It is well known that the best outcomes for patients with rheumatoid arthritis (RA) are achieved with a treat-to-target strategy, but recent research has also focused on tapering therapy, especially biologics, in patients who are in prolonged disease remission without synovitis. In the open-label, randomized, noninferiority ARCTIC REWIND trial, Lillegraven and colleagues looked at the effects of tapering tumor necrosis factor inhibitors (TNFi) in 84 patients at different sites in Norway. Patients who had been in remission for a year or more on stable therapy (including TNFi and conventional synthetic disease-modifying antirheumatic drugs [csDMARD]) were included in the study. Of the 43 randomly assigned to tapering TNFi therapy, nearly two-thirds had a flare in 12 months of follow-up, compared with 5% in the stable TNFi group; thus, noninferiority of tapering TNFi was not supported. This study is small and seems to highlight a greater disparity between the two groups than expected from prior studies. Given the stark difference between the two groups, however, caution is advised in tapering TNFi therapy in patients with RA, even those in "deep remission." This information is reassuring in that most patients who flared had a good response to reinstating TNFi therapy, and it is helpful in counseling patients who prefer to try to reduce their medication burden despite the potential for flare.

The impact of chronic steroid use in RA has also received a lot of scrutiny in recent literature due to possible long-term side effects such as bone loss, hyperglycemia, and accelerated atherosclerotic disease. Palmowski and colleagues conducted a pooled analysis of several European randomized trials comparing the use of low-dose glucocorticoids (< 7.5 mg/d prednisone) vs placebo in combination with targeted therapy for RA. Data from over 1100 patients in five trials were analyzed. Over the course of 2 years, participants in both groups had gained weight, more so in the glucocorticoid group compared with the control group (1.8 kg vs 0.7 kg), with negligible effects on blood pressure. While use of moderate and high doses of glucocorticoids is not advisable for the long term, the use of low doses appears to be tolerable, with relatively minor effects on weight and blood pressure.

Given the chronic nature of RA and increasing incidence with age, comorbidities and multimorbidity (two or more comorbidities) are common in patients with RA. Stevens and colleagues used a national claims database to examine the burden of multimorbidity in people with RA and its association with sex and age in two different age groups (18-50 years and older than 51 years). Over 154,000 patients with RA were matched 1:1 to those without. The risk for multimorbidity was higher in women vs men with RA, though the absolute difference in risk was not large. The magnitude of these differences (between women and men, and between those with and without RA) was more pronounced in the younger age group and, as expected, decreased in the older age group. Of note, men with RA, compared with women with RA, had a higher risk for cardiovascular disease, including hypertension, high cholesterol, coronary artery disease, valvular disease, and heart failure. Women with RA had more psychological, neurologic, and comorbid noninflammatory musculoskeletal conditions, such as chronic lower back pain. These differences stress the need for attention to individualized care to improve patients' quality of life and reduce adverse effects on other areas of health.

It is well known that the best outcomes for patients with rheumatoid arthritis (RA) are achieved with a treat-to-target strategy, but recent research has also focused on tapering therapy, especially biologics, in patients who are in prolonged disease remission without synovitis. In the open-label, randomized, noninferiority ARCTIC REWIND trial, Lillegraven and colleagues looked at the effects of tapering tumor necrosis factor inhibitors (TNFi) in 84 patients at different sites in Norway. Patients who had been in remission for a year or more on stable therapy (including TNFi and conventional synthetic disease-modifying antirheumatic drugs [csDMARD]) were included in the study. Of the 43 randomly assigned to tapering TNFi therapy, nearly two-thirds had a flare in 12 months of follow-up, compared with 5% in the stable TNFi group; thus, noninferiority of tapering TNFi was not supported. This study is small and seems to highlight a greater disparity between the two groups than expected from prior studies. Given the stark difference between the two groups, however, caution is advised in tapering TNFi therapy in patients with RA, even those in "deep remission." This information is reassuring in that most patients who flared had a good response to reinstating TNFi therapy, and it is helpful in counseling patients who prefer to try to reduce their medication burden despite the potential for flare.

The impact of chronic steroid use in RA has also received a lot of scrutiny in recent literature due to possible long-term side effects such as bone loss, hyperglycemia, and accelerated atherosclerotic disease. Palmowski and colleagues conducted a pooled analysis of several European randomized trials comparing the use of low-dose glucocorticoids (< 7.5 mg/d prednisone) vs placebo in combination with targeted therapy for RA. Data from over 1100 patients in five trials were analyzed. Over the course of 2 years, participants in both groups had gained weight, more so in the glucocorticoid group compared with the control group (1.8 kg vs 0.7 kg), with negligible effects on blood pressure. While use of moderate and high doses of glucocorticoids is not advisable for the long term, the use of low doses appears to be tolerable, with relatively minor effects on weight and blood pressure.

Given the chronic nature of RA and increasing incidence with age, comorbidities and multimorbidity (two or more comorbidities) are common in patients with RA. Stevens and colleagues used a national claims database to examine the burden of multimorbidity in people with RA and its association with sex and age in two different age groups (18-50 years and older than 51 years). Over 154,000 patients with RA were matched 1:1 to those without. The risk for multimorbidity was higher in women vs men with RA, though the absolute difference in risk was not large. The magnitude of these differences (between women and men, and between those with and without RA) was more pronounced in the younger age group and, as expected, decreased in the older age group. Of note, men with RA, compared with women with RA, had a higher risk for cardiovascular disease, including hypertension, high cholesterol, coronary artery disease, valvular disease, and heart failure. Women with RA had more psychological, neurologic, and comorbid noninflammatory musculoskeletal conditions, such as chronic lower back pain. These differences stress the need for attention to individualized care to improve patients' quality of life and reduce adverse effects on other areas of health.

It is well known that the best outcomes for patients with rheumatoid arthritis (RA) are achieved with a treat-to-target strategy, but recent research has also focused on tapering therapy, especially biologics, in patients who are in prolonged disease remission without synovitis. In the open-label, randomized, noninferiority ARCTIC REWIND trial, Lillegraven and colleagues looked at the effects of tapering tumor necrosis factor inhibitors (TNFi) in 84 patients at different sites in Norway. Patients who had been in remission for a year or more on stable therapy (including TNFi and conventional synthetic disease-modifying antirheumatic drugs [csDMARD]) were included in the study. Of the 43 randomly assigned to tapering TNFi therapy, nearly two-thirds had a flare in 12 months of follow-up, compared with 5% in the stable TNFi group; thus, noninferiority of tapering TNFi was not supported. This study is small and seems to highlight a greater disparity between the two groups than expected from prior studies. Given the stark difference between the two groups, however, caution is advised in tapering TNFi therapy in patients with RA, even those in "deep remission." This information is reassuring in that most patients who flared had a good response to reinstating TNFi therapy, and it is helpful in counseling patients who prefer to try to reduce their medication burden despite the potential for flare.

The impact of chronic steroid use in RA has also received a lot of scrutiny in recent literature due to possible long-term side effects such as bone loss, hyperglycemia, and accelerated atherosclerotic disease. Palmowski and colleagues conducted a pooled analysis of several European randomized trials comparing the use of low-dose glucocorticoids (< 7.5 mg/d prednisone) vs placebo in combination with targeted therapy for RA. Data from over 1100 patients in five trials were analyzed. Over the course of 2 years, participants in both groups had gained weight, more so in the glucocorticoid group compared with the control group (1.8 kg vs 0.7 kg), with negligible effects on blood pressure. While use of moderate and high doses of glucocorticoids is not advisable for the long term, the use of low doses appears to be tolerable, with relatively minor effects on weight and blood pressure.

Given the chronic nature of RA and increasing incidence with age, comorbidities and multimorbidity (two or more comorbidities) are common in patients with RA. Stevens and colleagues used a national claims database to examine the burden of multimorbidity in people with RA and its association with sex and age in two different age groups (18-50 years and older than 51 years). Over 154,000 patients with RA were matched 1:1 to those without. The risk for multimorbidity was higher in women vs men with RA, though the absolute difference in risk was not large. The magnitude of these differences (between women and men, and between those with and without RA) was more pronounced in the younger age group and, as expected, decreased in the older age group. Of note, men with RA, compared with women with RA, had a higher risk for cardiovascular disease, including hypertension, high cholesterol, coronary artery disease, valvular disease, and heart failure. Women with RA had more psychological, neurologic, and comorbid noninflammatory musculoskeletal conditions, such as chronic lower back pain. These differences stress the need for attention to individualized care to improve patients' quality of life and reduce adverse effects on other areas of health.

The treatment of mantle cell lymphoma (MCL) continues to evolve. In the front-line setting, studies are evaluating the role of novel therapies as well as consolidation with autologous stem cell transplantation. In the relapsed/refractory setting, patients can be considered for treatment with Bruton tyrosine kinase (BTK) inhibitors, other targeted therapies, or chimeric antigen receptor (CAR) T-cell therapy. Other novel therapies, including bispecific antibodies and novel antibody drug conjugates, are being studied as well.

Despite the availability of novel agents, a subset of patients continues to have difficult-to-treat disease and a poor prognosis. Established prognostic tools that aid in identifying high-risk patients include alternations in TP53, high proliferation rates, nonclassic morphology, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which incorporates age, performance status, lactate dehydrogenase levels, and white blood cell count. The Nordic study group recently published a paper which provides additional prognostic information beyond these known variables (Rodrigues et al). They examined MYC expression in a cohort of 251 patients with MCL and structural aberrations in MYC and MYC mRNA levels in a smaller cohort. They found that patients with tumors comprising 20% or more cells with MYC overexpression (MYC^high tumors) vs MYC^low tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04), when adjusted for additional high-risk features. Patients with tumors with concomitant MYC^high expression and TP53/p53 alterations vs MYC^low tumors had a particularly poor prognosis, with significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of only 0.9 years (both P < .001). Though MYC overexpression was rare, this study identified a high-risk group of patients, especially those harboring concurrent TP53 aberrations, that may benefit from novel treatment approaches.

Another study recently aimed to identify patients who are at risk for poor outcomes after treatment with brexucabtagene autoleucel (brexu-cel) infusion. Though brexu-cel is an active therapy for patients with relapsed/refractory MCL, there are known toxicities, including cytokine release syndrome, neurologic toxicity, and hematologic toxicity. Given the potential for prolonged cytopenias and immune suppression, patients are also at risk for severe infections, which currently represent the driving determinant of nonrelapse mortality.¹ The CAR-HEMATOTOX (HT) score was previously found to identify patients who are at increased risk for hematologic toxicity after CAR T-cell therapy in diffuse large B-cell lymphoma.² In the current multicenter observational study, which included 103 patients receiving brexu-cel, the authors reported an association between baseline HT score and outcome in MCL as well. Patients with high (2-7) vs low (0-1) HT scores had significantly longer median duration of severe neutropenia (P < .0001), higher rates of severe infections (P = .001), and lower overall response rates (P = .003). The HT score represented an independent predictor of poor progression-free (aHR 3.7; P < .001) and overall (aHR 5.6; P = .002) survival. This tool may provide a helpful guide when counseling patients on treatment options and allow for more personalized toxicity management.

Despite availability of BTK inhibitors and CAR T-cell therapy for patients with MCL, relapses remain common. As upregulation of phosphoinositide 3-kinase (PI3K) is known to play a critical role in lymphomagenesis, there has been interest in targeting this pathway across lymphoma subtypes. Though PI3K inhibitors have been found to be active agents, they have also been associated with poor tolerability and safety concerns. Parsaclisib is a selective PI3K delta inhibitor that showed encouraging data in the phase 1/2 study in patients with non-Hodgkin lymphoma.³ More recently, the phase 2 CITADEL-205 study, which included adult patients with relapsed or refractory MCL previously treated with one to three systemic therapies, with (n = 53) or without (n = 108) prior BTK inhibitor treatment, was published (Zinazni et al). Patients received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily. Among BTK inhibitor–naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 months (95% CI 9.0 to not evaluable). Responses were not thought to be clinically meaningful in the patients treated with prior BTK inhibitors. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions. A total of 30% of patients required drug discontinuation due to adverse events. Though parsaclisib demonstrated activity in patients with relapsed/refractory MCL, the role of this drug in clinical practice is not clear given the increased use of BTK inhibitors as a preferred second-line therapy and ongoing concerns regarding PI3K inhibitor-related toxicity.

Additional References

1.      Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594-2606. doi: 10.1200/JCO.22.01797

2.      Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: A model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138:2499-2513. doi: 10.1182/blood.2020010543

3.      Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742-1752. doi: 10.1182/blood-2018-08-867499

The treatment of mantle cell lymphoma (MCL) continues to evolve. In the front-line setting, studies are evaluating the role of novel therapies as well as consolidation with autologous stem cell transplantation. In the relapsed/refractory setting, patients can be considered for treatment with Bruton tyrosine kinase (BTK) inhibitors, other targeted therapies, or chimeric antigen receptor (CAR) T-cell therapy. Other novel therapies, including bispecific antibodies and novel antibody drug conjugates, are being studied as well.

Despite the availability of novel agents, a subset of patients continues to have difficult-to-treat disease and a poor prognosis. Established prognostic tools that aid in identifying high-risk patients include alternations in TP53, high proliferation rates, nonclassic morphology, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which incorporates age, performance status, lactate dehydrogenase levels, and white blood cell count. The Nordic study group recently published a paper which provides additional prognostic information beyond these known variables (Rodrigues et al). They examined MYC expression in a cohort of 251 patients with MCL and structural aberrations in MYC and MYC mRNA levels in a smaller cohort. They found that patients with tumors comprising 20% or more cells with MYC overexpression (MYC^high tumors) vs MYC^low tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04), when adjusted for additional high-risk features. Patients with tumors with concomitant MYC^high expression and TP53/p53 alterations vs MYC^low tumors had a particularly poor prognosis, with significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of only 0.9 years (both P < .001). Though MYC overexpression was rare, this study identified a high-risk group of patients, especially those harboring concurrent TP53 aberrations, that may benefit from novel treatment approaches.

Another study recently aimed to identify patients who are at risk for poor outcomes after treatment with brexucabtagene autoleucel (brexu-cel) infusion. Though brexu-cel is an active therapy for patients with relapsed/refractory MCL, there are known toxicities, including cytokine release syndrome, neurologic toxicity, and hematologic toxicity. Given the potential for prolonged cytopenias and immune suppression, patients are also at risk for severe infections, which currently represent the driving determinant of nonrelapse mortality.¹ The CAR-HEMATOTOX (HT) score was previously found to identify patients who are at increased risk for hematologic toxicity after CAR T-cell therapy in diffuse large B-cell lymphoma.² In the current multicenter observational study, which included 103 patients receiving brexu-cel, the authors reported an association between baseline HT score and outcome in MCL as well. Patients with high (2-7) vs low (0-1) HT scores had significantly longer median duration of severe neutropenia (P < .0001), higher rates of severe infections (P = .001), and lower overall response rates (P = .003). The HT score represented an independent predictor of poor progression-free (aHR 3.7; P < .001) and overall (aHR 5.6; P = .002) survival. This tool may provide a helpful guide when counseling patients on treatment options and allow for more personalized toxicity management.

Despite availability of BTK inhibitors and CAR T-cell therapy for patients with MCL, relapses remain common. As upregulation of phosphoinositide 3-kinase (PI3K) is known to play a critical role in lymphomagenesis, there has been interest in targeting this pathway across lymphoma subtypes. Though PI3K inhibitors have been found to be active agents, they have also been associated with poor tolerability and safety concerns. Parsaclisib is a selective PI3K delta inhibitor that showed encouraging data in the phase 1/2 study in patients with non-Hodgkin lymphoma.³ More recently, the phase 2 CITADEL-205 study, which included adult patients with relapsed or refractory MCL previously treated with one to three systemic therapies, with (n = 53) or without (n = 108) prior BTK inhibitor treatment, was published (Zinazni et al). Patients received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily. Among BTK inhibitor–naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 months (95% CI 9.0 to not evaluable). Responses were not thought to be clinically meaningful in the patients treated with prior BTK inhibitors. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions. A total of 30% of patients required drug discontinuation due to adverse events. Though parsaclisib demonstrated activity in patients with relapsed/refractory MCL, the role of this drug in clinical practice is not clear given the increased use of BTK inhibitors as a preferred second-line therapy and ongoing concerns regarding PI3K inhibitor-related toxicity.

Additional References

1.      Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594-2606. doi: 10.1200/JCO.22.01797

2.      Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: A model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138:2499-2513. doi: 10.1182/blood.2020010543

3.      Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742-1752. doi: 10.1182/blood-2018-08-867499

The treatment of mantle cell lymphoma (MCL) continues to evolve. In the front-line setting, studies are evaluating the role of novel therapies as well as consolidation with autologous stem cell transplantation. In the relapsed/refractory setting, patients can be considered for treatment with Bruton tyrosine kinase (BTK) inhibitors, other targeted therapies, or chimeric antigen receptor (CAR) T-cell therapy. Other novel therapies, including bispecific antibodies and novel antibody drug conjugates, are being studied as well.

Despite the availability of novel agents, a subset of patients continues to have difficult-to-treat disease and a poor prognosis. Established prognostic tools that aid in identifying high-risk patients include alternations in TP53, high proliferation rates, nonclassic morphology, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which incorporates age, performance status, lactate dehydrogenase levels, and white blood cell count. The Nordic study group recently published a paper which provides additional prognostic information beyond these known variables (Rodrigues et al). They examined MYC expression in a cohort of 251 patients with MCL and structural aberrations in MYC and MYC mRNA levels in a smaller cohort. They found that patients with tumors comprising 20% or more cells with MYC overexpression (MYC^high tumors) vs MYC^low tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04), when adjusted for additional high-risk features. Patients with tumors with concomitant MYC^high expression and TP53/p53 alterations vs MYC^low tumors had a particularly poor prognosis, with significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of only 0.9 years (both P < .001). Though MYC overexpression was rare, this study identified a high-risk group of patients, especially those harboring concurrent TP53 aberrations, that may benefit from novel treatment approaches.

Another study recently aimed to identify patients who are at risk for poor outcomes after treatment with brexucabtagene autoleucel (brexu-cel) infusion. Though brexu-cel is an active therapy for patients with relapsed/refractory MCL, there are known toxicities, including cytokine release syndrome, neurologic toxicity, and hematologic toxicity. Given the potential for prolonged cytopenias and immune suppression, patients are also at risk for severe infections, which currently represent the driving determinant of nonrelapse mortality.¹ The CAR-HEMATOTOX (HT) score was previously found to identify patients who are at increased risk for hematologic toxicity after CAR T-cell therapy in diffuse large B-cell lymphoma.² In the current multicenter observational study, which included 103 patients receiving brexu-cel, the authors reported an association between baseline HT score and outcome in MCL as well. Patients with high (2-7) vs low (0-1) HT scores had significantly longer median duration of severe neutropenia (P < .0001), higher rates of severe infections (P = .001), and lower overall response rates (P = .003). The HT score represented an independent predictor of poor progression-free (aHR 3.7; P < .001) and overall (aHR 5.6; P = .002) survival. This tool may provide a helpful guide when counseling patients on treatment options and allow for more personalized toxicity management.

Despite availability of BTK inhibitors and CAR T-cell therapy for patients with MCL, relapses remain common. As upregulation of phosphoinositide 3-kinase (PI3K) is known to play a critical role in lymphomagenesis, there has been interest in targeting this pathway across lymphoma subtypes. Though PI3K inhibitors have been found to be active agents, they have also been associated with poor tolerability and safety concerns. Parsaclisib is a selective PI3K delta inhibitor that showed encouraging data in the phase 1/2 study in patients with non-Hodgkin lymphoma.³ More recently, the phase 2 CITADEL-205 study, which included adult patients with relapsed or refractory MCL previously treated with one to three systemic therapies, with (n = 53) or without (n = 108) prior BTK inhibitor treatment, was published (Zinazni et al). Patients received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily. Among BTK inhibitor–naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 months (95% CI 9.0 to not evaluable). Responses were not thought to be clinically meaningful in the patients treated with prior BTK inhibitors. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions. A total of 30% of patients required drug discontinuation due to adverse events. Though parsaclisib demonstrated activity in patients with relapsed/refractory MCL, the role of this drug in clinical practice is not clear given the increased use of BTK inhibitors as a preferred second-line therapy and ongoing concerns regarding PI3K inhibitor-related toxicity.

Additional References

1.      Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594-2606. doi: 10.1200/JCO.22.01797

2.      Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: A model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138:2499-2513. doi: 10.1182/blood.2020010543

3.      Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742-1752. doi: 10.1182/blood-2018-08-867499

TOPLINE:

When patients deal directly with their insurance companies for answers about copayments and other issues, they are more likely to experience delays in cancer care and to be nonadherent.

METHODOLOGY:

• Navigating the complexities of insurance coverage is difficult for cancer patients, and the clinical impact of managing these intricacies remains unclear.
• To understand the issue, investigators surveyed 510 insured cancer patients in the United States about how often they estimate out-of-pocket costs for medications, doctors’ visits, and lab tests and scans, as well as how often they ask their insurance company to help them understand their coverage and how often they appeal coverage decisions.
• The team then correlated the answers with how often patients reported postponing or skipping doctors’ appointments and lab tests and how often they delayed filling prescriptions or skipped doses.
• Breast, colorectal, lung, and prostate cancer were the most common diagnoses among respondents.

TAKEAWAY:

• Overall, 55% of participants said they “never” or “rarely” engaged in any insurance-related cost tasks. The most frequently performed administrative tasks included finding out the cost before filling a prescription (28%) or before undergoing lab tests or scans (20%), as well as estimating the cost before agreeing to a treatment (20%), asking an insurance company for help understanding coverage (18%), or appealing a denial (17%).
• After adjusting for age, race/ethnicity, education, and monthly out-of-pocket costs, participants who engaged in any cost task were 18% more likely to experience treatment delays or forgo care.
• Every additional cost task or increase in frequency of a cost task was associated with 32% higher frequency of treatment delay or nonadherence.
• Age, race, and monthly out-of-pocket costs were more strongly associated with treatment delays/nonadherence than cost-task burden. Younger patients and Black patients were more likely than others to experience cost-related delays/nonadherence.

IN PRACTICE:

• “Reductions to administrative burden on patients, whether through patient-level education interventions, the adaptation of hospital-based navigation programs, or policy-focused changes to insurance systems, will be crucial” for helping patients with cancer to overcome administrative burdens and improve access to care, the authors said.

SOURCE:

• The study, led by Meredith Doherty, PhD, of the University of Pennsylvania, Philadelphia, was published in Cancer Epidemiology, Biomarkers and Prevention.

LIMITATIONS:

The survey was voluntary, which raises the possibility of self-selection bias. Recall bias may also have occurred, particularly among patients farther out from diagnosis and treatment. The investigators did not include uninsured patients and did not stratify patients by insurance type, and they did not measure or account for health care literacy.

DISCLOSURES:

The study was funded by the American Cancer Society. The investigators have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

When patients deal directly with their insurance companies for answers about copayments and other issues, they are more likely to experience delays in cancer care and to be nonadherent.

METHODOLOGY:

• Navigating the complexities of insurance coverage is difficult for cancer patients, and the clinical impact of managing these intricacies remains unclear.
• To understand the issue, investigators surveyed 510 insured cancer patients in the United States about how often they estimate out-of-pocket costs for medications, doctors’ visits, and lab tests and scans, as well as how often they ask their insurance company to help them understand their coverage and how often they appeal coverage decisions.
• The team then correlated the answers with how often patients reported postponing or skipping doctors’ appointments and lab tests and how often they delayed filling prescriptions or skipped doses.
• Breast, colorectal, lung, and prostate cancer were the most common diagnoses among respondents.

TAKEAWAY:

• Overall, 55% of participants said they “never” or “rarely” engaged in any insurance-related cost tasks. The most frequently performed administrative tasks included finding out the cost before filling a prescription (28%) or before undergoing lab tests or scans (20%), as well as estimating the cost before agreeing to a treatment (20%), asking an insurance company for help understanding coverage (18%), or appealing a denial (17%).
• After adjusting for age, race/ethnicity, education, and monthly out-of-pocket costs, participants who engaged in any cost task were 18% more likely to experience treatment delays or forgo care.
• Every additional cost task or increase in frequency of a cost task was associated with 32% higher frequency of treatment delay or nonadherence.
• Age, race, and monthly out-of-pocket costs were more strongly associated with treatment delays/nonadherence than cost-task burden. Younger patients and Black patients were more likely than others to experience cost-related delays/nonadherence.

IN PRACTICE:

• “Reductions to administrative burden on patients, whether through patient-level education interventions, the adaptation of hospital-based navigation programs, or policy-focused changes to insurance systems, will be crucial” for helping patients with cancer to overcome administrative burdens and improve access to care, the authors said.

SOURCE:

• The study, led by Meredith Doherty, PhD, of the University of Pennsylvania, Philadelphia, was published in Cancer Epidemiology, Biomarkers and Prevention.

LIMITATIONS:

The survey was voluntary, which raises the possibility of self-selection bias. Recall bias may also have occurred, particularly among patients farther out from diagnosis and treatment. The investigators did not include uninsured patients and did not stratify patients by insurance type, and they did not measure or account for health care literacy.

DISCLOSURES:

The study was funded by the American Cancer Society. The investigators have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

When patients deal directly with their insurance companies for answers about copayments and other issues, they are more likely to experience delays in cancer care and to be nonadherent.

METHODOLOGY:

• Navigating the complexities of insurance coverage is difficult for cancer patients, and the clinical impact of managing these intricacies remains unclear.
• To understand the issue, investigators surveyed 510 insured cancer patients in the United States about how often they estimate out-of-pocket costs for medications, doctors’ visits, and lab tests and scans, as well as how often they ask their insurance company to help them understand their coverage and how often they appeal coverage decisions.
• The team then correlated the answers with how often patients reported postponing or skipping doctors’ appointments and lab tests and how often they delayed filling prescriptions or skipped doses.
• Breast, colorectal, lung, and prostate cancer were the most common diagnoses among respondents.

TAKEAWAY:

• Overall, 55% of participants said they “never” or “rarely” engaged in any insurance-related cost tasks. The most frequently performed administrative tasks included finding out the cost before filling a prescription (28%) or before undergoing lab tests or scans (20%), as well as estimating the cost before agreeing to a treatment (20%), asking an insurance company for help understanding coverage (18%), or appealing a denial (17%).
• After adjusting for age, race/ethnicity, education, and monthly out-of-pocket costs, participants who engaged in any cost task were 18% more likely to experience treatment delays or forgo care.
• Every additional cost task or increase in frequency of a cost task was associated with 32% higher frequency of treatment delay or nonadherence.
• Age, race, and monthly out-of-pocket costs were more strongly associated with treatment delays/nonadherence than cost-task burden. Younger patients and Black patients were more likely than others to experience cost-related delays/nonadherence.

IN PRACTICE:

• “Reductions to administrative burden on patients, whether through patient-level education interventions, the adaptation of hospital-based navigation programs, or policy-focused changes to insurance systems, will be crucial” for helping patients with cancer to overcome administrative burdens and improve access to care, the authors said.

SOURCE:

• The study, led by Meredith Doherty, PhD, of the University of Pennsylvania, Philadelphia, was published in Cancer Epidemiology, Biomarkers and Prevention.

LIMITATIONS:

The survey was voluntary, which raises the possibility of self-selection bias. Recall bias may also have occurred, particularly among patients farther out from diagnosis and treatment. The investigators did not include uninsured patients and did not stratify patients by insurance type, and they did not measure or account for health care literacy.

DISCLOSURES:

The study was funded by the American Cancer Society. The investigators have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Endocrine therapy (ET) remains the backbone of treatment for hormone receptor–positive breast cancer; however, 15%-20% of tumors are initially resistant to ET and endocrine resistance develops over time in approximately 30%-40%.² In an effort to overcome limitations with historical standard-of-care endocrine agents, the class of oral potent selective estrogen receptor degraders (SERD) is evolving. The phase 2, randomized, controlled coopERA Breast Cancer trial evaluated the antiproliferative effect of giredestrant (a highly potent nonsteroidal oral SERD) compared with anastrozole (each combined with palbociclib after 2-week window-of-opportunity phase) among postmenopausal women with early-stage (cT1c-cT4) ER+/HER2- breast cancer with a Ki67 score ≥ 5% (Hurvitz et al). Among 221 enrolled patients (giredestrant group n = 112, and anastrozole group n = 109), giredestrant led to a significantly greater relative geometric mean reduction of Ki67 at 2 weeks from baseline compared with anastrozole (-75% vs -67%; P = 0.043). Neutropenia (26% and 27%) and decreased neutrophil count (15% and 15%) were the most common grade 3-4 adverse events in the giredestrant-palbociclib and anastrozole-palbociclib groups, respectively. The value of Ki67 as a biomarker for efficacy and outcome was demonstrated in the phase 3 POETIC trial, which showed that the degree of Ki67 reduction after 2 weeks of ET correlated with 5-year recurrence risk.³ These data encourage further investigation of oral SERD combinations, predictors of response, and long-term outcomes that may influence agent selection and sequencing.

Anticancer properties have been demonstrated with aspirin, statins, and metformin, although the data on the prognostic impact of these agents in breast cancer have shown mixed results.⁴ A nationwide population-based cohort study including 26,190 women aged 50 years or older diagnosed with breast cancer and surviving 12 months or more after diagnosis was performed to evaluate the postdiagnosis use of aspirin, statins, and metformin and association with breast cancer-specific survival (BCSS) (Löfling et al). At 6.1 years of follow-up, there were 2169 deaths related to breast cancer and the results supported an association of postdiagnostic use of statins and metformin with survival (hazard ratio for association between use of statins vs no use and BCSS was 0.84 [95% CI 0.75-0.94]; hazard ratio for association between metformin use vs use of nonmetformin antidiabetics and BCSS was 0.70 [95% CI 0.51-0.96]). Furthermore, there appeared to be differences in association by ER status. An important relationship exists between cardiovascular health and breast cancer, and future efforts should continue to study pharmacologic and lifestyle interventions that may optimize metabolic profiles and improve outcomes for patients.

Additional References

1. Kunkler IH, Williams LJ, Jack WJL, et al. Breast-conserving surgery with or without irradiation in early breast cancer. N Engl J Med. 2023;388:585-594. doi: 10.1056/NEJMoa2207586  
2. Lei JT, Anurag M, Haricharan S, et al. Endocrine therapy resistance: New insights. Breast. 2019;48:S26-S30. doi: 10.1016/S0960-9776(19)31118-X  
3. Smith I, Robertson J, Kilburn L, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): An open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020;21:1443-1454. doi: 10.1016/S1470-2045(20)30458-7
4. Nowakowska MK, Lei X, Thompson MT, et al. Association of statin use with clinical outcomes in patients with triple-negative breast cancer. Cancer. 2021;127:4142-4150. doi: 10.1002/cncr.33797

Endocrine therapy (ET) remains the backbone of treatment for hormone receptor–positive breast cancer; however, 15%-20% of tumors are initially resistant to ET and endocrine resistance develops over time in approximately 30%-40%.² In an effort to overcome limitations with historical standard-of-care endocrine agents, the class of oral potent selective estrogen receptor degraders (SERD) is evolving. The phase 2, randomized, controlled coopERA Breast Cancer trial evaluated the antiproliferative effect of giredestrant (a highly potent nonsteroidal oral SERD) compared with anastrozole (each combined with palbociclib after 2-week window-of-opportunity phase) among postmenopausal women with early-stage (cT1c-cT4) ER+/HER2- breast cancer with a Ki67 score ≥ 5% (Hurvitz et al). Among 221 enrolled patients (giredestrant group n = 112, and anastrozole group n = 109), giredestrant led to a significantly greater relative geometric mean reduction of Ki67 at 2 weeks from baseline compared with anastrozole (-75% vs -67%; P = 0.043). Neutropenia (26% and 27%) and decreased neutrophil count (15% and 15%) were the most common grade 3-4 adverse events in the giredestrant-palbociclib and anastrozole-palbociclib groups, respectively. The value of Ki67 as a biomarker for efficacy and outcome was demonstrated in the phase 3 POETIC trial, which showed that the degree of Ki67 reduction after 2 weeks of ET correlated with 5-year recurrence risk.³ These data encourage further investigation of oral SERD combinations, predictors of response, and long-term outcomes that may influence agent selection and sequencing.

Anticancer properties have been demonstrated with aspirin, statins, and metformin, although the data on the prognostic impact of these agents in breast cancer have shown mixed results.⁴ A nationwide population-based cohort study including 26,190 women aged 50 years or older diagnosed with breast cancer and surviving 12 months or more after diagnosis was performed to evaluate the postdiagnosis use of aspirin, statins, and metformin and association with breast cancer-specific survival (BCSS) (Löfling et al). At 6.1 years of follow-up, there were 2169 deaths related to breast cancer and the results supported an association of postdiagnostic use of statins and metformin with survival (hazard ratio for association between use of statins vs no use and BCSS was 0.84 [95% CI 0.75-0.94]; hazard ratio for association between metformin use vs use of nonmetformin antidiabetics and BCSS was 0.70 [95% CI 0.51-0.96]). Furthermore, there appeared to be differences in association by ER status. An important relationship exists between cardiovascular health and breast cancer, and future efforts should continue to study pharmacologic and lifestyle interventions that may optimize metabolic profiles and improve outcomes for patients.

Additional References

1. Kunkler IH, Williams LJ, Jack WJL, et al. Breast-conserving surgery with or without irradiation in early breast cancer. N Engl J Med. 2023;388:585-594. doi: 10.1056/NEJMoa2207586  
2. Lei JT, Anurag M, Haricharan S, et al. Endocrine therapy resistance: New insights. Breast. 2019;48:S26-S30. doi: 10.1016/S0960-9776(19)31118-X  
3. Smith I, Robertson J, Kilburn L, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): An open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020;21:1443-1454. doi: 10.1016/S1470-2045(20)30458-7
4. Nowakowska MK, Lei X, Thompson MT, et al. Association of statin use with clinical outcomes in patients with triple-negative breast cancer. Cancer. 2021;127:4142-4150. doi: 10.1002/cncr.33797

Endocrine therapy (ET) remains the backbone of treatment for hormone receptor–positive breast cancer; however, 15%-20% of tumors are initially resistant to ET and endocrine resistance develops over time in approximately 30%-40%.² In an effort to overcome limitations with historical standard-of-care endocrine agents, the class of oral potent selective estrogen receptor degraders (SERD) is evolving. The phase 2, randomized, controlled coopERA Breast Cancer trial evaluated the antiproliferative effect of giredestrant (a highly potent nonsteroidal oral SERD) compared with anastrozole (each combined with palbociclib after 2-week window-of-opportunity phase) among postmenopausal women with early-stage (cT1c-cT4) ER+/HER2- breast cancer with a Ki67 score ≥ 5% (Hurvitz et al). Among 221 enrolled patients (giredestrant group n = 112, and anastrozole group n = 109), giredestrant led to a significantly greater relative geometric mean reduction of Ki67 at 2 weeks from baseline compared with anastrozole (-75% vs -67%; P = 0.043). Neutropenia (26% and 27%) and decreased neutrophil count (15% and 15%) were the most common grade 3-4 adverse events in the giredestrant-palbociclib and anastrozole-palbociclib groups, respectively. The value of Ki67 as a biomarker for efficacy and outcome was demonstrated in the phase 3 POETIC trial, which showed that the degree of Ki67 reduction after 2 weeks of ET correlated with 5-year recurrence risk.³ These data encourage further investigation of oral SERD combinations, predictors of response, and long-term outcomes that may influence agent selection and sequencing.

Anticancer properties have been demonstrated with aspirin, statins, and metformin, although the data on the prognostic impact of these agents in breast cancer have shown mixed results.⁴ A nationwide population-based cohort study including 26,190 women aged 50 years or older diagnosed with breast cancer and surviving 12 months or more after diagnosis was performed to evaluate the postdiagnosis use of aspirin, statins, and metformin and association with breast cancer-specific survival (BCSS) (Löfling et al). At 6.1 years of follow-up, there were 2169 deaths related to breast cancer and the results supported an association of postdiagnostic use of statins and metformin with survival (hazard ratio for association between use of statins vs no use and BCSS was 0.84 [95% CI 0.75-0.94]; hazard ratio for association between metformin use vs use of nonmetformin antidiabetics and BCSS was 0.70 [95% CI 0.51-0.96]). Furthermore, there appeared to be differences in association by ER status. An important relationship exists between cardiovascular health and breast cancer, and future efforts should continue to study pharmacologic and lifestyle interventions that may optimize metabolic profiles and improve outcomes for patients.

Additional References

1. Kunkler IH, Williams LJ, Jack WJL, et al. Breast-conserving surgery with or without irradiation in early breast cancer. N Engl J Med. 2023;388:585-594. doi: 10.1056/NEJMoa2207586  
2. Lei JT, Anurag M, Haricharan S, et al. Endocrine therapy resistance: New insights. Breast. 2019;48:S26-S30. doi: 10.1016/S0960-9776(19)31118-X  
3. Smith I, Robertson J, Kilburn L, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): An open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020;21:1443-1454. doi: 10.1016/S1470-2045(20)30458-7
4. Nowakowska MK, Lei X, Thompson MT, et al. Association of statin use with clinical outcomes in patients with triple-negative breast cancer. Cancer. 2021;127:4142-4150. doi: 10.1002/cncr.33797

A recently published study by Rugo and colleagues presented the final analysis of overall survival and endpoints by trophoblast cell surface antigen 2 (Trop-2) expression. Results showed that at the 12.5-month median follow-up, sacituzumab govitecan vs chemotherapy improved overall survival by 3.2 months (hazard ratio 0.79; P = .020). The survival benefit was consistent across different levels of Trop-2 expression. No new adverse events were reported; however, one fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. These updated data continue to support the use of sacituzumab govitecan as a new treatment option for patients with endocrine-resistant HR+ and HER2- MBC.

It remains unclear whether anti-HER2 therapy alone (without chemotherapy) is an effective treatment approach for patients with ERBB2-positive MBC in the first-line setting. Huober and the Swiss Group for Clinical Cancer Research, the Unicancer Breast Group, and the Dutch Breast Cancer Research Group report a phase 2 trial that included 210 patients with ERBB2+ MBC who were randomly assigned to receive pertuzumab plus trastuzumab with or without chemotherapy followed by trastuzumab-emtansine as the second-line therapy in both groups. Despite worse progression-free survival in the nonchemotherapy vs the chemotherapy group (8.4 months [95% CI 7.9-12.0] vs 23.3 months [95% CI 18.9-33.1]), overall survival rates were comparable at 2 years of follow-up (79.0% [90% CI 71.4%-85.4%] vs 78.1% [90% CI 70.4%-84.5%]). Furthermore, adverse events were more frequent in the chemotherapy cohort, with small quality-of-life improvements from baseline in the nonchemotherapy cohort. Further prospective data are needed to confirm whether a chemotherapy-free approach is an acceptable treatment approach in certain population of patients, without unfavorable effects on overall survival.

Prior results from the SOFT and TEXT trials have shown improved survival with the addition of ovarian function suppression (OFS) in premenopausal women after chemotherapy. The ASTRRA trial is a similar phase 3 study that included 1282 premenopausal women with estrogen receptor–positive BC who remained premenopausal or regained ovarian function after chemotherapy and were randomly assigned to receive tamoxifen with or without OFS. The results showed a consistent disease-free survival benefit in women who received tamoxifen plus OFS vs tamoxifen alone (85.4% vs 80.2%; hazard ratio 0.67; P = .003) after a median follow-up of 8 years. There were no significant differences in 8-year OS rates between the two groups (P = .305), although both cohorts had high OS rates overall (> 95%). This trial highlights the overall excellent prognosis in this patient population and underscores the importance of OFS in the subgroup of patients who remain in a premenopausal state or resume ovarian function after chemotherapy.

The ICE study (Ibandronate with or without Capecitabine in Elderly patients with early breast cancer) was a phase 3 trial looking at 1358 patients age ≥ 65 years with node-positive or high-risk node-negative early BC who were randomly assigned to receive 2 years of ibandronate with or without capecitabine for six cycles in the adjuvant setting. At a median follow-up of 61 months, the 5-year invasive disease-free survival rates were similar amongst patients treated with adjuvant ibandronate plus capecitabine and ibandronate alone (hazard ratio 0.96; 95% CI 0.78-1.19). Outcomes were independent of age, nodal status, and hormone receptor status. The incidences of high-grade gastrointestinal disorders (6.7% vs 1.0%; P < .001) and skin toxicity (14.6% vs 0.6%; P < .01) were significantly higher in the capecitabine plus ibandronate arm vs the ibandronate alone arm.

Adjuvant capecitabine plus ibandronate failed to show improved survival outcomes compared with ibandronate alone in older patients with node-positive/high-risk node-negative BC. This was similar to results of the CALGB 49907 trial, which showed inferior survival for adjuvant capecitabine compared with standard adjuvant chemotherapy in patients ≥ 65 years of age.¹ Therefore, although oral capecitabine may be more tolerable than intravenous polychemotherapy in older patients with high-risk BC, this should be weighed against lower efficacy.

Additional Reference

1. Muss HB, Berry DA, Cirrincione CT, et al, for the CALGB Investigators. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009;360:2055-2065. doi: 10.1056/NEJMoa0810266

A recently published study by Rugo and colleagues presented the final analysis of overall survival and endpoints by trophoblast cell surface antigen 2 (Trop-2) expression. Results showed that at the 12.5-month median follow-up, sacituzumab govitecan vs chemotherapy improved overall survival by 3.2 months (hazard ratio 0.79; P = .020). The survival benefit was consistent across different levels of Trop-2 expression. No new adverse events were reported; however, one fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. These updated data continue to support the use of sacituzumab govitecan as a new treatment option for patients with endocrine-resistant HR+ and HER2- MBC.

It remains unclear whether anti-HER2 therapy alone (without chemotherapy) is an effective treatment approach for patients with ERBB2-positive MBC in the first-line setting. Huober and the Swiss Group for Clinical Cancer Research, the Unicancer Breast Group, and the Dutch Breast Cancer Research Group report a phase 2 trial that included 210 patients with ERBB2+ MBC who were randomly assigned to receive pertuzumab plus trastuzumab with or without chemotherapy followed by trastuzumab-emtansine as the second-line therapy in both groups. Despite worse progression-free survival in the nonchemotherapy vs the chemotherapy group (8.4 months [95% CI 7.9-12.0] vs 23.3 months [95% CI 18.9-33.1]), overall survival rates were comparable at 2 years of follow-up (79.0% [90% CI 71.4%-85.4%] vs 78.1% [90% CI 70.4%-84.5%]). Furthermore, adverse events were more frequent in the chemotherapy cohort, with small quality-of-life improvements from baseline in the nonchemotherapy cohort. Further prospective data are needed to confirm whether a chemotherapy-free approach is an acceptable treatment approach in certain population of patients, without unfavorable effects on overall survival.

Prior results from the SOFT and TEXT trials have shown improved survival with the addition of ovarian function suppression (OFS) in premenopausal women after chemotherapy. The ASTRRA trial is a similar phase 3 study that included 1282 premenopausal women with estrogen receptor–positive BC who remained premenopausal or regained ovarian function after chemotherapy and were randomly assigned to receive tamoxifen with or without OFS. The results showed a consistent disease-free survival benefit in women who received tamoxifen plus OFS vs tamoxifen alone (85.4% vs 80.2%; hazard ratio 0.67; P = .003) after a median follow-up of 8 years. There were no significant differences in 8-year OS rates between the two groups (P = .305), although both cohorts had high OS rates overall (> 95%). This trial highlights the overall excellent prognosis in this patient population and underscores the importance of OFS in the subgroup of patients who remain in a premenopausal state or resume ovarian function after chemotherapy.

The ICE study (Ibandronate with or without Capecitabine in Elderly patients with early breast cancer) was a phase 3 trial looking at 1358 patients age ≥ 65 years with node-positive or high-risk node-negative early BC who were randomly assigned to receive 2 years of ibandronate with or without capecitabine for six cycles in the adjuvant setting. At a median follow-up of 61 months, the 5-year invasive disease-free survival rates were similar amongst patients treated with adjuvant ibandronate plus capecitabine and ibandronate alone (hazard ratio 0.96; 95% CI 0.78-1.19). Outcomes were independent of age, nodal status, and hormone receptor status. The incidences of high-grade gastrointestinal disorders (6.7% vs 1.0%; P < .001) and skin toxicity (14.6% vs 0.6%; P < .01) were significantly higher in the capecitabine plus ibandronate arm vs the ibandronate alone arm.

Adjuvant capecitabine plus ibandronate failed to show improved survival outcomes compared with ibandronate alone in older patients with node-positive/high-risk node-negative BC. This was similar to results of the CALGB 49907 trial, which showed inferior survival for adjuvant capecitabine compared with standard adjuvant chemotherapy in patients ≥ 65 years of age.¹ Therefore, although oral capecitabine may be more tolerable than intravenous polychemotherapy in older patients with high-risk BC, this should be weighed against lower efficacy.

Additional Reference

1. Muss HB, Berry DA, Cirrincione CT, et al, for the CALGB Investigators. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009;360:2055-2065. doi: 10.1056/NEJMoa0810266

A recently published study by Rugo and colleagues presented the final analysis of overall survival and endpoints by trophoblast cell surface antigen 2 (Trop-2) expression. Results showed that at the 12.5-month median follow-up, sacituzumab govitecan vs chemotherapy improved overall survival by 3.2 months (hazard ratio 0.79; P = .020). The survival benefit was consistent across different levels of Trop-2 expression. No new adverse events were reported; however, one fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. These updated data continue to support the use of sacituzumab govitecan as a new treatment option for patients with endocrine-resistant HR+ and HER2- MBC.

It remains unclear whether anti-HER2 therapy alone (without chemotherapy) is an effective treatment approach for patients with ERBB2-positive MBC in the first-line setting. Huober and the Swiss Group for Clinical Cancer Research, the Unicancer Breast Group, and the Dutch Breast Cancer Research Group report a phase 2 trial that included 210 patients with ERBB2+ MBC who were randomly assigned to receive pertuzumab plus trastuzumab with or without chemotherapy followed by trastuzumab-emtansine as the second-line therapy in both groups. Despite worse progression-free survival in the nonchemotherapy vs the chemotherapy group (8.4 months [95% CI 7.9-12.0] vs 23.3 months [95% CI 18.9-33.1]), overall survival rates were comparable at 2 years of follow-up (79.0% [90% CI 71.4%-85.4%] vs 78.1% [90% CI 70.4%-84.5%]). Furthermore, adverse events were more frequent in the chemotherapy cohort, with small quality-of-life improvements from baseline in the nonchemotherapy cohort. Further prospective data are needed to confirm whether a chemotherapy-free approach is an acceptable treatment approach in certain population of patients, without unfavorable effects on overall survival.

Prior results from the SOFT and TEXT trials have shown improved survival with the addition of ovarian function suppression (OFS) in premenopausal women after chemotherapy. The ASTRRA trial is a similar phase 3 study that included 1282 premenopausal women with estrogen receptor–positive BC who remained premenopausal or regained ovarian function after chemotherapy and were randomly assigned to receive tamoxifen with or without OFS. The results showed a consistent disease-free survival benefit in women who received tamoxifen plus OFS vs tamoxifen alone (85.4% vs 80.2%; hazard ratio 0.67; P = .003) after a median follow-up of 8 years. There were no significant differences in 8-year OS rates between the two groups (P = .305), although both cohorts had high OS rates overall (> 95%). This trial highlights the overall excellent prognosis in this patient population and underscores the importance of OFS in the subgroup of patients who remain in a premenopausal state or resume ovarian function after chemotherapy.

The ICE study (Ibandronate with or without Capecitabine in Elderly patients with early breast cancer) was a phase 3 trial looking at 1358 patients age ≥ 65 years with node-positive or high-risk node-negative early BC who were randomly assigned to receive 2 years of ibandronate with or without capecitabine for six cycles in the adjuvant setting. At a median follow-up of 61 months, the 5-year invasive disease-free survival rates were similar amongst patients treated with adjuvant ibandronate plus capecitabine and ibandronate alone (hazard ratio 0.96; 95% CI 0.78-1.19). Outcomes were independent of age, nodal status, and hormone receptor status. The incidences of high-grade gastrointestinal disorders (6.7% vs 1.0%; P < .001) and skin toxicity (14.6% vs 0.6%; P < .01) were significantly higher in the capecitabine plus ibandronate arm vs the ibandronate alone arm.

Adjuvant capecitabine plus ibandronate failed to show improved survival outcomes compared with ibandronate alone in older patients with node-positive/high-risk node-negative BC. This was similar to results of the CALGB 49907 trial, which showed inferior survival for adjuvant capecitabine compared with standard adjuvant chemotherapy in patients ≥ 65 years of age.¹ Therefore, although oral capecitabine may be more tolerable than intravenous polychemotherapy in older patients with high-risk BC, this should be weighed against lower efficacy.

Additional Reference

1. Muss HB, Berry DA, Cirrincione CT, et al, for the CALGB Investigators. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009;360:2055-2065. doi: 10.1056/NEJMoa0810266

The quest to find an anticoagulant that can prevent strokes, cardiovascular events, and venous thrombosis without significantly increasing risk of bleeding is something of a holy grail in cardiovascular medicine. Could the latest focus of interest in this field – the factor XI inhibitors – be the long–sought-after answer?

Topline results from the largest study so far of a factor XI inhibitor – released on Sep. 18 – are indeed very encouraging. The phase 2 AZALEA-TIMI 71 study was stopped early because of an “overwhelming” reduction in major and clinically relevant nonmajor bleeding shown with the factor XI inhibitor abelacimab (Anthos), compared with apixaban for patients with atrial fibrillation (AFib).

Very few other data from this study have yet been released. Full results are due to be presented at the scientific sessions of the American Heart Association in November. Researchers in the field are optimistic that this new class of drugs may allow millions more patients who are at risk of thrombotic events but are concerned about bleeding risk to be treated, with a consequent reduction in strokes and possibly cardiovascular events as well.
 

Why factor XI?

The hope that factor XI inhibitors will prevent pathologic thrombosis with a lower bleeding risk, compared with other anticoagulants, comes down to the role of factor XI in the coagulation cascade.

In natural physiology, there are two ongoing processes: hemostasis – a set of actions that cause bleeding to stop after an injury – and thrombosis – a pathologic clotting process in which thrombus is formed and causes a stroke, MI, or deep venous thrombosis (DVT).

In patients prone to pathologic clotting, such as those with AFib, the balance of these two processes has shifted toward thrombosis, so anticoagulants are used to reduce the thrombotic risks. For many years, the only available oral anticoagulant was warfarin, a vitamin K antagonist that was very effective at preventing strokes but that comes with a high risk for bleeding, including intracranial hemorrhage (ICH) and fatal bleeding.

The introduction of the direct-acting anticoagulants (DOACs) a few years ago was a step forward in that these drugs have been shown to be as effective as warfarin but are associated with a lower risk of bleeding, particularly of ICH and fatal bleeding. But they still cause bleeding, and concerns over that risk of bleeding prevent millions of patients from taking these drugs and receiving protection against stroke.

John Alexander, MD, professor of medicine at Duke University Medical Center, Durham, N.C., a researcher active in this area, notes that “while the DOACs cause less bleeding than warfarin, they still cause two or three times more bleeding than placebo, and there is a huge, unmet need for safer anticoagulants that don’t cause as much bleeding. We are hopeful that factor XI inhibitors might be those anticoagulants.”

The lead investigator the AZALEA study, Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, explained why it is thought that factor XI inhibitors may be different.

“There’s a lot of different clotting factors, and most of them converge in a central pathway. The problem, therefore, with anticoagulants used to date that block one of these factors is that they prevent clotting but also cause bleeding.

“It has been discovered that factor XI has a really unique position in the cascade of how our body forms clots in that it seems to be important in clot formation, but it doesn’t seem to play a major role in our ability to heal and repair blood vessels.”

Another doctor involved in the field, Manesh Patel, MD, chief of cardiology at Duke University Medical Center, added, “We think that factor XI inhibitors may prevent the pathologic formation of thrombosis while allowing formation of thrombus for natural hemostasis to prevent bleeding. That is why they are so promising.”

This correlates with epidemiologic data suggesting that patients with a genetic factor XI deficiency have low rates of stroke and MI but don’t appear to bleed spontaneously, Dr. Patel notes.
 

Candidates in development

The pharmaceutical industry is on the case with several factor XI inhibitors now in clinical development. At present, three main candidates lead the field. These are abelacimab (Anthos), a monoclonal antibody given by subcutaneous injection once a month; and two small molecules, milvexian (BMS/Janssen) and asundexian (Bayer), which are both given orally.

Phase 3 trials of these three factor XI inhibitors have recently started for a variety of thrombotic indications, including the prevention of stroke in patients with AFib, prevention of recurrent stroke in patients with ischemic stroke, and prevention of future cardiovascular events in patients with acute coronary syndrome (ACS).

Dr. Alexander, who has been involved in clinical trials of both milvexian and asundexian, commented: “We have pretty good data from a number of phase 2 trials now that these factor XI inhibitors at the doses used in these studies cause a lot less bleeding than therapeutic doses of DOACs and low-molecular-weight heparins.”

He pointed out that, in addition to the AZALEA trial with abelacimab, the phase 2 PACIFIC program of studies has shown less bleeding with asundexian than with apixaban in patients with AFib and a similar amount of bleeding as placebo in ACS/stroke patients on top of antiplatelet therapy. Milvexian has also shown similar results in the AXIOMATIC program of studies.

Dr. Ruff noted that the biggest need for new anticoagulants in general is in the AFib population. “Atrial fibrillation is one of the most common medical conditions in the world. Approximately one in every three people will develop AFib in their lifetime, and it is associated with more than a fivefold increased risk of stroke. But up to half of patients with AFib currently do not take anticoagulants because of concerns about bleeding risks, so these patients are being left unprotected from stroke risk.”

Dr. Ruff pointed out that the AZALEA study was the largest and longest study of a factor XI inhibitor to date; 1,287 patients were followed for a median of 2 years.

“This was the first trial of long-term administration of factor XI inhibitor against a full-dose DOAC, and it was stopped because of an overwhelming reduction in a major bleeding with abelacimab, compared with rivaroxaban,” he noted. “That is very encouraging. It looks like our quest to develop a safe anticoagulant with much lower rates of bleeding, compared with standard of care, seems to have been borne out. I think the field is very excited that we may finally have something that protects patients from thrombosis whilst being much safer than current agents.”

While all this sounds very promising, for these drugs to be successful, in addition to reducing bleeding risk, they will also have to be effective at preventing strokes and other thrombotic events.

“While we are pretty sure that factor XI inhibitors will cause less bleeding than current anticoagulants, what is unknown still is how effective they will be at preventing pathologic blood clots,” Dr. Alexander points out.

“We have some data from studies of these drugs in DVT prophylaxis after orthopedic surgery which suggest that they are effective in preventing blood clots in that scenario. But we don’t know yet about whether they can prevent pathologic blood clots that occur in AFib patients or in poststroke or post-ACS patients. Phase 3 studies are now underway with these three leading drug candidates which will answer some of these questions.”

Dr. Patel agrees that the efficacy data in the phase 3 trials will be key to the success of these drugs. “That is a very important part of the puzzle that is still missing,” he says.

Dr. Ruff notes that the AZALEA study will provide some data on efficacy. “But we already know that in the orthopedic surgery trials there was a 70%-80% reduction in VTE with abelacimab (at the 150-mg dose going forward) vs. prophylactic doses of low-molecular-weight heparin. And we know from the DOACs that the doses preventing clots on the venous side also translated into preventing strokes on the [AFib] side. So that is very encouraging,” Dr. Ruff adds.
 

Potential indications

The three leading factor XI inhibitors have slightly different phase 3 development programs.

Dr. Ruff notes that not every agent is being investigated in phase 3 trials for all the potential indications, but all three are going for the AFib indication. “This is by far the biggest population, the biggest market, and the biggest clinical need for these agents,” he says.

While the milvexian and asundexian trials are using an active comparator – pitting the factor XI inhibitors against apixaban in AFib patients – the Anthos LILAC trial is taking a slightly different approach and is comparing abelacimab with placebo in patients with AFib who are not currently taking an anticoagulant because of concerns about bleeding risk.

Janssen/BMS is conducting two other phase 3 trials of milvexian in their LIBREXIA phase 3 program. Those trials involve poststroke patients and ACS patients. Bayer is also involved in a poststroke trial of asundexian as part of its OCEANIC phase 3 program.

Dr. Ruff points out that anticoagulants currently do not have a large role in the poststroke or post-ACS population. “But the hope is that, if factor XI inhibitors are so safe, then there will be more enthusiasm about using an anticoagulant on top of antiplatelet therapy, which is the cornerstone of therapy in atherosclerotic cardiovascular disease.”

In addition to its phase 3 LILAC study in patients with AFib, Anthos is conducting two major phase 3 trials with abelacimab for the treatment of cancer-associated venous thromboembolism.

Dr. Ruff notes that the indication of postsurgery or general prevention of VTE is not being pursued at present.

“The orthopedic surgery studies were done mainly for dose finding and proof of principle reasons,” he explains. “In orthopedic surgery the window for anticoagulation is quite short – a few weeks or months. And for the prevention of recurrent VTE in general in the community, those people are at a relatively low risk of bleeding, so there may not be much advantage of the factor XI inhibitors, whereas AFib patients and those with stroke or ACS are usually older and have a much higher bleeding risk. I think this is where the advantages of an anticoagulant with a lower bleeding risk are most needed.”

Dr. Alexander points out that to date anticoagulants have shown more efficacy in venous clotting, which appears to be more dependent on coagulation factors and less dependent on platelets. “Atrial fibrillation is a mix between venous and arterial clotting, but it has more similarities to venous, so I think AFib is a place where new anticoagulants such as the factor XI inhibitors are more likely to have success,” he suggests.

“So far, anticoagulants have had a less clear long-term role in the poststroke and post-ACS populations, so these indications may be a more difficult goal,” he added.

The phase 3 studies are just starting and will take a few years before results are known.
 

Differences between the agents

The three factor XI inhibitors also have some differences. Dr. Ruff points out that most important will be the safety and efficacy of the drugs in phase 3 trials.

“Early data suggest that the various agents being developed may not have equal inhibition of factor XI. The monoclonal antibody abelacimab may produce a higher degree of inhibition than the small molecules. But we don’t know if that matters or not – whether we need to achieve a certain threshold to prevent stroke. The efficacy and safety data from the phase 3 trials are what will primarily guide use.”

There are also differences in formulations and dosage. Abelacimab is administered by subcutaneous injection once a month and has a long duration of activity, whereas the small molecules are taken orally and their duration of action is much shorter.

Dr. Ruff notes: “If these drugs cause bleeding, having a long-acting drug like abelacimab could be a disadvantage because we wouldn’t be able to stop it. But if they are very safe with regard to bleeding, then having the drug hang around for a long time is not necessarily a disadvantage, and it may improve compliance. These older patients often miss doses, and with a shorter-acting drug, that will mean they will be unprotected from stroke risk for a period of time, so there is a trade-off here.”

Dr. Ruff says that the AZALEA phase 2 study will provide some data on patients being managed around procedures. “The hope is that these drugs are so safe that they will not have to be stopped for procedures. And then the compliance issue of a once-a-month dosing would be an advantage.”

Dr. Patel says he believes there is a place for different formations. “Some patients may prefer a once-monthly injection; others will prefer a daily tablet. It may come down to patient preference, but a lot will depend on the study results with the different agents,” he commented.
 

What effect could these drugs have?

If these drugs do show efficacy in these phase 3 trials, what difference will they make to clinical practice? The potential appears to be very large.

“If these drugs are as effective at preventing strokes as DOACs, they will be a huge breakthrough, and there is good reason to think they would replace the DOACs,” Dr. Alexander says. “It would be a really big deal to have an anticoagulant that causes almost no bleeding and could prevent clots as well as the DOACs. This would enable a lot more patients to receive protection against stroke.”

Dr. Alexander believes the surgery studies are hopeful. “They show that the factor XI inhibitors are doing something to prevent blood clots. The big question is whether they are as effective as what we already have for the prevention of stroke and if not, what is the trade-off with bleeding?”

He points out that, even if the factor XI inhibitors are not as effective as DOACs but are found to be much safer, they might still have a potential clinical role, especially for those patients who currently do not take an anticoagulant because of concerns regarding bleeding.

But Dr. Patel points out that there is always the issue of costs with new drugs. “New drugs are always expensive. The DOACS are just about to become generic, and there will inevitably be concerns about access to an expensive new therapy.”

Dr. Alexander adds: “Yes, costs could be an issue, but a safer drug will definitely help to get more patients treated and in preventing more strokes, which would be a great thing.”

Dr. Patel has received grants from and acts as an adviser to Bayer (asundexian) and Janssen (milvexian). Dr. Alexander receives research funding from Bayer. Dr. Ruff receives research funding from Anthos for abelacimab trials, is on an AFib executive committee for BMS/Janssen, and has been on an advisory board for Bayer.

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

The quest to find an anticoagulant that can prevent strokes, cardiovascular events, and venous thrombosis without significantly increasing risk of bleeding is something of a holy grail in cardiovascular medicine. Could the latest focus of interest in this field – the factor XI inhibitors – be the long–sought-after answer?

Topline results from the largest study so far of a factor XI inhibitor – released on Sep. 18 – are indeed very encouraging. The phase 2 AZALEA-TIMI 71 study was stopped early because of an “overwhelming” reduction in major and clinically relevant nonmajor bleeding shown with the factor XI inhibitor abelacimab (Anthos), compared with apixaban for patients with atrial fibrillation (AFib).

Very few other data from this study have yet been released. Full results are due to be presented at the scientific sessions of the American Heart Association in November. Researchers in the field are optimistic that this new class of drugs may allow millions more patients who are at risk of thrombotic events but are concerned about bleeding risk to be treated, with a consequent reduction in strokes and possibly cardiovascular events as well.
 

Why factor XI?

The hope that factor XI inhibitors will prevent pathologic thrombosis with a lower bleeding risk, compared with other anticoagulants, comes down to the role of factor XI in the coagulation cascade.

In natural physiology, there are two ongoing processes: hemostasis – a set of actions that cause bleeding to stop after an injury – and thrombosis – a pathologic clotting process in which thrombus is formed and causes a stroke, MI, or deep venous thrombosis (DVT).

In patients prone to pathologic clotting, such as those with AFib, the balance of these two processes has shifted toward thrombosis, so anticoagulants are used to reduce the thrombotic risks. For many years, the only available oral anticoagulant was warfarin, a vitamin K antagonist that was very effective at preventing strokes but that comes with a high risk for bleeding, including intracranial hemorrhage (ICH) and fatal bleeding.

The introduction of the direct-acting anticoagulants (DOACs) a few years ago was a step forward in that these drugs have been shown to be as effective as warfarin but are associated with a lower risk of bleeding, particularly of ICH and fatal bleeding. But they still cause bleeding, and concerns over that risk of bleeding prevent millions of patients from taking these drugs and receiving protection against stroke.

John Alexander, MD, professor of medicine at Duke University Medical Center, Durham, N.C., a researcher active in this area, notes that “while the DOACs cause less bleeding than warfarin, they still cause two or three times more bleeding than placebo, and there is a huge, unmet need for safer anticoagulants that don’t cause as much bleeding. We are hopeful that factor XI inhibitors might be those anticoagulants.”

The lead investigator the AZALEA study, Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, explained why it is thought that factor XI inhibitors may be different.

“There’s a lot of different clotting factors, and most of them converge in a central pathway. The problem, therefore, with anticoagulants used to date that block one of these factors is that they prevent clotting but also cause bleeding.

“It has been discovered that factor XI has a really unique position in the cascade of how our body forms clots in that it seems to be important in clot formation, but it doesn’t seem to play a major role in our ability to heal and repair blood vessels.”

Another doctor involved in the field, Manesh Patel, MD, chief of cardiology at Duke University Medical Center, added, “We think that factor XI inhibitors may prevent the pathologic formation of thrombosis while allowing formation of thrombus for natural hemostasis to prevent bleeding. That is why they are so promising.”

This correlates with epidemiologic data suggesting that patients with a genetic factor XI deficiency have low rates of stroke and MI but don’t appear to bleed spontaneously, Dr. Patel notes.
 

Candidates in development

The pharmaceutical industry is on the case with several factor XI inhibitors now in clinical development. At present, three main candidates lead the field. These are abelacimab (Anthos), a monoclonal antibody given by subcutaneous injection once a month; and two small molecules, milvexian (BMS/Janssen) and asundexian (Bayer), which are both given orally.

Phase 3 trials of these three factor XI inhibitors have recently started for a variety of thrombotic indications, including the prevention of stroke in patients with AFib, prevention of recurrent stroke in patients with ischemic stroke, and prevention of future cardiovascular events in patients with acute coronary syndrome (ACS).

Dr. Alexander, who has been involved in clinical trials of both milvexian and asundexian, commented: “We have pretty good data from a number of phase 2 trials now that these factor XI inhibitors at the doses used in these studies cause a lot less bleeding than therapeutic doses of DOACs and low-molecular-weight heparins.”

He pointed out that, in addition to the AZALEA trial with abelacimab, the phase 2 PACIFIC program of studies has shown less bleeding with asundexian than with apixaban in patients with AFib and a similar amount of bleeding as placebo in ACS/stroke patients on top of antiplatelet therapy. Milvexian has also shown similar results in the AXIOMATIC program of studies.

Dr. Ruff noted that the biggest need for new anticoagulants in general is in the AFib population. “Atrial fibrillation is one of the most common medical conditions in the world. Approximately one in every three people will develop AFib in their lifetime, and it is associated with more than a fivefold increased risk of stroke. But up to half of patients with AFib currently do not take anticoagulants because of concerns about bleeding risks, so these patients are being left unprotected from stroke risk.”

Dr. Ruff pointed out that the AZALEA study was the largest and longest study of a factor XI inhibitor to date; 1,287 patients were followed for a median of 2 years.

“This was the first trial of long-term administration of factor XI inhibitor against a full-dose DOAC, and it was stopped because of an overwhelming reduction in a major bleeding with abelacimab, compared with rivaroxaban,” he noted. “That is very encouraging. It looks like our quest to develop a safe anticoagulant with much lower rates of bleeding, compared with standard of care, seems to have been borne out. I think the field is very excited that we may finally have something that protects patients from thrombosis whilst being much safer than current agents.”

While all this sounds very promising, for these drugs to be successful, in addition to reducing bleeding risk, they will also have to be effective at preventing strokes and other thrombotic events.

“While we are pretty sure that factor XI inhibitors will cause less bleeding than current anticoagulants, what is unknown still is how effective they will be at preventing pathologic blood clots,” Dr. Alexander points out.

“We have some data from studies of these drugs in DVT prophylaxis after orthopedic surgery which suggest that they are effective in preventing blood clots in that scenario. But we don’t know yet about whether they can prevent pathologic blood clots that occur in AFib patients or in poststroke or post-ACS patients. Phase 3 studies are now underway with these three leading drug candidates which will answer some of these questions.”

Dr. Patel agrees that the efficacy data in the phase 3 trials will be key to the success of these drugs. “That is a very important part of the puzzle that is still missing,” he says.

Dr. Ruff notes that the AZALEA study will provide some data on efficacy. “But we already know that in the orthopedic surgery trials there was a 70%-80% reduction in VTE with abelacimab (at the 150-mg dose going forward) vs. prophylactic doses of low-molecular-weight heparin. And we know from the DOACs that the doses preventing clots on the venous side also translated into preventing strokes on the [AFib] side. So that is very encouraging,” Dr. Ruff adds.
 

Potential indications

The three leading factor XI inhibitors have slightly different phase 3 development programs.

Dr. Ruff notes that not every agent is being investigated in phase 3 trials for all the potential indications, but all three are going for the AFib indication. “This is by far the biggest population, the biggest market, and the biggest clinical need for these agents,” he says.

While the milvexian and asundexian trials are using an active comparator – pitting the factor XI inhibitors against apixaban in AFib patients – the Anthos LILAC trial is taking a slightly different approach and is comparing abelacimab with placebo in patients with AFib who are not currently taking an anticoagulant because of concerns about bleeding risk.

Janssen/BMS is conducting two other phase 3 trials of milvexian in their LIBREXIA phase 3 program. Those trials involve poststroke patients and ACS patients. Bayer is also involved in a poststroke trial of asundexian as part of its OCEANIC phase 3 program.

Dr. Ruff points out that anticoagulants currently do not have a large role in the poststroke or post-ACS population. “But the hope is that, if factor XI inhibitors are so safe, then there will be more enthusiasm about using an anticoagulant on top of antiplatelet therapy, which is the cornerstone of therapy in atherosclerotic cardiovascular disease.”

In addition to its phase 3 LILAC study in patients with AFib, Anthos is conducting two major phase 3 trials with abelacimab for the treatment of cancer-associated venous thromboembolism.

Dr. Ruff notes that the indication of postsurgery or general prevention of VTE is not being pursued at present.

“The orthopedic surgery studies were done mainly for dose finding and proof of principle reasons,” he explains. “In orthopedic surgery the window for anticoagulation is quite short – a few weeks or months. And for the prevention of recurrent VTE in general in the community, those people are at a relatively low risk of bleeding, so there may not be much advantage of the factor XI inhibitors, whereas AFib patients and those with stroke or ACS are usually older and have a much higher bleeding risk. I think this is where the advantages of an anticoagulant with a lower bleeding risk are most needed.”

Dr. Alexander points out that to date anticoagulants have shown more efficacy in venous clotting, which appears to be more dependent on coagulation factors and less dependent on platelets. “Atrial fibrillation is a mix between venous and arterial clotting, but it has more similarities to venous, so I think AFib is a place where new anticoagulants such as the factor XI inhibitors are more likely to have success,” he suggests.

“So far, anticoagulants have had a less clear long-term role in the poststroke and post-ACS populations, so these indications may be a more difficult goal,” he added.

The phase 3 studies are just starting and will take a few years before results are known.
 

Differences between the agents

The three factor XI inhibitors also have some differences. Dr. Ruff points out that most important will be the safety and efficacy of the drugs in phase 3 trials.

“Early data suggest that the various agents being developed may not have equal inhibition of factor XI. The monoclonal antibody abelacimab may produce a higher degree of inhibition than the small molecules. But we don’t know if that matters or not – whether we need to achieve a certain threshold to prevent stroke. The efficacy and safety data from the phase 3 trials are what will primarily guide use.”

There are also differences in formulations and dosage. Abelacimab is administered by subcutaneous injection once a month and has a long duration of activity, whereas the small molecules are taken orally and their duration of action is much shorter.

Dr. Ruff notes: “If these drugs cause bleeding, having a long-acting drug like abelacimab could be a disadvantage because we wouldn’t be able to stop it. But if they are very safe with regard to bleeding, then having the drug hang around for a long time is not necessarily a disadvantage, and it may improve compliance. These older patients often miss doses, and with a shorter-acting drug, that will mean they will be unprotected from stroke risk for a period of time, so there is a trade-off here.”

Dr. Ruff says that the AZALEA phase 2 study will provide some data on patients being managed around procedures. “The hope is that these drugs are so safe that they will not have to be stopped for procedures. And then the compliance issue of a once-a-month dosing would be an advantage.”

Dr. Patel says he believes there is a place for different formations. “Some patients may prefer a once-monthly injection; others will prefer a daily tablet. It may come down to patient preference, but a lot will depend on the study results with the different agents,” he commented.
 

What effect could these drugs have?

If these drugs do show efficacy in these phase 3 trials, what difference will they make to clinical practice? The potential appears to be very large.

“If these drugs are as effective at preventing strokes as DOACs, they will be a huge breakthrough, and there is good reason to think they would replace the DOACs,” Dr. Alexander says. “It would be a really big deal to have an anticoagulant that causes almost no bleeding and could prevent clots as well as the DOACs. This would enable a lot more patients to receive protection against stroke.”

Dr. Alexander believes the surgery studies are hopeful. “They show that the factor XI inhibitors are doing something to prevent blood clots. The big question is whether they are as effective as what we already have for the prevention of stroke and if not, what is the trade-off with bleeding?”

He points out that, even if the factor XI inhibitors are not as effective as DOACs but are found to be much safer, they might still have a potential clinical role, especially for those patients who currently do not take an anticoagulant because of concerns regarding bleeding.

But Dr. Patel points out that there is always the issue of costs with new drugs. “New drugs are always expensive. The DOACS are just about to become generic, and there will inevitably be concerns about access to an expensive new therapy.”

Dr. Alexander adds: “Yes, costs could be an issue, but a safer drug will definitely help to get more patients treated and in preventing more strokes, which would be a great thing.”

Dr. Patel has received grants from and acts as an adviser to Bayer (asundexian) and Janssen (milvexian). Dr. Alexander receives research funding from Bayer. Dr. Ruff receives research funding from Anthos for abelacimab trials, is on an AFib executive committee for BMS/Janssen, and has been on an advisory board for Bayer.

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

The quest to find an anticoagulant that can prevent strokes, cardiovascular events, and venous thrombosis without significantly increasing risk of bleeding is something of a holy grail in cardiovascular medicine. Could the latest focus of interest in this field – the factor XI inhibitors – be the long–sought-after answer?

Topline results from the largest study so far of a factor XI inhibitor – released on Sep. 18 – are indeed very encouraging. The phase 2 AZALEA-TIMI 71 study was stopped early because of an “overwhelming” reduction in major and clinically relevant nonmajor bleeding shown with the factor XI inhibitor abelacimab (Anthos), compared with apixaban for patients with atrial fibrillation (AFib).

Very few other data from this study have yet been released. Full results are due to be presented at the scientific sessions of the American Heart Association in November. Researchers in the field are optimistic that this new class of drugs may allow millions more patients who are at risk of thrombotic events but are concerned about bleeding risk to be treated, with a consequent reduction in strokes and possibly cardiovascular events as well.
 

Why factor XI?

The hope that factor XI inhibitors will prevent pathologic thrombosis with a lower bleeding risk, compared with other anticoagulants, comes down to the role of factor XI in the coagulation cascade.

In natural physiology, there are two ongoing processes: hemostasis – a set of actions that cause bleeding to stop after an injury – and thrombosis – a pathologic clotting process in which thrombus is formed and causes a stroke, MI, or deep venous thrombosis (DVT).

In patients prone to pathologic clotting, such as those with AFib, the balance of these two processes has shifted toward thrombosis, so anticoagulants are used to reduce the thrombotic risks. For many years, the only available oral anticoagulant was warfarin, a vitamin K antagonist that was very effective at preventing strokes but that comes with a high risk for bleeding, including intracranial hemorrhage (ICH) and fatal bleeding.

The introduction of the direct-acting anticoagulants (DOACs) a few years ago was a step forward in that these drugs have been shown to be as effective as warfarin but are associated with a lower risk of bleeding, particularly of ICH and fatal bleeding. But they still cause bleeding, and concerns over that risk of bleeding prevent millions of patients from taking these drugs and receiving protection against stroke.

John Alexander, MD, professor of medicine at Duke University Medical Center, Durham, N.C., a researcher active in this area, notes that “while the DOACs cause less bleeding than warfarin, they still cause two or three times more bleeding than placebo, and there is a huge, unmet need for safer anticoagulants that don’t cause as much bleeding. We are hopeful that factor XI inhibitors might be those anticoagulants.”

The lead investigator the AZALEA study, Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, explained why it is thought that factor XI inhibitors may be different.

“There’s a lot of different clotting factors, and most of them converge in a central pathway. The problem, therefore, with anticoagulants used to date that block one of these factors is that they prevent clotting but also cause bleeding.

“It has been discovered that factor XI has a really unique position in the cascade of how our body forms clots in that it seems to be important in clot formation, but it doesn’t seem to play a major role in our ability to heal and repair blood vessels.”

Another doctor involved in the field, Manesh Patel, MD, chief of cardiology at Duke University Medical Center, added, “We think that factor XI inhibitors may prevent the pathologic formation of thrombosis while allowing formation of thrombus for natural hemostasis to prevent bleeding. That is why they are so promising.”

This correlates with epidemiologic data suggesting that patients with a genetic factor XI deficiency have low rates of stroke and MI but don’t appear to bleed spontaneously, Dr. Patel notes.
 

Candidates in development

The pharmaceutical industry is on the case with several factor XI inhibitors now in clinical development. At present, three main candidates lead the field. These are abelacimab (Anthos), a monoclonal antibody given by subcutaneous injection once a month; and two small molecules, milvexian (BMS/Janssen) and asundexian (Bayer), which are both given orally.

Phase 3 trials of these three factor XI inhibitors have recently started for a variety of thrombotic indications, including the prevention of stroke in patients with AFib, prevention of recurrent stroke in patients with ischemic stroke, and prevention of future cardiovascular events in patients with acute coronary syndrome (ACS).

Dr. Alexander, who has been involved in clinical trials of both milvexian and asundexian, commented: “We have pretty good data from a number of phase 2 trials now that these factor XI inhibitors at the doses used in these studies cause a lot less bleeding than therapeutic doses of DOACs and low-molecular-weight heparins.”

He pointed out that, in addition to the AZALEA trial with abelacimab, the phase 2 PACIFIC program of studies has shown less bleeding with asundexian than with apixaban in patients with AFib and a similar amount of bleeding as placebo in ACS/stroke patients on top of antiplatelet therapy. Milvexian has also shown similar results in the AXIOMATIC program of studies.

Dr. Ruff noted that the biggest need for new anticoagulants in general is in the AFib population. “Atrial fibrillation is one of the most common medical conditions in the world. Approximately one in every three people will develop AFib in their lifetime, and it is associated with more than a fivefold increased risk of stroke. But up to half of patients with AFib currently do not take anticoagulants because of concerns about bleeding risks, so these patients are being left unprotected from stroke risk.”

Dr. Ruff pointed out that the AZALEA study was the largest and longest study of a factor XI inhibitor to date; 1,287 patients were followed for a median of 2 years.

“This was the first trial of long-term administration of factor XI inhibitor against a full-dose DOAC, and it was stopped because of an overwhelming reduction in a major bleeding with abelacimab, compared with rivaroxaban,” he noted. “That is very encouraging. It looks like our quest to develop a safe anticoagulant with much lower rates of bleeding, compared with standard of care, seems to have been borne out. I think the field is very excited that we may finally have something that protects patients from thrombosis whilst being much safer than current agents.”

While all this sounds very promising, for these drugs to be successful, in addition to reducing bleeding risk, they will also have to be effective at preventing strokes and other thrombotic events.

“While we are pretty sure that factor XI inhibitors will cause less bleeding than current anticoagulants, what is unknown still is how effective they will be at preventing pathologic blood clots,” Dr. Alexander points out.

“We have some data from studies of these drugs in DVT prophylaxis after orthopedic surgery which suggest that they are effective in preventing blood clots in that scenario. But we don’t know yet about whether they can prevent pathologic blood clots that occur in AFib patients or in poststroke or post-ACS patients. Phase 3 studies are now underway with these three leading drug candidates which will answer some of these questions.”

Dr. Patel agrees that the efficacy data in the phase 3 trials will be key to the success of these drugs. “That is a very important part of the puzzle that is still missing,” he says.

Dr. Ruff notes that the AZALEA study will provide some data on efficacy. “But we already know that in the orthopedic surgery trials there was a 70%-80% reduction in VTE with abelacimab (at the 150-mg dose going forward) vs. prophylactic doses of low-molecular-weight heparin. And we know from the DOACs that the doses preventing clots on the venous side also translated into preventing strokes on the [AFib] side. So that is very encouraging,” Dr. Ruff adds.
 

Potential indications

The three leading factor XI inhibitors have slightly different phase 3 development programs.

Dr. Ruff notes that not every agent is being investigated in phase 3 trials for all the potential indications, but all three are going for the AFib indication. “This is by far the biggest population, the biggest market, and the biggest clinical need for these agents,” he says.

While the milvexian and asundexian trials are using an active comparator – pitting the factor XI inhibitors against apixaban in AFib patients – the Anthos LILAC trial is taking a slightly different approach and is comparing abelacimab with placebo in patients with AFib who are not currently taking an anticoagulant because of concerns about bleeding risk.

Janssen/BMS is conducting two other phase 3 trials of milvexian in their LIBREXIA phase 3 program. Those trials involve poststroke patients and ACS patients. Bayer is also involved in a poststroke trial of asundexian as part of its OCEANIC phase 3 program.

Dr. Ruff points out that anticoagulants currently do not have a large role in the poststroke or post-ACS population. “But the hope is that, if factor XI inhibitors are so safe, then there will be more enthusiasm about using an anticoagulant on top of antiplatelet therapy, which is the cornerstone of therapy in atherosclerotic cardiovascular disease.”

In addition to its phase 3 LILAC study in patients with AFib, Anthos is conducting two major phase 3 trials with abelacimab for the treatment of cancer-associated venous thromboembolism.

Dr. Ruff notes that the indication of postsurgery or general prevention of VTE is not being pursued at present.

“The orthopedic surgery studies were done mainly for dose finding and proof of principle reasons,” he explains. “In orthopedic surgery the window for anticoagulation is quite short – a few weeks or months. And for the prevention of recurrent VTE in general in the community, those people are at a relatively low risk of bleeding, so there may not be much advantage of the factor XI inhibitors, whereas AFib patients and those with stroke or ACS are usually older and have a much higher bleeding risk. I think this is where the advantages of an anticoagulant with a lower bleeding risk are most needed.”

Dr. Alexander points out that to date anticoagulants have shown more efficacy in venous clotting, which appears to be more dependent on coagulation factors and less dependent on platelets. “Atrial fibrillation is a mix between venous and arterial clotting, but it has more similarities to venous, so I think AFib is a place where new anticoagulants such as the factor XI inhibitors are more likely to have success,” he suggests.

“So far, anticoagulants have had a less clear long-term role in the poststroke and post-ACS populations, so these indications may be a more difficult goal,” he added.

The phase 3 studies are just starting and will take a few years before results are known.
 

Differences between the agents

The three factor XI inhibitors also have some differences. Dr. Ruff points out that most important will be the safety and efficacy of the drugs in phase 3 trials.

“Early data suggest that the various agents being developed may not have equal inhibition of factor XI. The monoclonal antibody abelacimab may produce a higher degree of inhibition than the small molecules. But we don’t know if that matters or not – whether we need to achieve a certain threshold to prevent stroke. The efficacy and safety data from the phase 3 trials are what will primarily guide use.”

There are also differences in formulations and dosage. Abelacimab is administered by subcutaneous injection once a month and has a long duration of activity, whereas the small molecules are taken orally and their duration of action is much shorter.

Dr. Ruff notes: “If these drugs cause bleeding, having a long-acting drug like abelacimab could be a disadvantage because we wouldn’t be able to stop it. But if they are very safe with regard to bleeding, then having the drug hang around for a long time is not necessarily a disadvantage, and it may improve compliance. These older patients often miss doses, and with a shorter-acting drug, that will mean they will be unprotected from stroke risk for a period of time, so there is a trade-off here.”

Dr. Ruff says that the AZALEA phase 2 study will provide some data on patients being managed around procedures. “The hope is that these drugs are so safe that they will not have to be stopped for procedures. And then the compliance issue of a once-a-month dosing would be an advantage.”

Dr. Patel says he believes there is a place for different formations. “Some patients may prefer a once-monthly injection; others will prefer a daily tablet. It may come down to patient preference, but a lot will depend on the study results with the different agents,” he commented.
 

What effect could these drugs have?

If these drugs do show efficacy in these phase 3 trials, what difference will they make to clinical practice? The potential appears to be very large.

“If these drugs are as effective at preventing strokes as DOACs, they will be a huge breakthrough, and there is good reason to think they would replace the DOACs,” Dr. Alexander says. “It would be a really big deal to have an anticoagulant that causes almost no bleeding and could prevent clots as well as the DOACs. This would enable a lot more patients to receive protection against stroke.”

Dr. Alexander believes the surgery studies are hopeful. “They show that the factor XI inhibitors are doing something to prevent blood clots. The big question is whether they are as effective as what we already have for the prevention of stroke and if not, what is the trade-off with bleeding?”

He points out that, even if the factor XI inhibitors are not as effective as DOACs but are found to be much safer, they might still have a potential clinical role, especially for those patients who currently do not take an anticoagulant because of concerns regarding bleeding.

But Dr. Patel points out that there is always the issue of costs with new drugs. “New drugs are always expensive. The DOACS are just about to become generic, and there will inevitably be concerns about access to an expensive new therapy.”

Dr. Alexander adds: “Yes, costs could be an issue, but a safer drug will definitely help to get more patients treated and in preventing more strokes, which would be a great thing.”

Dr. Patel has received grants from and acts as an adviser to Bayer (asundexian) and Janssen (milvexian). Dr. Alexander receives research funding from Bayer. Dr. Ruff receives research funding from Anthos for abelacimab trials, is on an AFib executive committee for BMS/Janssen, and has been on an advisory board for Bayer.

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

Moving from one residence to another after an acute myocardial infarction (AMI) significantly increases the risk for death or transition to a long-term care facility as an end-of-life measure, data suggest.

In a prospective study that followed more than 3,000 patients with AMI over 2 decades, each residential move was associated with a 12% higher rate of death.

“This study determined that residential mobility was more important than any other social factor that we studied,” investigator David Alter, MD, PhD, chair of cardiovascular and metabolic research at the University Health Network–Toronto Rehabilitation Institute and associate professor of medicine at the University of Toronto, said in an interview.

The results were published online in the Canadian Journal of Cardiology.
 

Moving and mortality

“There’s been very little work, surprisingly, on what happens when individuals move from community to community,” said Dr. Alter. “It is that movement from community to community that is a factor within the social context that needs to be explored better. To the best of our knowledge, up until our study, it has been studied very briefly in the literature.”

The prospective cohort study sample included 3,369 patients who had an AMI between Dec. 1, 1999, and March 30, 2023. The investigators followed participants until death or the last available follow-up date of March 30, 2020. They defined a residential move as a relocation from one postal code region to another.

The investigators drew data from multiple sources, including the prospective, observational Socio-Economic Status and Acute Myocardial Infarction study, which encompassed more than 35,000 patient life-years following hospitalization for a first heart attack in Ontario. Mortality data were collected from the Ontario Registered Persons Data Base. Other sources included Statistics Canada for information on neighborhood income, the Canadian Institutes for Health Information for patients’ clinical factors and comorbidities, and the Ontario Health Insurance Plan (OHIP) database for physician visits. Information on long-term care admissions came from the Continuous Care Reporting System-Long Term Care, OHIP, and the Ontario Drugs Benefit databases, the latter of which also provided information on medication prescriptions for individuals aged 65 years and older.

Patients’ ages ranged from 19 to 101 years (median age, 65 years). About 69% of patients were men. Of the study population, 1,828 patients (54.3%) had at least one residential move during the study period. Approximately 87% died in the community or moved from home into a long-term care facility as an end-of-life destination. Overall, 84.8% of patients who were admitted to long-term care facilities died.

The study also tracked the socioeconomic status of persons living in the postal code regions from and to which patients moved. About 32% of patients moved to a neighborhood with a lower socioeconomic status, and 30.5% moved to an area with a higher socioeconomic status.

Each residential move was associated with a 12% higher rate of death and a 26% higher rate of long-term institutionalization for end-of-life care. In unadjusted analyses, the rate of death was almost double for those who moved more frequently: 44.3% for those who moved two or more times versus 24.8% for those who moved once in 10 years.

Accounting for a multitude of variables, such as the socioeconomic status of areas that patients moved between, is a strength of the study, said Dr. Alter. But the study lacked information about why people moved.

“Where this study has a huge amount of strength is that it was designed specifically to really understand a patient’s clinical and psychosocial profile at the start of their journey, their first AMI. But the fact that we took it from heart attack onward is also a strength because it characterizes and anchors a clinical context in which we were following patients out,” said Dr. Alter.
 

‘An important marker’

In a comment, Paul Oh, MD, medical director of the cardiovascular disease prevention and rehabilitation program at University Health Network, said: “This is a very well-designed study and analysis from a cohort that has provided important insights about the role of socioeconomic factors and long-term outcomes post MI over many years.” Dr. Oh did not participate in the study.

“A few covariates that could impact on outcomes, like institutionalization, were not available to include in adjusted analyses – e.g., functional status, frailty, mild cognitive changes, and availability of social supports in the home,” he said.

The findings add another variable that cardiologists who care for post-MI patients need to be aware of, Dr. Oh added. “Clinicians need better awareness that the need to change residence is an important marker of changing health status and may portend end-of-life events in the near future. The need to change residence can signal an important change in physical, cognitive, and social circumstances that needs to be further explored during clinical encounters, with the goal of identifying and addressing any potentially reversible issues and identifying additional supports that may help that individual continue to live independently in their own home.”

The study was supported by ICES, which receives funding from the Ontario Ministry of Health. The investigators disclosed no relevant financial relationships. Dr. Oh serves on research boards for Lilly and Novartis and receives research funding from Apple.

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

Moving from one residence to another after an acute myocardial infarction (AMI) significantly increases the risk for death or transition to a long-term care facility as an end-of-life measure, data suggest.

In a prospective study that followed more than 3,000 patients with AMI over 2 decades, each residential move was associated with a 12% higher rate of death.

“This study determined that residential mobility was more important than any other social factor that we studied,” investigator David Alter, MD, PhD, chair of cardiovascular and metabolic research at the University Health Network–Toronto Rehabilitation Institute and associate professor of medicine at the University of Toronto, said in an interview.

The results were published online in the Canadian Journal of Cardiology.
 

Moving and mortality

“There’s been very little work, surprisingly, on what happens when individuals move from community to community,” said Dr. Alter. “It is that movement from community to community that is a factor within the social context that needs to be explored better. To the best of our knowledge, up until our study, it has been studied very briefly in the literature.”

The prospective cohort study sample included 3,369 patients who had an AMI between Dec. 1, 1999, and March 30, 2023. The investigators followed participants until death or the last available follow-up date of March 30, 2020. They defined a residential move as a relocation from one postal code region to another.

The investigators drew data from multiple sources, including the prospective, observational Socio-Economic Status and Acute Myocardial Infarction study, which encompassed more than 35,000 patient life-years following hospitalization for a first heart attack in Ontario. Mortality data were collected from the Ontario Registered Persons Data Base. Other sources included Statistics Canada for information on neighborhood income, the Canadian Institutes for Health Information for patients’ clinical factors and comorbidities, and the Ontario Health Insurance Plan (OHIP) database for physician visits. Information on long-term care admissions came from the Continuous Care Reporting System-Long Term Care, OHIP, and the Ontario Drugs Benefit databases, the latter of which also provided information on medication prescriptions for individuals aged 65 years and older.

Patients’ ages ranged from 19 to 101 years (median age, 65 years). About 69% of patients were men. Of the study population, 1,828 patients (54.3%) had at least one residential move during the study period. Approximately 87% died in the community or moved from home into a long-term care facility as an end-of-life destination. Overall, 84.8% of patients who were admitted to long-term care facilities died.

The study also tracked the socioeconomic status of persons living in the postal code regions from and to which patients moved. About 32% of patients moved to a neighborhood with a lower socioeconomic status, and 30.5% moved to an area with a higher socioeconomic status.

Each residential move was associated with a 12% higher rate of death and a 26% higher rate of long-term institutionalization for end-of-life care. In unadjusted analyses, the rate of death was almost double for those who moved more frequently: 44.3% for those who moved two or more times versus 24.8% for those who moved once in 10 years.

Accounting for a multitude of variables, such as the socioeconomic status of areas that patients moved between, is a strength of the study, said Dr. Alter. But the study lacked information about why people moved.

“Where this study has a huge amount of strength is that it was designed specifically to really understand a patient’s clinical and psychosocial profile at the start of their journey, their first AMI. But the fact that we took it from heart attack onward is also a strength because it characterizes and anchors a clinical context in which we were following patients out,” said Dr. Alter.
 

‘An important marker’

In a comment, Paul Oh, MD, medical director of the cardiovascular disease prevention and rehabilitation program at University Health Network, said: “This is a very well-designed study and analysis from a cohort that has provided important insights about the role of socioeconomic factors and long-term outcomes post MI over many years.” Dr. Oh did not participate in the study.

“A few covariates that could impact on outcomes, like institutionalization, were not available to include in adjusted analyses – e.g., functional status, frailty, mild cognitive changes, and availability of social supports in the home,” he said.

The findings add another variable that cardiologists who care for post-MI patients need to be aware of, Dr. Oh added. “Clinicians need better awareness that the need to change residence is an important marker of changing health status and may portend end-of-life events in the near future. The need to change residence can signal an important change in physical, cognitive, and social circumstances that needs to be further explored during clinical encounters, with the goal of identifying and addressing any potentially reversible issues and identifying additional supports that may help that individual continue to live independently in their own home.”

The study was supported by ICES, which receives funding from the Ontario Ministry of Health. The investigators disclosed no relevant financial relationships. Dr. Oh serves on research boards for Lilly and Novartis and receives research funding from Apple.

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

Moving from one residence to another after an acute myocardial infarction (AMI) significantly increases the risk for death or transition to a long-term care facility as an end-of-life measure, data suggest.

In a prospective study that followed more than 3,000 patients with AMI over 2 decades, each residential move was associated with a 12% higher rate of death.

“This study determined that residential mobility was more important than any other social factor that we studied,” investigator David Alter, MD, PhD, chair of cardiovascular and metabolic research at the University Health Network–Toronto Rehabilitation Institute and associate professor of medicine at the University of Toronto, said in an interview.

The results were published online in the Canadian Journal of Cardiology.
 

Moving and mortality

“There’s been very little work, surprisingly, on what happens when individuals move from community to community,” said Dr. Alter. “It is that movement from community to community that is a factor within the social context that needs to be explored better. To the best of our knowledge, up until our study, it has been studied very briefly in the literature.”

The prospective cohort study sample included 3,369 patients who had an AMI between Dec. 1, 1999, and March 30, 2023. The investigators followed participants until death or the last available follow-up date of March 30, 2020. They defined a residential move as a relocation from one postal code region to another.

The investigators drew data from multiple sources, including the prospective, observational Socio-Economic Status and Acute Myocardial Infarction study, which encompassed more than 35,000 patient life-years following hospitalization for a first heart attack in Ontario. Mortality data were collected from the Ontario Registered Persons Data Base. Other sources included Statistics Canada for information on neighborhood income, the Canadian Institutes for Health Information for patients’ clinical factors and comorbidities, and the Ontario Health Insurance Plan (OHIP) database for physician visits. Information on long-term care admissions came from the Continuous Care Reporting System-Long Term Care, OHIP, and the Ontario Drugs Benefit databases, the latter of which also provided information on medication prescriptions for individuals aged 65 years and older.

Patients’ ages ranged from 19 to 101 years (median age, 65 years). About 69% of patients were men. Of the study population, 1,828 patients (54.3%) had at least one residential move during the study period. Approximately 87% died in the community or moved from home into a long-term care facility as an end-of-life destination. Overall, 84.8% of patients who were admitted to long-term care facilities died.

The study also tracked the socioeconomic status of persons living in the postal code regions from and to which patients moved. About 32% of patients moved to a neighborhood with a lower socioeconomic status, and 30.5% moved to an area with a higher socioeconomic status.

Each residential move was associated with a 12% higher rate of death and a 26% higher rate of long-term institutionalization for end-of-life care. In unadjusted analyses, the rate of death was almost double for those who moved more frequently: 44.3% for those who moved two or more times versus 24.8% for those who moved once in 10 years.

Accounting for a multitude of variables, such as the socioeconomic status of areas that patients moved between, is a strength of the study, said Dr. Alter. But the study lacked information about why people moved.

“Where this study has a huge amount of strength is that it was designed specifically to really understand a patient’s clinical and psychosocial profile at the start of their journey, their first AMI. But the fact that we took it from heart attack onward is also a strength because it characterizes and anchors a clinical context in which we were following patients out,” said Dr. Alter.
 

‘An important marker’

In a comment, Paul Oh, MD, medical director of the cardiovascular disease prevention and rehabilitation program at University Health Network, said: “This is a very well-designed study and analysis from a cohort that has provided important insights about the role of socioeconomic factors and long-term outcomes post MI over many years.” Dr. Oh did not participate in the study.

“A few covariates that could impact on outcomes, like institutionalization, were not available to include in adjusted analyses – e.g., functional status, frailty, mild cognitive changes, and availability of social supports in the home,” he said.

The findings add another variable that cardiologists who care for post-MI patients need to be aware of, Dr. Oh added. “Clinicians need better awareness that the need to change residence is an important marker of changing health status and may portend end-of-life events in the near future. The need to change residence can signal an important change in physical, cognitive, and social circumstances that needs to be further explored during clinical encounters, with the goal of identifying and addressing any potentially reversible issues and identifying additional supports that may help that individual continue to live independently in their own home.”

The study was supported by ICES, which receives funding from the Ontario Ministry of Health. The investigators disclosed no relevant financial relationships. Dr. Oh serves on research boards for Lilly and Novartis and receives research funding from Apple.

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

Novel biomarker tests have met or exceeded the performance of common lab tests for diagnosing nonalcoholic steatohepatitis (NASH, now known as metabolic dysfunction–associated steatohepatitis or MASH), laying the groundwork for noninvasive alternatives to liver biopsy, new research suggests.

The blood-based tests could expand diagnostic options at health care facilities and facilitate enrollment in NASH clinical trials, which now require a biopsy for inclusion.

“The current study meets a key milestone for qualification of the biomarker panels studied for identification of at-risk NASH,” Arun Sanyal, MD, of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University, Richmond, told this news organization.

“It sets the stage for further validation of these outcomes,” he said. “These data will inform development of full qualification plans for these biomarker panels that will be submitted to the U.S. Food and Drug Administration. Once these are accepted by the FDA, the final steps toward qualification can be initiated.”

The study, published online in Nature Medicine, was conducted as part of the Foundation for the National Institutes of Health – Biomarkers Consortium’s Noninvasive Biomarkers of Metabolic Liver Disease (FNIH-NIMBLE), a multistakeholder project to support regulatory approval of NASH-related biomarkers.
 

Multiple biomarkers move forward

The investigators evaluated the diagnostic performance of five blood-based panels in an observational cohort derived from the NASH Clinical Research Network study, which included 4,094 participants; 2,479 individuals were excluded from the current study because of age, lack of samples, or lack of evaluable liver biopsies.

The remaining 1,073 patients (mean age, 52.5 years; 62% women) represented the full spectrum of nonalcoholic fatty liver disease (NAFLD, now known as metabolic dysfunction–associated steatotic liver disease or MASLD). In total, 225 individuals had NAFLD, 835 had NASH, and 13 had cirrhosis with an indeterminate NAFLD phenotype.

Those without fibrosis were younger and had mainly fatty liver, not steatohepatitis. They also had a lower NAFLD activity score, compared with those with stage 2 or higher fibrosis.

The study population for one of the five tests, FibroMeter VCTE, was a smaller subset (n = 396) of the larger population, with baseline features similar to the larger cohort.

The biomarker panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver), or fibrosis stages greater than 2, greater than 3, or 4 (enhanced liver fibrosis [ELF] test, PROC3, and FibroMeter VCTE). At-risk NASH was defined by the presence of NASH, high histologic activity, and fibrosis stage greater than or equal to 2.

The performance metric was an area under the receiver operating characteristic curve (AUROC) greater than or equal to 0.7 and superiority over alanine aminotransferase (ALT) for disease activity and the FIB-4 test for fibrosis severity.

Multiple biomarkers met the required metrics. For example, NIS4 had an AUROC of 0.81 for at-risk NASH. AUROCs for the ELF test (for clinically significant fibrosis, ≥ stage 2), PROC3 (advanced fibrosis, ≥ stage 3), and FibroMeter VCTE (cirrhosis, stage 4) were all greater than or equal to 0.8.

For all fibrosis endpoints, ELF and FibroMeter VCTE also outperformed FIB-4.

“The current study was a first step to determine if the biomarker panels not only identified the relevant phenotypes based on their intended use but also if they were superior to some commonly used clinical laboratory tools, such as ALT and FIB-4,” the authors write. “These will serve as criteria, to be finalized with feedback from the FDA, to move the panels with the most promising performance metrics to the final qualification steps.”

“Individual developers of specific biomarker panels will need to determine their strategy; that is, have separate rule-in and rule-out cutoffs or a single optimized cutoff as they [formulate] the full qualification plans,” Dr. Sanyal noted. “Also, it may be necessary to validate these cutoffs and performance in independent cohorts reflecting the populations where these are planned to be used.”

“We hope that by 2025, the first wave of biomarkers will have enough data to support approval for diagnostic purposes, and the data for prognostic biomarkers will follow within 1-2 years after that,” Dr. Sanyal added.
 

Are practice changes ahead?

“Findings from this study and subsequent planned studies have the potential to redefine our approach to MASH and fibrosis diagnosis and staging, both in clinical practice and as part of clinical trials for the multiple new therapeutics being evaluated for MASLD/MASH,” Tatyana Kushner, MD, gastroenterologist/hepatologist and associate professor of medicine in the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai, New York City, told this news organization.

Dr. Kushner noted that the study population “may not represent the diverse population affected by MASH in the United States, or even the clinical trial population.” The cohort was predominantly White, with relatively low representation from people of Hispanic ethnicity, who are known to have a higher prevalence of MASH.

“Furthermore, the study population was specifically curated to have representative numbers across liver disease/fibrosis stages, and this may have biased the results,” she added.

In addition, other MASH-related biomarkers were developed after the current study started, including the FAST, Agile, and ADAPT scores, she said. “After validation of the biomarkers in this study, it will also be important to see how this newer wave of biomarkers performs.”

“If subsequent efforts validate the current findings, and there is buy-in from all of the stakeholders, including the FDA, NIH, industry, and academic leaders, this can truly lead to practice-changing approaches to the clinical management and study of MASLD/MASH,” Dr. Kushner concluded.

The study was partially funded by the National Institute of Diabetes and Digestive and Kidney Diseases and a grant from the National Center for Advancing Translational Sciences. The NIMBLE project is sponsored by the FNIH and is a public-private partnership supported by numerous entities. Support was also provided by the Global Liver Institute and FDA. Dr. Sanyal has disclosed financial relationships with multiple companies. He recused himself from the analysis and interpretation of NIS4. Dr. Kushner has declared being an adviser for Gilead, AbbVie, Eiger, and Bausch, and receiving research support from Gilead. None are MASH/NASH-related.

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

Novel biomarker tests have met or exceeded the performance of common lab tests for diagnosing nonalcoholic steatohepatitis (NASH, now known as metabolic dysfunction–associated steatohepatitis or MASH), laying the groundwork for noninvasive alternatives to liver biopsy, new research suggests.

The blood-based tests could expand diagnostic options at health care facilities and facilitate enrollment in NASH clinical trials, which now require a biopsy for inclusion.

“The current study meets a key milestone for qualification of the biomarker panels studied for identification of at-risk NASH,” Arun Sanyal, MD, of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University, Richmond, told this news organization.

“It sets the stage for further validation of these outcomes,” he said. “These data will inform development of full qualification plans for these biomarker panels that will be submitted to the U.S. Food and Drug Administration. Once these are accepted by the FDA, the final steps toward qualification can be initiated.”

The study, published online in Nature Medicine, was conducted as part of the Foundation for the National Institutes of Health – Biomarkers Consortium’s Noninvasive Biomarkers of Metabolic Liver Disease (FNIH-NIMBLE), a multistakeholder project to support regulatory approval of NASH-related biomarkers.
 

Multiple biomarkers move forward

The investigators evaluated the diagnostic performance of five blood-based panels in an observational cohort derived from the NASH Clinical Research Network study, which included 4,094 participants; 2,479 individuals were excluded from the current study because of age, lack of samples, or lack of evaluable liver biopsies.

The remaining 1,073 patients (mean age, 52.5 years; 62% women) represented the full spectrum of nonalcoholic fatty liver disease (NAFLD, now known as metabolic dysfunction–associated steatotic liver disease or MASLD). In total, 225 individuals had NAFLD, 835 had NASH, and 13 had cirrhosis with an indeterminate NAFLD phenotype.

Those without fibrosis were younger and had mainly fatty liver, not steatohepatitis. They also had a lower NAFLD activity score, compared with those with stage 2 or higher fibrosis.

The study population for one of the five tests, FibroMeter VCTE, was a smaller subset (n = 396) of the larger population, with baseline features similar to the larger cohort.

The biomarker panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver), or fibrosis stages greater than 2, greater than 3, or 4 (enhanced liver fibrosis [ELF] test, PROC3, and FibroMeter VCTE). At-risk NASH was defined by the presence of NASH, high histologic activity, and fibrosis stage greater than or equal to 2.

The performance metric was an area under the receiver operating characteristic curve (AUROC) greater than or equal to 0.7 and superiority over alanine aminotransferase (ALT) for disease activity and the FIB-4 test for fibrosis severity.

Multiple biomarkers met the required metrics. For example, NIS4 had an AUROC of 0.81 for at-risk NASH. AUROCs for the ELF test (for clinically significant fibrosis, ≥ stage 2), PROC3 (advanced fibrosis, ≥ stage 3), and FibroMeter VCTE (cirrhosis, stage 4) were all greater than or equal to 0.8.

For all fibrosis endpoints, ELF and FibroMeter VCTE also outperformed FIB-4.

“The current study was a first step to determine if the biomarker panels not only identified the relevant phenotypes based on their intended use but also if they were superior to some commonly used clinical laboratory tools, such as ALT and FIB-4,” the authors write. “These will serve as criteria, to be finalized with feedback from the FDA, to move the panels with the most promising performance metrics to the final qualification steps.”

“Individual developers of specific biomarker panels will need to determine their strategy; that is, have separate rule-in and rule-out cutoffs or a single optimized cutoff as they [formulate] the full qualification plans,” Dr. Sanyal noted. “Also, it may be necessary to validate these cutoffs and performance in independent cohorts reflecting the populations where these are planned to be used.”

“We hope that by 2025, the first wave of biomarkers will have enough data to support approval for diagnostic purposes, and the data for prognostic biomarkers will follow within 1-2 years after that,” Dr. Sanyal added.
 

Are practice changes ahead?

“Findings from this study and subsequent planned studies have the potential to redefine our approach to MASH and fibrosis diagnosis and staging, both in clinical practice and as part of clinical trials for the multiple new therapeutics being evaluated for MASLD/MASH,” Tatyana Kushner, MD, gastroenterologist/hepatologist and associate professor of medicine in the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai, New York City, told this news organization.

Dr. Kushner noted that the study population “may not represent the diverse population affected by MASH in the United States, or even the clinical trial population.” The cohort was predominantly White, with relatively low representation from people of Hispanic ethnicity, who are known to have a higher prevalence of MASH.

“Furthermore, the study population was specifically curated to have representative numbers across liver disease/fibrosis stages, and this may have biased the results,” she added.

In addition, other MASH-related biomarkers were developed after the current study started, including the FAST, Agile, and ADAPT scores, she said. “After validation of the biomarkers in this study, it will also be important to see how this newer wave of biomarkers performs.”

“If subsequent efforts validate the current findings, and there is buy-in from all of the stakeholders, including the FDA, NIH, industry, and academic leaders, this can truly lead to practice-changing approaches to the clinical management and study of MASLD/MASH,” Dr. Kushner concluded.

The study was partially funded by the National Institute of Diabetes and Digestive and Kidney Diseases and a grant from the National Center for Advancing Translational Sciences. The NIMBLE project is sponsored by the FNIH and is a public-private partnership supported by numerous entities. Support was also provided by the Global Liver Institute and FDA. Dr. Sanyal has disclosed financial relationships with multiple companies. He recused himself from the analysis and interpretation of NIS4. Dr. Kushner has declared being an adviser for Gilead, AbbVie, Eiger, and Bausch, and receiving research support from Gilead. None are MASH/NASH-related.

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

Novel biomarker tests have met or exceeded the performance of common lab tests for diagnosing nonalcoholic steatohepatitis (NASH, now known as metabolic dysfunction–associated steatohepatitis or MASH), laying the groundwork for noninvasive alternatives to liver biopsy, new research suggests.

The blood-based tests could expand diagnostic options at health care facilities and facilitate enrollment in NASH clinical trials, which now require a biopsy for inclusion.

“The current study meets a key milestone for qualification of the biomarker panels studied for identification of at-risk NASH,” Arun Sanyal, MD, of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University, Richmond, told this news organization.

“It sets the stage for further validation of these outcomes,” he said. “These data will inform development of full qualification plans for these biomarker panels that will be submitted to the U.S. Food and Drug Administration. Once these are accepted by the FDA, the final steps toward qualification can be initiated.”

The study, published online in Nature Medicine, was conducted as part of the Foundation for the National Institutes of Health – Biomarkers Consortium’s Noninvasive Biomarkers of Metabolic Liver Disease (FNIH-NIMBLE), a multistakeholder project to support regulatory approval of NASH-related biomarkers.
 

Multiple biomarkers move forward

The investigators evaluated the diagnostic performance of five blood-based panels in an observational cohort derived from the NASH Clinical Research Network study, which included 4,094 participants; 2,479 individuals were excluded from the current study because of age, lack of samples, or lack of evaluable liver biopsies.

The remaining 1,073 patients (mean age, 52.5 years; 62% women) represented the full spectrum of nonalcoholic fatty liver disease (NAFLD, now known as metabolic dysfunction–associated steatotic liver disease or MASLD). In total, 225 individuals had NAFLD, 835 had NASH, and 13 had cirrhosis with an indeterminate NAFLD phenotype.

Those without fibrosis were younger and had mainly fatty liver, not steatohepatitis. They also had a lower NAFLD activity score, compared with those with stage 2 or higher fibrosis.

The study population for one of the five tests, FibroMeter VCTE, was a smaller subset (n = 396) of the larger population, with baseline features similar to the larger cohort.

The biomarker panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver), or fibrosis stages greater than 2, greater than 3, or 4 (enhanced liver fibrosis [ELF] test, PROC3, and FibroMeter VCTE). At-risk NASH was defined by the presence of NASH, high histologic activity, and fibrosis stage greater than or equal to 2.

The performance metric was an area under the receiver operating characteristic curve (AUROC) greater than or equal to 0.7 and superiority over alanine aminotransferase (ALT) for disease activity and the FIB-4 test for fibrosis severity.

Multiple biomarkers met the required metrics. For example, NIS4 had an AUROC of 0.81 for at-risk NASH. AUROCs for the ELF test (for clinically significant fibrosis, ≥ stage 2), PROC3 (advanced fibrosis, ≥ stage 3), and FibroMeter VCTE (cirrhosis, stage 4) were all greater than or equal to 0.8.

For all fibrosis endpoints, ELF and FibroMeter VCTE also outperformed FIB-4.

“The current study was a first step to determine if the biomarker panels not only identified the relevant phenotypes based on their intended use but also if they were superior to some commonly used clinical laboratory tools, such as ALT and FIB-4,” the authors write. “These will serve as criteria, to be finalized with feedback from the FDA, to move the panels with the most promising performance metrics to the final qualification steps.”

“Individual developers of specific biomarker panels will need to determine their strategy; that is, have separate rule-in and rule-out cutoffs or a single optimized cutoff as they [formulate] the full qualification plans,” Dr. Sanyal noted. “Also, it may be necessary to validate these cutoffs and performance in independent cohorts reflecting the populations where these are planned to be used.”

“We hope that by 2025, the first wave of biomarkers will have enough data to support approval for diagnostic purposes, and the data for prognostic biomarkers will follow within 1-2 years after that,” Dr. Sanyal added.
 

Are practice changes ahead?

“Findings from this study and subsequent planned studies have the potential to redefine our approach to MASH and fibrosis diagnosis and staging, both in clinical practice and as part of clinical trials for the multiple new therapeutics being evaluated for MASLD/MASH,” Tatyana Kushner, MD, gastroenterologist/hepatologist and associate professor of medicine in the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai, New York City, told this news organization.

Dr. Kushner noted that the study population “may not represent the diverse population affected by MASH in the United States, or even the clinical trial population.” The cohort was predominantly White, with relatively low representation from people of Hispanic ethnicity, who are known to have a higher prevalence of MASH.

“Furthermore, the study population was specifically curated to have representative numbers across liver disease/fibrosis stages, and this may have biased the results,” she added.

In addition, other MASH-related biomarkers were developed after the current study started, including the FAST, Agile, and ADAPT scores, she said. “After validation of the biomarkers in this study, it will also be important to see how this newer wave of biomarkers performs.”

“If subsequent efforts validate the current findings, and there is buy-in from all of the stakeholders, including the FDA, NIH, industry, and academic leaders, this can truly lead to practice-changing approaches to the clinical management and study of MASLD/MASH,” Dr. Kushner concluded.

The study was partially funded by the National Institute of Diabetes and Digestive and Kidney Diseases and a grant from the National Center for Advancing Translational Sciences. The NIMBLE project is sponsored by the FNIH and is a public-private partnership supported by numerous entities. Support was also provided by the Global Liver Institute and FDA. Dr. Sanyal has disclosed financial relationships with multiple companies. He recused himself from the analysis and interpretation of NIS4. Dr. Kushner has declared being an adviser for Gilead, AbbVie, Eiger, and Bausch, and receiving research support from Gilead. None are MASH/NASH-related.

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

TOPLINE:

Dyspareunia is a major indicator of urinary tract infections, being present in 83% of cases. The symptom is especially accurate at identifying UTIs in nonmenopausal women, researchers have found.

METHODOLOGY:

• Dyspareunia is a common symptom of UTIs, especially in premenopausal women, but is rarely inquired about during patient evaluations, according to researchers from Florida Atlantic University. 
• In 2010, the researchers found that among 3,000 of their female Latinx patients aged 17-72 years in South Florida, 80% of those with UTIs reported experiencing pain during sexual intercourse. 
• Since then, they have studied an additional 2,500 patients from the same population.

TAKEAWAY:

• Among all 5,500 patients, 83% of those who had UTIs experienced dyspareunia.
• Eighty percent of women of reproductive age with dyspareunia had an undiagnosed UTI.
• During the perimenopausal and postmenopausal years, dyspareunia was more often associated with genitourinary syndrome than UTIs.
• Ninety-four percent of women with UTI-associated dyspareunia responded positively to antibiotics.

IN PRACTICE:

“We have found that this symptom is extremely important as part of the symptomatology of UTI [and is] frequently found along with the classical symptoms,” the researchers reported. “Why has something so clear, so frequently present, never been described? The answer is simple: Physicians and patients do not talk about sex, despite dyspareunia being more a clinical symptom than a sexual one. Medical schools and residency programs in all areas, especially in obstetrics and gynecology, urology, and psychiatry, have been neglecting the education of physicians-in-training in this important aspect of human health. In conclusion, this is [proof] of how medicine has sometimes been influenced by religion, culture, and social norms far away from science.”

SOURCE:

The data were presented at the 2023 meeting of the Menopause Society. The study was led by Alberto Dominguez-Bali, MD, from Florida Atlantic University, Boca Raton, Fla.

LIMITATIONS:

The study authors reported no limitations.

DISCLOSURES:

The authors reported no relevant financial relationships.

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

TOPLINE:

Dyspareunia is a major indicator of urinary tract infections, being present in 83% of cases. The symptom is especially accurate at identifying UTIs in nonmenopausal women, researchers have found.

METHODOLOGY:

• Dyspareunia is a common symptom of UTIs, especially in premenopausal women, but is rarely inquired about during patient evaluations, according to researchers from Florida Atlantic University. 
• In 2010, the researchers found that among 3,000 of their female Latinx patients aged 17-72 years in South Florida, 80% of those with UTIs reported experiencing pain during sexual intercourse. 
• Since then, they have studied an additional 2,500 patients from the same population.

TAKEAWAY:

• Among all 5,500 patients, 83% of those who had UTIs experienced dyspareunia.
• Eighty percent of women of reproductive age with dyspareunia had an undiagnosed UTI.
• During the perimenopausal and postmenopausal years, dyspareunia was more often associated with genitourinary syndrome than UTIs.
• Ninety-four percent of women with UTI-associated dyspareunia responded positively to antibiotics.

IN PRACTICE:

“We have found that this symptom is extremely important as part of the symptomatology of UTI [and is] frequently found along with the classical symptoms,” the researchers reported. “Why has something so clear, so frequently present, never been described? The answer is simple: Physicians and patients do not talk about sex, despite dyspareunia being more a clinical symptom than a sexual one. Medical schools and residency programs in all areas, especially in obstetrics and gynecology, urology, and psychiatry, have been neglecting the education of physicians-in-training in this important aspect of human health. In conclusion, this is [proof] of how medicine has sometimes been influenced by religion, culture, and social norms far away from science.”

SOURCE:

The data were presented at the 2023 meeting of the Menopause Society. The study was led by Alberto Dominguez-Bali, MD, from Florida Atlantic University, Boca Raton, Fla.

LIMITATIONS:

The study authors reported no limitations.

DISCLOSURES:

The authors reported no relevant financial relationships.

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

TOPLINE:

Dyspareunia is a major indicator of urinary tract infections, being present in 83% of cases. The symptom is especially accurate at identifying UTIs in nonmenopausal women, researchers have found.

METHODOLOGY:

• Dyspareunia is a common symptom of UTIs, especially in premenopausal women, but is rarely inquired about during patient evaluations, according to researchers from Florida Atlantic University. 
• In 2010, the researchers found that among 3,000 of their female Latinx patients aged 17-72 years in South Florida, 80% of those with UTIs reported experiencing pain during sexual intercourse. 
• Since then, they have studied an additional 2,500 patients from the same population.

TAKEAWAY:

• Among all 5,500 patients, 83% of those who had UTIs experienced dyspareunia.
• Eighty percent of women of reproductive age with dyspareunia had an undiagnosed UTI.
• During the perimenopausal and postmenopausal years, dyspareunia was more often associated with genitourinary syndrome than UTIs.
• Ninety-four percent of women with UTI-associated dyspareunia responded positively to antibiotics.

IN PRACTICE:

“We have found that this symptom is extremely important as part of the symptomatology of UTI [and is] frequently found along with the classical symptoms,” the researchers reported. “Why has something so clear, so frequently present, never been described? The answer is simple: Physicians and patients do not talk about sex, despite dyspareunia being more a clinical symptom than a sexual one. Medical schools and residency programs in all areas, especially in obstetrics and gynecology, urology, and psychiatry, have been neglecting the education of physicians-in-training in this important aspect of human health. In conclusion, this is [proof] of how medicine has sometimes been influenced by religion, culture, and social norms far away from science.”

SOURCE:

The data were presented at the 2023 meeting of the Menopause Society. The study was led by Alberto Dominguez-Bali, MD, from Florida Atlantic University, Boca Raton, Fla.

LIMITATIONS:

The study authors reported no limitations.

DISCLOSURES:

The authors reported no relevant financial relationships.

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

The risk for inflammatory bowel disease (IBD) was increased among children and adults with atopic dermatitis (AD), with the risk increasing with AD severity, according to data from a large cohort study published recently in JAMA Dermatology.

The study also found an increased risk for Crohn’s disease (CD) in adults and children with AD, as well as an increased risk for ulcerative colitis (UC) in adults with AD and in children with severe AD, researchers reported.

“It is imperative for clinicians to understand atopic dermatitis and the trajectory of our patients with it in order to provide the best standard of care,” senior author Joel M. Gelfand, MD, MSCE, professor in clinical investigation with the department of dermatology at the University of Pennsylvania, Philadelphia, said in a news release.

Courtesy Dr. Gelfand

“There are new and better treatments for AD today, and there will likely continue to be more,” continued Dr. Gelfand. “But providers have to understand how those treatments could impact other autoimmune diseases. For patients with AD and another autoimmune disease, some currently available medications can exacerbate symptoms of their other disease or can help treat two immune diseases at the same time.”

The study results support the idea that AD and IBD may have some common underlying causes, said Sheilagh Maguiness, MD, pediatric dermatologist and associate professor in the department of dermatology at the University of Minnesota, Minneapolis, who was asked to comment on the findings.

“As the pathogenesis of AD is becoming better understood, we are recognizing that, rather than simply a cutaneous disease, the underlying inflammation and immune dysregulation that leads to AD best categorizes it as a systemic inflammatory disease with significant comorbidities,” she told this news organization. “I will be more likely to ask patients and families about GI symptoms, and if positive, may plan to refer to GI more readily than in the past,” added Dr. Maguiness, who was not involved in the study.

UK general practice cohort

AD has been associated with an increasing number of comorbidities, including IBD, but studies linking AD with IBD, including UC, have had mixed results, the authors wrote. And few studies have separately examined how AD or AD severity may be linked with UC or CD risk.

To examine the risk for new-onset IBD, UC, and CD in children and adults with atopic dermatitis, the researchers conducted a population-based cohort study using the THIN (The Health Improvement Network) electronic medical record database of patients registered with United Kingdom general practices. They used 21 years of data collected from January 1994 to February 2015.

The researchers matched each patient who had AD with up to five controls based on age, practice, and index date. Because THIN does not capture AD severity, they used treatment exposure assessed by dermatologic referrals and treatments patients received as proxy for severity. The authors used logistic regression to examine the risks for IBD, UC, and CD in children (aged 1-10) with AD, and in adults (aged 30-68) with AD, and they compared their outcomes with the outcomes for controls.

In the pediatric cohort, the team compared 409,431 children who had AD with 1.8 million children without AD. Slightly more than half were boys. In the adult cohort, they compared 625,083 people who had AD with 2.68 million controls, and slightly more than half were women. Data on race or ethnicity were not available, the authors wrote, but the THIN database is considered to be representative of the UK population.
 

AD severity linked with IBD risk

The risk for new-onset inflammatory bowel disease appears to be higher in children and adults with AD, and the risk varies based on age, AD severity, and subtype of inflammatory bowel disease, the authors reported.

Overall, AD in children was associated with a 44% increased risk for IBD (adjusted hazard ratio (HR), 1.44; 95% confidence interval [CI], 1.31-1.58) compared with controls, the authors reported. They found a 74% increased risk for CD in children with AD compared with controls (HR, 1.74; 95% CI, 1.54-1.97). More severe AD was linked with increased risk for both IBD and CD.

AD did not appear to increase risk for UC in children, except those with severe AD (HR, 1.65; 95% CI, 1.02-2.67).

Overall, adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk for IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk for CD, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk for UC, with risk increasing with increased AD severity.

Robust data with cautionary note

“This study provides the most robust data to date on the association between IBD and AD. It provides clear evidence for an association that most dermatologists or primary care providers are not typically taught in training,” Kelly Scarberry, MD, assistant professor of dermatology at Case Western Reserve University in Cleveland, told this news organization. “I will be much more likely to pursue diagnostic workup in my AD patients who have GI complaints.”

Case Western Reserve University

However, AD severity was measured by proxy, added Dr. Scarberry, who was not involved in the study, and the study lacked important racial and ethnic data.

Lindsay C. Strowd, MD, associate professor of dermatology at Wake Forest University, Winston-Salem, N.C., also not involved in the study, said in an interview that she found the size of the cohort and the longitudinal data to be strengths of the study.

Wake Forest University

But, she added, the “lack of family IBD history, race and ethnicity, and comorbidities, are limitations, as is treatment exposure used as a proxy for disease severity, given that physician treatment practices differ.”

For Steven R. Feldman, MD, PhD, professor of dermatology at Wake Forest, “the most important conclusion, and it is a definitive finding, [is] that IBD is uncommon, even in patients with AD.

“The findings could be misinterpreted,” cautioned Dr. Feldman, who was not involved in the study. “While there is an increased relative risk, the absolute risk is small.” The study found that “the highest relative risk group is children with severe AD, who have a roughly fivefold increased risk for CD.” However, he added, the incidence rates of CD were 0.68 per 1,000 person-years in children with severe AD and 0.08 per 1,000 person-years in controls.

Wake Forest University

“Basically, because Crohn’s disease and IBD don’t happen very often, the modest increase in relative risk the investigators found doesn’t amount to much we’d have to worry about,” he said. “The findings do not show any need to screen patients with atopic dermatitis for IBD any more than we’d need to screen patients without atopic dermatitis.”

The increased relative risk “could be a clue to possible genetic connections between diseases,” he added. “But when we’re making clinical decisions, those decisions should be based on the absolute risk that some event may occur.”

Susan Massick, MD, dermatologist and associate professor at The Ohio State University in Columbus, who was not involved with the study, said in an interview, “We are still scratching the surface of the complexity of the immune and inflammatory pathways in AD and IBD.

The Ohio State Wexner Medical Center

“It is important to remember that correlation does not mean causation,” Dr. Massick said. “It would be premature to draw direct conclusions based on this study alone.”

The authors recommend future related studies in more diverse populations.

Dr. Gelfand and two coauthors reported ties with Pfizer, which supported the study. Dr. Gelfand and three coauthors reported ties with other pharmaceutical companies. Dr. Maguiness, Dr. Scarberry, Dr. Strowd, and Dr. Massick reported having no relevant disclosures. Dr. Feldman reported ties with Pfizer and other pharmaceutical companies.

A version of this article appeared on Medscape.com.

The risk for inflammatory bowel disease (IBD) was increased among children and adults with atopic dermatitis (AD), with the risk increasing with AD severity, according to data from a large cohort study published recently in JAMA Dermatology.

The study also found an increased risk for Crohn’s disease (CD) in adults and children with AD, as well as an increased risk for ulcerative colitis (UC) in adults with AD and in children with severe AD, researchers reported.

“It is imperative for clinicians to understand atopic dermatitis and the trajectory of our patients with it in order to provide the best standard of care,” senior author Joel M. Gelfand, MD, MSCE, professor in clinical investigation with the department of dermatology at the University of Pennsylvania, Philadelphia, said in a news release.

Courtesy Dr. Gelfand

“There are new and better treatments for AD today, and there will likely continue to be more,” continued Dr. Gelfand. “But providers have to understand how those treatments could impact other autoimmune diseases. For patients with AD and another autoimmune disease, some currently available medications can exacerbate symptoms of their other disease or can help treat two immune diseases at the same time.”

The study results support the idea that AD and IBD may have some common underlying causes, said Sheilagh Maguiness, MD, pediatric dermatologist and associate professor in the department of dermatology at the University of Minnesota, Minneapolis, who was asked to comment on the findings.

“As the pathogenesis of AD is becoming better understood, we are recognizing that, rather than simply a cutaneous disease, the underlying inflammation and immune dysregulation that leads to AD best categorizes it as a systemic inflammatory disease with significant comorbidities,” she told this news organization. “I will be more likely to ask patients and families about GI symptoms, and if positive, may plan to refer to GI more readily than in the past,” added Dr. Maguiness, who was not involved in the study.

UK general practice cohort

AD has been associated with an increasing number of comorbidities, including IBD, but studies linking AD with IBD, including UC, have had mixed results, the authors wrote. And few studies have separately examined how AD or AD severity may be linked with UC or CD risk.

To examine the risk for new-onset IBD, UC, and CD in children and adults with atopic dermatitis, the researchers conducted a population-based cohort study using the THIN (The Health Improvement Network) electronic medical record database of patients registered with United Kingdom general practices. They used 21 years of data collected from January 1994 to February 2015.

The researchers matched each patient who had AD with up to five controls based on age, practice, and index date. Because THIN does not capture AD severity, they used treatment exposure assessed by dermatologic referrals and treatments patients received as proxy for severity. The authors used logistic regression to examine the risks for IBD, UC, and CD in children (aged 1-10) with AD, and in adults (aged 30-68) with AD, and they compared their outcomes with the outcomes for controls.

In the pediatric cohort, the team compared 409,431 children who had AD with 1.8 million children without AD. Slightly more than half were boys. In the adult cohort, they compared 625,083 people who had AD with 2.68 million controls, and slightly more than half were women. Data on race or ethnicity were not available, the authors wrote, but the THIN database is considered to be representative of the UK population.
 

AD severity linked with IBD risk

The risk for new-onset inflammatory bowel disease appears to be higher in children and adults with AD, and the risk varies based on age, AD severity, and subtype of inflammatory bowel disease, the authors reported.

Overall, AD in children was associated with a 44% increased risk for IBD (adjusted hazard ratio (HR), 1.44; 95% confidence interval [CI], 1.31-1.58) compared with controls, the authors reported. They found a 74% increased risk for CD in children with AD compared with controls (HR, 1.74; 95% CI, 1.54-1.97). More severe AD was linked with increased risk for both IBD and CD.

AD did not appear to increase risk for UC in children, except those with severe AD (HR, 1.65; 95% CI, 1.02-2.67).

Overall, adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk for IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk for CD, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk for UC, with risk increasing with increased AD severity.

Robust data with cautionary note

“This study provides the most robust data to date on the association between IBD and AD. It provides clear evidence for an association that most dermatologists or primary care providers are not typically taught in training,” Kelly Scarberry, MD, assistant professor of dermatology at Case Western Reserve University in Cleveland, told this news organization. “I will be much more likely to pursue diagnostic workup in my AD patients who have GI complaints.”

Case Western Reserve University

However, AD severity was measured by proxy, added Dr. Scarberry, who was not involved in the study, and the study lacked important racial and ethnic data.

Lindsay C. Strowd, MD, associate professor of dermatology at Wake Forest University, Winston-Salem, N.C., also not involved in the study, said in an interview that she found the size of the cohort and the longitudinal data to be strengths of the study.

Wake Forest University

But, she added, the “lack of family IBD history, race and ethnicity, and comorbidities, are limitations, as is treatment exposure used as a proxy for disease severity, given that physician treatment practices differ.”

For Steven R. Feldman, MD, PhD, professor of dermatology at Wake Forest, “the most important conclusion, and it is a definitive finding, [is] that IBD is uncommon, even in patients with AD.

“The findings could be misinterpreted,” cautioned Dr. Feldman, who was not involved in the study. “While there is an increased relative risk, the absolute risk is small.” The study found that “the highest relative risk group is children with severe AD, who have a roughly fivefold increased risk for CD.” However, he added, the incidence rates of CD were 0.68 per 1,000 person-years in children with severe AD and 0.08 per 1,000 person-years in controls.

Wake Forest University

“Basically, because Crohn’s disease and IBD don’t happen very often, the modest increase in relative risk the investigators found doesn’t amount to much we’d have to worry about,” he said. “The findings do not show any need to screen patients with atopic dermatitis for IBD any more than we’d need to screen patients without atopic dermatitis.”

The increased relative risk “could be a clue to possible genetic connections between diseases,” he added. “But when we’re making clinical decisions, those decisions should be based on the absolute risk that some event may occur.”

Susan Massick, MD, dermatologist and associate professor at The Ohio State University in Columbus, who was not involved with the study, said in an interview, “We are still scratching the surface of the complexity of the immune and inflammatory pathways in AD and IBD.

The Ohio State Wexner Medical Center

“It is important to remember that correlation does not mean causation,” Dr. Massick said. “It would be premature to draw direct conclusions based on this study alone.”

The authors recommend future related studies in more diverse populations.

Dr. Gelfand and two coauthors reported ties with Pfizer, which supported the study. Dr. Gelfand and three coauthors reported ties with other pharmaceutical companies. Dr. Maguiness, Dr. Scarberry, Dr. Strowd, and Dr. Massick reported having no relevant disclosures. Dr. Feldman reported ties with Pfizer and other pharmaceutical companies.

A version of this article appeared on Medscape.com.

The risk for inflammatory bowel disease (IBD) was increased among children and adults with atopic dermatitis (AD), with the risk increasing with AD severity, according to data from a large cohort study published recently in JAMA Dermatology.

The study also found an increased risk for Crohn’s disease (CD) in adults and children with AD, as well as an increased risk for ulcerative colitis (UC) in adults with AD and in children with severe AD, researchers reported.

“It is imperative for clinicians to understand atopic dermatitis and the trajectory of our patients with it in order to provide the best standard of care,” senior author Joel M. Gelfand, MD, MSCE, professor in clinical investigation with the department of dermatology at the University of Pennsylvania, Philadelphia, said in a news release.

Courtesy Dr. Gelfand

“There are new and better treatments for AD today, and there will likely continue to be more,” continued Dr. Gelfand. “But providers have to understand how those treatments could impact other autoimmune diseases. For patients with AD and another autoimmune disease, some currently available medications can exacerbate symptoms of their other disease or can help treat two immune diseases at the same time.”

The study results support the idea that AD and IBD may have some common underlying causes, said Sheilagh Maguiness, MD, pediatric dermatologist and associate professor in the department of dermatology at the University of Minnesota, Minneapolis, who was asked to comment on the findings.

“As the pathogenesis of AD is becoming better understood, we are recognizing that, rather than simply a cutaneous disease, the underlying inflammation and immune dysregulation that leads to AD best categorizes it as a systemic inflammatory disease with significant comorbidities,” she told this news organization. “I will be more likely to ask patients and families about GI symptoms, and if positive, may plan to refer to GI more readily than in the past,” added Dr. Maguiness, who was not involved in the study.

UK general practice cohort

AD has been associated with an increasing number of comorbidities, including IBD, but studies linking AD with IBD, including UC, have had mixed results, the authors wrote. And few studies have separately examined how AD or AD severity may be linked with UC or CD risk.

To examine the risk for new-onset IBD, UC, and CD in children and adults with atopic dermatitis, the researchers conducted a population-based cohort study using the THIN (The Health Improvement Network) electronic medical record database of patients registered with United Kingdom general practices. They used 21 years of data collected from January 1994 to February 2015.

The researchers matched each patient who had AD with up to five controls based on age, practice, and index date. Because THIN does not capture AD severity, they used treatment exposure assessed by dermatologic referrals and treatments patients received as proxy for severity. The authors used logistic regression to examine the risks for IBD, UC, and CD in children (aged 1-10) with AD, and in adults (aged 30-68) with AD, and they compared their outcomes with the outcomes for controls.

In the pediatric cohort, the team compared 409,431 children who had AD with 1.8 million children without AD. Slightly more than half were boys. In the adult cohort, they compared 625,083 people who had AD with 2.68 million controls, and slightly more than half were women. Data on race or ethnicity were not available, the authors wrote, but the THIN database is considered to be representative of the UK population.
 

AD severity linked with IBD risk

The risk for new-onset inflammatory bowel disease appears to be higher in children and adults with AD, and the risk varies based on age, AD severity, and subtype of inflammatory bowel disease, the authors reported.

Overall, AD in children was associated with a 44% increased risk for IBD (adjusted hazard ratio (HR), 1.44; 95% confidence interval [CI], 1.31-1.58) compared with controls, the authors reported. They found a 74% increased risk for CD in children with AD compared with controls (HR, 1.74; 95% CI, 1.54-1.97). More severe AD was linked with increased risk for both IBD and CD.

AD did not appear to increase risk for UC in children, except those with severe AD (HR, 1.65; 95% CI, 1.02-2.67).

Overall, adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk for IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk for CD, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk for UC, with risk increasing with increased AD severity.

Robust data with cautionary note

“This study provides the most robust data to date on the association between IBD and AD. It provides clear evidence for an association that most dermatologists or primary care providers are not typically taught in training,” Kelly Scarberry, MD, assistant professor of dermatology at Case Western Reserve University in Cleveland, told this news organization. “I will be much more likely to pursue diagnostic workup in my AD patients who have GI complaints.”

Case Western Reserve University

However, AD severity was measured by proxy, added Dr. Scarberry, who was not involved in the study, and the study lacked important racial and ethnic data.

Lindsay C. Strowd, MD, associate professor of dermatology at Wake Forest University, Winston-Salem, N.C., also not involved in the study, said in an interview that she found the size of the cohort and the longitudinal data to be strengths of the study.

Wake Forest University

But, she added, the “lack of family IBD history, race and ethnicity, and comorbidities, are limitations, as is treatment exposure used as a proxy for disease severity, given that physician treatment practices differ.”

For Steven R. Feldman, MD, PhD, professor of dermatology at Wake Forest, “the most important conclusion, and it is a definitive finding, [is] that IBD is uncommon, even in patients with AD.

“The findings could be misinterpreted,” cautioned Dr. Feldman, who was not involved in the study. “While there is an increased relative risk, the absolute risk is small.” The study found that “the highest relative risk group is children with severe AD, who have a roughly fivefold increased risk for CD.” However, he added, the incidence rates of CD were 0.68 per 1,000 person-years in children with severe AD and 0.08 per 1,000 person-years in controls.

Wake Forest University

“Basically, because Crohn’s disease and IBD don’t happen very often, the modest increase in relative risk the investigators found doesn’t amount to much we’d have to worry about,” he said. “The findings do not show any need to screen patients with atopic dermatitis for IBD any more than we’d need to screen patients without atopic dermatitis.”

The increased relative risk “could be a clue to possible genetic connections between diseases,” he added. “But when we’re making clinical decisions, those decisions should be based on the absolute risk that some event may occur.”

Susan Massick, MD, dermatologist and associate professor at The Ohio State University in Columbus, who was not involved with the study, said in an interview, “We are still scratching the surface of the complexity of the immune and inflammatory pathways in AD and IBD.

The Ohio State Wexner Medical Center

“It is important to remember that correlation does not mean causation,” Dr. Massick said. “It would be premature to draw direct conclusions based on this study alone.”

The authors recommend future related studies in more diverse populations.

Dr. Gelfand and two coauthors reported ties with Pfizer, which supported the study. Dr. Gelfand and three coauthors reported ties with other pharmaceutical companies. Dr. Maguiness, Dr. Scarberry, Dr. Strowd, and Dr. Massick reported having no relevant disclosures. Dr. Feldman reported ties with Pfizer and other pharmaceutical companies.

A version of this article appeared on Medscape.com.