed meaningful migraine pain relief, restoration of normal function after a migraine, and treatment satisfaction. By hour 2, 61.6% of patients reported achieving migraine pain relief, rising to 80.4% by hour 4. Return to normal function occurred in 34.7% at hour 2 and 55.5% by hour 4.¹³ The long-term safety and efficacy of combining erenumab and rimegepant were described in a case series involving 2 patients. Both patients reported that the concomitant CGRP-targeted therapies were effective and reported no AEs.¹⁴

The retrospective design of this study meant that there was potential for limited documentation and introduction of bias into the results. Data were collected at a single VA health care system, and thus, results may not be generalizable to a broader population. However, the study population was consistent with the higher incidence of migraine expected in females in the general population. The sample size was limited, particularly in the exploratory efficacy endpoint assessment.

Limitations were observed due to inconsistent documentation regarding headache characteristics, making it challenging to draw meaningful conclusions from this data set. Additional confounding factors, including polypharmacy, nonadherence to medications, and comorbidities, may have skewed results. For example, while our study design required that the preventive CGRP-targeting medication be stable for 12 weeks for inclusion in further efficacy analysis, other medications commonly used for migraine prevention may have been adjusted (which was not accounted for in this analysis). Given this, more large-scale, placebo-controlled, randomized studies are needed to continue to assess the safety and efficacy of these combination treatment regimens.

Conclusions

Few AEs or safety events were reported with combination CGRP-targeting treatment for acute and preventive treatment of migraine. Those that were identified were considered mild. Efficacy data were limited, and further studies are needed to fully assess outcomes.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a key role in migraine pathophysiology by promoting the dilation of cerebral blood vessels and transmitting pain signals.¹ CGRP has generated interest for the prevention and acute treatment of migraine. Since 2018, 8 novel CGRP-targeting therapies have been approved by the US Food and Drug Administration (FDA) for the management of migraines.^2,3 For migraine prevention, there are 4 injectable monoclonal antibodies (mAbs) directed against the CGRP receptor (erenumab) or the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab). There are also 2 oral small-molecule CGRP receptor antagonists, termed gepants, that also are approved for migraine prevention (atogepant and rimegepant). Three gepants are approved for acute migraine treatment and are administered orally (rimegepant and ubrogepant) or intranasally (zavegepant) (Table 1).

CGRP-targeting therapies have received attention for their role in vasodilation within the cerebral, coronary, and renal vasculature.⁴ CGRP-mediated vasodilatory effects cause systemic regulation of blood pressure (BP) and play a protective role in hypertension.² Some studies, particularly with erenumab, have shown that the inhibitory role of the agent leads to an increase in BP, as well as gastrointestinal issues such as constipation.^2,5 The FDA recently updated monitoring recommendations for all CGRP-targeting therapies to include the potential for BP elevations and hypertension. Outside of this, there is no definitive evidence linking dual CGRP-targeted therapy to higher cardiovascular or gastrointestinal risks and prescribing information does not carry contraindications.⁶

In a 2021 consensus statement, the American Headache Society (AHS) recommended CGRP-targeting therapies for migraine prevention after inability to tolerate or inadequate response to an 8-week trial of ≥ 2 drug classes including antihypertensives, antiseizure medications, antidepressants, and onabotulinumtoxinA.⁷ For acute treatment, AHS recommended gepant use after contraindication to or inadequate response to ≥ 2 triptans. Guidance on combination CGRP-targeting therapies for both prevention and acute treatment was not provided.⁷ More recently, the AHS published a position statement noting substantial efficacy and safety data for CGRP-targeting therapies and suggested its consideration as a first-line option for migraine prevention, though use for acute treatment or combination CGRP-targeting therapies for both prevention and acute treatment were not addressed.⁸

The International Headache Society guidelines for the acute treatment of migraines recommend nonopioid analgesics as first-line therapy for mild migraine attacks. For moderate to severe attacks, triptans with or without a nonopioid analgesic were recommended as first-line therapy, prior to consideration of CGRP-targeted therapy.⁹ The increased use of this new drug class has also led to combination use of CGRP-targeting therapies for migraine prevention and acute treatment as seen in clinical practice and reflected by some case reports, case series, and small studies describing such use.^10-14 In light of the similar mechanism of action of these therapies and the physiologic role of CGRP, there have been calls for safety evaluation.¹⁵

To our knowledge, no studies have evaluated dual CGRP-targeting regimens for migraine in the veteran population. In 2023, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD) updated their clinical practice guidelines for the management of headache.³ For migraine prevention, the VA/DoD guidelines include a strong recommendation for the use of erenumab, fremanezumab, and galcanezumab; a weak recommendation for the use of atogepant; and a recommendation neither for nor against the use of rimegepant. For acute treatment, the guidelines assign a weak recommendation for the use of rimegepant and ubrogepant. Combination use was not addressed.³

Prior to the VA/DoD guidelines, the Veterans Health Administration restricted the dual use of CGRP-targeting therapies for both preventive and acute migraine treatment. However, the VA Pharmacy Benefit Management Service removed the restriction in the Criteria for Use documents, allowing broader access to these medications for veterans.^16-22 This change permits the use of CGRP-targeting drugs for both acute and preventive migraine treatment after initial data reflecting real-world case reports and open-label studies suggested possible efficacy without a clear safety concern.^11,12 This study aims to fill the gap in the literature by evaluating the safety, efficacy, and overall outcomes of combination CGRP-targeting treatment for migraine prevention and acute treatment in a veteran population.

Methods

This single-center, retrospective, medication use evaluation at the Ralph H. Johnson VA Medical Center (RHJVAMC) was reviewed by the RHJVAMC Research and Development Committee and Quality Improvement Program Evaluation Self Certification Tool, which both determined that institutional review board approval was not required because it was considered part of routine care and quality improvement. Computerized Patient Record System (CPRS) data were reviewed between April 1, 2023 (after the Criteria for Use for CGRP-targeting therapies was updated), through January 31, 2025. Patients were included if they had a confirmed diagnosis of migraine using the International Classification of Headache Disorders, 3rd edition criteria and had concomitant active prescriptions for both a preventive and acute treatment CGRP-targeting agent during the project period.²³ Only patients receiving care from the RHJVAMC neurology department were included.

The primary objective was to assess the safety of dual CGRP-targeting therapies for migraine treatment. Key safety endpoints included effects on liver function, kidney function, and BP. Safety outcomes were graded using Common Terminology Criteria for Adverse Events.²⁴ Changes in liver function were categorized as grade 1, 2, or 3 elevations: grade 1 (aspartate aminotransferase [AST]/alanine aminotransferase [ALT] up to 3x the upper limit of normal [ULN] or bilirubin > 1.5 x ULN); grade 2 (AST/ALT 3-6 x ULN or bilirubin 1.5-3 x ULN); and grade 3 (AST/ALT 5-10 x ULN or bilirubin 3-10 x ULN). Kidney function changes were assessed by serum creatinine levels using a similar grading system: Grade 1 (≤ 1.5 x ULN); grade 2 (1.5-3 x baseline of normal); and grade 3 (3-6 x ULN or baseline). Changes in BP were monitored from baseline to the time of the first neurology follow-up. Elevations were grouped into 2 categories, defined as BP ≥ 140 mm Hg systolic and/or 90 mm Hg diastolic (category 1) and ≥ 160 mm Hg systolic and/or 100 mm Hg diastolic (category 2). Neurology documentation was also reviewed in CPRS for individual patient-reported adverse effects (AEs). Safety endpoints were tracked for any occurrence during the project period.

The secondary objective was to describe the patient-reported efficacy of adding a gepant for acute migraine treatment to existing CGRP-targeting therapies for migraine prevention, in those patients who were stable for ≥ 12 weeks on the preventive therapy. Neurology documentation of headache characteristics, including headache severity as rated on a numerical pain score from 0 (no pain) to 10 (worst pain), and duration of headaches (in hours) were recorded during the project period. Changes in headache characteristics were tracked from baseline (ie, the neurology visit when the gepant was first requested) to the first neurology follow-up within 6 months of initiating gepant for acute treatment. If ranges were provided within documentation, a mean was calculated and used for data collection. Neurology documentation was also reviewed for any patient report of overall effectiveness with the added gepant, and categorized as symptoms improved, worsened, or did not change based on subjective report. Descriptive statistics were used for data analysis. A 1-sample Wilcoxon signed rank test was performed as an exploratory analysis for change in headache characteristics from baseline to first neurology follow-up within 6 months. Each individual CGRP regimen was counted as a unique data point to adequately describe changes associated with each new medication and/or dose adjustment. Therefore, patients could be included more than once to account for each distinct treatment regimen.

Results

From April 1, 2023, to January 31, 2025, 96 patients were identified with active prescriptions for dual CGRP-targeting therapies. Of the 96 patients, 89 were included in the final analysis; 1 patient lacked a migraine diagnosis and 6 did not have a concomitant dual CGRP-targeted regimen and were excluded. The mean age of patients was 46.8 years and 54 (61%) were female. The most common migraine diagnosis was chronic migraine in 68 patients (76%). Triptans, ibuprofen, and acetaminophen were the most commonly used acute treatment medications (Table 2).

Safety Assessment

Many of the 89 unique patients trialed > 1 regimen. Thus, for the safety analysis, we analyzed 149 patients on unique dual CGRP-targeting regimens (Table 3). Ubrogepant was used by 126 patients (84.6%) for acute treatment. For preventive therapy, 63 patients (42.3%) used erenumab injections and 55 (36.9%) used fremanezumab injections. Seven patients (4.7%) reported AEs (Table 4). Five of the 7 AEs were noted in the package inserts.^25-32 One patient taking both atogepant and ubrogepant reported brain fog that resolved after a dose reduction of atogepant to every other day dosing. A patient taking fremanezumab and rimegepant reported myalgia/joint pain after the first fremanezumab injection, which resolved after a few days and did not recur during the study period.

Nine of 149 patient regimens (6.0%) were associated with changes in liver function tests or serum creatinine, though all but 1 were grade 1 (1 patient had a grade 2 ALT elevation). Twenty-five patients (16.8%) experienced changes in BP, most of which were category 1 elevations. Four patients had systolic or diastolic BP ≥ 160 mm Hg or 100 mm Hg, respectively (Table 5).

Efficacy Assessment

Of the 149 unique dual CGRP regimens, 59 were eligible for the exploratory efficacy analysis. Data were excluded from the efficacy analysis if patients had not been on a stable CGRP preventive migraine regimen for ≥ 12 weeks prior to the addition of a gepant. Fourteen regimens were excluded due to a lack of clear documentation on efficacy, leaving 45 analyzed regimens. Of the 45 regimens, 34 were from unique patients. There was no median change in migraine intensity or duration found in the efficacy analysis (0.0, P = .18, and 0.0, P = .92, respectively). Ten patients on dual CGRP therapy reported that the addition of a gepant for acute treatment improved their symptoms, 20 reported that their symptoms were unchanged and/or worsened, and 29 lacked documentation.

Discussion

This study aimed to describe the safety and efficacy of concomitant CGRP regimens for migraine prevention and acute treatment. To our knowledge, this was the first descriptive study of these agents in a veteran population. The potential for increased AEs with concomitant use of CGRP antagonists is due to the similarities in the mechanism of action between the agents, which both target the same receptor/ligand pathway. Given CGRP activity in both the gastrointestinal and cardiovascular systems, the potential for related AEs is speculative. Patient-reported AEs occurred in 7 of 149 unique treatment regimens reviewed for an incidence rate < 5%. All AEs were nonserious and self-limiting.

Our findings are consistent with available research. A 2024 retrospective, exploratory real-world study evaluating the safety and tolerability of combining CGRP-targeting mAbs with gepants reported findings consistent with our results. This analysis included adult patients treated with ≥ 1 previous anti-CGRP mAb and found that 234 of 516 patients included received a combination of a gepant in addition to a CGRP-targeting mAb. Of these 234 patients, 1.3% reported nonserious AEs.³³ Similarly, in a multicenter, open-label, long-term safety study in adults experiencing multiple monthly migraine attacks, a subgroup of 13 participants taking a stable dose of an anti-CGRP mAb also took rimegepant 75 mg as needed for acute treatment for 12 weeks. These patients experienced no serious AEs or any AEs leading to discontinuation.¹⁴ A study evaluating the drug-drug interaction, safety, and tolerability of dual therapy (atogepant 60 mg daily and ubrogepant 100 mg every 3 days) in 26 patients found no serious AEs, including no significant changes from baseline in laboratory results, vital signs, or safety-related 12-lead electrocardiogram parameters.¹⁵The TANDEM real-world, open-label, prospective study demonstrated similar results. It evaluated the safety and tolerability of concomitant use of ubrogepant and atogepant in patients with episodic migraines and found no increase in AEs when comparing atogepant alone with combination therapy. Twenty-six patients (9.9%) discontinued treatment due to AEs. The most common treatment-related AEs were constipation, nausea, decreased appetite, and fatigue. Efficacy data were also noted to be an exploratory endpoint in the TANDEM study; however, results have not been published.¹²

Within this safety analysis, new onset gastrointestinal AEs, specifically nausea, only occurred in 1 patient. Hypertension occurred in 25 treatment regimens (16.8%) for 21 unique patients (4 BP elevations occurred in 1 patient on 4 different regimens). However, the retrospective nature of reporting may limit accurate assessment. A closer analysis determined that elevated BP readings correlated with elevated pain scores at the time of the readings, which could have factored into the BP elevations. However, ongoing monitoring is needed due to an increased risk of hypertension, particularly given recent FDA labeling updates for CGRP-targeting therapies including gepants. In light of this, and the overall low incidence of hypertension reported, no new safety concerns were identified.

Limitations

Efficacy data in this project were exploratory. This evaluation did not show a significant difference in migraine intensity or duration after adding a gepant for acute treatment. The study was not powered to detect a significant difference. Limited data exist assessing efficacy outcomes with dual CGRP-targeting treatment regimens. The COURAGE study assessed the real-world effectiveness of ubrogepant and CGRP mAbs with or without the addition of onabotulinumtoxinA. The final analysis of the ubrogepant and CGRP mAb arm included 245 total patients and assessed meaningful migraine pain relief, restoration of normal function after a migraine, and treatment satisfaction. By hour 2, 61.6% of patients reported achieving migraine pain relief, rising to 80.4% by hour 4. Return to normal function occurred in 34.7% at hour 2 and 55.5% by hour 4.¹³ The long-term safety and efficacy of combining erenumab and rimegepant were described in a case series involving 2 patients. Both patients reported that the concomitant CGRP-targeted therapies were effective and reported no AEs.¹⁴

The retrospective design of this study meant that there was potential for limited documentation and introduction of bias into the results. Data were collected at a single VA health care system, and thus, results may not be generalizable to a broader population. However, the study population was consistent with the higher incidence of migraine expected in females in the general population. The sample size was limited, particularly in the exploratory efficacy endpoint assessment.

Limitations were observed due to inconsistent documentation regarding headache characteristics, making it challenging to draw meaningful conclusions from this data set. Additional confounding factors, including polypharmacy, nonadherence to medications, and comorbidities, may have skewed results. For example, while our study design required that the preventive CGRP-targeting medication be stable for 12 weeks for inclusion in further efficacy analysis, other medications commonly used for migraine prevention may have been adjusted (which was not accounted for in this analysis). Given this, more large-scale, placebo-controlled, randomized studies are needed to continue to assess the safety and efficacy of these combination treatment regimens.

Conclusions

Few AEs or safety events were reported with combination CGRP-targeting treatment for acute and preventive treatment of migraine. Those that were identified were considered mild. Efficacy data were limited, and further studies are needed to fully assess outcomes.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a key role in migraine pathophysiology by promoting the dilation of cerebral blood vessels and transmitting pain signals.¹ CGRP has generated interest for the prevention and acute treatment of migraine. Since 2018, 8 novel CGRP-targeting therapies have been approved by the US Food and Drug Administration (FDA) for the management of migraines.^2,3 For migraine prevention, there are 4 injectable monoclonal antibodies (mAbs) directed against the CGRP receptor (erenumab) or the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab). There are also 2 oral small-molecule CGRP receptor antagonists, termed gepants, that also are approved for migraine prevention (atogepant and rimegepant). Three gepants are approved for acute migraine treatment and are administered orally (rimegepant and ubrogepant) or intranasally (zavegepant) (Table 1).

CGRP-targeting therapies have received attention for their role in vasodilation within the cerebral, coronary, and renal vasculature.⁴ CGRP-mediated vasodilatory effects cause systemic regulation of blood pressure (BP) and play a protective role in hypertension.² Some studies, particularly with erenumab, have shown that the inhibitory role of the agent leads to an increase in BP, as well as gastrointestinal issues such as constipation.^2,5 The FDA recently updated monitoring recommendations for all CGRP-targeting therapies to include the potential for BP elevations and hypertension. Outside of this, there is no definitive evidence linking dual CGRP-targeted therapy to higher cardiovascular or gastrointestinal risks and prescribing information does not carry contraindications.⁶

In a 2021 consensus statement, the American Headache Society (AHS) recommended CGRP-targeting therapies for migraine prevention after inability to tolerate or inadequate response to an 8-week trial of ≥ 2 drug classes including antihypertensives, antiseizure medications, antidepressants, and onabotulinumtoxinA.⁷ For acute treatment, AHS recommended gepant use after contraindication to or inadequate response to ≥ 2 triptans. Guidance on combination CGRP-targeting therapies for both prevention and acute treatment was not provided.⁷ More recently, the AHS published a position statement noting substantial efficacy and safety data for CGRP-targeting therapies and suggested its consideration as a first-line option for migraine prevention, though use for acute treatment or combination CGRP-targeting therapies for both prevention and acute treatment were not addressed.⁸

The International Headache Society guidelines for the acute treatment of migraines recommend nonopioid analgesics as first-line therapy for mild migraine attacks. For moderate to severe attacks, triptans with or without a nonopioid analgesic were recommended as first-line therapy, prior to consideration of CGRP-targeted therapy.⁹ The increased use of this new drug class has also led to combination use of CGRP-targeting therapies for migraine prevention and acute treatment as seen in clinical practice and reflected by some case reports, case series, and small studies describing such use.^10-14 In light of the similar mechanism of action of these therapies and the physiologic role of CGRP, there have been calls for safety evaluation.¹⁵

To our knowledge, no studies have evaluated dual CGRP-targeting regimens for migraine in the veteran population. In 2023, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD) updated their clinical practice guidelines for the management of headache.³ For migraine prevention, the VA/DoD guidelines include a strong recommendation for the use of erenumab, fremanezumab, and galcanezumab; a weak recommendation for the use of atogepant; and a recommendation neither for nor against the use of rimegepant. For acute treatment, the guidelines assign a weak recommendation for the use of rimegepant and ubrogepant. Combination use was not addressed.³

Prior to the VA/DoD guidelines, the Veterans Health Administration restricted the dual use of CGRP-targeting therapies for both preventive and acute migraine treatment. However, the VA Pharmacy Benefit Management Service removed the restriction in the Criteria for Use documents, allowing broader access to these medications for veterans.^16-22 This change permits the use of CGRP-targeting drugs for both acute and preventive migraine treatment after initial data reflecting real-world case reports and open-label studies suggested possible efficacy without a clear safety concern.^11,12 This study aims to fill the gap in the literature by evaluating the safety, efficacy, and overall outcomes of combination CGRP-targeting treatment for migraine prevention and acute treatment in a veteran population.

Methods

This single-center, retrospective, medication use evaluation at the Ralph H. Johnson VA Medical Center (RHJVAMC) was reviewed by the RHJVAMC Research and Development Committee and Quality Improvement Program Evaluation Self Certification Tool, which both determined that institutional review board approval was not required because it was considered part of routine care and quality improvement. Computerized Patient Record System (CPRS) data were reviewed between April 1, 2023 (after the Criteria for Use for CGRP-targeting therapies was updated), through January 31, 2025. Patients were included if they had a confirmed diagnosis of migraine using the International Classification of Headache Disorders, 3rd edition criteria and had concomitant active prescriptions for both a preventive and acute treatment CGRP-targeting agent during the project period.²³ Only patients receiving care from the RHJVAMC neurology department were included.

The primary objective was to assess the safety of dual CGRP-targeting therapies for migraine treatment. Key safety endpoints included effects on liver function, kidney function, and BP. Safety outcomes were graded using Common Terminology Criteria for Adverse Events.²⁴ Changes in liver function were categorized as grade 1, 2, or 3 elevations: grade 1 (aspartate aminotransferase [AST]/alanine aminotransferase [ALT] up to 3x the upper limit of normal [ULN] or bilirubin > 1.5 x ULN); grade 2 (AST/ALT 3-6 x ULN or bilirubin 1.5-3 x ULN); and grade 3 (AST/ALT 5-10 x ULN or bilirubin 3-10 x ULN). Kidney function changes were assessed by serum creatinine levels using a similar grading system: Grade 1 (≤ 1.5 x ULN); grade 2 (1.5-3 x baseline of normal); and grade 3 (3-6 x ULN or baseline). Changes in BP were monitored from baseline to the time of the first neurology follow-up. Elevations were grouped into 2 categories, defined as BP ≥ 140 mm Hg systolic and/or 90 mm Hg diastolic (category 1) and ≥ 160 mm Hg systolic and/or 100 mm Hg diastolic (category 2). Neurology documentation was also reviewed in CPRS for individual patient-reported adverse effects (AEs). Safety endpoints were tracked for any occurrence during the project period.

The secondary objective was to describe the patient-reported efficacy of adding a gepant for acute migraine treatment to existing CGRP-targeting therapies for migraine prevention, in those patients who were stable for ≥ 12 weeks on the preventive therapy. Neurology documentation of headache characteristics, including headache severity as rated on a numerical pain score from 0 (no pain) to 10 (worst pain), and duration of headaches (in hours) were recorded during the project period. Changes in headache characteristics were tracked from baseline (ie, the neurology visit when the gepant was first requested) to the first neurology follow-up within 6 months of initiating gepant for acute treatment. If ranges were provided within documentation, a mean was calculated and used for data collection. Neurology documentation was also reviewed for any patient report of overall effectiveness with the added gepant, and categorized as symptoms improved, worsened, or did not change based on subjective report. Descriptive statistics were used for data analysis. A 1-sample Wilcoxon signed rank test was performed as an exploratory analysis for change in headache characteristics from baseline to first neurology follow-up within 6 months. Each individual CGRP regimen was counted as a unique data point to adequately describe changes associated with each new medication and/or dose adjustment. Therefore, patients could be included more than once to account for each distinct treatment regimen.

Results

From April 1, 2023, to January 31, 2025, 96 patients were identified with active prescriptions for dual CGRP-targeting therapies. Of the 96 patients, 89 were included in the final analysis; 1 patient lacked a migraine diagnosis and 6 did not have a concomitant dual CGRP-targeted regimen and were excluded. The mean age of patients was 46.8 years and 54 (61%) were female. The most common migraine diagnosis was chronic migraine in 68 patients (76%). Triptans, ibuprofen, and acetaminophen were the most commonly used acute treatment medications (Table 2).

Safety Assessment

Many of the 89 unique patients trialed > 1 regimen. Thus, for the safety analysis, we analyzed 149 patients on unique dual CGRP-targeting regimens (Table 3). Ubrogepant was used by 126 patients (84.6%) for acute treatment. For preventive therapy, 63 patients (42.3%) used erenumab injections and 55 (36.9%) used fremanezumab injections. Seven patients (4.7%) reported AEs (Table 4). Five of the 7 AEs were noted in the package inserts.^25-32 One patient taking both atogepant and ubrogepant reported brain fog that resolved after a dose reduction of atogepant to every other day dosing. A patient taking fremanezumab and rimegepant reported myalgia/joint pain after the first fremanezumab injection, which resolved after a few days and did not recur during the study period.

Nine of 149 patient regimens (6.0%) were associated with changes in liver function tests or serum creatinine, though all but 1 were grade 1 (1 patient had a grade 2 ALT elevation). Twenty-five patients (16.8%) experienced changes in BP, most of which were category 1 elevations. Four patients had systolic or diastolic BP ≥ 160 mm Hg or 100 mm Hg, respectively (Table 5).

Efficacy Assessment

Of the 149 unique dual CGRP regimens, 59 were eligible for the exploratory efficacy analysis. Data were excluded from the efficacy analysis if patients had not been on a stable CGRP preventive migraine regimen for ≥ 12 weeks prior to the addition of a gepant. Fourteen regimens were excluded due to a lack of clear documentation on efficacy, leaving 45 analyzed regimens. Of the 45 regimens, 34 were from unique patients. There was no median change in migraine intensity or duration found in the efficacy analysis (0.0, P = .18, and 0.0, P = .92, respectively). Ten patients on dual CGRP therapy reported that the addition of a gepant for acute treatment improved their symptoms, 20 reported that their symptoms were unchanged and/or worsened, and 29 lacked documentation.

Discussion

This study aimed to describe the safety and efficacy of concomitant CGRP regimens for migraine prevention and acute treatment. To our knowledge, this was the first descriptive study of these agents in a veteran population. The potential for increased AEs with concomitant use of CGRP antagonists is due to the similarities in the mechanism of action between the agents, which both target the same receptor/ligand pathway. Given CGRP activity in both the gastrointestinal and cardiovascular systems, the potential for related AEs is speculative. Patient-reported AEs occurred in 7 of 149 unique treatment regimens reviewed for an incidence rate < 5%. All AEs were nonserious and self-limiting.

Our findings are consistent with available research. A 2024 retrospective, exploratory real-world study evaluating the safety and tolerability of combining CGRP-targeting mAbs with gepants reported findings consistent with our results. This analysis included adult patients treated with ≥ 1 previous anti-CGRP mAb and found that 234 of 516 patients included received a combination of a gepant in addition to a CGRP-targeting mAb. Of these 234 patients, 1.3% reported nonserious AEs.³³ Similarly, in a multicenter, open-label, long-term safety study in adults experiencing multiple monthly migraine attacks, a subgroup of 13 participants taking a stable dose of an anti-CGRP mAb also took rimegepant 75 mg as needed for acute treatment for 12 weeks. These patients experienced no serious AEs or any AEs leading to discontinuation.¹⁴ A study evaluating the drug-drug interaction, safety, and tolerability of dual therapy (atogepant 60 mg daily and ubrogepant 100 mg every 3 days) in 26 patients found no serious AEs, including no significant changes from baseline in laboratory results, vital signs, or safety-related 12-lead electrocardiogram parameters.¹⁵The TANDEM real-world, open-label, prospective study demonstrated similar results. It evaluated the safety and tolerability of concomitant use of ubrogepant and atogepant in patients with episodic migraines and found no increase in AEs when comparing atogepant alone with combination therapy. Twenty-six patients (9.9%) discontinued treatment due to AEs. The most common treatment-related AEs were constipation, nausea, decreased appetite, and fatigue. Efficacy data were also noted to be an exploratory endpoint in the TANDEM study; however, results have not been published.¹²

Within this safety analysis, new onset gastrointestinal AEs, specifically nausea, only occurred in 1 patient. Hypertension occurred in 25 treatment regimens (16.8%) for 21 unique patients (4 BP elevations occurred in 1 patient on 4 different regimens). However, the retrospective nature of reporting may limit accurate assessment. A closer analysis determined that elevated BP readings correlated with elevated pain scores at the time of the readings, which could have factored into the BP elevations. However, ongoing monitoring is needed due to an increased risk of hypertension, particularly given recent FDA labeling updates for CGRP-targeting therapies including gepants. In light of this, and the overall low incidence of hypertension reported, no new safety concerns were identified.

Limitations

Efficacy data in this project were exploratory. This evaluation did not show a significant difference in migraine intensity or duration after adding a gepant for acute treatment. The study was not powered to detect a significant difference. Limited data exist assessing efficacy outcomes with dual CGRP-targeting treatment regimens. The COURAGE study assessed the real-world effectiveness of ubrogepant and CGRP mAbs with or without the addition of onabotulinumtoxinA. The final analysis of the ubrogepant and CGRP mAb arm included 245 total patients and assessed meaningful migraine pain relief, restoration of normal function after a migraine, and treatment satisfaction. By hour 2, 61.6% of patients reported achieving migraine pain relief, rising to 80.4% by hour 4. Return to normal function occurred in 34.7% at hour 2 and 55.5% by hour 4.¹³ The long-term safety and efficacy of combining erenumab and rimegepant were described in a case series involving 2 patients. Both patients reported that the concomitant CGRP-targeted therapies were effective and reported no AEs.¹⁴

The retrospective design of this study meant that there was potential for limited documentation and introduction of bias into the results. Data were collected at a single VA health care system, and thus, results may not be generalizable to a broader population. However, the study population was consistent with the higher incidence of migraine expected in females in the general population. The sample size was limited, particularly in the exploratory efficacy endpoint assessment.

Limitations were observed due to inconsistent documentation regarding headache characteristics, making it challenging to draw meaningful conclusions from this data set. Additional confounding factors, including polypharmacy, nonadherence to medications, and comorbidities, may have skewed results. For example, while our study design required that the preventive CGRP-targeting medication be stable for 12 weeks for inclusion in further efficacy analysis, other medications commonly used for migraine prevention may have been adjusted (which was not accounted for in this analysis). Given this, more large-scale, placebo-controlled, randomized studies are needed to continue to assess the safety and efficacy of these combination treatment regimens.

Conclusions

Few AEs or safety events were reported with combination CGRP-targeting treatment for acute and preventive treatment of migraine. Those that were identified were considered mild. Efficacy data were limited, and further studies are needed to fully assess outcomes.

Patients make unplanned appointments after elective soft tissue hand surgery for real or perceived complications when they experience pain, anxiety, or fear. Unplanned appointments can create travel and financial burdens for patients and families. These appointments take time away from scheduled appointments and can contribute to late arrivals and delays in other clinics. Unscheduled appointments contribute to poor access when staff are diverted from scheduled appointments. If predictive factors can be identified, unplanned appointments may either be ameliorated or avoided with better perioperative risk management or education.

Methods

The US Department of Veterans Affairs (VA) North Florida/South Georgia Veterans Health System (NFSGVAHS) and University of Florida Institutional Review Board approved a retrospective chart review of all plastic surgery cases performed at the Malcom Randall VA Medical Center (MRVAMC) and Lake City VAMC operating rooms from July 1, 2018, through December 31, 2019, and January 1, 2021, through June 30, 2022 (nonurgent surgeries were discouraged during the COVID-19 pandemic). Elective soft tissue hand surgery cases were identified based on the operative description found in the Surgical Service Surgeon Staffing Report reviewed monthly by the Service Chief. Potential indicators of unplanned visits were recorded, including age; sex; diagnosis of diabetes, depression, anxiety, or posttraumatic stress disorder (PTSD); current smoking status; and residential zip code. We used the first 3 digits of the patients’ zip codes, which indicate region, as an estimate of proximity to the MRVAMC, which has a 50-county catchment area across North Florida and South Georgia. Diagnoses were found on the “problem list” from the electronic health record documented in the history and physical examinations before surgery. Clinic notes were examined for 3 months postsurgery to identify unplanned postoperative visits and the reason for the appointment. A χ² analysis was conducted using Excel Version 2402. P < .05 was used to determine whether age (> 60 years), sex, proximity to MRVAMC, diabetes, smoking, depression, anxiety, or PTSD were statistically significant independent risk factors for these appointments.

Results

A total of 1009 elective soft tissue hand surgeries at MRVAMC were reviewed. The patients median age was 61 years. Patients included 173 women (17.1%) and 836 men (82.9%). Eighty-one patients (8.0%) returned for unplanned visits. Age (P = .82); proximity to MRVAMC (P = .34); and diabetes (P = .60), smoking (P = .55), anxiety (P = .33), or PTSD (P = .37) were not statistically significant predictors of unplanned appointments. Depression diagnosis (P = .04) and female sex (P = .03) were found to be independent risk factors for an unplanned appointment (Table 1). The most common indication for the requested appointment was pain-related, followed closely by noninfectious wound concerns and persistent symptoms (Table 2).

Discussion

Improved access, quality, and efficiency for patients are goals for the VA.^1-3 The MRVAMC Plastic and Hand Surgery service provides care for the NFSGVAHS and receives an average of 15 to 20 consultation requests daily. The Veterans Health Administration is frequently challenged by staff shortages, and surgical services struggle to respond to consultation requests and treat patients within reasonable time frames.^4,5

The objective of this study was to identify risk factors for unplanned postoperative appointments following elective hand surgery. Unplanned appointments prevent scheduled patients from being seen on time and contribute to backlogs and delays. When patients schedule multiple appointments on the same day, delays in the first clinic’s scheduled appointments create delays for the second and third clinics. Hand surgery clinics can provide a better experience for patients and staff by identifying and mitigating factors prompting unplanned visits.

We anticipated that wound complications would prompt unscheduled visits. Diabetes is a known risk factor for wound healing complications after plastic and hand surgery.^6,7 A hemoglobin A_1c (HbA_1c) screening protocol used by the NFSGVAHS plastic surgery service since 2015 to identify poorly controlled patients with diabetes before surgery may partially explain this finding.⁸ We did not find a statistically significant difference between patients with diabetes and patients without diabetes for scheduling unplanned appointments. The plastic surgery service does not perform elective hand surgery unless the patient’s HbA_1c level is < 9%, or violate the flexor sheath unless HbA_1c level is < 8%. However, Zhuang et al found an increase in soft tissue infections after hand surgery with HbA_1c levels ≥ 7%.⁹

Smoking is a potential factor in postoperative hand surgery complications.^10,11 Lans et al found an increased incidence of 30-day emergency room visits in current and former smokers after outpatient upper extremity fracture surgery.¹² The MRVAMC Plastic Surgery Service counsels patients about the risk of skin necrosis and delayed wound healing, but does not cancel cases or obtain laboratory values to verify abstinence in patients undergoing hand surgery. The VA has multiple resources available for patients interested in smoking cessation through mental health services.¹³

MRVAMC patients have been known to resist returning for scheduled appointments due to the costs or availability of transportation. We suspected that patients who lived further from MRVAMC would be less likely to return for unscheduled visits. We used the first 3 digits of the patients’ mailing zip code to estimate residential proximity to MRVAMC. An acknowledged limitation to this approach is that some veterans have primary addresses in other regions but still spend significant time in the MRVAMC catchment area and use the facility for their health care during the winter months. These “snowbirds” might reside near the facility despite having official addresses that are more distant. Additionally, there was no increased risk of unplanned visits after hand surgery in patients aged > 61 years (the median age of study participants) (P = .82). Dependence on a third party for transportation in older veterans could impact this finding.

Based on the observation that most patients needed reassurance rather than an intervention when they returned for unscheduled appointments, diagnoses of depression, anxiety, and PTSD were evaluated as separate predictive factors. In previous research, anxiety was found to be a risk factor for problematic recovery following carpal tunnel surgery.¹⁴ In the current study, depression was found to be a statistically significant predictor of unscheduled postoperative appointments (P = .04), while anxiety (P = .33) and PTSD (P = .37) were not statistically significant predictors. This is consistent with other studies that have found preexisting depression can predict complications after hand surgery.^15,16 Vranceanu et al found that depression predicted pain intensity and disability after elective hand surgery.¹⁶ Similarly, Oflazoglu et al found a 12% incidence of depression based on the Patient Health Questionnaire-9 in new and returning hand patients who presented to an academic practice.¹⁷ They suggest patients should be assessed at all levels of care and that those with poor responses to surgical or nonsurgical management should be evaluated for depression. MRVAMC has a large mental health service consisting of psychiatrists, psychologists, addiction specialists, social workers, and homeless outreach, and patients tend to already have a diagnosis and mental health practitioner when they present to the clinic.

Recent studies found that wound problems, pain, and stiffness were the most common reasons for return visits.^18,19 Shetty et al identified younger age, worse preoperative pain scores, and poor access to transportation as predictors of preventable emergency room visits, which generate higher health care expenditures than an office visit.¹⁹ Our study’s top reasons for appointments (pain, wound/scar concerns, persistent symptoms) can be addressed with additional presurgery patient and family education. Additionally, clinicians encourage nonnarcotic pain management strategies including anti-inflammatories, acetaminophen, elevation, splinting, and hand therapy, and the hospital employs experienced, fellowship-trained anesthesia block faculty who help limit perioperative narcotic use. Patients are advised that pain can be used to guide them through the postoperative recovery by preventing overuse and alerting them to a problem that would be masked with narcotics, and long-standing problems such as chronic nerve compressions may continue to cause pain after surgery.

Patients and families can be given consistent and repetitive verbal and written information, instructions, and expectations at the initial consultation, preoperative appointment, and on the day of surgery. Postoperatively, outside their scheduled appointments, patients are encouraged to use the My HealtheVet secure messaging system or call the clinic to access an experienced registered nurse before making a long drive. Access to virtual or phone visits can reduce emergent in-person visits in a VA population.²⁰

Ozdag et al found that 42% of patients who had elective carpal tunnel surgery made unplanned electronic messages or phone contact within 2 weeks postsurgery. The authors point out the uncompensated administrative burden on the staff answering these messages and suggest pre-empting the contacts with more up-front education regarding postoperative pain expectations and management strategies.²¹

Fisher et al found that attending hand therapy reduced the number of emergency department visits in postoperative infection cases.²² At MRVAMC, a postoperative emergency department visit for a patient prompts an urgent unplanned appointment to the plastic surgery clinic, often on the same day. The MRVAMC occupational therapy clinic employed 3 on-site certified hand therapists during the study period. Because all hand surgery patients at the clinic receive hand therapy on the same day as their first postoperative appointment, attendance at hand therapy was not evaluated as a predictor of unplanned visits. Scheduled hand therapy is another point of contact where the clinic can provide reassurance and patient education.

While females made up 17.1% of the patients in this study, they constituted 12.5% of all veterans in Florida in fiscal year 2023.²³ This study found that women were more likely to present for unplanned postoperative appointments (P = .03). This is consistent with existing literature which has found that women are higher users of health care and office-based appointments.^24,25 This finding suggests the need for further study into whether our methods of communicating instructions to female patients undergoing plastic surgery may not be optimal.

Strengths and Limitations

As a retrospective review, the authors used information documented by multiple different health care practitioners, including trainees. The electronic medical record problem lists and templates provide consistency of information; however, less seasoned clinicians may interpret what they see and hear differently from more experienced clinicians in the postoperative setting. This study occurred in one part of the country with demographics that may not mirror other VA systems or the general population. The authors hope this study can be a starting point for other health care facilities to investigate ways to minimize the burden of unscheduled appointments. A strength of the study is that it was conducted within a closed system, as patients tend to stay within the VA system and documentation and communication among clinicians, even outside the immediate facility, are easily accessed through the electronic health record.

Conclusions

This study found that depression diagnosis and female sex are statistically significant predictors of unplanned postoperative visits after elective soft tissue hand surgery. More effective patient education during the preoperative period, particularly in patients with depression, may be warranted.

Patients make unplanned appointments after elective soft tissue hand surgery for real or perceived complications when they experience pain, anxiety, or fear. Unplanned appointments can create travel and financial burdens for patients and families. These appointments take time away from scheduled appointments and can contribute to late arrivals and delays in other clinics. Unscheduled appointments contribute to poor access when staff are diverted from scheduled appointments. If predictive factors can be identified, unplanned appointments may either be ameliorated or avoided with better perioperative risk management or education.

Methods

The US Department of Veterans Affairs (VA) North Florida/South Georgia Veterans Health System (NFSGVAHS) and University of Florida Institutional Review Board approved a retrospective chart review of all plastic surgery cases performed at the Malcom Randall VA Medical Center (MRVAMC) and Lake City VAMC operating rooms from July 1, 2018, through December 31, 2019, and January 1, 2021, through June 30, 2022 (nonurgent surgeries were discouraged during the COVID-19 pandemic). Elective soft tissue hand surgery cases were identified based on the operative description found in the Surgical Service Surgeon Staffing Report reviewed monthly by the Service Chief. Potential indicators of unplanned visits were recorded, including age; sex; diagnosis of diabetes, depression, anxiety, or posttraumatic stress disorder (PTSD); current smoking status; and residential zip code. We used the first 3 digits of the patients’ zip codes, which indicate region, as an estimate of proximity to the MRVAMC, which has a 50-county catchment area across North Florida and South Georgia. Diagnoses were found on the “problem list” from the electronic health record documented in the history and physical examinations before surgery. Clinic notes were examined for 3 months postsurgery to identify unplanned postoperative visits and the reason for the appointment. A χ² analysis was conducted using Excel Version 2402. P < .05 was used to determine whether age (> 60 years), sex, proximity to MRVAMC, diabetes, smoking, depression, anxiety, or PTSD were statistically significant independent risk factors for these appointments.

Results

A total of 1009 elective soft tissue hand surgeries at MRVAMC were reviewed. The patients median age was 61 years. Patients included 173 women (17.1%) and 836 men (82.9%). Eighty-one patients (8.0%) returned for unplanned visits. Age (P = .82); proximity to MRVAMC (P = .34); and diabetes (P = .60), smoking (P = .55), anxiety (P = .33), or PTSD (P = .37) were not statistically significant predictors of unplanned appointments. Depression diagnosis (P = .04) and female sex (P = .03) were found to be independent risk factors for an unplanned appointment (Table 1). The most common indication for the requested appointment was pain-related, followed closely by noninfectious wound concerns and persistent symptoms (Table 2).

Discussion

Improved access, quality, and efficiency for patients are goals for the VA.^1-3 The MRVAMC Plastic and Hand Surgery service provides care for the NFSGVAHS and receives an average of 15 to 20 consultation requests daily. The Veterans Health Administration is frequently challenged by staff shortages, and surgical services struggle to respond to consultation requests and treat patients within reasonable time frames.^4,5

The objective of this study was to identify risk factors for unplanned postoperative appointments following elective hand surgery. Unplanned appointments prevent scheduled patients from being seen on time and contribute to backlogs and delays. When patients schedule multiple appointments on the same day, delays in the first clinic’s scheduled appointments create delays for the second and third clinics. Hand surgery clinics can provide a better experience for patients and staff by identifying and mitigating factors prompting unplanned visits.

We anticipated that wound complications would prompt unscheduled visits. Diabetes is a known risk factor for wound healing complications after plastic and hand surgery.^6,7 A hemoglobin A_1c (HbA_1c) screening protocol used by the NFSGVAHS plastic surgery service since 2015 to identify poorly controlled patients with diabetes before surgery may partially explain this finding.⁸ We did not find a statistically significant difference between patients with diabetes and patients without diabetes for scheduling unplanned appointments. The plastic surgery service does not perform elective hand surgery unless the patient’s HbA_1c level is < 9%, or violate the flexor sheath unless HbA_1c level is < 8%. However, Zhuang et al found an increase in soft tissue infections after hand surgery with HbA_1c levels ≥ 7%.⁹

Smoking is a potential factor in postoperative hand surgery complications.^10,11 Lans et al found an increased incidence of 30-day emergency room visits in current and former smokers after outpatient upper extremity fracture surgery.¹² The MRVAMC Plastic Surgery Service counsels patients about the risk of skin necrosis and delayed wound healing, but does not cancel cases or obtain laboratory values to verify abstinence in patients undergoing hand surgery. The VA has multiple resources available for patients interested in smoking cessation through mental health services.¹³

MRVAMC patients have been known to resist returning for scheduled appointments due to the costs or availability of transportation. We suspected that patients who lived further from MRVAMC would be less likely to return for unscheduled visits. We used the first 3 digits of the patients’ mailing zip code to estimate residential proximity to MRVAMC. An acknowledged limitation to this approach is that some veterans have primary addresses in other regions but still spend significant time in the MRVAMC catchment area and use the facility for their health care during the winter months. These “snowbirds” might reside near the facility despite having official addresses that are more distant. Additionally, there was no increased risk of unplanned visits after hand surgery in patients aged > 61 years (the median age of study participants) (P = .82). Dependence on a third party for transportation in older veterans could impact this finding.

Based on the observation that most patients needed reassurance rather than an intervention when they returned for unscheduled appointments, diagnoses of depression, anxiety, and PTSD were evaluated as separate predictive factors. In previous research, anxiety was found to be a risk factor for problematic recovery following carpal tunnel surgery.¹⁴ In the current study, depression was found to be a statistically significant predictor of unscheduled postoperative appointments (P = .04), while anxiety (P = .33) and PTSD (P = .37) were not statistically significant predictors. This is consistent with other studies that have found preexisting depression can predict complications after hand surgery.^15,16 Vranceanu et al found that depression predicted pain intensity and disability after elective hand surgery.¹⁶ Similarly, Oflazoglu et al found a 12% incidence of depression based on the Patient Health Questionnaire-9 in new and returning hand patients who presented to an academic practice.¹⁷ They suggest patients should be assessed at all levels of care and that those with poor responses to surgical or nonsurgical management should be evaluated for depression. MRVAMC has a large mental health service consisting of psychiatrists, psychologists, addiction specialists, social workers, and homeless outreach, and patients tend to already have a diagnosis and mental health practitioner when they present to the clinic.

Recent studies found that wound problems, pain, and stiffness were the most common reasons for return visits.^18,19 Shetty et al identified younger age, worse preoperative pain scores, and poor access to transportation as predictors of preventable emergency room visits, which generate higher health care expenditures than an office visit.¹⁹ Our study’s top reasons for appointments (pain, wound/scar concerns, persistent symptoms) can be addressed with additional presurgery patient and family education. Additionally, clinicians encourage nonnarcotic pain management strategies including anti-inflammatories, acetaminophen, elevation, splinting, and hand therapy, and the hospital employs experienced, fellowship-trained anesthesia block faculty who help limit perioperative narcotic use. Patients are advised that pain can be used to guide them through the postoperative recovery by preventing overuse and alerting them to a problem that would be masked with narcotics, and long-standing problems such as chronic nerve compressions may continue to cause pain after surgery.

Patients and families can be given consistent and repetitive verbal and written information, instructions, and expectations at the initial consultation, preoperative appointment, and on the day of surgery. Postoperatively, outside their scheduled appointments, patients are encouraged to use the My HealtheVet secure messaging system or call the clinic to access an experienced registered nurse before making a long drive. Access to virtual or phone visits can reduce emergent in-person visits in a VA population.²⁰

Ozdag et al found that 42% of patients who had elective carpal tunnel surgery made unplanned electronic messages or phone contact within 2 weeks postsurgery. The authors point out the uncompensated administrative burden on the staff answering these messages and suggest pre-empting the contacts with more up-front education regarding postoperative pain expectations and management strategies.²¹

Fisher et al found that attending hand therapy reduced the number of emergency department visits in postoperative infection cases.²² At MRVAMC, a postoperative emergency department visit for a patient prompts an urgent unplanned appointment to the plastic surgery clinic, often on the same day. The MRVAMC occupational therapy clinic employed 3 on-site certified hand therapists during the study period. Because all hand surgery patients at the clinic receive hand therapy on the same day as their first postoperative appointment, attendance at hand therapy was not evaluated as a predictor of unplanned visits. Scheduled hand therapy is another point of contact where the clinic can provide reassurance and patient education.

While females made up 17.1% of the patients in this study, they constituted 12.5% of all veterans in Florida in fiscal year 2023.²³ This study found that women were more likely to present for unplanned postoperative appointments (P = .03). This is consistent with existing literature which has found that women are higher users of health care and office-based appointments.^24,25 This finding suggests the need for further study into whether our methods of communicating instructions to female patients undergoing plastic surgery may not be optimal.

Strengths and Limitations

As a retrospective review, the authors used information documented by multiple different health care practitioners, including trainees. The electronic medical record problem lists and templates provide consistency of information; however, less seasoned clinicians may interpret what they see and hear differently from more experienced clinicians in the postoperative setting. This study occurred in one part of the country with demographics that may not mirror other VA systems or the general population. The authors hope this study can be a starting point for other health care facilities to investigate ways to minimize the burden of unscheduled appointments. A strength of the study is that it was conducted within a closed system, as patients tend to stay within the VA system and documentation and communication among clinicians, even outside the immediate facility, are easily accessed through the electronic health record.

Conclusions

This study found that depression diagnosis and female sex are statistically significant predictors of unplanned postoperative visits after elective soft tissue hand surgery. More effective patient education during the preoperative period, particularly in patients with depression, may be warranted.

Patients make unplanned appointments after elective soft tissue hand surgery for real or perceived complications when they experience pain, anxiety, or fear. Unplanned appointments can create travel and financial burdens for patients and families. These appointments take time away from scheduled appointments and can contribute to late arrivals and delays in other clinics. Unscheduled appointments contribute to poor access when staff are diverted from scheduled appointments. If predictive factors can be identified, unplanned appointments may either be ameliorated or avoided with better perioperative risk management or education.

Methods

The US Department of Veterans Affairs (VA) North Florida/South Georgia Veterans Health System (NFSGVAHS) and University of Florida Institutional Review Board approved a retrospective chart review of all plastic surgery cases performed at the Malcom Randall VA Medical Center (MRVAMC) and Lake City VAMC operating rooms from July 1, 2018, through December 31, 2019, and January 1, 2021, through June 30, 2022 (nonurgent surgeries were discouraged during the COVID-19 pandemic). Elective soft tissue hand surgery cases were identified based on the operative description found in the Surgical Service Surgeon Staffing Report reviewed monthly by the Service Chief. Potential indicators of unplanned visits were recorded, including age; sex; diagnosis of diabetes, depression, anxiety, or posttraumatic stress disorder (PTSD); current smoking status; and residential zip code. We used the first 3 digits of the patients’ zip codes, which indicate region, as an estimate of proximity to the MRVAMC, which has a 50-county catchment area across North Florida and South Georgia. Diagnoses were found on the “problem list” from the electronic health record documented in the history and physical examinations before surgery. Clinic notes were examined for 3 months postsurgery to identify unplanned postoperative visits and the reason for the appointment. A χ² analysis was conducted using Excel Version 2402. P < .05 was used to determine whether age (> 60 years), sex, proximity to MRVAMC, diabetes, smoking, depression, anxiety, or PTSD were statistically significant independent risk factors for these appointments.

Results

A total of 1009 elective soft tissue hand surgeries at MRVAMC were reviewed. The patients median age was 61 years. Patients included 173 women (17.1%) and 836 men (82.9%). Eighty-one patients (8.0%) returned for unplanned visits. Age (P = .82); proximity to MRVAMC (P = .34); and diabetes (P = .60), smoking (P = .55), anxiety (P = .33), or PTSD (P = .37) were not statistically significant predictors of unplanned appointments. Depression diagnosis (P = .04) and female sex (P = .03) were found to be independent risk factors for an unplanned appointment (Table 1). The most common indication for the requested appointment was pain-related, followed closely by noninfectious wound concerns and persistent symptoms (Table 2).

Discussion

Improved access, quality, and efficiency for patients are goals for the VA.^1-3 The MRVAMC Plastic and Hand Surgery service provides care for the NFSGVAHS and receives an average of 15 to 20 consultation requests daily. The Veterans Health Administration is frequently challenged by staff shortages, and surgical services struggle to respond to consultation requests and treat patients within reasonable time frames.^4,5

The objective of this study was to identify risk factors for unplanned postoperative appointments following elective hand surgery. Unplanned appointments prevent scheduled patients from being seen on time and contribute to backlogs and delays. When patients schedule multiple appointments on the same day, delays in the first clinic’s scheduled appointments create delays for the second and third clinics. Hand surgery clinics can provide a better experience for patients and staff by identifying and mitigating factors prompting unplanned visits.

We anticipated that wound complications would prompt unscheduled visits. Diabetes is a known risk factor for wound healing complications after plastic and hand surgery.^6,7 A hemoglobin A_1c (HbA_1c) screening protocol used by the NFSGVAHS plastic surgery service since 2015 to identify poorly controlled patients with diabetes before surgery may partially explain this finding.⁸ We did not find a statistically significant difference between patients with diabetes and patients without diabetes for scheduling unplanned appointments. The plastic surgery service does not perform elective hand surgery unless the patient’s HbA_1c level is < 9%, or violate the flexor sheath unless HbA_1c level is < 8%. However, Zhuang et al found an increase in soft tissue infections after hand surgery with HbA_1c levels ≥ 7%.⁹

Smoking is a potential factor in postoperative hand surgery complications.^10,11 Lans et al found an increased incidence of 30-day emergency room visits in current and former smokers after outpatient upper extremity fracture surgery.¹² The MRVAMC Plastic Surgery Service counsels patients about the risk of skin necrosis and delayed wound healing, but does not cancel cases or obtain laboratory values to verify abstinence in patients undergoing hand surgery. The VA has multiple resources available for patients interested in smoking cessation through mental health services.¹³

MRVAMC patients have been known to resist returning for scheduled appointments due to the costs or availability of transportation. We suspected that patients who lived further from MRVAMC would be less likely to return for unscheduled visits. We used the first 3 digits of the patients’ mailing zip code to estimate residential proximity to MRVAMC. An acknowledged limitation to this approach is that some veterans have primary addresses in other regions but still spend significant time in the MRVAMC catchment area and use the facility for their health care during the winter months. These “snowbirds” might reside near the facility despite having official addresses that are more distant. Additionally, there was no increased risk of unplanned visits after hand surgery in patients aged > 61 years (the median age of study participants) (P = .82). Dependence on a third party for transportation in older veterans could impact this finding.

Based on the observation that most patients needed reassurance rather than an intervention when they returned for unscheduled appointments, diagnoses of depression, anxiety, and PTSD were evaluated as separate predictive factors. In previous research, anxiety was found to be a risk factor for problematic recovery following carpal tunnel surgery.¹⁴ In the current study, depression was found to be a statistically significant predictor of unscheduled postoperative appointments (P = .04), while anxiety (P = .33) and PTSD (P = .37) were not statistically significant predictors. This is consistent with other studies that have found preexisting depression can predict complications after hand surgery.^15,16 Vranceanu et al found that depression predicted pain intensity and disability after elective hand surgery.¹⁶ Similarly, Oflazoglu et al found a 12% incidence of depression based on the Patient Health Questionnaire-9 in new and returning hand patients who presented to an academic practice.¹⁷ They suggest patients should be assessed at all levels of care and that those with poor responses to surgical or nonsurgical management should be evaluated for depression. MRVAMC has a large mental health service consisting of psychiatrists, psychologists, addiction specialists, social workers, and homeless outreach, and patients tend to already have a diagnosis and mental health practitioner when they present to the clinic.

Recent studies found that wound problems, pain, and stiffness were the most common reasons for return visits.^18,19 Shetty et al identified younger age, worse preoperative pain scores, and poor access to transportation as predictors of preventable emergency room visits, which generate higher health care expenditures than an office visit.¹⁹ Our study’s top reasons for appointments (pain, wound/scar concerns, persistent symptoms) can be addressed with additional presurgery patient and family education. Additionally, clinicians encourage nonnarcotic pain management strategies including anti-inflammatories, acetaminophen, elevation, splinting, and hand therapy, and the hospital employs experienced, fellowship-trained anesthesia block faculty who help limit perioperative narcotic use. Patients are advised that pain can be used to guide them through the postoperative recovery by preventing overuse and alerting them to a problem that would be masked with narcotics, and long-standing problems such as chronic nerve compressions may continue to cause pain after surgery.

Patients and families can be given consistent and repetitive verbal and written information, instructions, and expectations at the initial consultation, preoperative appointment, and on the day of surgery. Postoperatively, outside their scheduled appointments, patients are encouraged to use the My HealtheVet secure messaging system or call the clinic to access an experienced registered nurse before making a long drive. Access to virtual or phone visits can reduce emergent in-person visits in a VA population.²⁰

Ozdag et al found that 42% of patients who had elective carpal tunnel surgery made unplanned electronic messages or phone contact within 2 weeks postsurgery. The authors point out the uncompensated administrative burden on the staff answering these messages and suggest pre-empting the contacts with more up-front education regarding postoperative pain expectations and management strategies.²¹

Fisher et al found that attending hand therapy reduced the number of emergency department visits in postoperative infection cases.²² At MRVAMC, a postoperative emergency department visit for a patient prompts an urgent unplanned appointment to the plastic surgery clinic, often on the same day. The MRVAMC occupational therapy clinic employed 3 on-site certified hand therapists during the study period. Because all hand surgery patients at the clinic receive hand therapy on the same day as their first postoperative appointment, attendance at hand therapy was not evaluated as a predictor of unplanned visits. Scheduled hand therapy is another point of contact where the clinic can provide reassurance and patient education.

While females made up 17.1% of the patients in this study, they constituted 12.5% of all veterans in Florida in fiscal year 2023.²³ This study found that women were more likely to present for unplanned postoperative appointments (P = .03). This is consistent with existing literature which has found that women are higher users of health care and office-based appointments.^24,25 This finding suggests the need for further study into whether our methods of communicating instructions to female patients undergoing plastic surgery may not be optimal.

Strengths and Limitations

As a retrospective review, the authors used information documented by multiple different health care practitioners, including trainees. The electronic medical record problem lists and templates provide consistency of information; however, less seasoned clinicians may interpret what they see and hear differently from more experienced clinicians in the postoperative setting. This study occurred in one part of the country with demographics that may not mirror other VA systems or the general population. The authors hope this study can be a starting point for other health care facilities to investigate ways to minimize the burden of unscheduled appointments. A strength of the study is that it was conducted within a closed system, as patients tend to stay within the VA system and documentation and communication among clinicians, even outside the immediate facility, are easily accessed through the electronic health record.

Conclusions

This study found that depression diagnosis and female sex are statistically significant predictors of unplanned postoperative visits after elective soft tissue hand surgery. More effective patient education during the preoperative period, particularly in patients with depression, may be warranted.

Mostly it is loss that teaches us about the worth of things.
Arthur Schopenhauer¹

One of the leaders I most respected in my US Department of Veterans Affairs (VA) career was a man who had worked his way up through the ranks to become a medical center director. Usually calm, cool, and collected, he would wax poetic when discussing the hero of the VA Health Care System revolution, Ken Kizer, MD, MPH.

In this issue of Federal Practitioner, journalist Randy Dotinga interviews Kizer about the current challenges facing the VA. Though many readers will have participated in or at least know about Kizer’s unprecedented overhaul of the agency, many others, especially those new to VA, may not. It seemed a fitting time to offer an outline of the immense and positive accomplishments that occurred in the agency during his tenure, especially as, under the current administration, many of his most forward-thinking initiatives seem to be moving backward.²

When President Clinton nominated Kizer to serve as the Under Secretary for Health for the Veterans Health Administration in 1994, the poor quality care the agency delivered was castigated in popular movies like Born on the Fourth of July. Veterans who were seen in that era, and who eventually returned to a far better, kinder VA thanks to Kizer, would often tell me, “Doc, the VA was really bad then, and I was afraid to come back.” The critique of VA health care in the mid-1990s sounds like a bureaucratic déjà vu of many of the concerns Kizer raised in his interview, including fragmentation of care, access barriers, and poor coordination of treatment.³

If anyone was prepared and qualified to take on this seeming mission impossible, it was Kizer. A US Navy veteran with 6 board certifications, he came to the VA following a brave and innovative stint as the top health official in California, where he successfully took on the tobacco lobby and dramatically reduced the state’s rates of smoking and related diseases.⁴

Long before it was the subject of reality TV shows, Kizer dubbed his major renovation of the VA’s antiquated structure an “extreme makeover.”³ Though this description is an oversimplification of Kizer’s monumental efforts, the makeover can be considered in 4 to 6 buckets, depending on how various health policy experts parse the re-engineering efforts.^5-7

Decentralization. Kizer instituted the Veterans Integrated Service Network (VISN) system to coordinate the management and operations of all the hospitals, clinics, and other VA health care entities in what is roughly a region. The locus of decision-making shifted from the VA Central Office to the VISNs, intended to promote more efficient, economical, and streamlined health care delivery.

Capitation. Accompanying this restructuring was a shift to a capitated system focused on preventive care. The Veterans Equitable Resource Allocation system was designed to logically link workload and funding. This was a major shift away from VA’s previous emphasis on inpatient and specialty care and resulted in the closing of multiple hospitals.⁴

Information Systems. I can still remember the first time I sat down at a prehistoric computer to use the Computerized Patient Record System (CPRS). Though now much maligned, then it was like something out of Star Trek, at a time when almost every other health care institution was buried in paper charts. With CPRS, VA suddenly had a pioneering and much-envied electronic medical record that facilitated continuity of care, communication between professionals, and accuracy and completeness of documentation.

Data Driven Performance Improvement. The VISNs and information systems inaugurated a new era of data-driven quality improvement. The assembly and analysis of data enabled VISNs to have real-time input about comparative facility performance.

Performance Measures. The data enabled evidence-based performance measures to be developed and monitored. Though these have now become the bane of many Federal Practitioner readers’ existence, they were originally intended for VISN directors and members of the senior executive service at VA central office. These were tied to incentives that, though recently the subject of watchdog investigation, were intended to motivate and reward high-quality care.⁶

Even this cursory look at Kizer’s accomplishments is more than enough to demonstrate the magnitude of the makeover, and when the time frame of the achievements is factored in, the transformation is the equivalent of a planet changing its orbit at light speed. Rhetoric aside, there are now hundreds of research articles published in top medical and health policy journals, many of them authored by Kizer,^7,8 that have amply demonstrated that when he departed the VA in 1999, it had become “the best care anywhere.” ⁹ For example, a 2000 New England Journal of Medicine article found that from 1994 to 2000, the percentage of veterans whose care met ≥ 90% of 9 of 17 quality standards was > 70% for 13 of the measures, outperforming fee-for-service Medicare.¹⁰

There had been uncertainty about whether Kizer would seek a second term as Under Secretary when he announced that he was leaving. With concise modesty, Kizer said he had met his charge to, “re-engineer the veterans’ health care system so that it could effectively function in the 21^st century.”¹¹

Despite openly and critically discussing the many difficulties the VA currently confronts, Kizer ends his interview on a note of hope. Since he likely knows more about VA than any person alive, we need to trust his judgment that his legacy, which currently seems more in jeopardy than ever before, will somehow prevail. Perhaps I am too melancholic, but I believe it will take a professional of the stature of Dr. Kizer to take us back to that future, and I fear we will not see his likes again.

Mostly it is loss that teaches us about the worth of things.
Arthur Schopenhauer¹

One of the leaders I most respected in my US Department of Veterans Affairs (VA) career was a man who had worked his way up through the ranks to become a medical center director. Usually calm, cool, and collected, he would wax poetic when discussing the hero of the VA Health Care System revolution, Ken Kizer, MD, MPH.

In this issue of Federal Practitioner, journalist Randy Dotinga interviews Kizer about the current challenges facing the VA. Though many readers will have participated in or at least know about Kizer’s unprecedented overhaul of the agency, many others, especially those new to VA, may not. It seemed a fitting time to offer an outline of the immense and positive accomplishments that occurred in the agency during his tenure, especially as, under the current administration, many of his most forward-thinking initiatives seem to be moving backward.²

When President Clinton nominated Kizer to serve as the Under Secretary for Health for the Veterans Health Administration in 1994, the poor quality care the agency delivered was castigated in popular movies like Born on the Fourth of July. Veterans who were seen in that era, and who eventually returned to a far better, kinder VA thanks to Kizer, would often tell me, “Doc, the VA was really bad then, and I was afraid to come back.” The critique of VA health care in the mid-1990s sounds like a bureaucratic déjà vu of many of the concerns Kizer raised in his interview, including fragmentation of care, access barriers, and poor coordination of treatment.³

If anyone was prepared and qualified to take on this seeming mission impossible, it was Kizer. A US Navy veteran with 6 board certifications, he came to the VA following a brave and innovative stint as the top health official in California, where he successfully took on the tobacco lobby and dramatically reduced the state’s rates of smoking and related diseases.⁴

Long before it was the subject of reality TV shows, Kizer dubbed his major renovation of the VA’s antiquated structure an “extreme makeover.”³ Though this description is an oversimplification of Kizer’s monumental efforts, the makeover can be considered in 4 to 6 buckets, depending on how various health policy experts parse the re-engineering efforts.^5-7

Decentralization. Kizer instituted the Veterans Integrated Service Network (VISN) system to coordinate the management and operations of all the hospitals, clinics, and other VA health care entities in what is roughly a region. The locus of decision-making shifted from the VA Central Office to the VISNs, intended to promote more efficient, economical, and streamlined health care delivery.

Capitation. Accompanying this restructuring was a shift to a capitated system focused on preventive care. The Veterans Equitable Resource Allocation system was designed to logically link workload and funding. This was a major shift away from VA’s previous emphasis on inpatient and specialty care and resulted in the closing of multiple hospitals.⁴

Information Systems. I can still remember the first time I sat down at a prehistoric computer to use the Computerized Patient Record System (CPRS). Though now much maligned, then it was like something out of Star Trek, at a time when almost every other health care institution was buried in paper charts. With CPRS, VA suddenly had a pioneering and much-envied electronic medical record that facilitated continuity of care, communication between professionals, and accuracy and completeness of documentation.

Data Driven Performance Improvement. The VISNs and information systems inaugurated a new era of data-driven quality improvement. The assembly and analysis of data enabled VISNs to have real-time input about comparative facility performance.

Performance Measures. The data enabled evidence-based performance measures to be developed and monitored. Though these have now become the bane of many Federal Practitioner readers’ existence, they were originally intended for VISN directors and members of the senior executive service at VA central office. These were tied to incentives that, though recently the subject of watchdog investigation, were intended to motivate and reward high-quality care.⁶

Even this cursory look at Kizer’s accomplishments is more than enough to demonstrate the magnitude of the makeover, and when the time frame of the achievements is factored in, the transformation is the equivalent of a planet changing its orbit at light speed. Rhetoric aside, there are now hundreds of research articles published in top medical and health policy journals, many of them authored by Kizer,^7,8 that have amply demonstrated that when he departed the VA in 1999, it had become “the best care anywhere.” ⁹ For example, a 2000 New England Journal of Medicine article found that from 1994 to 2000, the percentage of veterans whose care met ≥ 90% of 9 of 17 quality standards was > 70% for 13 of the measures, outperforming fee-for-service Medicare.¹⁰

There had been uncertainty about whether Kizer would seek a second term as Under Secretary when he announced that he was leaving. With concise modesty, Kizer said he had met his charge to, “re-engineer the veterans’ health care system so that it could effectively function in the 21^st century.”¹¹

Despite openly and critically discussing the many difficulties the VA currently confronts, Kizer ends his interview on a note of hope. Since he likely knows more about VA than any person alive, we need to trust his judgment that his legacy, which currently seems more in jeopardy than ever before, will somehow prevail. Perhaps I am too melancholic, but I believe it will take a professional of the stature of Dr. Kizer to take us back to that future, and I fear we will not see his likes again.

Mostly it is loss that teaches us about the worth of things.
Arthur Schopenhauer¹

One of the leaders I most respected in my US Department of Veterans Affairs (VA) career was a man who had worked his way up through the ranks to become a medical center director. Usually calm, cool, and collected, he would wax poetic when discussing the hero of the VA Health Care System revolution, Ken Kizer, MD, MPH.

In this issue of Federal Practitioner, journalist Randy Dotinga interviews Kizer about the current challenges facing the VA. Though many readers will have participated in or at least know about Kizer’s unprecedented overhaul of the agency, many others, especially those new to VA, may not. It seemed a fitting time to offer an outline of the immense and positive accomplishments that occurred in the agency during his tenure, especially as, under the current administration, many of his most forward-thinking initiatives seem to be moving backward.²

When President Clinton nominated Kizer to serve as the Under Secretary for Health for the Veterans Health Administration in 1994, the poor quality care the agency delivered was castigated in popular movies like Born on the Fourth of July. Veterans who were seen in that era, and who eventually returned to a far better, kinder VA thanks to Kizer, would often tell me, “Doc, the VA was really bad then, and I was afraid to come back.” The critique of VA health care in the mid-1990s sounds like a bureaucratic déjà vu of many of the concerns Kizer raised in his interview, including fragmentation of care, access barriers, and poor coordination of treatment.³

If anyone was prepared and qualified to take on this seeming mission impossible, it was Kizer. A US Navy veteran with 6 board certifications, he came to the VA following a brave and innovative stint as the top health official in California, where he successfully took on the tobacco lobby and dramatically reduced the state’s rates of smoking and related diseases.⁴

Long before it was the subject of reality TV shows, Kizer dubbed his major renovation of the VA’s antiquated structure an “extreme makeover.”³ Though this description is an oversimplification of Kizer’s monumental efforts, the makeover can be considered in 4 to 6 buckets, depending on how various health policy experts parse the re-engineering efforts.^5-7

Decentralization. Kizer instituted the Veterans Integrated Service Network (VISN) system to coordinate the management and operations of all the hospitals, clinics, and other VA health care entities in what is roughly a region. The locus of decision-making shifted from the VA Central Office to the VISNs, intended to promote more efficient, economical, and streamlined health care delivery.

Capitation. Accompanying this restructuring was a shift to a capitated system focused on preventive care. The Veterans Equitable Resource Allocation system was designed to logically link workload and funding. This was a major shift away from VA’s previous emphasis on inpatient and specialty care and resulted in the closing of multiple hospitals.⁴

Information Systems. I can still remember the first time I sat down at a prehistoric computer to use the Computerized Patient Record System (CPRS). Though now much maligned, then it was like something out of Star Trek, at a time when almost every other health care institution was buried in paper charts. With CPRS, VA suddenly had a pioneering and much-envied electronic medical record that facilitated continuity of care, communication between professionals, and accuracy and completeness of documentation.

Data Driven Performance Improvement. The VISNs and information systems inaugurated a new era of data-driven quality improvement. The assembly and analysis of data enabled VISNs to have real-time input about comparative facility performance.

Performance Measures. The data enabled evidence-based performance measures to be developed and monitored. Though these have now become the bane of many Federal Practitioner readers’ existence, they were originally intended for VISN directors and members of the senior executive service at VA central office. These were tied to incentives that, though recently the subject of watchdog investigation, were intended to motivate and reward high-quality care.⁶

Even this cursory look at Kizer’s accomplishments is more than enough to demonstrate the magnitude of the makeover, and when the time frame of the achievements is factored in, the transformation is the equivalent of a planet changing its orbit at light speed. Rhetoric aside, there are now hundreds of research articles published in top medical and health policy journals, many of them authored by Kizer,^7,8 that have amply demonstrated that when he departed the VA in 1999, it had become “the best care anywhere.” ⁹ For example, a 2000 New England Journal of Medicine article found that from 1994 to 2000, the percentage of veterans whose care met ≥ 90% of 9 of 17 quality standards was > 70% for 13 of the measures, outperforming fee-for-service Medicare.¹⁰

There had been uncertainty about whether Kizer would seek a second term as Under Secretary when he announced that he was leaving. With concise modesty, Kizer said he had met his charge to, “re-engineer the veterans’ health care system so that it could effectively function in the 21^st century.”¹¹

Despite openly and critically discussing the many difficulties the VA currently confronts, Kizer ends his interview on a note of hope. Since he likely knows more about VA than any person alive, we need to trust his judgment that his legacy, which currently seems more in jeopardy than ever before, will somehow prevail. Perhaps I am too melancholic, but I believe it will take a professional of the stature of Dr. Kizer to take us back to that future, and I fear we will not see his likes again.

TOPLINE:

Among adults with obesity, nonsurgical weight loss was significantly associated with reduced odds for developing obesity-related and other cancers at 3 and 5 years, a study of real-world data found.

METHODOLOGY:

• Although weight loss after bariatric surgery is linked to a reduced risk for cancer, the effect of nonsurgical weight loss on cancer risk remains unclear.
• Researchers conducted a retrospective observational study using electronic health record data from a US health system to assess the association between nonsurgical weight loss and the risk for cancer among adults with obesity.
• The inclusion criteria were age of ≥ 20 years, BMI > 30, and at least seven health system visits over 3 years. Patients with a history of alcohol or substance abuse, amputations, HIV infection, organ transplant, thyroid problems, or those who underwent bariatric surgery were excluded.
• The 143,630 patients who met inclusion criteria (7703 cancer cases and 135,927 controls) were divided into 3 cohorts based on weight change over time intervals of 3 years (115,942 patients), 5 years (105,472 patients), and 10 years (59,112 patients).
• Primary endpoints included obesity-related cancers (esophageal cancer, liver cancer, gallbladder cancer, pancreatic cancer, colorectal cancer, renal cell carcinoma, endometrial cancer, multiple myeloma, and postmenopausal breast cancer), and secondary endpoints included all malignant neoplasms.

TAKEAWAY:

• Each 1% reduction in BMI was associated with reduced odds of obesity-related cancers at 3 years and 5 years (odds ratio [OR], 0.99 and 0.989, respectively; P < .001 for both). These results translate to 5% weight loss corresponding to 4.9% and 5.4% reductions in obesity-related cancer odds at 3 and 5 years, respectively.
• Weight loss was associated with reduced odds of endometrial cancer at 3, 5, and 10 years (OR, 0.978; P < .05), of renal cell carcinoma at 3 and 5 years (OR, 0.983; P < .05), and of multiple myeloma at 10 years (OR, 0.969; P = .004).
• Weight loss was also associated with reduced odds of developing any malignancy at 3 years (OR, 0.992), 5 years (OR, 0.994), and 10 years (OR, 0.991; P = .001 for all). These results translate into a 5% weight loss corresponding to 3.9%, 3%, and 4.4% lower odds of any malignancy at 3, 5, and 10 years, respectively.

IN PRACTICE:

"Real-world weight loss was associated with a decreased risk of developing obesity-related cancers and all other cancers. Our study serves as a call for action and a strong public health message to healthcare stakeholders to intensify efforts and resources to treat obesity as a chronic disease to help reduce the risk of developing cancer," the author wrote.

SOURCE:

This study, led by endocrinologist Kenda Alkwatli, MD, Starling Physicians, Wethersfield, Connecticut, was published online in Obesity.

LIMITATIONS:

The study included only individuals with sufficient longitudinal health records, which may have introduced selection bias. It could not distinguish between intentional and unintentional weight loss or differentiate between fat and lean mass. Due to its observational nature, the study could not assess whether weight loss preceding cancer diagnosis was related to delay in diagnosis.

DISCLOSURES:

The study was funded in part by the Cleveland Clinic Center for Quantitative Metabolic Research. Three authors reported receiving research funding, consulting fees, honoraria, grants, or research support and holding patent applications, license agreements, leadership roles, or equity in healthcare and biotechnology companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

Among adults with obesity, nonsurgical weight loss was significantly associated with reduced odds for developing obesity-related and other cancers at 3 and 5 years, a study of real-world data found.

METHODOLOGY:

• Although weight loss after bariatric surgery is linked to a reduced risk for cancer, the effect of nonsurgical weight loss on cancer risk remains unclear.
• Researchers conducted a retrospective observational study using electronic health record data from a US health system to assess the association between nonsurgical weight loss and the risk for cancer among adults with obesity.
• The inclusion criteria were age of ≥ 20 years, BMI > 30, and at least seven health system visits over 3 years. Patients with a history of alcohol or substance abuse, amputations, HIV infection, organ transplant, thyroid problems, or those who underwent bariatric surgery were excluded.
• The 143,630 patients who met inclusion criteria (7703 cancer cases and 135,927 controls) were divided into 3 cohorts based on weight change over time intervals of 3 years (115,942 patients), 5 years (105,472 patients), and 10 years (59,112 patients).
• Primary endpoints included obesity-related cancers (esophageal cancer, liver cancer, gallbladder cancer, pancreatic cancer, colorectal cancer, renal cell carcinoma, endometrial cancer, multiple myeloma, and postmenopausal breast cancer), and secondary endpoints included all malignant neoplasms.

TAKEAWAY:

• Each 1% reduction in BMI was associated with reduced odds of obesity-related cancers at 3 years and 5 years (odds ratio [OR], 0.99 and 0.989, respectively; P < .001 for both). These results translate to 5% weight loss corresponding to 4.9% and 5.4% reductions in obesity-related cancer odds at 3 and 5 years, respectively.
• Weight loss was associated with reduced odds of endometrial cancer at 3, 5, and 10 years (OR, 0.978; P < .05), of renal cell carcinoma at 3 and 5 years (OR, 0.983; P < .05), and of multiple myeloma at 10 years (OR, 0.969; P = .004).
• Weight loss was also associated with reduced odds of developing any malignancy at 3 years (OR, 0.992), 5 years (OR, 0.994), and 10 years (OR, 0.991; P = .001 for all). These results translate into a 5% weight loss corresponding to 3.9%, 3%, and 4.4% lower odds of any malignancy at 3, 5, and 10 years, respectively.

IN PRACTICE:

"Real-world weight loss was associated with a decreased risk of developing obesity-related cancers and all other cancers. Our study serves as a call for action and a strong public health message to healthcare stakeholders to intensify efforts and resources to treat obesity as a chronic disease to help reduce the risk of developing cancer," the author wrote.

SOURCE:

This study, led by endocrinologist Kenda Alkwatli, MD, Starling Physicians, Wethersfield, Connecticut, was published online in Obesity.

LIMITATIONS:

The study included only individuals with sufficient longitudinal health records, which may have introduced selection bias. It could not distinguish between intentional and unintentional weight loss or differentiate between fat and lean mass. Due to its observational nature, the study could not assess whether weight loss preceding cancer diagnosis was related to delay in diagnosis.

DISCLOSURES:

The study was funded in part by the Cleveland Clinic Center for Quantitative Metabolic Research. Three authors reported receiving research funding, consulting fees, honoraria, grants, or research support and holding patent applications, license agreements, leadership roles, or equity in healthcare and biotechnology companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

Among adults with obesity, nonsurgical weight loss was significantly associated with reduced odds for developing obesity-related and other cancers at 3 and 5 years, a study of real-world data found.

METHODOLOGY:

• Although weight loss after bariatric surgery is linked to a reduced risk for cancer, the effect of nonsurgical weight loss on cancer risk remains unclear.
• Researchers conducted a retrospective observational study using electronic health record data from a US health system to assess the association between nonsurgical weight loss and the risk for cancer among adults with obesity.
• The inclusion criteria were age of ≥ 20 years, BMI > 30, and at least seven health system visits over 3 years. Patients with a history of alcohol or substance abuse, amputations, HIV infection, organ transplant, thyroid problems, or those who underwent bariatric surgery were excluded.
• The 143,630 patients who met inclusion criteria (7703 cancer cases and 135,927 controls) were divided into 3 cohorts based on weight change over time intervals of 3 years (115,942 patients), 5 years (105,472 patients), and 10 years (59,112 patients).
• Primary endpoints included obesity-related cancers (esophageal cancer, liver cancer, gallbladder cancer, pancreatic cancer, colorectal cancer, renal cell carcinoma, endometrial cancer, multiple myeloma, and postmenopausal breast cancer), and secondary endpoints included all malignant neoplasms.

TAKEAWAY:

• Each 1% reduction in BMI was associated with reduced odds of obesity-related cancers at 3 years and 5 years (odds ratio [OR], 0.99 and 0.989, respectively; P < .001 for both). These results translate to 5% weight loss corresponding to 4.9% and 5.4% reductions in obesity-related cancer odds at 3 and 5 years, respectively.
• Weight loss was associated with reduced odds of endometrial cancer at 3, 5, and 10 years (OR, 0.978; P < .05), of renal cell carcinoma at 3 and 5 years (OR, 0.983; P < .05), and of multiple myeloma at 10 years (OR, 0.969; P = .004).
• Weight loss was also associated with reduced odds of developing any malignancy at 3 years (OR, 0.992), 5 years (OR, 0.994), and 10 years (OR, 0.991; P = .001 for all). These results translate into a 5% weight loss corresponding to 3.9%, 3%, and 4.4% lower odds of any malignancy at 3, 5, and 10 years, respectively.

IN PRACTICE:

"Real-world weight loss was associated with a decreased risk of developing obesity-related cancers and all other cancers. Our study serves as a call for action and a strong public health message to healthcare stakeholders to intensify efforts and resources to treat obesity as a chronic disease to help reduce the risk of developing cancer," the author wrote.

SOURCE:

This study, led by endocrinologist Kenda Alkwatli, MD, Starling Physicians, Wethersfield, Connecticut, was published online in Obesity.

LIMITATIONS:

The study included only individuals with sufficient longitudinal health records, which may have introduced selection bias. It could not distinguish between intentional and unintentional weight loss or differentiate between fat and lean mass. Due to its observational nature, the study could not assess whether weight loss preceding cancer diagnosis was related to delay in diagnosis.

DISCLOSURES:

The study was funded in part by the Cleveland Clinic Center for Quantitative Metabolic Research. Three authors reported receiving research funding, consulting fees, honoraria, grants, or research support and holding patent applications, license agreements, leadership roles, or equity in healthcare and biotechnology companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.