Four medications comprise the drug category known as direct oral anticoagulants (DOACs). Dabigatran (Pradaxa)¹ was the first to gain approval. It was approved by the US Food and Drug Administration (FDA) in 2010 for the reduction of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). This was followed by approvals for rivaroxaban (Xarelto)² in 2011, apixaban (Eliquis)³ in 2012, and edoxaban (Savaysa)⁴ in 2015. Betrixaban (Bevyxxa)⁵ was approved in 2017 for venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized patients with restricted mobility, but it was removed from the market in 2020.

IMAGE: © KO STUDIOS

In addition to stroke prevention in nonvalvular AF, each DOAC has been approved for other indications and has been addressed further in guideline-based recommendations outside FDA-approved indications. This review highlights the evolving use of DOACs and the expansion of applications for multiple adult patient populations.

Overview of DOACs

Dabigatran is the only direct thrombin inhibitor; the other agents inhibit factor Xa. TABLE 1^1-4 summarizes FDA-­approved indications and dosing and guideline-based dosing. Dabigatran and edoxaban require parenteral anticoagulation for 5 to 10 days prior to initiation for acute VTE, limiting their use.^1,4TABLE 2^1-4 highlights pharmacokinetic differences among the agents. For example, dabigatran is 80% renally cleared, is somewhat dialyzable, and can accumulate in patients with renal dysfunction.¹ Edoxaban is contraindicated for nonvalvular AF in patients with a creatinine clearance (CrCl) > 95 mL/min because an increased stroke risk was demonstrated.⁴ Therefore, rivaroxaban and apixaban are prescribed most often in the United States.^6,7

Applications in special patient populations

Obesity

As of 2020, more than 40% of adults in the United States were obese (body mass index [BMI] ≥ 30), with 9% classified as class 3 or severely obese (BMI ≥ 40).⁸ Altered drug pharmacokinetics in patients with severe obesity raises concern for undertreatment with fixed-dose DOACs. Phase III DOAC approval trials included patients with obesity, but weight cutoffs differed, making extrapolating efficacy and safety data difficult across different obesity stages.⁹ Although no FDA-labeled dosing adjustments exist for patients with obesity, the International Society on Thrombosis and Haemostasis (ISTH) does provide such recommendations.

ISTH changes position on measuring drug levels. ISTH previously recommended avoiding DOACs in those with a BMI > 40 or body weight > 120 kg. If a DOAC was used, ISTH advised obtaining peak and trough drug levels.¹⁰ However, DOAC drug levels have not been associated with clinical outcomes or sufficient degrees of anticoagulation.¹¹

Men and women are affected equally by fibrolipomas. Prevalence does not differ by race or ethnicity.

In April 2021, ISTH updated guidance on DOACs in obesity, indicating standard doses of rivaroxaban or apixaban can be used for the treatment and prevention of VTE in all patients regardless of weight or BMI. Because data in obesity are lacking for dabigatran and edoxaban, avoid using these agents in patients with a BMI > 40 or weight > 120 kg. Additionally, assessing drug levels is no longer recommended, as there is insufficient evidence that these impact clinical outcomes.¹²

The 2021 American College of Chest Physicians (CHEST) guideline update does not recommend adjustments based on weight,¹³ and the 2019 European Society of Cardiology (ESC) guidelines make no mention of weight when treating acute pulmonary embolism.¹⁴

Continue to: Effectiveness of DOACs for AF in patients with obesity isn't clear

Effectiveness of DOACs for AF in patients with obesity isn’t clear, as most data are from retrospective cohort analyses. In patients weighing > 120 kg, dabigatran has shown efficacy in thrombosis prevention similar to that achieved in those weighing ≤ 120 kg, but it has increased the risk for gastrointestinal (GI) bleeding.¹⁵ Another study indicated a 15-mg dose of rivaroxaban may be associated with increased thromboembolic complications in patients with a BMI ≥ 35.¹⁶ Alternatively, another retrospective study of rivaroxaban demonstrated a small absolute risk reduction in ischemic stroke among patients in all stages of obesity and no difference in significant bleeding events.¹⁷ One further retrospective cohort showed that, in patients with a BMI ≥ 50 kg, the effectiveness of rivaroxaban and apixaban in thrombosis prevention and bleeding safety outcomes was comparable to that seen in those with a BMI < 30.¹⁸

As a result of conflicting data, and a lack of prospective randomized controlled trials (RCTs), ISTH continued recommending international normalized ratio (INR)–based dosing of warfarin for class 3 or severely obese patients with AF. The 2018 CHEST guidelines¹⁹ and the 2020 ESC guidelines²⁰ make no mention of DOAC avoidance in patients with obesity and AF.

Advanced and end-stage renal disease

DOACs are renally dosed based on indication, drug-drug interactions, and degree of renal function (TABLE 3^1-4). For example, patients with AF who are anticoagulated with apixaban are prescribed 2.5 mg twice daily when 2 of the 3 following criteria are met: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL. However, no dosage adjustment is necessary for VTE treatment or prophylaxis with apixaban regardless of renal function.³

Data supporting the safety and efficacy of DOACs in end-stage renal disease (ESRD) are sparse. All DOACs are renally cleared to varying degrees (TABLE 2^1-4), theoretically increasing bleeding risk as kidney disease progresses. Apixaban is the least renally cleared of the DOACs and has been evaluated in the greatest number of trials for patients with ESRD for both VTE treatment and prevention and nonvalvular AF.²¹ As a result, the FDA approved standard-dose apixaban (5 mg twice daily) for VTE treatment and prevention and nonvalvular AF in patients with ESRD, even those requiring dialysis. Use the reduced apixaban dose (2.5 mg twice daily) in patients with ESRD and AF only if they are ≥ 80 years of age or their body weight is ≤ 60 kg.³

Patients with cancer

Cancer-associated acute VTE treatment. Cancer is an established risk factor for acute VTE but it also increases the risk for treatment-­associated bleeding compared with patients without cancer.²² Historically, low-molecular-weight heparin (LMWH) was recommended over warfarin and DOACs for cancer-associated thromboses (CAT).²³ Compared with warfarin, LMWH reduced the rate of recurrent VTE and had similar or reduced bleeding rates at 6 to 12 months.^24-26 However, clinicians and patients often chose warfarin to avoid subcutaneous injections.²⁷

CHEST guidelines recommend oral Xa inhibitors over LMWH for the treatment of CAT.¹³ The 2020 guidelines of the National Institute for Health and Care Excellence (NICE) recommend DOACs as an option for CAT along with LMWH or LMWH transitioned to warfarin.²⁸ The American Society of Clinical Oncology (ASCO) recommends rivaroxaban for acute VTE treatment in CAT. No head-to-head trials have evaluated comparative efficacy of DOACs for CAT. However, edoxaban and rivaroxaban are associated with a greater risk for GI bleeding; therefore, apixaban is preferred in patients with GI malignancies.²⁹ Standard DOAC VTE treatment dosing is recommended for all 3 agents.^2-4

When using DOACs for patients with CAT, consider potential drug-drug interactions with chemotherapy regimens. All DOACs­ are transported by p-glycoprotein, while rivaroxaban and apixaban are substrates of cytochrome P450, leading to potentially significant drug-drug interactions.³⁰ These interactions could affect the patient’s chemotherapeutic regimen, decrease the efficacy of the DOAC, or increase the risk for bleeding. Therefore, anticoagulation choice should be made in collaboration with the ­hematology/oncology team.

Continue to: Cancer-associated VTE prophylaxis...

Cancer-associated VTE prophylaxis. VTE prophylaxis for patients with cancer is complex and necessitates a global assessment of cancer location and treatment regimen and setting. Hospitalized patients receiving chemotherapy are at high risk for VTE if mobility is reduced or if other VTE risk factors are present. The International Initiative on Thrombosis and Cancer (ITAC)³¹ and ISTH³² recommend VTE prophylaxis with unfractionated heparin or LMWH (ISTH recommends LMWH more strongly). The 2020 ASCO Guidelines recommend pharmacologic anticoagulation but make no drug-specific recommendation.²⁹ Parenteral treatment in hospitalized patients is not as burdensome as it is in ambulatory patients; therefore, these recommendations are less likely to elicit inpatient opposition.

In the ambulatory setting, patient avoidance of subcutaneous injections necessitates consideration of DOACs for CAT prophylaxis. The Khorana Risk Score (KRS) is a validated tool (scale, 0-7) to predict VTE risk in ambulatory patients receiving chemotherapy.³³ KRS scores ≥ 2 indicate high thrombotic risk and the need for prophylactic anticoagulation. ASCO recommends apixaban, rivaroxaban, or LMWH.²⁹ ISTH and ITAC both recommend apixaban or rivaroxaban over LMWH.^31,34 An RCT published in June 2023 confirmed that, for adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE for 6 months.³⁵ The recommended doses for apixaban (2.5 mg twice daily) and rivaroxaban (10 mg daily) for CAT VTE prophylaxis are lower than FDA-approved treatment doses.³¹

Patients with thrombophilia: VTE prevention

Thrombophilias are broadly categorized as inherited or acquired, with inherited thrombophilia being more prevalent. The Factor V Leiden (FVL) variant affects 2% to 7% of the population, and prothrombin gene mutation (PGM) affects 1% to 2% of the population.³⁶ Other forms of inherited thrombophilia, such as protein C deficiency, protein S deficiency, and antithrombin deficiency, occur less commonly (< 0.7% of the population).³⁶ Antiphospholipid syndrome (APS), the most common acquired thrombophilia, affects approximately 2% of the population.³⁶ APS involves multiple antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-beta-2 glycoprotein 1 antibodies. Establishing risk for thrombosis across the varying types of thrombophilia has proven difficult, but APS is considered the most thrombogenic thrombophilia apart from extremely rare homozygous inherited thrombophilias.³⁶ Therefore, DOAC recommendations are thrombophilia specific.

Assessing DOAC blood levels is no longer recommended for patients with obesity, as there is insufficient evidence that these measures affect clinical outcomes.

A prospective cohort study evaluated DOACs compared with heparin/warfarin for VTE treatment in patients with inherited thrombophilias.³⁷ Although all 4 available DOACs were included, most patients (61.1%) received rivaroxaban. Patients with an array of inherited thrombophilias, including rare homozygous mutations, were enrolled in this trial. While most patients (66.9%) had a “mild thrombophilia” defined as either FVL or PGM, the remainder had more severe thrombophilias.³⁷ VTE recurrence was similar and uncommon in the DOAC and heparin/warfarin groups, consistent with a previous meta-analysis.³⁸ Surprisingly, an increase in the cumulative risk for bleeding was seen in the DOAC group compared with the warfarin group, a finding inconsistent with prior trials.³⁸ There were no major bleeding events in the DOAC group, but 3 such events occurred in the heparin/warfarin group, including 2 intracranial hemorrhages.

Currently NICE, CHEST, and ISTH do not make a recommendation for a preferred agent in patients with an acute VTE and inherited thrombophilia; however, DOACs would not be inappropriate.^23,28,32 The American Society of Hematology (ASH) had planned to release recommendations related to the treatment of thrombophilia in 2020, but they were delayed by the COVID-19 pandemic.³⁹

APS presents challenges for acute VTE anticoagulation. First, it causes a strongly thrombogenic state necessitating therapeutic anticoagulation. Second, for patients with positive lupus anticoagulant, INR monitoring and standardized INR goals may be inadequate.⁴⁰ Therefore, using fixed-dose DOACs without the need for therapeutic monitoring is appealing, but significant concerns exist for using DOACs in patients with APS.^41-45 ISTH and CHEST recommend warfarin for the treatment and prevention of acute VTE in patients with APS, especially those with triple-­positive (anticardiolipin, lupus anticoagulant, and anti-beta-2 glycoprotein 1) APS.^13,46 Package labeling for all DOACs recommends avoidance in triple-positive APS.^1-4

ASTRO-APS is the most recent RCT to compare apixaban and warfarin for patients with APS,⁴⁷ and it was terminated early after 6 of 23 patients in the apixaban group had thrombotic events, while no one in the warfarin group had such an event.⁴⁸ Subsequently, a meta-analysis⁴⁹ demonstrated that patients with thrombotic APS appear to have a greater risk for arterial thrombosis when treated with DOACs compared with warfarin. These 2 studies may lead to changes in recommendations to avoid DOACs in all patients with APS or may prompt more focused trials for DOAC use in patients with APS plus an antiplatelet to mitigate arterial thrombotic risk.

Continue to: Expanded clinical indications

Expanded clinical indications

Superficial vein thrombosis

Superficial thrombophlebitis or superficial vein thrombosis (SVT) is estimated to occur 6 times more frequently than VTE.⁵⁰ Management of patients with isolated, uncomplicated thrombophlebitis who are at low risk for extension of the SVT involves symptomatic treatment with nonsteroidal anti-inflammatory drugs, topical agents, or compression therapy. However, depending on risk for progression, anticoagulation may be recommended.⁵¹

Patients at intermediate risk for extension or propagation of SVT are candidates for anticoagulation. The CHEST guidelines recommend fondaparinux 2.5 mg subcutaneous injections daily for 45 days instead of LMWH or warfarin.¹³ However, if patients decline 6 weeks of daily injections, the guidelines acknowledge that rivaroxaban 10 mg daily may be an alternative.¹³

Certain situations should prompt one to consider using a treatment dose of a DOAC for 3 months. These include cases in which the SVT is located within 3 cm of the deep venous system, expands despite an appropriate prophylactic regimen, or recurs after discontinuation of prophylactic anticoagulation.^13,50

Acute coronary syndrome

The American College of Cardiology/­American Heart Association (ACC/AHA) recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.⁵² Data are mixed regarding longer-term anticoagulation in addition to dual antiplatelet therapy in outpatient settings to prevent thrombosis recurrence in the absence of AF.

For patients at intermediate risk for extension of superficial vein thrombosis who decline daily subcutaneous injections of fondaparinux, rivaroxaban 10 mg/d may be an alternative.

The APPRAISE-2 trial enrolled high-risk patients with ACS within 7 days of the event.⁵³ Apixaban 5 mg twice daily was compared with placebo in patients taking aspirin or aspirin plus clopidogrel. The trial was terminated early because major bleeding events increased with apixaban without reduction in recurrent ischemic events. The ATLAS ACS-TIMI 46 trial evaluated different rivaroxaban doses (5-20 mg daily) in ACS patients.⁵⁴ The study revealed possible thrombosis benefit but also increased risk for bleeding, particularly at higher doses. As a result, another study—ATLAS ACS 2-TIMI 51—was conducted and compared the use of low-dose rivaroxaban (2.5 mg twice daily or 5 mg twice daily) vs placebo for patients with recent ACS.⁵⁵ All patients were receiving low-dose aspirin, and approximately 93% of patients in each group also were receiving clopidogrel or ticlopidine. As in the APPRAISE-2 trial, rivaroxaban increased the rate of major bleeding and intracranial hemorrhage; however, it did not increase the incidence of fatal bleeding. Unlike APPRAISE-2, rivaroxaban significantly reduced the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, or stroke (absolute risk reduction = 1.8%; number needed to treat = 56 for combined rivaroxaban doses).⁵⁵

A secondary subgroup analysis combined data from the ATLAS ACMS-TIMI 46 and ATLAS ACS 2-TIMI 51 trials to evaluate outcomes in patients receiving aspirin monotherapy when combined with rivaroxaban 2.5 mg twice daily or 5 mg twice daily or with placebo.⁵⁶ The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. When the 2 trials were evaluated separately, neither rivaroxaban dose was associated with reduction of the primary efficacy outcomes compared with aspirin alone. However, when the data were pooled, both the combined rivaroxaban doses (particularly the 5-mg dose) were associated with reduced cardiovascular outcomes. From a safety perspective, the 2.5-mg twice-daily dose of rivaroxaban was the only dose not associated with increased major bleeding risk. Thus, the 2.5-mg twice-daily dose of rivaroxaban may not provide sufficient cardiovascular benefit in patients with ACS, while the larger dose may increase the risk for nonfatal major bleeding events.⁵⁶

The European Medicines Agency⁵⁷ approved rivaroxaban 2.5 mg twice daily for ACS, and the 2020 ESC guidelines⁵⁸ consider it an appropriate therapeutic option in addition to aspirin for patients at high ischemic risk and low bleeding risk. ACS is not an FDA-approved indication for DOACs, and the ACC/AHA Guideline for the Management of ACS, last updated in 2014, does not include DOACs for ACS unless patients have AF.⁵² Ongoing trials are further investigating rivaroxaban for ACS, so the use of DOACs in the post-acute phase of ACS may become clearer in the future.⁵⁹

Continue to: Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia

Historically, nonheparin parenteral anticoagulants argatroban, bivalirudin, and fondaparinux were recommended for patients at risk for or who had heparin-induced thrombocytopenia (HIT). Argatroban is the only drug FDA approved for the treatment and prophylaxis of HIT; recommendations for the others are based on guideline recommendations.^23,60,61 The nonheparin parenteral anticoagulants cost between $700 and $1500 per day; therefore most patients with HIT are transitioned to warfarin.⁶² However, protein C and S inhibition and a subsequent prothrombotic state conveyed by warfarin initiation necessitates a minimum 5-day bridge to therapeutic warfarin with a nonheparin parenteral anticoagulant.

In vitro tests show that DOACs do not promote development of HIT antibodies⁶³ or affect platelet activation or aggregation.⁶⁴ A literature summary of DOACs for HIT determined that in 104 patients, all but 1 achieved platelet recovery (defined as > 150,000/mcL) within a median time of 7 days. Therapeutically, DOACs prevented new or recurrent VTE in 102/104 cases (98%), and only 3% of patients experienced significant bleeding events.⁶²

The ACC/AHA recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.

The 2018 ASH guidelines for VTE management in HIT include (with very low certainty of evidence) dabigatran, rivaroxaban, or apixaban for consideration in addition to previously recommended nonheparin parenteral anticoagulants.⁶¹ The dosing of each agent is contingent upon treatment of patients with HIT and an acute thrombosis (HITT) or HIT in the absence of VTE. For patients with HITT, treatment doses for acute VTE should be used for the appropriate duration of therapy (ie, 3 months). Importantly, dabigatran requires a 5-day pretreatment period with a parenteral anticoagulant, so it is not an ideal option. When treating isolated HIT (in the absence of VTE), ASH recommends all agents be dosed twice daily—dabigatran 150 mg twice daily (no 5-day parenteral pretreatment necessary), rivaroxaban 15 mg twice daily, or apixaban 5 mg twice daily—until platelet recovery (≥ 150,000/mcL) is achieved.⁶¹

CORRESPONDENCE
Kevin Schleich, PharmD, BCACP, Departments of Pharmaceutical Care and Family Medicine, University of Iowa, 200 Hawkins Drive, 01102-D PFP, Iowa City, IA, 52242; [email protected]

Four medications comprise the drug category known as direct oral anticoagulants (DOACs). Dabigatran (Pradaxa)¹ was the first to gain approval. It was approved by the US Food and Drug Administration (FDA) in 2010 for the reduction of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). This was followed by approvals for rivaroxaban (Xarelto)² in 2011, apixaban (Eliquis)³ in 2012, and edoxaban (Savaysa)⁴ in 2015. Betrixaban (Bevyxxa)⁵ was approved in 2017 for venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized patients with restricted mobility, but it was removed from the market in 2020.

IMAGE: © KO STUDIOS

In addition to stroke prevention in nonvalvular AF, each DOAC has been approved for other indications and has been addressed further in guideline-based recommendations outside FDA-approved indications. This review highlights the evolving use of DOACs and the expansion of applications for multiple adult patient populations.

Overview of DOACs

Dabigatran is the only direct thrombin inhibitor; the other agents inhibit factor Xa. TABLE 1^1-4 summarizes FDA-­approved indications and dosing and guideline-based dosing. Dabigatran and edoxaban require parenteral anticoagulation for 5 to 10 days prior to initiation for acute VTE, limiting their use.^1,4TABLE 2^1-4 highlights pharmacokinetic differences among the agents. For example, dabigatran is 80% renally cleared, is somewhat dialyzable, and can accumulate in patients with renal dysfunction.¹ Edoxaban is contraindicated for nonvalvular AF in patients with a creatinine clearance (CrCl) > 95 mL/min because an increased stroke risk was demonstrated.⁴ Therefore, rivaroxaban and apixaban are prescribed most often in the United States.^6,7

Applications in special patient populations

Obesity

As of 2020, more than 40% of adults in the United States were obese (body mass index [BMI] ≥ 30), with 9% classified as class 3 or severely obese (BMI ≥ 40).⁸ Altered drug pharmacokinetics in patients with severe obesity raises concern for undertreatment with fixed-dose DOACs. Phase III DOAC approval trials included patients with obesity, but weight cutoffs differed, making extrapolating efficacy and safety data difficult across different obesity stages.⁹ Although no FDA-labeled dosing adjustments exist for patients with obesity, the International Society on Thrombosis and Haemostasis (ISTH) does provide such recommendations.

ISTH changes position on measuring drug levels. ISTH previously recommended avoiding DOACs in those with a BMI > 40 or body weight > 120 kg. If a DOAC was used, ISTH advised obtaining peak and trough drug levels.¹⁰ However, DOAC drug levels have not been associated with clinical outcomes or sufficient degrees of anticoagulation.¹¹

Men and women are affected equally by fibrolipomas. Prevalence does not differ by race or ethnicity.

In April 2021, ISTH updated guidance on DOACs in obesity, indicating standard doses of rivaroxaban or apixaban can be used for the treatment and prevention of VTE in all patients regardless of weight or BMI. Because data in obesity are lacking for dabigatran and edoxaban, avoid using these agents in patients with a BMI > 40 or weight > 120 kg. Additionally, assessing drug levels is no longer recommended, as there is insufficient evidence that these impact clinical outcomes.¹²

The 2021 American College of Chest Physicians (CHEST) guideline update does not recommend adjustments based on weight,¹³ and the 2019 European Society of Cardiology (ESC) guidelines make no mention of weight when treating acute pulmonary embolism.¹⁴

Continue to: Effectiveness of DOACs for AF in patients with obesity isn't clear

Effectiveness of DOACs for AF in patients with obesity isn’t clear, as most data are from retrospective cohort analyses. In patients weighing > 120 kg, dabigatran has shown efficacy in thrombosis prevention similar to that achieved in those weighing ≤ 120 kg, but it has increased the risk for gastrointestinal (GI) bleeding.¹⁵ Another study indicated a 15-mg dose of rivaroxaban may be associated with increased thromboembolic complications in patients with a BMI ≥ 35.¹⁶ Alternatively, another retrospective study of rivaroxaban demonstrated a small absolute risk reduction in ischemic stroke among patients in all stages of obesity and no difference in significant bleeding events.¹⁷ One further retrospective cohort showed that, in patients with a BMI ≥ 50 kg, the effectiveness of rivaroxaban and apixaban in thrombosis prevention and bleeding safety outcomes was comparable to that seen in those with a BMI < 30.¹⁸

As a result of conflicting data, and a lack of prospective randomized controlled trials (RCTs), ISTH continued recommending international normalized ratio (INR)–based dosing of warfarin for class 3 or severely obese patients with AF. The 2018 CHEST guidelines¹⁹ and the 2020 ESC guidelines²⁰ make no mention of DOAC avoidance in patients with obesity and AF.

Advanced and end-stage renal disease

DOACs are renally dosed based on indication, drug-drug interactions, and degree of renal function (TABLE 3^1-4). For example, patients with AF who are anticoagulated with apixaban are prescribed 2.5 mg twice daily when 2 of the 3 following criteria are met: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL. However, no dosage adjustment is necessary for VTE treatment or prophylaxis with apixaban regardless of renal function.³

Data supporting the safety and efficacy of DOACs in end-stage renal disease (ESRD) are sparse. All DOACs are renally cleared to varying degrees (TABLE 2^1-4), theoretically increasing bleeding risk as kidney disease progresses. Apixaban is the least renally cleared of the DOACs and has been evaluated in the greatest number of trials for patients with ESRD for both VTE treatment and prevention and nonvalvular AF.²¹ As a result, the FDA approved standard-dose apixaban (5 mg twice daily) for VTE treatment and prevention and nonvalvular AF in patients with ESRD, even those requiring dialysis. Use the reduced apixaban dose (2.5 mg twice daily) in patients with ESRD and AF only if they are ≥ 80 years of age or their body weight is ≤ 60 kg.³

Patients with cancer

Cancer-associated acute VTE treatment. Cancer is an established risk factor for acute VTE but it also increases the risk for treatment-­associated bleeding compared with patients without cancer.²² Historically, low-molecular-weight heparin (LMWH) was recommended over warfarin and DOACs for cancer-associated thromboses (CAT).²³ Compared with warfarin, LMWH reduced the rate of recurrent VTE and had similar or reduced bleeding rates at 6 to 12 months.^24-26 However, clinicians and patients often chose warfarin to avoid subcutaneous injections.²⁷

CHEST guidelines recommend oral Xa inhibitors over LMWH for the treatment of CAT.¹³ The 2020 guidelines of the National Institute for Health and Care Excellence (NICE) recommend DOACs as an option for CAT along with LMWH or LMWH transitioned to warfarin.²⁸ The American Society of Clinical Oncology (ASCO) recommends rivaroxaban for acute VTE treatment in CAT. No head-to-head trials have evaluated comparative efficacy of DOACs for CAT. However, edoxaban and rivaroxaban are associated with a greater risk for GI bleeding; therefore, apixaban is preferred in patients with GI malignancies.²⁹ Standard DOAC VTE treatment dosing is recommended for all 3 agents.^2-4

When using DOACs for patients with CAT, consider potential drug-drug interactions with chemotherapy regimens. All DOACs­ are transported by p-glycoprotein, while rivaroxaban and apixaban are substrates of cytochrome P450, leading to potentially significant drug-drug interactions.³⁰ These interactions could affect the patient’s chemotherapeutic regimen, decrease the efficacy of the DOAC, or increase the risk for bleeding. Therefore, anticoagulation choice should be made in collaboration with the ­hematology/oncology team.

Continue to: Cancer-associated VTE prophylaxis...

Cancer-associated VTE prophylaxis. VTE prophylaxis for patients with cancer is complex and necessitates a global assessment of cancer location and treatment regimen and setting. Hospitalized patients receiving chemotherapy are at high risk for VTE if mobility is reduced or if other VTE risk factors are present. The International Initiative on Thrombosis and Cancer (ITAC)³¹ and ISTH³² recommend VTE prophylaxis with unfractionated heparin or LMWH (ISTH recommends LMWH more strongly). The 2020 ASCO Guidelines recommend pharmacologic anticoagulation but make no drug-specific recommendation.²⁹ Parenteral treatment in hospitalized patients is not as burdensome as it is in ambulatory patients; therefore, these recommendations are less likely to elicit inpatient opposition.

In the ambulatory setting, patient avoidance of subcutaneous injections necessitates consideration of DOACs for CAT prophylaxis. The Khorana Risk Score (KRS) is a validated tool (scale, 0-7) to predict VTE risk in ambulatory patients receiving chemotherapy.³³ KRS scores ≥ 2 indicate high thrombotic risk and the need for prophylactic anticoagulation. ASCO recommends apixaban, rivaroxaban, or LMWH.²⁹ ISTH and ITAC both recommend apixaban or rivaroxaban over LMWH.^31,34 An RCT published in June 2023 confirmed that, for adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE for 6 months.³⁵ The recommended doses for apixaban (2.5 mg twice daily) and rivaroxaban (10 mg daily) for CAT VTE prophylaxis are lower than FDA-approved treatment doses.³¹

Patients with thrombophilia: VTE prevention

Thrombophilias are broadly categorized as inherited or acquired, with inherited thrombophilia being more prevalent. The Factor V Leiden (FVL) variant affects 2% to 7% of the population, and prothrombin gene mutation (PGM) affects 1% to 2% of the population.³⁶ Other forms of inherited thrombophilia, such as protein C deficiency, protein S deficiency, and antithrombin deficiency, occur less commonly (< 0.7% of the population).³⁶ Antiphospholipid syndrome (APS), the most common acquired thrombophilia, affects approximately 2% of the population.³⁶ APS involves multiple antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-beta-2 glycoprotein 1 antibodies. Establishing risk for thrombosis across the varying types of thrombophilia has proven difficult, but APS is considered the most thrombogenic thrombophilia apart from extremely rare homozygous inherited thrombophilias.³⁶ Therefore, DOAC recommendations are thrombophilia specific.

Assessing DOAC blood levels is no longer recommended for patients with obesity, as there is insufficient evidence that these measures affect clinical outcomes.

A prospective cohort study evaluated DOACs compared with heparin/warfarin for VTE treatment in patients with inherited thrombophilias.³⁷ Although all 4 available DOACs were included, most patients (61.1%) received rivaroxaban. Patients with an array of inherited thrombophilias, including rare homozygous mutations, were enrolled in this trial. While most patients (66.9%) had a “mild thrombophilia” defined as either FVL or PGM, the remainder had more severe thrombophilias.³⁷ VTE recurrence was similar and uncommon in the DOAC and heparin/warfarin groups, consistent with a previous meta-analysis.³⁸ Surprisingly, an increase in the cumulative risk for bleeding was seen in the DOAC group compared with the warfarin group, a finding inconsistent with prior trials.³⁸ There were no major bleeding events in the DOAC group, but 3 such events occurred in the heparin/warfarin group, including 2 intracranial hemorrhages.

Currently NICE, CHEST, and ISTH do not make a recommendation for a preferred agent in patients with an acute VTE and inherited thrombophilia; however, DOACs would not be inappropriate.^23,28,32 The American Society of Hematology (ASH) had planned to release recommendations related to the treatment of thrombophilia in 2020, but they were delayed by the COVID-19 pandemic.³⁹

APS presents challenges for acute VTE anticoagulation. First, it causes a strongly thrombogenic state necessitating therapeutic anticoagulation. Second, for patients with positive lupus anticoagulant, INR monitoring and standardized INR goals may be inadequate.⁴⁰ Therefore, using fixed-dose DOACs without the need for therapeutic monitoring is appealing, but significant concerns exist for using DOACs in patients with APS.^41-45 ISTH and CHEST recommend warfarin for the treatment and prevention of acute VTE in patients with APS, especially those with triple-­positive (anticardiolipin, lupus anticoagulant, and anti-beta-2 glycoprotein 1) APS.^13,46 Package labeling for all DOACs recommends avoidance in triple-positive APS.^1-4

ASTRO-APS is the most recent RCT to compare apixaban and warfarin for patients with APS,⁴⁷ and it was terminated early after 6 of 23 patients in the apixaban group had thrombotic events, while no one in the warfarin group had such an event.⁴⁸ Subsequently, a meta-analysis⁴⁹ demonstrated that patients with thrombotic APS appear to have a greater risk for arterial thrombosis when treated with DOACs compared with warfarin. These 2 studies may lead to changes in recommendations to avoid DOACs in all patients with APS or may prompt more focused trials for DOAC use in patients with APS plus an antiplatelet to mitigate arterial thrombotic risk.

Continue to: Expanded clinical indications

Expanded clinical indications

Superficial vein thrombosis

Superficial thrombophlebitis or superficial vein thrombosis (SVT) is estimated to occur 6 times more frequently than VTE.⁵⁰ Management of patients with isolated, uncomplicated thrombophlebitis who are at low risk for extension of the SVT involves symptomatic treatment with nonsteroidal anti-inflammatory drugs, topical agents, or compression therapy. However, depending on risk for progression, anticoagulation may be recommended.⁵¹

Patients at intermediate risk for extension or propagation of SVT are candidates for anticoagulation. The CHEST guidelines recommend fondaparinux 2.5 mg subcutaneous injections daily for 45 days instead of LMWH or warfarin.¹³ However, if patients decline 6 weeks of daily injections, the guidelines acknowledge that rivaroxaban 10 mg daily may be an alternative.¹³

Certain situations should prompt one to consider using a treatment dose of a DOAC for 3 months. These include cases in which the SVT is located within 3 cm of the deep venous system, expands despite an appropriate prophylactic regimen, or recurs after discontinuation of prophylactic anticoagulation.^13,50

Acute coronary syndrome

The American College of Cardiology/­American Heart Association (ACC/AHA) recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.⁵² Data are mixed regarding longer-term anticoagulation in addition to dual antiplatelet therapy in outpatient settings to prevent thrombosis recurrence in the absence of AF.

For patients at intermediate risk for extension of superficial vein thrombosis who decline daily subcutaneous injections of fondaparinux, rivaroxaban 10 mg/d may be an alternative.

The APPRAISE-2 trial enrolled high-risk patients with ACS within 7 days of the event.⁵³ Apixaban 5 mg twice daily was compared with placebo in patients taking aspirin or aspirin plus clopidogrel. The trial was terminated early because major bleeding events increased with apixaban without reduction in recurrent ischemic events. The ATLAS ACS-TIMI 46 trial evaluated different rivaroxaban doses (5-20 mg daily) in ACS patients.⁵⁴ The study revealed possible thrombosis benefit but also increased risk for bleeding, particularly at higher doses. As a result, another study—ATLAS ACS 2-TIMI 51—was conducted and compared the use of low-dose rivaroxaban (2.5 mg twice daily or 5 mg twice daily) vs placebo for patients with recent ACS.⁵⁵ All patients were receiving low-dose aspirin, and approximately 93% of patients in each group also were receiving clopidogrel or ticlopidine. As in the APPRAISE-2 trial, rivaroxaban increased the rate of major bleeding and intracranial hemorrhage; however, it did not increase the incidence of fatal bleeding. Unlike APPRAISE-2, rivaroxaban significantly reduced the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, or stroke (absolute risk reduction = 1.8%; number needed to treat = 56 for combined rivaroxaban doses).⁵⁵

A secondary subgroup analysis combined data from the ATLAS ACMS-TIMI 46 and ATLAS ACS 2-TIMI 51 trials to evaluate outcomes in patients receiving aspirin monotherapy when combined with rivaroxaban 2.5 mg twice daily or 5 mg twice daily or with placebo.⁵⁶ The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. When the 2 trials were evaluated separately, neither rivaroxaban dose was associated with reduction of the primary efficacy outcomes compared with aspirin alone. However, when the data were pooled, both the combined rivaroxaban doses (particularly the 5-mg dose) were associated with reduced cardiovascular outcomes. From a safety perspective, the 2.5-mg twice-daily dose of rivaroxaban was the only dose not associated with increased major bleeding risk. Thus, the 2.5-mg twice-daily dose of rivaroxaban may not provide sufficient cardiovascular benefit in patients with ACS, while the larger dose may increase the risk for nonfatal major bleeding events.⁵⁶

The European Medicines Agency⁵⁷ approved rivaroxaban 2.5 mg twice daily for ACS, and the 2020 ESC guidelines⁵⁸ consider it an appropriate therapeutic option in addition to aspirin for patients at high ischemic risk and low bleeding risk. ACS is not an FDA-approved indication for DOACs, and the ACC/AHA Guideline for the Management of ACS, last updated in 2014, does not include DOACs for ACS unless patients have AF.⁵² Ongoing trials are further investigating rivaroxaban for ACS, so the use of DOACs in the post-acute phase of ACS may become clearer in the future.⁵⁹

Continue to: Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia

Historically, nonheparin parenteral anticoagulants argatroban, bivalirudin, and fondaparinux were recommended for patients at risk for or who had heparin-induced thrombocytopenia (HIT). Argatroban is the only drug FDA approved for the treatment and prophylaxis of HIT; recommendations for the others are based on guideline recommendations.^23,60,61 The nonheparin parenteral anticoagulants cost between $700 and $1500 per day; therefore most patients with HIT are transitioned to warfarin.⁶² However, protein C and S inhibition and a subsequent prothrombotic state conveyed by warfarin initiation necessitates a minimum 5-day bridge to therapeutic warfarin with a nonheparin parenteral anticoagulant.

In vitro tests show that DOACs do not promote development of HIT antibodies⁶³ or affect platelet activation or aggregation.⁶⁴ A literature summary of DOACs for HIT determined that in 104 patients, all but 1 achieved platelet recovery (defined as > 150,000/mcL) within a median time of 7 days. Therapeutically, DOACs prevented new or recurrent VTE in 102/104 cases (98%), and only 3% of patients experienced significant bleeding events.⁶²

The ACC/AHA recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.

The 2018 ASH guidelines for VTE management in HIT include (with very low certainty of evidence) dabigatran, rivaroxaban, or apixaban for consideration in addition to previously recommended nonheparin parenteral anticoagulants.⁶¹ The dosing of each agent is contingent upon treatment of patients with HIT and an acute thrombosis (HITT) or HIT in the absence of VTE. For patients with HITT, treatment doses for acute VTE should be used for the appropriate duration of therapy (ie, 3 months). Importantly, dabigatran requires a 5-day pretreatment period with a parenteral anticoagulant, so it is not an ideal option. When treating isolated HIT (in the absence of VTE), ASH recommends all agents be dosed twice daily—dabigatran 150 mg twice daily (no 5-day parenteral pretreatment necessary), rivaroxaban 15 mg twice daily, or apixaban 5 mg twice daily—until platelet recovery (≥ 150,000/mcL) is achieved.⁶¹

CORRESPONDENCE
Kevin Schleich, PharmD, BCACP, Departments of Pharmaceutical Care and Family Medicine, University of Iowa, 200 Hawkins Drive, 01102-D PFP, Iowa City, IA, 52242; [email protected]

Four medications comprise the drug category known as direct oral anticoagulants (DOACs). Dabigatran (Pradaxa)¹ was the first to gain approval. It was approved by the US Food and Drug Administration (FDA) in 2010 for the reduction of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). This was followed by approvals for rivaroxaban (Xarelto)² in 2011, apixaban (Eliquis)³ in 2012, and edoxaban (Savaysa)⁴ in 2015. Betrixaban (Bevyxxa)⁵ was approved in 2017 for venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized patients with restricted mobility, but it was removed from the market in 2020.

IMAGE: © KO STUDIOS

In addition to stroke prevention in nonvalvular AF, each DOAC has been approved for other indications and has been addressed further in guideline-based recommendations outside FDA-approved indications. This review highlights the evolving use of DOACs and the expansion of applications for multiple adult patient populations.

Overview of DOACs

Dabigatran is the only direct thrombin inhibitor; the other agents inhibit factor Xa. TABLE 1^1-4 summarizes FDA-­approved indications and dosing and guideline-based dosing. Dabigatran and edoxaban require parenteral anticoagulation for 5 to 10 days prior to initiation for acute VTE, limiting their use.^1,4TABLE 2^1-4 highlights pharmacokinetic differences among the agents. For example, dabigatran is 80% renally cleared, is somewhat dialyzable, and can accumulate in patients with renal dysfunction.¹ Edoxaban is contraindicated for nonvalvular AF in patients with a creatinine clearance (CrCl) > 95 mL/min because an increased stroke risk was demonstrated.⁴ Therefore, rivaroxaban and apixaban are prescribed most often in the United States.^6,7

Applications in special patient populations

Obesity

As of 2020, more than 40% of adults in the United States were obese (body mass index [BMI] ≥ 30), with 9% classified as class 3 or severely obese (BMI ≥ 40).⁸ Altered drug pharmacokinetics in patients with severe obesity raises concern for undertreatment with fixed-dose DOACs. Phase III DOAC approval trials included patients with obesity, but weight cutoffs differed, making extrapolating efficacy and safety data difficult across different obesity stages.⁹ Although no FDA-labeled dosing adjustments exist for patients with obesity, the International Society on Thrombosis and Haemostasis (ISTH) does provide such recommendations.

ISTH changes position on measuring drug levels. ISTH previously recommended avoiding DOACs in those with a BMI > 40 or body weight > 120 kg. If a DOAC was used, ISTH advised obtaining peak and trough drug levels.¹⁰ However, DOAC drug levels have not been associated with clinical outcomes or sufficient degrees of anticoagulation.¹¹

Men and women are affected equally by fibrolipomas. Prevalence does not differ by race or ethnicity.

In April 2021, ISTH updated guidance on DOACs in obesity, indicating standard doses of rivaroxaban or apixaban can be used for the treatment and prevention of VTE in all patients regardless of weight or BMI. Because data in obesity are lacking for dabigatran and edoxaban, avoid using these agents in patients with a BMI > 40 or weight > 120 kg. Additionally, assessing drug levels is no longer recommended, as there is insufficient evidence that these impact clinical outcomes.¹²

The 2021 American College of Chest Physicians (CHEST) guideline update does not recommend adjustments based on weight,¹³ and the 2019 European Society of Cardiology (ESC) guidelines make no mention of weight when treating acute pulmonary embolism.¹⁴

Continue to: Effectiveness of DOACs for AF in patients with obesity isn't clear

Effectiveness of DOACs for AF in patients with obesity isn’t clear, as most data are from retrospective cohort analyses. In patients weighing > 120 kg, dabigatran has shown efficacy in thrombosis prevention similar to that achieved in those weighing ≤ 120 kg, but it has increased the risk for gastrointestinal (GI) bleeding.¹⁵ Another study indicated a 15-mg dose of rivaroxaban may be associated with increased thromboembolic complications in patients with a BMI ≥ 35.¹⁶ Alternatively, another retrospective study of rivaroxaban demonstrated a small absolute risk reduction in ischemic stroke among patients in all stages of obesity and no difference in significant bleeding events.¹⁷ One further retrospective cohort showed that, in patients with a BMI ≥ 50 kg, the effectiveness of rivaroxaban and apixaban in thrombosis prevention and bleeding safety outcomes was comparable to that seen in those with a BMI < 30.¹⁸

As a result of conflicting data, and a lack of prospective randomized controlled trials (RCTs), ISTH continued recommending international normalized ratio (INR)–based dosing of warfarin for class 3 or severely obese patients with AF. The 2018 CHEST guidelines¹⁹ and the 2020 ESC guidelines²⁰ make no mention of DOAC avoidance in patients with obesity and AF.

Advanced and end-stage renal disease

DOACs are renally dosed based on indication, drug-drug interactions, and degree of renal function (TABLE 3^1-4). For example, patients with AF who are anticoagulated with apixaban are prescribed 2.5 mg twice daily when 2 of the 3 following criteria are met: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL. However, no dosage adjustment is necessary for VTE treatment or prophylaxis with apixaban regardless of renal function.³

Data supporting the safety and efficacy of DOACs in end-stage renal disease (ESRD) are sparse. All DOACs are renally cleared to varying degrees (TABLE 2^1-4), theoretically increasing bleeding risk as kidney disease progresses. Apixaban is the least renally cleared of the DOACs and has been evaluated in the greatest number of trials for patients with ESRD for both VTE treatment and prevention and nonvalvular AF.²¹ As a result, the FDA approved standard-dose apixaban (5 mg twice daily) for VTE treatment and prevention and nonvalvular AF in patients with ESRD, even those requiring dialysis. Use the reduced apixaban dose (2.5 mg twice daily) in patients with ESRD and AF only if they are ≥ 80 years of age or their body weight is ≤ 60 kg.³

Patients with cancer

Cancer-associated acute VTE treatment. Cancer is an established risk factor for acute VTE but it also increases the risk for treatment-­associated bleeding compared with patients without cancer.²² Historically, low-molecular-weight heparin (LMWH) was recommended over warfarin and DOACs for cancer-associated thromboses (CAT).²³ Compared with warfarin, LMWH reduced the rate of recurrent VTE and had similar or reduced bleeding rates at 6 to 12 months.^24-26 However, clinicians and patients often chose warfarin to avoid subcutaneous injections.²⁷

CHEST guidelines recommend oral Xa inhibitors over LMWH for the treatment of CAT.¹³ The 2020 guidelines of the National Institute for Health and Care Excellence (NICE) recommend DOACs as an option for CAT along with LMWH or LMWH transitioned to warfarin.²⁸ The American Society of Clinical Oncology (ASCO) recommends rivaroxaban for acute VTE treatment in CAT. No head-to-head trials have evaluated comparative efficacy of DOACs for CAT. However, edoxaban and rivaroxaban are associated with a greater risk for GI bleeding; therefore, apixaban is preferred in patients with GI malignancies.²⁹ Standard DOAC VTE treatment dosing is recommended for all 3 agents.^2-4

When using DOACs for patients with CAT, consider potential drug-drug interactions with chemotherapy regimens. All DOACs­ are transported by p-glycoprotein, while rivaroxaban and apixaban are substrates of cytochrome P450, leading to potentially significant drug-drug interactions.³⁰ These interactions could affect the patient’s chemotherapeutic regimen, decrease the efficacy of the DOAC, or increase the risk for bleeding. Therefore, anticoagulation choice should be made in collaboration with the ­hematology/oncology team.

Continue to: Cancer-associated VTE prophylaxis...

Cancer-associated VTE prophylaxis. VTE prophylaxis for patients with cancer is complex and necessitates a global assessment of cancer location and treatment regimen and setting. Hospitalized patients receiving chemotherapy are at high risk for VTE if mobility is reduced or if other VTE risk factors are present. The International Initiative on Thrombosis and Cancer (ITAC)³¹ and ISTH³² recommend VTE prophylaxis with unfractionated heparin or LMWH (ISTH recommends LMWH more strongly). The 2020 ASCO Guidelines recommend pharmacologic anticoagulation but make no drug-specific recommendation.²⁹ Parenteral treatment in hospitalized patients is not as burdensome as it is in ambulatory patients; therefore, these recommendations are less likely to elicit inpatient opposition.

In the ambulatory setting, patient avoidance of subcutaneous injections necessitates consideration of DOACs for CAT prophylaxis. The Khorana Risk Score (KRS) is a validated tool (scale, 0-7) to predict VTE risk in ambulatory patients receiving chemotherapy.³³ KRS scores ≥ 2 indicate high thrombotic risk and the need for prophylactic anticoagulation. ASCO recommends apixaban, rivaroxaban, or LMWH.²⁹ ISTH and ITAC both recommend apixaban or rivaroxaban over LMWH.^31,34 An RCT published in June 2023 confirmed that, for adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE for 6 months.³⁵ The recommended doses for apixaban (2.5 mg twice daily) and rivaroxaban (10 mg daily) for CAT VTE prophylaxis are lower than FDA-approved treatment doses.³¹

Patients with thrombophilia: VTE prevention

Thrombophilias are broadly categorized as inherited or acquired, with inherited thrombophilia being more prevalent. The Factor V Leiden (FVL) variant affects 2% to 7% of the population, and prothrombin gene mutation (PGM) affects 1% to 2% of the population.³⁶ Other forms of inherited thrombophilia, such as protein C deficiency, protein S deficiency, and antithrombin deficiency, occur less commonly (< 0.7% of the population).³⁶ Antiphospholipid syndrome (APS), the most common acquired thrombophilia, affects approximately 2% of the population.³⁶ APS involves multiple antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-beta-2 glycoprotein 1 antibodies. Establishing risk for thrombosis across the varying types of thrombophilia has proven difficult, but APS is considered the most thrombogenic thrombophilia apart from extremely rare homozygous inherited thrombophilias.³⁶ Therefore, DOAC recommendations are thrombophilia specific.

Assessing DOAC blood levels is no longer recommended for patients with obesity, as there is insufficient evidence that these measures affect clinical outcomes.

A prospective cohort study evaluated DOACs compared with heparin/warfarin for VTE treatment in patients with inherited thrombophilias.³⁷ Although all 4 available DOACs were included, most patients (61.1%) received rivaroxaban. Patients with an array of inherited thrombophilias, including rare homozygous mutations, were enrolled in this trial. While most patients (66.9%) had a “mild thrombophilia” defined as either FVL or PGM, the remainder had more severe thrombophilias.³⁷ VTE recurrence was similar and uncommon in the DOAC and heparin/warfarin groups, consistent with a previous meta-analysis.³⁸ Surprisingly, an increase in the cumulative risk for bleeding was seen in the DOAC group compared with the warfarin group, a finding inconsistent with prior trials.³⁸ There were no major bleeding events in the DOAC group, but 3 such events occurred in the heparin/warfarin group, including 2 intracranial hemorrhages.

Currently NICE, CHEST, and ISTH do not make a recommendation for a preferred agent in patients with an acute VTE and inherited thrombophilia; however, DOACs would not be inappropriate.^23,28,32 The American Society of Hematology (ASH) had planned to release recommendations related to the treatment of thrombophilia in 2020, but they were delayed by the COVID-19 pandemic.³⁹

APS presents challenges for acute VTE anticoagulation. First, it causes a strongly thrombogenic state necessitating therapeutic anticoagulation. Second, for patients with positive lupus anticoagulant, INR monitoring and standardized INR goals may be inadequate.⁴⁰ Therefore, using fixed-dose DOACs without the need for therapeutic monitoring is appealing, but significant concerns exist for using DOACs in patients with APS.^41-45 ISTH and CHEST recommend warfarin for the treatment and prevention of acute VTE in patients with APS, especially those with triple-­positive (anticardiolipin, lupus anticoagulant, and anti-beta-2 glycoprotein 1) APS.^13,46 Package labeling for all DOACs recommends avoidance in triple-positive APS.^1-4

ASTRO-APS is the most recent RCT to compare apixaban and warfarin for patients with APS,⁴⁷ and it was terminated early after 6 of 23 patients in the apixaban group had thrombotic events, while no one in the warfarin group had such an event.⁴⁸ Subsequently, a meta-analysis⁴⁹ demonstrated that patients with thrombotic APS appear to have a greater risk for arterial thrombosis when treated with DOACs compared with warfarin. These 2 studies may lead to changes in recommendations to avoid DOACs in all patients with APS or may prompt more focused trials for DOAC use in patients with APS plus an antiplatelet to mitigate arterial thrombotic risk.

Continue to: Expanded clinical indications

Expanded clinical indications

Superficial vein thrombosis

Superficial thrombophlebitis or superficial vein thrombosis (SVT) is estimated to occur 6 times more frequently than VTE.⁵⁰ Management of patients with isolated, uncomplicated thrombophlebitis who are at low risk for extension of the SVT involves symptomatic treatment with nonsteroidal anti-inflammatory drugs, topical agents, or compression therapy. However, depending on risk for progression, anticoagulation may be recommended.⁵¹

Patients at intermediate risk for extension or propagation of SVT are candidates for anticoagulation. The CHEST guidelines recommend fondaparinux 2.5 mg subcutaneous injections daily for 45 days instead of LMWH or warfarin.¹³ However, if patients decline 6 weeks of daily injections, the guidelines acknowledge that rivaroxaban 10 mg daily may be an alternative.¹³

Certain situations should prompt one to consider using a treatment dose of a DOAC for 3 months. These include cases in which the SVT is located within 3 cm of the deep venous system, expands despite an appropriate prophylactic regimen, or recurs after discontinuation of prophylactic anticoagulation.^13,50

Acute coronary syndrome

The American College of Cardiology/­American Heart Association (ACC/AHA) recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.⁵² Data are mixed regarding longer-term anticoagulation in addition to dual antiplatelet therapy in outpatient settings to prevent thrombosis recurrence in the absence of AF.

For patients at intermediate risk for extension of superficial vein thrombosis who decline daily subcutaneous injections of fondaparinux, rivaroxaban 10 mg/d may be an alternative.

The APPRAISE-2 trial enrolled high-risk patients with ACS within 7 days of the event.⁵³ Apixaban 5 mg twice daily was compared with placebo in patients taking aspirin or aspirin plus clopidogrel. The trial was terminated early because major bleeding events increased with apixaban without reduction in recurrent ischemic events. The ATLAS ACS-TIMI 46 trial evaluated different rivaroxaban doses (5-20 mg daily) in ACS patients.⁵⁴ The study revealed possible thrombosis benefit but also increased risk for bleeding, particularly at higher doses. As a result, another study—ATLAS ACS 2-TIMI 51—was conducted and compared the use of low-dose rivaroxaban (2.5 mg twice daily or 5 mg twice daily) vs placebo for patients with recent ACS.⁵⁵ All patients were receiving low-dose aspirin, and approximately 93% of patients in each group also were receiving clopidogrel or ticlopidine. As in the APPRAISE-2 trial, rivaroxaban increased the rate of major bleeding and intracranial hemorrhage; however, it did not increase the incidence of fatal bleeding. Unlike APPRAISE-2, rivaroxaban significantly reduced the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, or stroke (absolute risk reduction = 1.8%; number needed to treat = 56 for combined rivaroxaban doses).⁵⁵

A secondary subgroup analysis combined data from the ATLAS ACMS-TIMI 46 and ATLAS ACS 2-TIMI 51 trials to evaluate outcomes in patients receiving aspirin monotherapy when combined with rivaroxaban 2.5 mg twice daily or 5 mg twice daily or with placebo.⁵⁶ The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. When the 2 trials were evaluated separately, neither rivaroxaban dose was associated with reduction of the primary efficacy outcomes compared with aspirin alone. However, when the data were pooled, both the combined rivaroxaban doses (particularly the 5-mg dose) were associated with reduced cardiovascular outcomes. From a safety perspective, the 2.5-mg twice-daily dose of rivaroxaban was the only dose not associated with increased major bleeding risk. Thus, the 2.5-mg twice-daily dose of rivaroxaban may not provide sufficient cardiovascular benefit in patients with ACS, while the larger dose may increase the risk for nonfatal major bleeding events.⁵⁶

The European Medicines Agency⁵⁷ approved rivaroxaban 2.5 mg twice daily for ACS, and the 2020 ESC guidelines⁵⁸ consider it an appropriate therapeutic option in addition to aspirin for patients at high ischemic risk and low bleeding risk. ACS is not an FDA-approved indication for DOACs, and the ACC/AHA Guideline for the Management of ACS, last updated in 2014, does not include DOACs for ACS unless patients have AF.⁵² Ongoing trials are further investigating rivaroxaban for ACS, so the use of DOACs in the post-acute phase of ACS may become clearer in the future.⁵⁹

Continue to: Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia

Historically, nonheparin parenteral anticoagulants argatroban, bivalirudin, and fondaparinux were recommended for patients at risk for or who had heparin-induced thrombocytopenia (HIT). Argatroban is the only drug FDA approved for the treatment and prophylaxis of HIT; recommendations for the others are based on guideline recommendations.^23,60,61 The nonheparin parenteral anticoagulants cost between $700 and $1500 per day; therefore most patients with HIT are transitioned to warfarin.⁶² However, protein C and S inhibition and a subsequent prothrombotic state conveyed by warfarin initiation necessitates a minimum 5-day bridge to therapeutic warfarin with a nonheparin parenteral anticoagulant.

In vitro tests show that DOACs do not promote development of HIT antibodies⁶³ or affect platelet activation or aggregation.⁶⁴ A literature summary of DOACs for HIT determined that in 104 patients, all but 1 achieved platelet recovery (defined as > 150,000/mcL) within a median time of 7 days. Therapeutically, DOACs prevented new or recurrent VTE in 102/104 cases (98%), and only 3% of patients experienced significant bleeding events.⁶²

The ACC/AHA recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.

The 2018 ASH guidelines for VTE management in HIT include (with very low certainty of evidence) dabigatran, rivaroxaban, or apixaban for consideration in addition to previously recommended nonheparin parenteral anticoagulants.⁶¹ The dosing of each agent is contingent upon treatment of patients with HIT and an acute thrombosis (HITT) or HIT in the absence of VTE. For patients with HITT, treatment doses for acute VTE should be used for the appropriate duration of therapy (ie, 3 months). Importantly, dabigatran requires a 5-day pretreatment period with a parenteral anticoagulant, so it is not an ideal option. When treating isolated HIT (in the absence of VTE), ASH recommends all agents be dosed twice daily—dabigatran 150 mg twice daily (no 5-day parenteral pretreatment necessary), rivaroxaban 15 mg twice daily, or apixaban 5 mg twice daily—until platelet recovery (≥ 150,000/mcL) is achieved.⁶¹

CORRESPONDENCE
Kevin Schleich, PharmD, BCACP, Departments of Pharmaceutical Care and Family Medicine, University of Iowa, 200 Hawkins Drive, 01102-D PFP, Iowa City, IA, 52242; [email protected]

Moderate to vigorous physical activity (MVPA) is a familiar and established approach to reducing cardiovascular (CV) risk, but it’s often believed that the exercise should be spread out across the week rather than concentrated within a couple of days.

A challenge to that view comes from an observational study of accelerometer-confirmed exercise in almost 90,000 people in their 60s. It suggests, among those who exercised at least 2.5 hours per week, similar CV-risk reductions in “weekend warriors” (WW) who focused their workouts on 1 or 2 days per week and those who spread their weekly exercise over more days.

Researchers compared three patterns of MVPA in their subjects who wore accelerometers on their wrists for 1 week. Active WW subjects obtained at least 2.5 hours of exercise weekly, with at least half the amount completed over 1-2 days; “active regular” subjects achieved that exercise level but not mostly during 1 or 2 days; and those who were “inactive” fell short of 2.5 hours of exercise during the week. The group used a median exercise threshold of 3 hours, 50 minutes in a separate analysis.

The “active” groups, compared with inactive subjects, achieved similar and significant reductions in risk for incident atrial fibrillation (AF), myocardial infarction (MI), stroke, and heart failure (HF) over a median follow-up of 6.3 years at both weekly exercise thresholds, the group reported.

“The take-home [message] is that efforts to optimize activity, even if concentrated within just a day or 2 each week, should be expected to result in improved cardiovascular risk profiles,” lead author Shaan Khurshid, MD, MPH, Massachusetts General Hospital, Boston, said in an interview.

The study was published online in JAMA.

The research “provides novel data on patterns of physical activity accumulation and the risk of developing cardiovascular diseases,” observed Peter Katzmarzyk, PhD, Pennington Biomedical Research Center, Baton Rouge, La., in an interview. He was not involved with the research. Its “marked strengths,” he noted, include a large sample population and “use of accelerometers to measure physical activity levels and patterns.”

Moreover, Dr. Katzmarzyk said, its findings are “important” for showing that physical activity “can be accumulated throughout the week in different ways, which opens up more options for busy people to get their physical activity in.”

Current guidelines from the World Health Organization and the American Heart Association recommend at least 150 minutes of MVPA weekly to lower risk for cardiovascular disease and death, but do not specify an optimal exercise time frame. The U.K. National Health Service recommends MVPA daily or spread evenly over perhaps 4-5 days.

“The weekend warrior pattern has been studied previously, but typically relying on self-reported data, which may be biased, or [in studies] too small to look at specific cardiovascular outcomes,” Dr. Khurshid explained.

In the UK Biobank database, he said, “We saw the opportunity to leverage the largest sample of measured activity to date” to address the question of whether exercise time pattern “affects specific major cardiovascular diseases differently,” Dr. Khurshid said

The primary analysis assessed exercise amount in a week based on the guideline-recommended threshold of at least 2.5 hours; a 3-hour, 50-minutes threshold was used in a secondary analysis. The group assessed multiple thresholds because optimal MVPS levels derived from wrist-based accelerometers are “unclear,” he said.

The sample consisted of 89,573 participants with a mean age 62; slightly more than half (56%) were women. Based on the weekly MVPA threshold of 2.5 hours , the WW, active regular, and inactive groups made up 42.2%, 24%, and 33.7% of the population, respectively.

Compared with the inactive group, the two active groups both showed significant risk reductions for the four clinical outcomes, to similar degrees, in multivariate analysis. The results were similar at the 230-minute weekly exercise threshold for incident AF, MI, and HF but not for stroke.

A version of this article appeared on Medscape.com.

Moderate to vigorous physical activity (MVPA) is a familiar and established approach to reducing cardiovascular (CV) risk, but it’s often believed that the exercise should be spread out across the week rather than concentrated within a couple of days.

A challenge to that view comes from an observational study of accelerometer-confirmed exercise in almost 90,000 people in their 60s. It suggests, among those who exercised at least 2.5 hours per week, similar CV-risk reductions in “weekend warriors” (WW) who focused their workouts on 1 or 2 days per week and those who spread their weekly exercise over more days.

Researchers compared three patterns of MVPA in their subjects who wore accelerometers on their wrists for 1 week. Active WW subjects obtained at least 2.5 hours of exercise weekly, with at least half the amount completed over 1-2 days; “active regular” subjects achieved that exercise level but not mostly during 1 or 2 days; and those who were “inactive” fell short of 2.5 hours of exercise during the week. The group used a median exercise threshold of 3 hours, 50 minutes in a separate analysis.

The “active” groups, compared with inactive subjects, achieved similar and significant reductions in risk for incident atrial fibrillation (AF), myocardial infarction (MI), stroke, and heart failure (HF) over a median follow-up of 6.3 years at both weekly exercise thresholds, the group reported.

“The take-home [message] is that efforts to optimize activity, even if concentrated within just a day or 2 each week, should be expected to result in improved cardiovascular risk profiles,” lead author Shaan Khurshid, MD, MPH, Massachusetts General Hospital, Boston, said in an interview.

The study was published online in JAMA.

The research “provides novel data on patterns of physical activity accumulation and the risk of developing cardiovascular diseases,” observed Peter Katzmarzyk, PhD, Pennington Biomedical Research Center, Baton Rouge, La., in an interview. He was not involved with the research. Its “marked strengths,” he noted, include a large sample population and “use of accelerometers to measure physical activity levels and patterns.”

Moreover, Dr. Katzmarzyk said, its findings are “important” for showing that physical activity “can be accumulated throughout the week in different ways, which opens up more options for busy people to get their physical activity in.”

Current guidelines from the World Health Organization and the American Heart Association recommend at least 150 minutes of MVPA weekly to lower risk for cardiovascular disease and death, but do not specify an optimal exercise time frame. The U.K. National Health Service recommends MVPA daily or spread evenly over perhaps 4-5 days.

“The weekend warrior pattern has been studied previously, but typically relying on self-reported data, which may be biased, or [in studies] too small to look at specific cardiovascular outcomes,” Dr. Khurshid explained.

In the UK Biobank database, he said, “We saw the opportunity to leverage the largest sample of measured activity to date” to address the question of whether exercise time pattern “affects specific major cardiovascular diseases differently,” Dr. Khurshid said

The primary analysis assessed exercise amount in a week based on the guideline-recommended threshold of at least 2.5 hours; a 3-hour, 50-minutes threshold was used in a secondary analysis. The group assessed multiple thresholds because optimal MVPS levels derived from wrist-based accelerometers are “unclear,” he said.

The sample consisted of 89,573 participants with a mean age 62; slightly more than half (56%) were women. Based on the weekly MVPA threshold of 2.5 hours , the WW, active regular, and inactive groups made up 42.2%, 24%, and 33.7% of the population, respectively.

Compared with the inactive group, the two active groups both showed significant risk reductions for the four clinical outcomes, to similar degrees, in multivariate analysis. The results were similar at the 230-minute weekly exercise threshold for incident AF, MI, and HF but not for stroke.

A version of this article appeared on Medscape.com.

Moderate to vigorous physical activity (MVPA) is a familiar and established approach to reducing cardiovascular (CV) risk, but it’s often believed that the exercise should be spread out across the week rather than concentrated within a couple of days.

A challenge to that view comes from an observational study of accelerometer-confirmed exercise in almost 90,000 people in their 60s. It suggests, among those who exercised at least 2.5 hours per week, similar CV-risk reductions in “weekend warriors” (WW) who focused their workouts on 1 or 2 days per week and those who spread their weekly exercise over more days.

Researchers compared three patterns of MVPA in their subjects who wore accelerometers on their wrists for 1 week. Active WW subjects obtained at least 2.5 hours of exercise weekly, with at least half the amount completed over 1-2 days; “active regular” subjects achieved that exercise level but not mostly during 1 or 2 days; and those who were “inactive” fell short of 2.5 hours of exercise during the week. The group used a median exercise threshold of 3 hours, 50 minutes in a separate analysis.

The “active” groups, compared with inactive subjects, achieved similar and significant reductions in risk for incident atrial fibrillation (AF), myocardial infarction (MI), stroke, and heart failure (HF) over a median follow-up of 6.3 years at both weekly exercise thresholds, the group reported.

“The take-home [message] is that efforts to optimize activity, even if concentrated within just a day or 2 each week, should be expected to result in improved cardiovascular risk profiles,” lead author Shaan Khurshid, MD, MPH, Massachusetts General Hospital, Boston, said in an interview.

The study was published online in JAMA.

The research “provides novel data on patterns of physical activity accumulation and the risk of developing cardiovascular diseases,” observed Peter Katzmarzyk, PhD, Pennington Biomedical Research Center, Baton Rouge, La., in an interview. He was not involved with the research. Its “marked strengths,” he noted, include a large sample population and “use of accelerometers to measure physical activity levels and patterns.”

Moreover, Dr. Katzmarzyk said, its findings are “important” for showing that physical activity “can be accumulated throughout the week in different ways, which opens up more options for busy people to get their physical activity in.”

Current guidelines from the World Health Organization and the American Heart Association recommend at least 150 minutes of MVPA weekly to lower risk for cardiovascular disease and death, but do not specify an optimal exercise time frame. The U.K. National Health Service recommends MVPA daily or spread evenly over perhaps 4-5 days.

“The weekend warrior pattern has been studied previously, but typically relying on self-reported data, which may be biased, or [in studies] too small to look at specific cardiovascular outcomes,” Dr. Khurshid explained.

In the UK Biobank database, he said, “We saw the opportunity to leverage the largest sample of measured activity to date” to address the question of whether exercise time pattern “affects specific major cardiovascular diseases differently,” Dr. Khurshid said

The primary analysis assessed exercise amount in a week based on the guideline-recommended threshold of at least 2.5 hours; a 3-hour, 50-minutes threshold was used in a secondary analysis. The group assessed multiple thresholds because optimal MVPS levels derived from wrist-based accelerometers are “unclear,” he said.

The sample consisted of 89,573 participants with a mean age 62; slightly more than half (56%) were women. Based on the weekly MVPA threshold of 2.5 hours , the WW, active regular, and inactive groups made up 42.2%, 24%, and 33.7% of the population, respectively.

Compared with the inactive group, the two active groups both showed significant risk reductions for the four clinical outcomes, to similar degrees, in multivariate analysis. The results were similar at the 230-minute weekly exercise threshold for incident AF, MI, and HF but not for stroke.

A version of this article appeared on Medscape.com.

The Committee for Medicinal Products for Human Use of the European Medicines Agency has granted a positive opinion for ritlecitinib, a once-daily 50-mg oral treatment for severe alopecia areata, paving the way for possible marketing authorization of the drug in the European Union for individuals 12 years of age and older. A final decision is expected in the coming months.

The development, which was announced by the manufacturer, Pfizer, on July 21, 2023, follows approval of ritlecitinib (Litfulo) for the treatment of severe alopecia areata in adults and adolescents 12 years and older by the Food and Drug Administration and the Japanese Ministry of Health, Labour, and Welfare in June 2023. According to a press release from Pfizer, submissions to other regulatory agencies for the use of ritlecitinib in alopecia areata are ongoing.

The Marketing Authorization Application for ritlecitinib was based on results from a randomized, placebo-controlled, double-blind ALLEGRO Phase 2b/3 study.






 

The Committee for Medicinal Products for Human Use of the European Medicines Agency has granted a positive opinion for ritlecitinib, a once-daily 50-mg oral treatment for severe alopecia areata, paving the way for possible marketing authorization of the drug in the European Union for individuals 12 years of age and older. A final decision is expected in the coming months.

The development, which was announced by the manufacturer, Pfizer, on July 21, 2023, follows approval of ritlecitinib (Litfulo) for the treatment of severe alopecia areata in adults and adolescents 12 years and older by the Food and Drug Administration and the Japanese Ministry of Health, Labour, and Welfare in June 2023. According to a press release from Pfizer, submissions to other regulatory agencies for the use of ritlecitinib in alopecia areata are ongoing.

The Marketing Authorization Application for ritlecitinib was based on results from a randomized, placebo-controlled, double-blind ALLEGRO Phase 2b/3 study.






 

The Committee for Medicinal Products for Human Use of the European Medicines Agency has granted a positive opinion for ritlecitinib, a once-daily 50-mg oral treatment for severe alopecia areata, paving the way for possible marketing authorization of the drug in the European Union for individuals 12 years of age and older. A final decision is expected in the coming months.

The development, which was announced by the manufacturer, Pfizer, on July 21, 2023, follows approval of ritlecitinib (Litfulo) for the treatment of severe alopecia areata in adults and adolescents 12 years and older by the Food and Drug Administration and the Japanese Ministry of Health, Labour, and Welfare in June 2023. According to a press release from Pfizer, submissions to other regulatory agencies for the use of ritlecitinib in alopecia areata are ongoing.

The Marketing Authorization Application for ritlecitinib was based on results from a randomized, placebo-controlled, double-blind ALLEGRO Phase 2b/3 study.






 

Among U.S. high school students, males and non-Whites are at greatest risk for not using sunscreen, a cornerstone of skin cancer prevention, according to results from a systematic review.

“We know that skin cancer is one of the most common malignancies in the world, and sun protection methods such as sunscreen make it highly preventable,” first author Carly R. Stevens, a student at Tulane University, New Orleans, said in an interview. “This study demonstrates the adolescent populations that are most vulnerable to sun damage and how we can help mitigate their risk of developing skin cancer through education methods, such as Sun Protection Outreach Teaching by Students.”  

Ms. Stevens and coauthors presented the findings during a poster session at the annual meeting of the Society for Pediatric Dermatology.

To investigate predictors of sunscreen use among high school students, they searched PubMed, Embase, and Web of Science using the terms (“sunscreen” or “SPF” or “sun protection”) and (“high school” or “teen” or “teenager” or “adolescent”) and limited the analysis to English studies reporting data on sunscreen use in U.S. high school students up to November 2021.

A total of 20 studies were included in the final review. The study populations ranged in number from 208 to 24,645. Of 11 studies that examined gender, all showed increased sunscreen use in females compared with males. Of five studies that examined age, all showed increased sunscreen use in younger adolescents, compared with their older counterparts.

Of four studies that examined the role of ethnicity on sunscreen use, White students were more likely to use sunscreen, compared with their peers of other ethnicities. “This may be due to perceived sun sensitivity, as [these four studies] also showed increased sunscreen use in populations that believed were more susceptible to sun damage,” the researchers wrote in their abstract.

Wavebreakmedia Ltd/Thinkstock

In other findings, two studies that examined perceived self-efficacy concluded that higher levels of sunscreen use correlated with higher self-efficacy, while four studies concluded that high school students were more likely to use sunscreen if their parents encouraged them the wear it or if the parent used it themselves.

“With 40%-50% of ultraviolet damage being done before the age of 20, it’s crucial that we find ways to educate adolescents on the importance of sunscreen use and target those populations who were found to rarely use sunscreen in our study,” Ms. Stevens said.

In one outreach program, Sun Protection Outreach Teaching by Students (SPOTS), medical students visit middle and high schools to educate them about the importance of practicing sun protection. The program began as a collaboration between Saint Louis University and Washington University in St. Louis, but has expanded nationwide. Ms. Stevens described SPOTS as “a great way for medical students to present the information to middle and high school students in a way that is engaging and interactive.”

The researchers reported having no disclosures.

Among U.S. high school students, males and non-Whites are at greatest risk for not using sunscreen, a cornerstone of skin cancer prevention, according to results from a systematic review.

“We know that skin cancer is one of the most common malignancies in the world, and sun protection methods such as sunscreen make it highly preventable,” first author Carly R. Stevens, a student at Tulane University, New Orleans, said in an interview. “This study demonstrates the adolescent populations that are most vulnerable to sun damage and how we can help mitigate their risk of developing skin cancer through education methods, such as Sun Protection Outreach Teaching by Students.”  

Ms. Stevens and coauthors presented the findings during a poster session at the annual meeting of the Society for Pediatric Dermatology.

To investigate predictors of sunscreen use among high school students, they searched PubMed, Embase, and Web of Science using the terms (“sunscreen” or “SPF” or “sun protection”) and (“high school” or “teen” or “teenager” or “adolescent”) and limited the analysis to English studies reporting data on sunscreen use in U.S. high school students up to November 2021.

A total of 20 studies were included in the final review. The study populations ranged in number from 208 to 24,645. Of 11 studies that examined gender, all showed increased sunscreen use in females compared with males. Of five studies that examined age, all showed increased sunscreen use in younger adolescents, compared with their older counterparts.

Of four studies that examined the role of ethnicity on sunscreen use, White students were more likely to use sunscreen, compared with their peers of other ethnicities. “This may be due to perceived sun sensitivity, as [these four studies] also showed increased sunscreen use in populations that believed were more susceptible to sun damage,” the researchers wrote in their abstract.

Wavebreakmedia Ltd/Thinkstock

In other findings, two studies that examined perceived self-efficacy concluded that higher levels of sunscreen use correlated with higher self-efficacy, while four studies concluded that high school students were more likely to use sunscreen if their parents encouraged them the wear it or if the parent used it themselves.

“With 40%-50% of ultraviolet damage being done before the age of 20, it’s crucial that we find ways to educate adolescents on the importance of sunscreen use and target those populations who were found to rarely use sunscreen in our study,” Ms. Stevens said.

In one outreach program, Sun Protection Outreach Teaching by Students (SPOTS), medical students visit middle and high schools to educate them about the importance of practicing sun protection. The program began as a collaboration between Saint Louis University and Washington University in St. Louis, but has expanded nationwide. Ms. Stevens described SPOTS as “a great way for medical students to present the information to middle and high school students in a way that is engaging and interactive.”

The researchers reported having no disclosures.

Among U.S. high school students, males and non-Whites are at greatest risk for not using sunscreen, a cornerstone of skin cancer prevention, according to results from a systematic review.

“We know that skin cancer is one of the most common malignancies in the world, and sun protection methods such as sunscreen make it highly preventable,” first author Carly R. Stevens, a student at Tulane University, New Orleans, said in an interview. “This study demonstrates the adolescent populations that are most vulnerable to sun damage and how we can help mitigate their risk of developing skin cancer through education methods, such as Sun Protection Outreach Teaching by Students.”  

Ms. Stevens and coauthors presented the findings during a poster session at the annual meeting of the Society for Pediatric Dermatology.

To investigate predictors of sunscreen use among high school students, they searched PubMed, Embase, and Web of Science using the terms (“sunscreen” or “SPF” or “sun protection”) and (“high school” or “teen” or “teenager” or “adolescent”) and limited the analysis to English studies reporting data on sunscreen use in U.S. high school students up to November 2021.

A total of 20 studies were included in the final review. The study populations ranged in number from 208 to 24,645. Of 11 studies that examined gender, all showed increased sunscreen use in females compared with males. Of five studies that examined age, all showed increased sunscreen use in younger adolescents, compared with their older counterparts.

Of four studies that examined the role of ethnicity on sunscreen use, White students were more likely to use sunscreen, compared with their peers of other ethnicities. “This may be due to perceived sun sensitivity, as [these four studies] also showed increased sunscreen use in populations that believed were more susceptible to sun damage,” the researchers wrote in their abstract.

Wavebreakmedia Ltd/Thinkstock

In other findings, two studies that examined perceived self-efficacy concluded that higher levels of sunscreen use correlated with higher self-efficacy, while four studies concluded that high school students were more likely to use sunscreen if their parents encouraged them the wear it or if the parent used it themselves.

“With 40%-50% of ultraviolet damage being done before the age of 20, it’s crucial that we find ways to educate adolescents on the importance of sunscreen use and target those populations who were found to rarely use sunscreen in our study,” Ms. Stevens said.

In one outreach program, Sun Protection Outreach Teaching by Students (SPOTS), medical students visit middle and high schools to educate them about the importance of practicing sun protection. The program began as a collaboration between Saint Louis University and Washington University in St. Louis, but has expanded nationwide. Ms. Stevens described SPOTS as “a great way for medical students to present the information to middle and high school students in a way that is engaging and interactive.”

The researchers reported having no disclosures.

ASHEVILLE, N.C. – Treating atopic dermatitis (AD) in most children­ – and working with parents – might be less dependent on the next, even better therapy than considering facets of poor response and dissatisfaction with treatment, according to a three-member expert panel mulling over strategies at the annual meeting of the Society for Pediatric Dermatology.

In introductory remarks, the three panelists briefly addressed different aspects for controlling AD, including drugs in the pipeline, the potential value of alternative therapies, and whom to blame when compliance is poor.

Northwestern Feinberg School of Medicine

Wake Forest University School of Medicine

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

ASHEVILLE, N.C. – Treating atopic dermatitis (AD) in most children­ – and working with parents – might be less dependent on the next, even better therapy than considering facets of poor response and dissatisfaction with treatment, according to a three-member expert panel mulling over strategies at the annual meeting of the Society for Pediatric Dermatology.

In introductory remarks, the three panelists briefly addressed different aspects for controlling AD, including drugs in the pipeline, the potential value of alternative therapies, and whom to blame when compliance is poor.

Northwestern Feinberg School of Medicine

Wake Forest University School of Medicine

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

ASHEVILLE, N.C. – Treating atopic dermatitis (AD) in most children­ – and working with parents – might be less dependent on the next, even better therapy than considering facets of poor response and dissatisfaction with treatment, according to a three-member expert panel mulling over strategies at the annual meeting of the Society for Pediatric Dermatology.

In introductory remarks, the three panelists briefly addressed different aspects for controlling AD, including drugs in the pipeline, the potential value of alternative therapies, and whom to blame when compliance is poor.

Northwestern Feinberg School of Medicine

Wake Forest University School of Medicine

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

SAN DIEGO – Although the glucagonlike peptide–1 (GLP-1) receptor agonists, such as liraglutide and semaglutide, have been revolutionary advances for the treatment of obesity, the cost-effectiveness of these agents for treating both obesity and type 2 diabetes remains uncertain based on published analyses.

But potential future changes in the cost-effectiveness dynamics of GLP-1 agonists could tip the balance in their favor. These include lower drug prices and a more nuanced and inclusive assessment of cost-effectiveness that considers broader consequences of treatment with GLP-1 agonists that are not traditionally included in such analyses.

Costs to people with obesity that are generally not part of cost-effectiveness calculations include pain, disability, depression, and bias that affect employment, Carol H. Wysham, MD, said at the recent scientific sessions of the American Diabetes Association.

Other costs to society left out of conventional calculations are items such as the incremental cost for fuel to transport a heavier population and the carbon-footprint costs for the production and transportation of the excess food produced to feed an over-fed population, added Dr. Wysham, an endocrinologist with MultiCare and the Rockwood Clinic in Spokane, Wash.
 

Analyses should include ‘things we don’t often think about’

“The impact of living with obesity is much greater than what we traditionally calculate in health economics,” commented Naveed Sattar, PhD, speaking from the floor during the session.

“Patient happiness and self-esteem are hard to measure and capture as cost impacts. We need to also add carbon dioxide effects and transportation costs, and governments are starting to get wise to this. How to run proper health economics analyses is the key question; we need to do better than what we currently do,” said Dr. Sattar, a professor of metabolic medicine at the University of Glasgow.

Dr. Sattar is lead author of a recent analysis that highlights the overwhelming importance of improved weight management in adults as they age to reduce their risk of developing a broad range of chronic disorders.

“Most chronic conditions are, to differing extents, caused or exacerbated by excess adiposity,” was a conclusion of his report.

“It’s important to include the costs to society, including things we don’t often think about. No one has ever done a cost analysis that includes all the factors” cited by Dr. Wysham, said Irl B. Hirsch, MD, another speaker at the session. “No one includes obstructive sleep apnea, degenerative arthritis, and the downstream effects of a high body mass index.”

The GLP-1 agonists “are great” for both weight loss and glycemic control, said Dr. Hirsch, an endocrinologist and professor at the University of Washington, Seattle. “We can’t afford not to use them. These agents have been transformational.”
 

U.S. has the highest drug costs

Another key factor driving cost-effectiveness is, of course, the relatively high cost of the agents in the class, especially in the United States. Dr. Hirsch cited a recently published report in Obesity that quoted monthly U.S. costs of $804 for weekly 2.4-mg injections of semaglutide (Wegovy) and $1418 for daily 3.0-mg injections of liraglutide (Saxenda). Highlighting the relatively high cost of medications in the United States, the report cited a monthly price tag of $95 for the same semaglutide regimen in Turkey and a monthly cost of $252 for the same liraglutide regimen in Norway.

U.S. prices for agents in this class may start to deflate as soon as 2024, when one or more generic versions of liraglutide are expected, following expiration of the U.S. patent later in 2023, Dr. Wysham said.

Another pending trigger for lower costs may be the possible decision by the World Health Organization to designate liraglutide an “essential medicine” later in 2023, she noted. The WHO received an application for this designation from four U.S. clinicians and is considering it as part of its planned 2023 update to the WHO’s Essential Medicines List. Dr. Wysham predicted this designation would “press international pharmaceutical companies to produce [liraglutide] at a much lower cost.”

“I’m not saying that drug companies should not profit, but they should not do it on the backs of patients,” Dr. Wysham declared. “What do we measure by ‘cost-effectiveness?’ There are so many complications of obesity. For patients with diabetes and obesity we need to look for a little different economic policy.”

Dr. Wysham has reported being an adviser to Abbott and CeQur and receiving research funding from Eli Lilly and Novo Nordisk. Dr. Hirsch has reported being a consultant for Abbott, Embecta, and Hagar, and receiving research funding from Dexcom and Insulet. Dr. Sattar has reported receiving consulting fees or speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, MSD, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi.

A version of this article appeared on Medscape.com.

SAN DIEGO – Although the glucagonlike peptide–1 (GLP-1) receptor agonists, such as liraglutide and semaglutide, have been revolutionary advances for the treatment of obesity, the cost-effectiveness of these agents for treating both obesity and type 2 diabetes remains uncertain based on published analyses.

But potential future changes in the cost-effectiveness dynamics of GLP-1 agonists could tip the balance in their favor. These include lower drug prices and a more nuanced and inclusive assessment of cost-effectiveness that considers broader consequences of treatment with GLP-1 agonists that are not traditionally included in such analyses.

Costs to people with obesity that are generally not part of cost-effectiveness calculations include pain, disability, depression, and bias that affect employment, Carol H. Wysham, MD, said at the recent scientific sessions of the American Diabetes Association.

Other costs to society left out of conventional calculations are items such as the incremental cost for fuel to transport a heavier population and the carbon-footprint costs for the production and transportation of the excess food produced to feed an over-fed population, added Dr. Wysham, an endocrinologist with MultiCare and the Rockwood Clinic in Spokane, Wash.
 

Analyses should include ‘things we don’t often think about’

“The impact of living with obesity is much greater than what we traditionally calculate in health economics,” commented Naveed Sattar, PhD, speaking from the floor during the session.

“Patient happiness and self-esteem are hard to measure and capture as cost impacts. We need to also add carbon dioxide effects and transportation costs, and governments are starting to get wise to this. How to run proper health economics analyses is the key question; we need to do better than what we currently do,” said Dr. Sattar, a professor of metabolic medicine at the University of Glasgow.

Dr. Sattar is lead author of a recent analysis that highlights the overwhelming importance of improved weight management in adults as they age to reduce their risk of developing a broad range of chronic disorders.

“Most chronic conditions are, to differing extents, caused or exacerbated by excess adiposity,” was a conclusion of his report.

“It’s important to include the costs to society, including things we don’t often think about. No one has ever done a cost analysis that includes all the factors” cited by Dr. Wysham, said Irl B. Hirsch, MD, another speaker at the session. “No one includes obstructive sleep apnea, degenerative arthritis, and the downstream effects of a high body mass index.”

The GLP-1 agonists “are great” for both weight loss and glycemic control, said Dr. Hirsch, an endocrinologist and professor at the University of Washington, Seattle. “We can’t afford not to use them. These agents have been transformational.”
 

U.S. has the highest drug costs

Another key factor driving cost-effectiveness is, of course, the relatively high cost of the agents in the class, especially in the United States. Dr. Hirsch cited a recently published report in Obesity that quoted monthly U.S. costs of $804 for weekly 2.4-mg injections of semaglutide (Wegovy) and $1418 for daily 3.0-mg injections of liraglutide (Saxenda). Highlighting the relatively high cost of medications in the United States, the report cited a monthly price tag of $95 for the same semaglutide regimen in Turkey and a monthly cost of $252 for the same liraglutide regimen in Norway.

U.S. prices for agents in this class may start to deflate as soon as 2024, when one or more generic versions of liraglutide are expected, following expiration of the U.S. patent later in 2023, Dr. Wysham said.

Another pending trigger for lower costs may be the possible decision by the World Health Organization to designate liraglutide an “essential medicine” later in 2023, she noted. The WHO received an application for this designation from four U.S. clinicians and is considering it as part of its planned 2023 update to the WHO’s Essential Medicines List. Dr. Wysham predicted this designation would “press international pharmaceutical companies to produce [liraglutide] at a much lower cost.”

“I’m not saying that drug companies should not profit, but they should not do it on the backs of patients,” Dr. Wysham declared. “What do we measure by ‘cost-effectiveness?’ There are so many complications of obesity. For patients with diabetes and obesity we need to look for a little different economic policy.”

Dr. Wysham has reported being an adviser to Abbott and CeQur and receiving research funding from Eli Lilly and Novo Nordisk. Dr. Hirsch has reported being a consultant for Abbott, Embecta, and Hagar, and receiving research funding from Dexcom and Insulet. Dr. Sattar has reported receiving consulting fees or speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, MSD, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi.

A version of this article appeared on Medscape.com.

SAN DIEGO – Although the glucagonlike peptide–1 (GLP-1) receptor agonists, such as liraglutide and semaglutide, have been revolutionary advances for the treatment of obesity, the cost-effectiveness of these agents for treating both obesity and type 2 diabetes remains uncertain based on published analyses.

But potential future changes in the cost-effectiveness dynamics of GLP-1 agonists could tip the balance in their favor. These include lower drug prices and a more nuanced and inclusive assessment of cost-effectiveness that considers broader consequences of treatment with GLP-1 agonists that are not traditionally included in such analyses.

Costs to people with obesity that are generally not part of cost-effectiveness calculations include pain, disability, depression, and bias that affect employment, Carol H. Wysham, MD, said at the recent scientific sessions of the American Diabetes Association.

Other costs to society left out of conventional calculations are items such as the incremental cost for fuel to transport a heavier population and the carbon-footprint costs for the production and transportation of the excess food produced to feed an over-fed population, added Dr. Wysham, an endocrinologist with MultiCare and the Rockwood Clinic in Spokane, Wash.
 

Analyses should include ‘things we don’t often think about’

“The impact of living with obesity is much greater than what we traditionally calculate in health economics,” commented Naveed Sattar, PhD, speaking from the floor during the session.

“Patient happiness and self-esteem are hard to measure and capture as cost impacts. We need to also add carbon dioxide effects and transportation costs, and governments are starting to get wise to this. How to run proper health economics analyses is the key question; we need to do better than what we currently do,” said Dr. Sattar, a professor of metabolic medicine at the University of Glasgow.

Dr. Sattar is lead author of a recent analysis that highlights the overwhelming importance of improved weight management in adults as they age to reduce their risk of developing a broad range of chronic disorders.

“Most chronic conditions are, to differing extents, caused or exacerbated by excess adiposity,” was a conclusion of his report.

“It’s important to include the costs to society, including things we don’t often think about. No one has ever done a cost analysis that includes all the factors” cited by Dr. Wysham, said Irl B. Hirsch, MD, another speaker at the session. “No one includes obstructive sleep apnea, degenerative arthritis, and the downstream effects of a high body mass index.”

The GLP-1 agonists “are great” for both weight loss and glycemic control, said Dr. Hirsch, an endocrinologist and professor at the University of Washington, Seattle. “We can’t afford not to use them. These agents have been transformational.”
 

U.S. has the highest drug costs

Another key factor driving cost-effectiveness is, of course, the relatively high cost of the agents in the class, especially in the United States. Dr. Hirsch cited a recently published report in Obesity that quoted monthly U.S. costs of $804 for weekly 2.4-mg injections of semaglutide (Wegovy) and $1418 for daily 3.0-mg injections of liraglutide (Saxenda). Highlighting the relatively high cost of medications in the United States, the report cited a monthly price tag of $95 for the same semaglutide regimen in Turkey and a monthly cost of $252 for the same liraglutide regimen in Norway.

U.S. prices for agents in this class may start to deflate as soon as 2024, when one or more generic versions of liraglutide are expected, following expiration of the U.S. patent later in 2023, Dr. Wysham said.

Another pending trigger for lower costs may be the possible decision by the World Health Organization to designate liraglutide an “essential medicine” later in 2023, she noted. The WHO received an application for this designation from four U.S. clinicians and is considering it as part of its planned 2023 update to the WHO’s Essential Medicines List. Dr. Wysham predicted this designation would “press international pharmaceutical companies to produce [liraglutide] at a much lower cost.”

“I’m not saying that drug companies should not profit, but they should not do it on the backs of patients,” Dr. Wysham declared. “What do we measure by ‘cost-effectiveness?’ There are so many complications of obesity. For patients with diabetes and obesity we need to look for a little different economic policy.”

Dr. Wysham has reported being an adviser to Abbott and CeQur and receiving research funding from Eli Lilly and Novo Nordisk. Dr. Hirsch has reported being a consultant for Abbott, Embecta, and Hagar, and receiving research funding from Dexcom and Insulet. Dr. Sattar has reported receiving consulting fees or speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, MSD, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi.

A version of this article appeared on Medscape.com.

The presence of a positive fungal culture in patients with bronchiectasis does not appear to correlate with disease severity or any increased risk of an adverse outcome, according to data pulled from the Bronchiectasis and NTM Registry and presented at the 6th World Bronchiectasis & NTM Conference.

“The question we were asking is whether there is some signal that suggests we need to take care of these patients differently, and the answer is no,” reported Pamela J. McShane, MD, a pulmonologist on the faculty at the University of Texas Health Science Center at Tyler.

When compared for outcome over time, those with a positive fungal culture at initial evaluation did not have more exacerbations, more hospitalizations, or other signs of a more severe disease or more complex course than did those without a positive fungal culture.

When fungal infections are detected in an initial microbiologic evaluation of patients with bronchiectasis or other lung diseases, first-line clinicians generally assume that coverage is needed. Dr. McShane noted that many of the patients referred to her with bronchiectasis and a positive fungal culture were already on an antifungal.

These data are not supportive of treatment in the absence of fungal-related complications. Dr. McShane suggested they even raise questions about the value of culturing beyond bacterial pathogens in the absence of suspicion that fungal organisms are playing a role in symptoms. She cautioned, however, that more studies specifically studying this possibility are needed.
 

Study details

The data were drawn in December 2022 from the U.S.-based Bronchiectasis and NTM Registry, which at that time had 22 participating sites. Of the more than 5,000 patients enrolled, the study looked at 2,230 after several exclusions, such as a diagnosis of allergic bronchopulmonary aspergillosis (ABPA).

Of these 2,230 patients, 949 had a fungal infection at the time of diagnosis and 1,281 did not. Those with a fungal infection were further subdivided into those with an aspergillosis (331 patients) and those with a nonaspergillosis fungal infection (751 patients). The total of these two numbers is greater than the total number of fungal infections because these were not mutually exclusive.

At enrollment into the registry, there were no statistical differences between groups for age. Some statistical differences were observed among groups stratified by race, but Dr. McShane doubted that these were clinically significant with the exception of a potential disparity among Asians that might deserve further analysis.
 

Infection results

Of clinical features evaluated for their association with fungal infection, there was no correlation with either body mass index or history of asthma. Eosinophilia was associated significantly with positive fungal cultures.

Baseline FEV₁ was slightly lower among those with a positive fungal culture even if the difference was highly significant (P = .0006). Again, Dr. McShane questioned the clinical significance of values that varied by only a few percentage points, even though she was willing to acknowledge that higher is always preferable to a lower FEV₁.

In the context of other pathogens, “generally speaking, those with a positive bacterial culture were more likely to have a fungal infection,” Dr. McShane reported, although there was some variation when looking at pathogenicity of the bacteria and other variables.

“Whether this [higher rate of fungal infection] just involves the environment or our antibiotics are driving the opportunity to permit the fungi to exist, we do not have the answer,” she added.

Nontuberculosis mycobacteria (NTM) infection was similarly represented in those with or without a fungal infection, according to Dr. McShane. Noting the high use of antibiotics in an NTM population, Dr. McShane conceded that this challenges the theory that antibiotic use is driving the risk of fungal infection, but these are what the data say.  

Steroid use was associated with a statistically significant risk of fungal infection, but Dr. McShane said it is unclear whether steroid use drives the risk or is an epiphenomenon.

“We looked at this a lot of different ways: oral vs. inhaled and oral vs. inhaled and oral, and it did not make much difference. Generally speaking, the fungal cultures were more likely to be positive in patients on any kind of steroid,” she said.

Finally, with the exception of the slightly lower FEV₁ in patients with fungal infections, Dr. McShane said that there was no discernible relationship between the presence of a fungal infection and severity of bronchiectasis.

Because of this evidence, Dr. McShane concluded that the presence of fungus in the culture of patients with bronchiectasis does not appear to correlate with outcome or severity. Since completing the study, she said she is now using these data to reassure patients who have a positive fungal culture.

While these data do not affect the need to diagnosis fungal infections in patients who are not responding typically to therapy or otherwise have an abnormal course of bronchiectasis, raising suspicion that fungal infection is participating in the disease course, the data provide a basis for questioning whether routine cultures are needed, according to the discussion that followed Dr. McShane’s presentation.
 

Expert opinion

Several of the experts at the presentation provided an opinion. Some reported that they would continue to order fungal cultures on a routine basis, while others said that they now, on the basis of these data, plan to order cultures only at the first visit or when fungal infection is suspected of exacerbating the disease.

Of this latter group, which seemed to be dominant, Juzar Ali, MD, professor of medicine, Louisiana State University, New Orleans, said that he has not been ordering fungal cultures on every visit. Rather, he has been doing so selectively. Examples include those who are on steroids or those with an unusual pattern of exacerbations.

“The value of these data is that they have now provided some data to support this approach,” Dr. Ali said in an interview. Noting that this is the first large study to address this question in a systematic way, he considers this to be a valuable contribution for approaching a common clinical issue.

Dr. McShane reports no relevant financial relationships. Dr. Ali reports a financial relationship with Insmed.
 

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

The presence of a positive fungal culture in patients with bronchiectasis does not appear to correlate with disease severity or any increased risk of an adverse outcome, according to data pulled from the Bronchiectasis and NTM Registry and presented at the 6th World Bronchiectasis & NTM Conference.

“The question we were asking is whether there is some signal that suggests we need to take care of these patients differently, and the answer is no,” reported Pamela J. McShane, MD, a pulmonologist on the faculty at the University of Texas Health Science Center at Tyler.

When compared for outcome over time, those with a positive fungal culture at initial evaluation did not have more exacerbations, more hospitalizations, or other signs of a more severe disease or more complex course than did those without a positive fungal culture.

When fungal infections are detected in an initial microbiologic evaluation of patients with bronchiectasis or other lung diseases, first-line clinicians generally assume that coverage is needed. Dr. McShane noted that many of the patients referred to her with bronchiectasis and a positive fungal culture were already on an antifungal.

These data are not supportive of treatment in the absence of fungal-related complications. Dr. McShane suggested they even raise questions about the value of culturing beyond bacterial pathogens in the absence of suspicion that fungal organisms are playing a role in symptoms. She cautioned, however, that more studies specifically studying this possibility are needed.
 

Study details

The data were drawn in December 2022 from the U.S.-based Bronchiectasis and NTM Registry, which at that time had 22 participating sites. Of the more than 5,000 patients enrolled, the study looked at 2,230 after several exclusions, such as a diagnosis of allergic bronchopulmonary aspergillosis (ABPA).

Of these 2,230 patients, 949 had a fungal infection at the time of diagnosis and 1,281 did not. Those with a fungal infection were further subdivided into those with an aspergillosis (331 patients) and those with a nonaspergillosis fungal infection (751 patients). The total of these two numbers is greater than the total number of fungal infections because these were not mutually exclusive.

At enrollment into the registry, there were no statistical differences between groups for age. Some statistical differences were observed among groups stratified by race, but Dr. McShane doubted that these were clinically significant with the exception of a potential disparity among Asians that might deserve further analysis.
 

Infection results

Of clinical features evaluated for their association with fungal infection, there was no correlation with either body mass index or history of asthma. Eosinophilia was associated significantly with positive fungal cultures.

Baseline FEV₁ was slightly lower among those with a positive fungal culture even if the difference was highly significant (P = .0006). Again, Dr. McShane questioned the clinical significance of values that varied by only a few percentage points, even though she was willing to acknowledge that higher is always preferable to a lower FEV₁.

In the context of other pathogens, “generally speaking, those with a positive bacterial culture were more likely to have a fungal infection,” Dr. McShane reported, although there was some variation when looking at pathogenicity of the bacteria and other variables.

“Whether this [higher rate of fungal infection] just involves the environment or our antibiotics are driving the opportunity to permit the fungi to exist, we do not have the answer,” she added.

Nontuberculosis mycobacteria (NTM) infection was similarly represented in those with or without a fungal infection, according to Dr. McShane. Noting the high use of antibiotics in an NTM population, Dr. McShane conceded that this challenges the theory that antibiotic use is driving the risk of fungal infection, but these are what the data say.  

Steroid use was associated with a statistically significant risk of fungal infection, but Dr. McShane said it is unclear whether steroid use drives the risk or is an epiphenomenon.

“We looked at this a lot of different ways: oral vs. inhaled and oral vs. inhaled and oral, and it did not make much difference. Generally speaking, the fungal cultures were more likely to be positive in patients on any kind of steroid,” she said.

Finally, with the exception of the slightly lower FEV₁ in patients with fungal infections, Dr. McShane said that there was no discernible relationship between the presence of a fungal infection and severity of bronchiectasis.

Because of this evidence, Dr. McShane concluded that the presence of fungus in the culture of patients with bronchiectasis does not appear to correlate with outcome or severity. Since completing the study, she said she is now using these data to reassure patients who have a positive fungal culture.

While these data do not affect the need to diagnosis fungal infections in patients who are not responding typically to therapy or otherwise have an abnormal course of bronchiectasis, raising suspicion that fungal infection is participating in the disease course, the data provide a basis for questioning whether routine cultures are needed, according to the discussion that followed Dr. McShane’s presentation.
 

Expert opinion

Several of the experts at the presentation provided an opinion. Some reported that they would continue to order fungal cultures on a routine basis, while others said that they now, on the basis of these data, plan to order cultures only at the first visit or when fungal infection is suspected of exacerbating the disease.

Of this latter group, which seemed to be dominant, Juzar Ali, MD, professor of medicine, Louisiana State University, New Orleans, said that he has not been ordering fungal cultures on every visit. Rather, he has been doing so selectively. Examples include those who are on steroids or those with an unusual pattern of exacerbations.

“The value of these data is that they have now provided some data to support this approach,” Dr. Ali said in an interview. Noting that this is the first large study to address this question in a systematic way, he considers this to be a valuable contribution for approaching a common clinical issue.

Dr. McShane reports no relevant financial relationships. Dr. Ali reports a financial relationship with Insmed.
 

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

The presence of a positive fungal culture in patients with bronchiectasis does not appear to correlate with disease severity or any increased risk of an adverse outcome, according to data pulled from the Bronchiectasis and NTM Registry and presented at the 6th World Bronchiectasis & NTM Conference.

“The question we were asking is whether there is some signal that suggests we need to take care of these patients differently, and the answer is no,” reported Pamela J. McShane, MD, a pulmonologist on the faculty at the University of Texas Health Science Center at Tyler.

When compared for outcome over time, those with a positive fungal culture at initial evaluation did not have more exacerbations, more hospitalizations, or other signs of a more severe disease or more complex course than did those without a positive fungal culture.

When fungal infections are detected in an initial microbiologic evaluation of patients with bronchiectasis or other lung diseases, first-line clinicians generally assume that coverage is needed. Dr. McShane noted that many of the patients referred to her with bronchiectasis and a positive fungal culture were already on an antifungal.

These data are not supportive of treatment in the absence of fungal-related complications. Dr. McShane suggested they even raise questions about the value of culturing beyond bacterial pathogens in the absence of suspicion that fungal organisms are playing a role in symptoms. She cautioned, however, that more studies specifically studying this possibility are needed.
 

Study details

The data were drawn in December 2022 from the U.S.-based Bronchiectasis and NTM Registry, which at that time had 22 participating sites. Of the more than 5,000 patients enrolled, the study looked at 2,230 after several exclusions, such as a diagnosis of allergic bronchopulmonary aspergillosis (ABPA).

Of these 2,230 patients, 949 had a fungal infection at the time of diagnosis and 1,281 did not. Those with a fungal infection were further subdivided into those with an aspergillosis (331 patients) and those with a nonaspergillosis fungal infection (751 patients). The total of these two numbers is greater than the total number of fungal infections because these were not mutually exclusive.

At enrollment into the registry, there were no statistical differences between groups for age. Some statistical differences were observed among groups stratified by race, but Dr. McShane doubted that these were clinically significant with the exception of a potential disparity among Asians that might deserve further analysis.
 

Infection results

Of clinical features evaluated for their association with fungal infection, there was no correlation with either body mass index or history of asthma. Eosinophilia was associated significantly with positive fungal cultures.

Baseline FEV₁ was slightly lower among those with a positive fungal culture even if the difference was highly significant (P = .0006). Again, Dr. McShane questioned the clinical significance of values that varied by only a few percentage points, even though she was willing to acknowledge that higher is always preferable to a lower FEV₁.

In the context of other pathogens, “generally speaking, those with a positive bacterial culture were more likely to have a fungal infection,” Dr. McShane reported, although there was some variation when looking at pathogenicity of the bacteria and other variables.

“Whether this [higher rate of fungal infection] just involves the environment or our antibiotics are driving the opportunity to permit the fungi to exist, we do not have the answer,” she added.

Nontuberculosis mycobacteria (NTM) infection was similarly represented in those with or without a fungal infection, according to Dr. McShane. Noting the high use of antibiotics in an NTM population, Dr. McShane conceded that this challenges the theory that antibiotic use is driving the risk of fungal infection, but these are what the data say.  

Steroid use was associated with a statistically significant risk of fungal infection, but Dr. McShane said it is unclear whether steroid use drives the risk or is an epiphenomenon.

“We looked at this a lot of different ways: oral vs. inhaled and oral vs. inhaled and oral, and it did not make much difference. Generally speaking, the fungal cultures were more likely to be positive in patients on any kind of steroid,” she said.

Finally, with the exception of the slightly lower FEV₁ in patients with fungal infections, Dr. McShane said that there was no discernible relationship between the presence of a fungal infection and severity of bronchiectasis.

Because of this evidence, Dr. McShane concluded that the presence of fungus in the culture of patients with bronchiectasis does not appear to correlate with outcome or severity. Since completing the study, she said she is now using these data to reassure patients who have a positive fungal culture.

While these data do not affect the need to diagnosis fungal infections in patients who are not responding typically to therapy or otherwise have an abnormal course of bronchiectasis, raising suspicion that fungal infection is participating in the disease course, the data provide a basis for questioning whether routine cultures are needed, according to the discussion that followed Dr. McShane’s presentation.
 

Expert opinion

Several of the experts at the presentation provided an opinion. Some reported that they would continue to order fungal cultures on a routine basis, while others said that they now, on the basis of these data, plan to order cultures only at the first visit or when fungal infection is suspected of exacerbating the disease.

Of this latter group, which seemed to be dominant, Juzar Ali, MD, professor of medicine, Louisiana State University, New Orleans, said that he has not been ordering fungal cultures on every visit. Rather, he has been doing so selectively. Examples include those who are on steroids or those with an unusual pattern of exacerbations.

“The value of these data is that they have now provided some data to support this approach,” Dr. Ali said in an interview. Noting that this is the first large study to address this question in a systematic way, he considers this to be a valuable contribution for approaching a common clinical issue.

Dr. McShane reports no relevant financial relationships. Dr. Ali reports a financial relationship with Insmed.
 

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

ASHEVILLE, N.C. – The relative absorption of topical corticosteroids, which can induce cataracts and glaucoma, is 300-fold greater across the eyelids than plantar skin, but pediatric dermatologists need not dwell on this ratio when employing steroids near the eye, according to one of several clinical messages from a pediatric ophthalmologist who spoke at the annual meeting of the Society for Pediatric Dermatology.  

“There is a lot of steroid fear out there, which you can argue is actually harmful in itself, because not treating periorbital eczema is related to a lot of eye problems, including chronic discomfort and the eye rubbing that can cause corneal abrasions and keratoconus,” said Sara Grace, MD, a pediatric ophthalmologist who is on the clinical staff at Duke University, Durham, N.C. She maintains a practice at North Carolina Eye, Ear, Nose, and Throat in Durham.

Although the risks of periorbital steroid absorption are real, a limited course of low potency topical steroids is generally adequate for common periorbital indications, and these appear to be safe.

“There is insufficient evidence to link weak periocular topical corticosteroids such as desonide or hydrocortisone with ocular complications,” said Dr. Grace, suggesting that pediatric dermatologists can be reassured when using these medications at low concentrations.

“Potent periocular steroids have been associated with ocular complications, but this has typically involved exposures over months to years,” Dr. Grace specified.

When topical corticosteroids are applied at high concentrations on the face away from the periorbital area, glaucoma and other feared ophthalmic complications cannot be entirely ruled out, but, again, the risk is low in the absence of “very large quantities” of potent topical agents applied for lengthy periods of time, according to Dr. Grace, basing this observation on case studies.

In children, as in adults, the potential exception is a child with existing ocular disease. In such cases, or in children with risk factors for ocular disease, Dr. Grace recommends referral to an ophthalmologist for a baseline examination prior to a course of topical corticosteroids with the potential of periocular absorption. With a baseline assessment, adverse effects are more easily documented if exposure is prolonged.

The message, although not identical, is similar for use of dupilumab (Dupixent) or other biologics that target the interleukin-13 (IL-13) pathway. The potential for complications cannot be ignored but these are often time-limited and the benefit is likely to exceed the risk in children who have severe atopic dermatitis or other skin conditions for which these treatments are effective.

There are several potential mechanisms by which biologics targeting IL-13 might increase risk of ocular complications, one of which is the role that IL-13 plays in ocular mucus production, regulation of conjunctival goblet cells, and tear production, according to several published reports.

“Up to 30% of children will get some type of eye complication but, fortunately, most of them will not have to stop therapy,” Dr. Grace said. These side effects include conjunctivitis, blepharitis, keratitis, dry eye, and itching, but they are typically manageable. Topical steroids or calcineurin inhibitors can be offered if needed, but many of these conditions will self-resolve. Dr. Grace estimated that less than 1% of patients need to stop treatment because of ophthalmic side effects.

Lesions that obstruct vision

Dr. Grace urged pediatric dermatologists to be aware of the risk for amblyopia in young children with lesions that obstruct vision in one eye. In early development, prolonged obstruction of vision in one eye can alter neural communication with the brain, producing permanent vision impairment.

She explained that clearing the obstructed vision, whether from a capillary hemangioma or any periorbital growth, should be considered urgent to avoid irreversible damage.

Similarly, periorbital port-wine stains associated with Sturge-Weber syndrome, which is primarily a vascular disorder that predisposes children to glaucoma, represents a condition that requires prompt attention. Sturge-Weber syndrome is often but not always identified at birth, but it is a condition for which evaluation and treatment should involve the participation of an ophthalmologist.

Meibomian gland disease is another disorder that is often seen first by a pediatric dermatologist but also requires collaborative management. The challenge is sorting out the underlying cause or causes and initiating a therapy that unclogs the gland without having to resort to incision and drainage.

“Drainage is hard to do and is not necessarily effective,” explained Dr. Grace. While scrubs, warmth, and massage frequently are adequate to unclog the gland – which secretes meibum, a complex of lipids that perform several functions in protecting the eye – therapies specific to the cause, such as Demodex-related blepharitis, chalazions, and styes, might be needed.

Dr. Grace indicated that patience is often needed. The process of unclogging these glands often takes time, but she emphasized that a first-line conservative approach is always appropriate to avoid the difficulty and potential problems of incisions.

In general, these messages are not novel, but they provide a refresher for pediatric dermatologists who do not regularly confront complications that involve the eyes. According to session moderator, Elizabeth Neiman, MD, assistant professor of pediatric dermatology, University of North Carolina at Chapel Hill, the messages regarding topical steroids on the face and the eyes are “important” and worth emphasizing.

“It’s useful to reinforce the point that corticosteroids should be used when needed in the periorbital area [to control skin diseases] if they are used in low concentrations,” Dr. Neiman told this news organization.

Similarly, conjunctivitis and other ocular complications of dupilumab are a source of concern for parents as well as dermatologists. Dr. Neiman indicated that a review of the benefit-to-risk ratio is important when considering these treatments in patients with indications for severe skin disorders.

Dr. Grace and Dr. Nieman have no potential financial conflicts related to this topic.

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

ASHEVILLE, N.C. – The relative absorption of topical corticosteroids, which can induce cataracts and glaucoma, is 300-fold greater across the eyelids than plantar skin, but pediatric dermatologists need not dwell on this ratio when employing steroids near the eye, according to one of several clinical messages from a pediatric ophthalmologist who spoke at the annual meeting of the Society for Pediatric Dermatology.  

“There is a lot of steroid fear out there, which you can argue is actually harmful in itself, because not treating periorbital eczema is related to a lot of eye problems, including chronic discomfort and the eye rubbing that can cause corneal abrasions and keratoconus,” said Sara Grace, MD, a pediatric ophthalmologist who is on the clinical staff at Duke University, Durham, N.C. She maintains a practice at North Carolina Eye, Ear, Nose, and Throat in Durham.

Although the risks of periorbital steroid absorption are real, a limited course of low potency topical steroids is generally adequate for common periorbital indications, and these appear to be safe.

“There is insufficient evidence to link weak periocular topical corticosteroids such as desonide or hydrocortisone with ocular complications,” said Dr. Grace, suggesting that pediatric dermatologists can be reassured when using these medications at low concentrations.

“Potent periocular steroids have been associated with ocular complications, but this has typically involved exposures over months to years,” Dr. Grace specified.

When topical corticosteroids are applied at high concentrations on the face away from the periorbital area, glaucoma and other feared ophthalmic complications cannot be entirely ruled out, but, again, the risk is low in the absence of “very large quantities” of potent topical agents applied for lengthy periods of time, according to Dr. Grace, basing this observation on case studies.

In children, as in adults, the potential exception is a child with existing ocular disease. In such cases, or in children with risk factors for ocular disease, Dr. Grace recommends referral to an ophthalmologist for a baseline examination prior to a course of topical corticosteroids with the potential of periocular absorption. With a baseline assessment, adverse effects are more easily documented if exposure is prolonged.

The message, although not identical, is similar for use of dupilumab (Dupixent) or other biologics that target the interleukin-13 (IL-13) pathway. The potential for complications cannot be ignored but these are often time-limited and the benefit is likely to exceed the risk in children who have severe atopic dermatitis or other skin conditions for which these treatments are effective.

There are several potential mechanisms by which biologics targeting IL-13 might increase risk of ocular complications, one of which is the role that IL-13 plays in ocular mucus production, regulation of conjunctival goblet cells, and tear production, according to several published reports.

“Up to 30% of children will get some type of eye complication but, fortunately, most of them will not have to stop therapy,” Dr. Grace said. These side effects include conjunctivitis, blepharitis, keratitis, dry eye, and itching, but they are typically manageable. Topical steroids or calcineurin inhibitors can be offered if needed, but many of these conditions will self-resolve. Dr. Grace estimated that less than 1% of patients need to stop treatment because of ophthalmic side effects.

Lesions that obstruct vision

Dr. Grace urged pediatric dermatologists to be aware of the risk for amblyopia in young children with lesions that obstruct vision in one eye. In early development, prolonged obstruction of vision in one eye can alter neural communication with the brain, producing permanent vision impairment.

She explained that clearing the obstructed vision, whether from a capillary hemangioma or any periorbital growth, should be considered urgent to avoid irreversible damage.

Similarly, periorbital port-wine stains associated with Sturge-Weber syndrome, which is primarily a vascular disorder that predisposes children to glaucoma, represents a condition that requires prompt attention. Sturge-Weber syndrome is often but not always identified at birth, but it is a condition for which evaluation and treatment should involve the participation of an ophthalmologist.

Meibomian gland disease is another disorder that is often seen first by a pediatric dermatologist but also requires collaborative management. The challenge is sorting out the underlying cause or causes and initiating a therapy that unclogs the gland without having to resort to incision and drainage.

“Drainage is hard to do and is not necessarily effective,” explained Dr. Grace. While scrubs, warmth, and massage frequently are adequate to unclog the gland – which secretes meibum, a complex of lipids that perform several functions in protecting the eye – therapies specific to the cause, such as Demodex-related blepharitis, chalazions, and styes, might be needed.

Dr. Grace indicated that patience is often needed. The process of unclogging these glands often takes time, but she emphasized that a first-line conservative approach is always appropriate to avoid the difficulty and potential problems of incisions.

In general, these messages are not novel, but they provide a refresher for pediatric dermatologists who do not regularly confront complications that involve the eyes. According to session moderator, Elizabeth Neiman, MD, assistant professor of pediatric dermatology, University of North Carolina at Chapel Hill, the messages regarding topical steroids on the face and the eyes are “important” and worth emphasizing.

“It’s useful to reinforce the point that corticosteroids should be used when needed in the periorbital area [to control skin diseases] if they are used in low concentrations,” Dr. Neiman told this news organization.

Similarly, conjunctivitis and other ocular complications of dupilumab are a source of concern for parents as well as dermatologists. Dr. Neiman indicated that a review of the benefit-to-risk ratio is important when considering these treatments in patients with indications for severe skin disorders.

Dr. Grace and Dr. Nieman have no potential financial conflicts related to this topic.

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

ASHEVILLE, N.C. – The relative absorption of topical corticosteroids, which can induce cataracts and glaucoma, is 300-fold greater across the eyelids than plantar skin, but pediatric dermatologists need not dwell on this ratio when employing steroids near the eye, according to one of several clinical messages from a pediatric ophthalmologist who spoke at the annual meeting of the Society for Pediatric Dermatology.  

“There is a lot of steroid fear out there, which you can argue is actually harmful in itself, because not treating periorbital eczema is related to a lot of eye problems, including chronic discomfort and the eye rubbing that can cause corneal abrasions and keratoconus,” said Sara Grace, MD, a pediatric ophthalmologist who is on the clinical staff at Duke University, Durham, N.C. She maintains a practice at North Carolina Eye, Ear, Nose, and Throat in Durham.

Although the risks of periorbital steroid absorption are real, a limited course of low potency topical steroids is generally adequate for common periorbital indications, and these appear to be safe.

“There is insufficient evidence to link weak periocular topical corticosteroids such as desonide or hydrocortisone with ocular complications,” said Dr. Grace, suggesting that pediatric dermatologists can be reassured when using these medications at low concentrations.

“Potent periocular steroids have been associated with ocular complications, but this has typically involved exposures over months to years,” Dr. Grace specified.

When topical corticosteroids are applied at high concentrations on the face away from the periorbital area, glaucoma and other feared ophthalmic complications cannot be entirely ruled out, but, again, the risk is low in the absence of “very large quantities” of potent topical agents applied for lengthy periods of time, according to Dr. Grace, basing this observation on case studies.

In children, as in adults, the potential exception is a child with existing ocular disease. In such cases, or in children with risk factors for ocular disease, Dr. Grace recommends referral to an ophthalmologist for a baseline examination prior to a course of topical corticosteroids with the potential of periocular absorption. With a baseline assessment, adverse effects are more easily documented if exposure is prolonged.

The message, although not identical, is similar for use of dupilumab (Dupixent) or other biologics that target the interleukin-13 (IL-13) pathway. The potential for complications cannot be ignored but these are often time-limited and the benefit is likely to exceed the risk in children who have severe atopic dermatitis or other skin conditions for which these treatments are effective.

There are several potential mechanisms by which biologics targeting IL-13 might increase risk of ocular complications, one of which is the role that IL-13 plays in ocular mucus production, regulation of conjunctival goblet cells, and tear production, according to several published reports.

“Up to 30% of children will get some type of eye complication but, fortunately, most of them will not have to stop therapy,” Dr. Grace said. These side effects include conjunctivitis, blepharitis, keratitis, dry eye, and itching, but they are typically manageable. Topical steroids or calcineurin inhibitors can be offered if needed, but many of these conditions will self-resolve. Dr. Grace estimated that less than 1% of patients need to stop treatment because of ophthalmic side effects.

Lesions that obstruct vision

Dr. Grace urged pediatric dermatologists to be aware of the risk for amblyopia in young children with lesions that obstruct vision in one eye. In early development, prolonged obstruction of vision in one eye can alter neural communication with the brain, producing permanent vision impairment.

She explained that clearing the obstructed vision, whether from a capillary hemangioma or any periorbital growth, should be considered urgent to avoid irreversible damage.

Similarly, periorbital port-wine stains associated with Sturge-Weber syndrome, which is primarily a vascular disorder that predisposes children to glaucoma, represents a condition that requires prompt attention. Sturge-Weber syndrome is often but not always identified at birth, but it is a condition for which evaluation and treatment should involve the participation of an ophthalmologist.

Meibomian gland disease is another disorder that is often seen first by a pediatric dermatologist but also requires collaborative management. The challenge is sorting out the underlying cause or causes and initiating a therapy that unclogs the gland without having to resort to incision and drainage.

“Drainage is hard to do and is not necessarily effective,” explained Dr. Grace. While scrubs, warmth, and massage frequently are adequate to unclog the gland – which secretes meibum, a complex of lipids that perform several functions in protecting the eye – therapies specific to the cause, such as Demodex-related blepharitis, chalazions, and styes, might be needed.

Dr. Grace indicated that patience is often needed. The process of unclogging these glands often takes time, but she emphasized that a first-line conservative approach is always appropriate to avoid the difficulty and potential problems of incisions.

In general, these messages are not novel, but they provide a refresher for pediatric dermatologists who do not regularly confront complications that involve the eyes. According to session moderator, Elizabeth Neiman, MD, assistant professor of pediatric dermatology, University of North Carolina at Chapel Hill, the messages regarding topical steroids on the face and the eyes are “important” and worth emphasizing.

“It’s useful to reinforce the point that corticosteroids should be used when needed in the periorbital area [to control skin diseases] if they are used in low concentrations,” Dr. Neiman told this news organization.

Similarly, conjunctivitis and other ocular complications of dupilumab are a source of concern for parents as well as dermatologists. Dr. Neiman indicated that a review of the benefit-to-risk ratio is important when considering these treatments in patients with indications for severe skin disorders.

Dr. Grace and Dr. Nieman have no potential financial conflicts related to this topic.

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

TOPLINE:

Immunological and quantitative mRNA assays support a pathogenesis role for histamine-releasing factor (HRF), its interaction with HRF-reactive immunoglobulin E and rhinovirus (RV) in asthma severity and exacerbation.

METHODOLOGY:

• Clinical data for healthy controls (HCs) were compared with data from patients with asthma for three distinct cohorts recruited from programs located in Pittsburg, Boston, and Virginia.
• Cohorts differed primarily by total number of participants, median age, description of asthma severity, RV status, and longitudinal follow-up.
• Enzyme-linked immunoassay tests quantified for comparisons total IgE, IgGs, and IgG1 levels occurring in human sera samples and for HRF-reactive IgE, IgG1, and IgG2b in sera from mice inoculated with mouse .
• Anti-IgE stimulation experiments characterized bronchoalveolar lavage (BAL) cell supernatants for tryptase and PGD2 by ELISA and the mRNAs for tryptase and FCER1A
• Effect of inoculated RV infections and/or house dust mite allergen on stimulating HRF secretion from respiratory epithelial cells and in vitro–grown lung BEAS-2B cells was evaluated by Western blots.

TAKEAWAY:

• HRF-reactive IgE and total IgE levels in serum were significantly higher from patients with severe asthma than from HCs and showed a rising trend as severity increased.
• HRF-reactive IgGs and IgG1 levels in serum were lower in people with asthma than in HCs.
• People with asthma with high HRF-reactive IgE, compared with those with low levels, tended to release more tryptase prostaglandin D2 with anti-IgE stimulation of BAL cells.
• RV infection induced HFR secretions from both in vivo– and in vitro–grown respiratory epithelial cells and was associated with higher levels of HRF-IgE at the time of asthma exacerbations, compared with after resolution.

IN PRACTICE:

Inhibiting HRF and HRF-reactive IgE interactions “can be a preventative/therapeutic target” for severe and RV-induced exacerbated asthma conditions.

SOURCE:

The study led by Yu Kawakami, MD, of La Jolla Institute for Allergy & Immunology, California, and colleagues was published in the Journal of Allergy and Clinical Immunology

LIMITATIONS:

Small sample sizes, large median age differences between cohorts, and lack of data for other demographic traits and variant asthma phenotypes or endotypes in some cohorts are noted limitations that may affect result extrapolations and conclusions.

DISCLOSURES:

The authors report there are no conflicts of interest directly related to this study.

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

TOPLINE:

Immunological and quantitative mRNA assays support a pathogenesis role for histamine-releasing factor (HRF), its interaction with HRF-reactive immunoglobulin E and rhinovirus (RV) in asthma severity and exacerbation.

METHODOLOGY:

• Clinical data for healthy controls (HCs) were compared with data from patients with asthma for three distinct cohorts recruited from programs located in Pittsburg, Boston, and Virginia.
• Cohorts differed primarily by total number of participants, median age, description of asthma severity, RV status, and longitudinal follow-up.
• Enzyme-linked immunoassay tests quantified for comparisons total IgE, IgGs, and IgG1 levels occurring in human sera samples and for HRF-reactive IgE, IgG1, and IgG2b in sera from mice inoculated with mouse .
• Anti-IgE stimulation experiments characterized bronchoalveolar lavage (BAL) cell supernatants for tryptase and PGD2 by ELISA and the mRNAs for tryptase and FCER1A
• Effect of inoculated RV infections and/or house dust mite allergen on stimulating HRF secretion from respiratory epithelial cells and in vitro–grown lung BEAS-2B cells was evaluated by Western blots.

TAKEAWAY:

• HRF-reactive IgE and total IgE levels in serum were significantly higher from patients with severe asthma than from HCs and showed a rising trend as severity increased.
• HRF-reactive IgGs and IgG1 levels in serum were lower in people with asthma than in HCs.
• People with asthma with high HRF-reactive IgE, compared with those with low levels, tended to release more tryptase prostaglandin D2 with anti-IgE stimulation of BAL cells.
• RV infection induced HFR secretions from both in vivo– and in vitro–grown respiratory epithelial cells and was associated with higher levels of HRF-IgE at the time of asthma exacerbations, compared with after resolution.

IN PRACTICE:

Inhibiting HRF and HRF-reactive IgE interactions “can be a preventative/therapeutic target” for severe and RV-induced exacerbated asthma conditions.

SOURCE:

The study led by Yu Kawakami, MD, of La Jolla Institute for Allergy & Immunology, California, and colleagues was published in the Journal of Allergy and Clinical Immunology

LIMITATIONS:

Small sample sizes, large median age differences between cohorts, and lack of data for other demographic traits and variant asthma phenotypes or endotypes in some cohorts are noted limitations that may affect result extrapolations and conclusions.

DISCLOSURES:

The authors report there are no conflicts of interest directly related to this study.

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

TOPLINE:

Immunological and quantitative mRNA assays support a pathogenesis role for histamine-releasing factor (HRF), its interaction with HRF-reactive immunoglobulin E and rhinovirus (RV) in asthma severity and exacerbation.

METHODOLOGY:

• Clinical data for healthy controls (HCs) were compared with data from patients with asthma for three distinct cohorts recruited from programs located in Pittsburg, Boston, and Virginia.
• Cohorts differed primarily by total number of participants, median age, description of asthma severity, RV status, and longitudinal follow-up.
• Enzyme-linked immunoassay tests quantified for comparisons total IgE, IgGs, and IgG1 levels occurring in human sera samples and for HRF-reactive IgE, IgG1, and IgG2b in sera from mice inoculated with mouse .
• Anti-IgE stimulation experiments characterized bronchoalveolar lavage (BAL) cell supernatants for tryptase and PGD2 by ELISA and the mRNAs for tryptase and FCER1A
• Effect of inoculated RV infections and/or house dust mite allergen on stimulating HRF secretion from respiratory epithelial cells and in vitro–grown lung BEAS-2B cells was evaluated by Western blots.

TAKEAWAY:

• HRF-reactive IgE and total IgE levels in serum were significantly higher from patients with severe asthma than from HCs and showed a rising trend as severity increased.
• HRF-reactive IgGs and IgG1 levels in serum were lower in people with asthma than in HCs.
• People with asthma with high HRF-reactive IgE, compared with those with low levels, tended to release more tryptase prostaglandin D2 with anti-IgE stimulation of BAL cells.
• RV infection induced HFR secretions from both in vivo– and in vitro–grown respiratory epithelial cells and was associated with higher levels of HRF-IgE at the time of asthma exacerbations, compared with after resolution.

IN PRACTICE:

Inhibiting HRF and HRF-reactive IgE interactions “can be a preventative/therapeutic target” for severe and RV-induced exacerbated asthma conditions.

SOURCE:

The study led by Yu Kawakami, MD, of La Jolla Institute for Allergy & Immunology, California, and colleagues was published in the Journal of Allergy and Clinical Immunology

LIMITATIONS:

Small sample sizes, large median age differences between cohorts, and lack of data for other demographic traits and variant asthma phenotypes or endotypes in some cohorts are noted limitations that may affect result extrapolations and conclusions.

DISCLOSURES:

The authors report there are no conflicts of interest directly related to this study.

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

Private equity ownership of medical practices was linked to consumer price increases for 8 of 10 specialties examined in a new report, with the most notable gains reported for oncology and gastroenterology.

The report was a collaboration of University of California, Berkeley, staff and researchers from two nonprofits, the American Antitrust Institute and the Washington Center for Equitable Growth. It provides “convincing evidence that incentives to put profits before patients have grown stronger with an increase in private equity ownership of physician practices,” lead author Richard Scheffler, PhD, of UC Berkeley said in a statement.

The report also noted that private equity acquisitions of physician groups have risen sixfold in just a decade, increasing from 75 deals in 2012 to 484 deals in 2021.

Separately, the American Medical Association earlier released a separate report on trends in physician practice arrangements, finding that the percentage of physicians working in private equity–owned groups was 4.5% in 2022, the same as in its previous 2020 report. The share of physicians working in private practices fell by 13 percentage points from 60.1% to 46.7% between 2012 and 2022, the AMA reported.

The Berkeley report and the AMA update come amid rising concerns about the effects of the decline of independent physician practices. The U.S. Senate Finance Committee, which oversees most federal health spending, held a June hearing examining the causes and consequences of increased corporate ownership in health care, including a look at physician practices.

“It’s increasingly clear that consolidation in health care is not lowering costs or increasing the quality of Americans’ health care,” Senate Finance Chairman Ron Wyden (D-Ore.) said in an email. “For private equity in health care in particular, there needs to be more transparency around ownership so the effect on these business relationships can be better understood.”

Federal and state agencies do not generally track acquisitions of physician practices.

The UC Berkeley report impressively documents the rising influence of private equity in health care, for which it’s tough to find good data, said Karen Joynt Maddox, MD, MPH, of Washington University in St. Louis. Dr. Maddox, a cardiologist and policy researcher who also has studied the effects of consolidation in health care, examined the new report at the request of this news organization.

“They did a great job with the data,” Dr. Maddox said. “One of the big issues around private equity, and in general, ‘corporatization’ and consolidation of health care, is that there’s not a great way to track ownership changes. It’s really difficult to study.”

Dr. Scheffler and colleagues used data from the commercial firm PitchBook to identify acquisitions of physician practices by private equity firms. They consulted IQVIA’s physician databases – OneKey and SK&A Office-Based Physicians Database – to learn about the location, size, and specialties of acquired practices. They also used data from the nonprofit Health Care Cost Institute, which tracks commercial health plan claims, to assess how private equity acquisitions affected prices.

The researchers then matched the findings for practices acquired by private equity firms from 2015 to 2021 against those for comparable physician practices that remained independent from 2012 to 2021.

The authors then tied private-equity ownership to the following price increases:

• Gastroenterology (14%; 95% confidence interval, 7.9%-20.4%
• Oncology (16.4%; 95% CI, 5.5%-28.4%)
• Dermatology (4.0%; 95% CI, 1%-7.1%)
• Ob.gyn. (8.8%; 95% CI, 3.8%-14%)
• Ophthalmology (8.7%; 95% CI, 5.1%-12.3%)
• Radiology (8.2%; 95% CI, 0.8%-16.1%)
• Orthopedics (7.1%; 95% CI, 2.2%-12.3%)
• Primary care (4.1%; 95% CI, 1.3%-7%)

The analysis also found higher prices for cardiology (8.7%; 95% CI, –6.4% to 26.1%) and urology (4.2%; 95% CI, –2.3% to 11.1%), but neither of these findings was statistically significant, one of the authors, Daniel R. Arnold, PhD, of UC Berkeley, said in an email. This was most likely caused by smaller sample sizes for these fields.
 

Factors driving consolidation

The two reports and the Senate Finance consolidation hearing raised similar issues, including calls to look at the factors driving more physicians out of independent practice, including Medicare reimbursement that may not keep up with rising inflation.

The Berkeley report authors called for Congress to add a broad inflation component to the Medicare physician fee schedule. It also called on Congress to add cases where Medicare, the biggest U.S. purchaser of health care, pays less for services when performed in independent practices than in hospital-affiliated ones.

Shawn Martin, executive vice president and CEO of the American Academy of Family Physicians, said his group appreciates how the report from UC Berkeley and nonprofit groups echoed recommendations many clinicians have made, including the call for a broad inflation adjustment for the fee schedule.

“To move the needle forward, Congress must advance site-neutral payment policies while also addressing the administrative requirements that take physicians away from the important work of caring for patients,” Mr. Martin said in an email.

Arnold Ventures provided funding for the report, which was a joint project of the American Antitrust Institute, the Nicholas C. Petris Center on Health Care Markets and Consumer Welfare, UC Berkeley, and the Washington Center for Equitable Growth.

A version of this article appeared on Medscape.com.

Private equity ownership of medical practices was linked to consumer price increases for 8 of 10 specialties examined in a new report, with the most notable gains reported for oncology and gastroenterology.

The report was a collaboration of University of California, Berkeley, staff and researchers from two nonprofits, the American Antitrust Institute and the Washington Center for Equitable Growth. It provides “convincing evidence that incentives to put profits before patients have grown stronger with an increase in private equity ownership of physician practices,” lead author Richard Scheffler, PhD, of UC Berkeley said in a statement.

The report also noted that private equity acquisitions of physician groups have risen sixfold in just a decade, increasing from 75 deals in 2012 to 484 deals in 2021.

Separately, the American Medical Association earlier released a separate report on trends in physician practice arrangements, finding that the percentage of physicians working in private equity–owned groups was 4.5% in 2022, the same as in its previous 2020 report. The share of physicians working in private practices fell by 13 percentage points from 60.1% to 46.7% between 2012 and 2022, the AMA reported.

The Berkeley report and the AMA update come amid rising concerns about the effects of the decline of independent physician practices. The U.S. Senate Finance Committee, which oversees most federal health spending, held a June hearing examining the causes and consequences of increased corporate ownership in health care, including a look at physician practices.

“It’s increasingly clear that consolidation in health care is not lowering costs or increasing the quality of Americans’ health care,” Senate Finance Chairman Ron Wyden (D-Ore.) said in an email. “For private equity in health care in particular, there needs to be more transparency around ownership so the effect on these business relationships can be better understood.”

Federal and state agencies do not generally track acquisitions of physician practices.

The UC Berkeley report impressively documents the rising influence of private equity in health care, for which it’s tough to find good data, said Karen Joynt Maddox, MD, MPH, of Washington University in St. Louis. Dr. Maddox, a cardiologist and policy researcher who also has studied the effects of consolidation in health care, examined the new report at the request of this news organization.

“They did a great job with the data,” Dr. Maddox said. “One of the big issues around private equity, and in general, ‘corporatization’ and consolidation of health care, is that there’s not a great way to track ownership changes. It’s really difficult to study.”

Dr. Scheffler and colleagues used data from the commercial firm PitchBook to identify acquisitions of physician practices by private equity firms. They consulted IQVIA’s physician databases – OneKey and SK&A Office-Based Physicians Database – to learn about the location, size, and specialties of acquired practices. They also used data from the nonprofit Health Care Cost Institute, which tracks commercial health plan claims, to assess how private equity acquisitions affected prices.

The researchers then matched the findings for practices acquired by private equity firms from 2015 to 2021 against those for comparable physician practices that remained independent from 2012 to 2021.

The authors then tied private-equity ownership to the following price increases:

• Gastroenterology (14%; 95% confidence interval, 7.9%-20.4%
• Oncology (16.4%; 95% CI, 5.5%-28.4%)
• Dermatology (4.0%; 95% CI, 1%-7.1%)
• Ob.gyn. (8.8%; 95% CI, 3.8%-14%)
• Ophthalmology (8.7%; 95% CI, 5.1%-12.3%)
• Radiology (8.2%; 95% CI, 0.8%-16.1%)
• Orthopedics (7.1%; 95% CI, 2.2%-12.3%)
• Primary care (4.1%; 95% CI, 1.3%-7%)

The analysis also found higher prices for cardiology (8.7%; 95% CI, –6.4% to 26.1%) and urology (4.2%; 95% CI, –2.3% to 11.1%), but neither of these findings was statistically significant, one of the authors, Daniel R. Arnold, PhD, of UC Berkeley, said in an email. This was most likely caused by smaller sample sizes for these fields.
 

Factors driving consolidation

The two reports and the Senate Finance consolidation hearing raised similar issues, including calls to look at the factors driving more physicians out of independent practice, including Medicare reimbursement that may not keep up with rising inflation.

The Berkeley report authors called for Congress to add a broad inflation component to the Medicare physician fee schedule. It also called on Congress to add cases where Medicare, the biggest U.S. purchaser of health care, pays less for services when performed in independent practices than in hospital-affiliated ones.

Shawn Martin, executive vice president and CEO of the American Academy of Family Physicians, said his group appreciates how the report from UC Berkeley and nonprofit groups echoed recommendations many clinicians have made, including the call for a broad inflation adjustment for the fee schedule.

“To move the needle forward, Congress must advance site-neutral payment policies while also addressing the administrative requirements that take physicians away from the important work of caring for patients,” Mr. Martin said in an email.

Arnold Ventures provided funding for the report, which was a joint project of the American Antitrust Institute, the Nicholas C. Petris Center on Health Care Markets and Consumer Welfare, UC Berkeley, and the Washington Center for Equitable Growth.

A version of this article appeared on Medscape.com.

Private equity ownership of medical practices was linked to consumer price increases for 8 of 10 specialties examined in a new report, with the most notable gains reported for oncology and gastroenterology.

The report was a collaboration of University of California, Berkeley, staff and researchers from two nonprofits, the American Antitrust Institute and the Washington Center for Equitable Growth. It provides “convincing evidence that incentives to put profits before patients have grown stronger with an increase in private equity ownership of physician practices,” lead author Richard Scheffler, PhD, of UC Berkeley said in a statement.

The report also noted that private equity acquisitions of physician groups have risen sixfold in just a decade, increasing from 75 deals in 2012 to 484 deals in 2021.

Separately, the American Medical Association earlier released a separate report on trends in physician practice arrangements, finding that the percentage of physicians working in private equity–owned groups was 4.5% in 2022, the same as in its previous 2020 report. The share of physicians working in private practices fell by 13 percentage points from 60.1% to 46.7% between 2012 and 2022, the AMA reported.

The Berkeley report and the AMA update come amid rising concerns about the effects of the decline of independent physician practices. The U.S. Senate Finance Committee, which oversees most federal health spending, held a June hearing examining the causes and consequences of increased corporate ownership in health care, including a look at physician practices.

“It’s increasingly clear that consolidation in health care is not lowering costs or increasing the quality of Americans’ health care,” Senate Finance Chairman Ron Wyden (D-Ore.) said in an email. “For private equity in health care in particular, there needs to be more transparency around ownership so the effect on these business relationships can be better understood.”

Federal and state agencies do not generally track acquisitions of physician practices.

The UC Berkeley report impressively documents the rising influence of private equity in health care, for which it’s tough to find good data, said Karen Joynt Maddox, MD, MPH, of Washington University in St. Louis. Dr. Maddox, a cardiologist and policy researcher who also has studied the effects of consolidation in health care, examined the new report at the request of this news organization.

“They did a great job with the data,” Dr. Maddox said. “One of the big issues around private equity, and in general, ‘corporatization’ and consolidation of health care, is that there’s not a great way to track ownership changes. It’s really difficult to study.”

Dr. Scheffler and colleagues used data from the commercial firm PitchBook to identify acquisitions of physician practices by private equity firms. They consulted IQVIA’s physician databases – OneKey and SK&A Office-Based Physicians Database – to learn about the location, size, and specialties of acquired practices. They also used data from the nonprofit Health Care Cost Institute, which tracks commercial health plan claims, to assess how private equity acquisitions affected prices.

The researchers then matched the findings for practices acquired by private equity firms from 2015 to 2021 against those for comparable physician practices that remained independent from 2012 to 2021.

The authors then tied private-equity ownership to the following price increases:

• Gastroenterology (14%; 95% confidence interval, 7.9%-20.4%
• Oncology (16.4%; 95% CI, 5.5%-28.4%)
• Dermatology (4.0%; 95% CI, 1%-7.1%)
• Ob.gyn. (8.8%; 95% CI, 3.8%-14%)
• Ophthalmology (8.7%; 95% CI, 5.1%-12.3%)
• Radiology (8.2%; 95% CI, 0.8%-16.1%)
• Orthopedics (7.1%; 95% CI, 2.2%-12.3%)
• Primary care (4.1%; 95% CI, 1.3%-7%)

The analysis also found higher prices for cardiology (8.7%; 95% CI, –6.4% to 26.1%) and urology (4.2%; 95% CI, –2.3% to 11.1%), but neither of these findings was statistically significant, one of the authors, Daniel R. Arnold, PhD, of UC Berkeley, said in an email. This was most likely caused by smaller sample sizes for these fields.
 

Factors driving consolidation

The two reports and the Senate Finance consolidation hearing raised similar issues, including calls to look at the factors driving more physicians out of independent practice, including Medicare reimbursement that may not keep up with rising inflation.

The Berkeley report authors called for Congress to add a broad inflation component to the Medicare physician fee schedule. It also called on Congress to add cases where Medicare, the biggest U.S. purchaser of health care, pays less for services when performed in independent practices than in hospital-affiliated ones.

Shawn Martin, executive vice president and CEO of the American Academy of Family Physicians, said his group appreciates how the report from UC Berkeley and nonprofit groups echoed recommendations many clinicians have made, including the call for a broad inflation adjustment for the fee schedule.

“To move the needle forward, Congress must advance site-neutral payment policies while also addressing the administrative requirements that take physicians away from the important work of caring for patients,” Mr. Martin said in an email.

Arnold Ventures provided funding for the report, which was a joint project of the American Antitrust Institute, the Nicholas C. Petris Center on Health Care Markets and Consumer Welfare, UC Berkeley, and the Washington Center for Equitable Growth.

A version of this article appeared on Medscape.com.