Study Overview

Objective. To investigate the relationship between prescription drug coverage, receipt of active myeloma therapy, and overall survival (OS) among Medicare beneficiaries with multiple myeloma.

Design. Case-control and retrospective cohort archival data research.

Setting and participants. Authors examined SEER-Medicare registry and extracted patients with histologically confirmed multiple myeloma diagnosed in the period 2006 to 2011. Availability of complete Medicare part A/B claims from 1 year before diagnosis until December 2013 was required for analysis. Patients with Medicare advantage or managed care plans did not have claims data available and hence were excluded. Beneficiaries with a diagnosis of diffuse large B-cell lymphoma (DLBCL), who typically receive parenteral drugs for lymphoma therapy, were used as a control cohort.

Main outcome measures. Association between prescription drug coverage status and OS was the primary outcome measure of interest. Authors reported 3-year restricted survival time (RMST) ratios to compare OS among the beneficiaries with different prescription drug coverages. Receipt of active myeloma therapy among beneficiaries was also studied. Relative risk, adjusting for patient and disease-related characteristics, was reported to examine receipt of active myeloma therapy.

Results. Records of 9755 Medicare beneficiaries were evaluated. Of these, 1460 (15%) had no prescription coverage at diagnosis, 3283 (34%) had part D plan prescription benefits, 3607 (37%) had sponsored prescription coverage through an employer, federal employer, or veterans plan, and 1405 (14%) had a Medicaid prescription plan. Beneficiaries without coverage had fewer comorbidities, including anemia, neuropathy, or renal disease, than those with part D prescription coverage or Medicaid. Of those without any prescription drug coverage, 41% obtained prescription plan coverage after diagnosis of myeloma by the following January. Conversely, only 19% of patients with DLBCL and no coverage obtained a prescription plan.

Patients with myeloma were followed for 4.9 years and median survival was 2.3 years, with a 3-year OS rate of 43.1% (95% confidence interval [CI], 42.1%-44.1%). Relative to the group without coverage, survival was 16% longer in the Medicare part D group and sponsored plan group (RMST 1.16; 95% CI, 1.12-1.21). Medicaid/Medicare dual beneficiaries had worse OS in both myeloma and DLBCL consistent with poor performance status and unfavorable baseline comorbidities. However, among patients with myeloma, Medicaid/Medicare dual beneficiaries had better survival (RMST 1.08; 95% CI, 1.03-1.13) compared to the group without coverage. There was no difference in OS for those with or without prescription drug coverage in the DLBCL cohort.

There were significant differences in treatment of myeloma based on types of prescription drug coverage. Due to increasing use of bortezomib following its approval by the U.S. Food and Drug Administration (FDA), parenteral chemotherapy use doubled from 24% to 48% from 2006 to 2011, and utility of active myeloma care increased from 88% to 91%. Medicare part D plan enrollees were 6% more likely to receive active myeloma care, and both Medicaid group and sponsored plan group beneficiaries were equally likely to receive active myeloma care compared to beneficiaries without prescription coverage. Medicaid enrollees were less likely to receive parenteral therapy.

Conclusion. Medicare beneficiaries with prescription drug coverage and multiple myeloma are more likely to receive myeloma therapy and have longer OS compared to those without prescription drug coverage.

Commentary

First-line therapy of multiple myeloma has evolved over the past 2 decades. Parenteral agents such as vincristine, adriamycin, dexamethasone, and cyclophosphamide and oral therapy with melphalan and prednisone were the mainstay of treatment in the past. In the past decade, the arrival of oral therapy using thalidomide or lenalidomide and parenteral therapy using bortezomib has increased OS in patients with myeloma. Most recently, a combination of lenalidomide, bortezomib, and dexamethasone has emerged as one of the frontline therapies of choice.¹ Incorporation of bortezomib or an oral immunomodulatory drug is almost universal in first-line therapy.

Oral antineoplastic therapy is increasingly being approved by the FDA and being utilized in the community. During the period 2016-2018, more than half the new FDA-approved oncology drugs were in oral formulation.² As such, access to these agents is crucial in cancer therapy. The cost of oral therapy in patients without prescription drug coverage is sometimes more than $10,000 per month, which represents a significant impediment to its adoption. Forty-three states and Washington, DC, have enacted drug parity laws that require patients to pay no more for an oral cancer treatment than they would for an infusion. However, currently there is no such federal law, and Medicare beneficiaries must participate either through part D, state Medicaid, or a sponsored program to obtain prescription drug coverage. Despite being enrolled in part D, many beneficiaries fall into the “doughnut hole” (the requirement of Part D beneficiaries with high prescription drug expenses to pay more once the total cost of their medicines reaches a certain threshold) for prescription drugs at the time of need. From 2019 onward, enrollees will see significant, yet sometimes still insufficient, coverage benefits due to ending of the doughnut hole.³ Only a very limited number of oral chemotherapy agents are covered through Medicare part B, and of those covered, only oral melphalan is used for myeloma.

The authors have acknowledged multiple limitations of their investigation, including possible unobserved clinical differences between beneficiaries. SEER-Medicare registry has limitations in obtaining individual level data and may not contain specific results of cytogenetics, laboratory risk markers, and response to therapy, which are important to determine overall outcome. A prospective evaluation may be more suitable to assess these variables independently or through a multivariate analysis in determining receipt of therapy on OS, although such a study is currently not feasible.

The indicator of active myeloma care was defined as 2 or more outpatient physician visits or receipt of parenteral chemotherapy. This definition is somewhat suboptimal, as often patients with myeloma are under surveillance and may not necessarily be receiving active treatment. Moreover, the exact prescription pattern of lenalidomide, the most active first-line oral therapy, could not be captured from this retrospective registry review. Therefore, definitive conclusions regarding use of lenalidomide and thalidomide and receipt of therapy in this population cannot be made.

A significant improvement in OS has been established using maintenance lenalidomide following high-dose chemotherapy and stem cell transplantation.⁴ Only 5% of this study population received stem cell transplantation. This may be due to a median age of 77 years at diagnosis in the group studied, higher than the 66 to 70 years previously published.⁵ Stem cell transplantation is now commonly being used even in the older population. The 3-year survival of 83% following stem cell transplantation in myeloma patients aged 75 to 84 years was nearly identical to that of the younger population.⁶ Since stem cell transplantation is feasible in older Medicare beneficiaries and maintenance lenalidomide for 2 years following transplant improves survival, the option of providing maintenance therapy with oral lenalidomide must be made available to Medicare beneficiaries. Due to a very limited use of transplantation in this study, the impact of oral lenalidomide maintenance in OS cannot be judged.

Of the patients reviewed in this study, 6% had a listed diagnosis of plasmacytoma. These individuals typically are treated with radiation therapy only. It is unclear if these patients also received any systemic myeloma therapy or if they ever progressed to myeloma. Availability of prescription drug coverage may not be relevant to this group. Also, the authors reported that part D participants were less likely to receive classic cytotoxic chemotherapy. This may be somewhat irrelevant in Medicare beneficiaries with a median age of 77 years for current practice, as frontline induction with old classic cytotoxic chemotherapy is less commonly used in this population.

Investigators have appropriately recognized a lack of ability to discern whether inferior survival in the group without prescription drug coverage was the result of not receiving therapy at all or inability to receive oral immunomodulatory drugs. There would have been little reason for not proceeding to parenteral therapy. As noted, 41% of beneficiaries without coverage at diagnosis subsequently obtained coverage but continued to have significantly worse survival. Cause of death, including whether related to myeloma, was not reported. The authors suggest that early separation of survival curves could therefore be reflective of suboptimal first-line therapy that lacked oral immunomodulatory drugs. During the study period 2006-2011, first-line use of lenalidomide was common.

Median survival of patients with myeloma in this study was only 27 months. According to the American Cancer Society, in 2018 median survival for stage I myeloma has not been reached, stage II myeloma is 83 months, and stage III myeloma is 43 months. A robust and dynamic landscape in myeloma therapy prevents a clear attribution to individual agents, whether oral or parenteral, in improving OS. Thus, 3-year RMST, while appropriate for 2006-2011, may not be relevant today.

Applications for Clinical Practice

The oncology community routinely encounters difficulty in initiating therapy using oral agents rapidly after diagnosis of myeloma. The retrospective data analyzed in the current study suggests that delay in initiating or unavailability of oral agents may adversely impact OS. The common approach of initiating parenteral therapy while awaiting approvals from payers or charity programs and subsequently adding oral therapy when available has not been studied in assessing OS. The oncology community should initiate plans to obtain prescription drug coverage through either Medicare part D, Medicaid, a sponsored plan, or financial assistance charity programs as soon as possible after diagnosis of myeloma. Moreover, continuation of these prescription drug plans should be strongly considered throughout the course of myeloma, as subsequent lines of treatment will quite likely involve other active and approved oral agents, such as pomalidomide, ixazomib, and panobinostat, besides other supportive therapy.

One of the mechanisms to obtain prescription drug coverage includes enrollment in state Medicaid programs for those who are eligible. Currently, 17 states have not yet adopted Medicaid expansion under the Affordable Care Act. Expansion of Medicaid in these states could increase availability of prescription drug benefits. In this study, 15.8% of Medicare and Medicaid dual enrollees with access to oral agents at low or no cost did not receive myeloma care, slightly higher than the 13.1% with no prescription drug coverage. Lower utilization in this population may be explained based on differences in comorbidities or socioeconomic conditions rather than availability of a prescription plan.

The incidence of myeloma is expected to be higher in Medicare beneficiaries, and according to one estimate, in 2030 and beyond nearly 75% of diagnosed myeloma patients will be aged 64 to 84 years, an increase from nearly 66% today.⁷ Changing demographics, increasing oral therapy options, and patient convenience demand attention to providing prescription drug coverage to all Medicare beneficiaries. This study lends support to that demand.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To investigate the relationship between prescription drug coverage, receipt of active myeloma therapy, and overall survival (OS) among Medicare beneficiaries with multiple myeloma.

Design. Case-control and retrospective cohort archival data research.

Setting and participants. Authors examined SEER-Medicare registry and extracted patients with histologically confirmed multiple myeloma diagnosed in the period 2006 to 2011. Availability of complete Medicare part A/B claims from 1 year before diagnosis until December 2013 was required for analysis. Patients with Medicare advantage or managed care plans did not have claims data available and hence were excluded. Beneficiaries with a diagnosis of diffuse large B-cell lymphoma (DLBCL), who typically receive parenteral drugs for lymphoma therapy, were used as a control cohort.

Main outcome measures. Association between prescription drug coverage status and OS was the primary outcome measure of interest. Authors reported 3-year restricted survival time (RMST) ratios to compare OS among the beneficiaries with different prescription drug coverages. Receipt of active myeloma therapy among beneficiaries was also studied. Relative risk, adjusting for patient and disease-related characteristics, was reported to examine receipt of active myeloma therapy.

Results. Records of 9755 Medicare beneficiaries were evaluated. Of these, 1460 (15%) had no prescription coverage at diagnosis, 3283 (34%) had part D plan prescription benefits, 3607 (37%) had sponsored prescription coverage through an employer, federal employer, or veterans plan, and 1405 (14%) had a Medicaid prescription plan. Beneficiaries without coverage had fewer comorbidities, including anemia, neuropathy, or renal disease, than those with part D prescription coverage or Medicaid. Of those without any prescription drug coverage, 41% obtained prescription plan coverage after diagnosis of myeloma by the following January. Conversely, only 19% of patients with DLBCL and no coverage obtained a prescription plan.

Patients with myeloma were followed for 4.9 years and median survival was 2.3 years, with a 3-year OS rate of 43.1% (95% confidence interval [CI], 42.1%-44.1%). Relative to the group without coverage, survival was 16% longer in the Medicare part D group and sponsored plan group (RMST 1.16; 95% CI, 1.12-1.21). Medicaid/Medicare dual beneficiaries had worse OS in both myeloma and DLBCL consistent with poor performance status and unfavorable baseline comorbidities. However, among patients with myeloma, Medicaid/Medicare dual beneficiaries had better survival (RMST 1.08; 95% CI, 1.03-1.13) compared to the group without coverage. There was no difference in OS for those with or without prescription drug coverage in the DLBCL cohort.

There were significant differences in treatment of myeloma based on types of prescription drug coverage. Due to increasing use of bortezomib following its approval by the U.S. Food and Drug Administration (FDA), parenteral chemotherapy use doubled from 24% to 48% from 2006 to 2011, and utility of active myeloma care increased from 88% to 91%. Medicare part D plan enrollees were 6% more likely to receive active myeloma care, and both Medicaid group and sponsored plan group beneficiaries were equally likely to receive active myeloma care compared to beneficiaries without prescription coverage. Medicaid enrollees were less likely to receive parenteral therapy.

Conclusion. Medicare beneficiaries with prescription drug coverage and multiple myeloma are more likely to receive myeloma therapy and have longer OS compared to those without prescription drug coverage.

Commentary

First-line therapy of multiple myeloma has evolved over the past 2 decades. Parenteral agents such as vincristine, adriamycin, dexamethasone, and cyclophosphamide and oral therapy with melphalan and prednisone were the mainstay of treatment in the past. In the past decade, the arrival of oral therapy using thalidomide or lenalidomide and parenteral therapy using bortezomib has increased OS in patients with myeloma. Most recently, a combination of lenalidomide, bortezomib, and dexamethasone has emerged as one of the frontline therapies of choice.¹ Incorporation of bortezomib or an oral immunomodulatory drug is almost universal in first-line therapy.

Oral antineoplastic therapy is increasingly being approved by the FDA and being utilized in the community. During the period 2016-2018, more than half the new FDA-approved oncology drugs were in oral formulation.² As such, access to these agents is crucial in cancer therapy. The cost of oral therapy in patients without prescription drug coverage is sometimes more than $10,000 per month, which represents a significant impediment to its adoption. Forty-three states and Washington, DC, have enacted drug parity laws that require patients to pay no more for an oral cancer treatment than they would for an infusion. However, currently there is no such federal law, and Medicare beneficiaries must participate either through part D, state Medicaid, or a sponsored program to obtain prescription drug coverage. Despite being enrolled in part D, many beneficiaries fall into the “doughnut hole” (the requirement of Part D beneficiaries with high prescription drug expenses to pay more once the total cost of their medicines reaches a certain threshold) for prescription drugs at the time of need. From 2019 onward, enrollees will see significant, yet sometimes still insufficient, coverage benefits due to ending of the doughnut hole.³ Only a very limited number of oral chemotherapy agents are covered through Medicare part B, and of those covered, only oral melphalan is used for myeloma.

The authors have acknowledged multiple limitations of their investigation, including possible unobserved clinical differences between beneficiaries. SEER-Medicare registry has limitations in obtaining individual level data and may not contain specific results of cytogenetics, laboratory risk markers, and response to therapy, which are important to determine overall outcome. A prospective evaluation may be more suitable to assess these variables independently or through a multivariate analysis in determining receipt of therapy on OS, although such a study is currently not feasible.

The indicator of active myeloma care was defined as 2 or more outpatient physician visits or receipt of parenteral chemotherapy. This definition is somewhat suboptimal, as often patients with myeloma are under surveillance and may not necessarily be receiving active treatment. Moreover, the exact prescription pattern of lenalidomide, the most active first-line oral therapy, could not be captured from this retrospective registry review. Therefore, definitive conclusions regarding use of lenalidomide and thalidomide and receipt of therapy in this population cannot be made.

A significant improvement in OS has been established using maintenance lenalidomide following high-dose chemotherapy and stem cell transplantation.⁴ Only 5% of this study population received stem cell transplantation. This may be due to a median age of 77 years at diagnosis in the group studied, higher than the 66 to 70 years previously published.⁵ Stem cell transplantation is now commonly being used even in the older population. The 3-year survival of 83% following stem cell transplantation in myeloma patients aged 75 to 84 years was nearly identical to that of the younger population.⁶ Since stem cell transplantation is feasible in older Medicare beneficiaries and maintenance lenalidomide for 2 years following transplant improves survival, the option of providing maintenance therapy with oral lenalidomide must be made available to Medicare beneficiaries. Due to a very limited use of transplantation in this study, the impact of oral lenalidomide maintenance in OS cannot be judged.

Of the patients reviewed in this study, 6% had a listed diagnosis of plasmacytoma. These individuals typically are treated with radiation therapy only. It is unclear if these patients also received any systemic myeloma therapy or if they ever progressed to myeloma. Availability of prescription drug coverage may not be relevant to this group. Also, the authors reported that part D participants were less likely to receive classic cytotoxic chemotherapy. This may be somewhat irrelevant in Medicare beneficiaries with a median age of 77 years for current practice, as frontline induction with old classic cytotoxic chemotherapy is less commonly used in this population.

Investigators have appropriately recognized a lack of ability to discern whether inferior survival in the group without prescription drug coverage was the result of not receiving therapy at all or inability to receive oral immunomodulatory drugs. There would have been little reason for not proceeding to parenteral therapy. As noted, 41% of beneficiaries without coverage at diagnosis subsequently obtained coverage but continued to have significantly worse survival. Cause of death, including whether related to myeloma, was not reported. The authors suggest that early separation of survival curves could therefore be reflective of suboptimal first-line therapy that lacked oral immunomodulatory drugs. During the study period 2006-2011, first-line use of lenalidomide was common.

Median survival of patients with myeloma in this study was only 27 months. According to the American Cancer Society, in 2018 median survival for stage I myeloma has not been reached, stage II myeloma is 83 months, and stage III myeloma is 43 months. A robust and dynamic landscape in myeloma therapy prevents a clear attribution to individual agents, whether oral or parenteral, in improving OS. Thus, 3-year RMST, while appropriate for 2006-2011, may not be relevant today.

Applications for Clinical Practice

The oncology community routinely encounters difficulty in initiating therapy using oral agents rapidly after diagnosis of myeloma. The retrospective data analyzed in the current study suggests that delay in initiating or unavailability of oral agents may adversely impact OS. The common approach of initiating parenteral therapy while awaiting approvals from payers or charity programs and subsequently adding oral therapy when available has not been studied in assessing OS. The oncology community should initiate plans to obtain prescription drug coverage through either Medicare part D, Medicaid, a sponsored plan, or financial assistance charity programs as soon as possible after diagnosis of myeloma. Moreover, continuation of these prescription drug plans should be strongly considered throughout the course of myeloma, as subsequent lines of treatment will quite likely involve other active and approved oral agents, such as pomalidomide, ixazomib, and panobinostat, besides other supportive therapy.

One of the mechanisms to obtain prescription drug coverage includes enrollment in state Medicaid programs for those who are eligible. Currently, 17 states have not yet adopted Medicaid expansion under the Affordable Care Act. Expansion of Medicaid in these states could increase availability of prescription drug benefits. In this study, 15.8% of Medicare and Medicaid dual enrollees with access to oral agents at low or no cost did not receive myeloma care, slightly higher than the 13.1% with no prescription drug coverage. Lower utilization in this population may be explained based on differences in comorbidities or socioeconomic conditions rather than availability of a prescription plan.

The incidence of myeloma is expected to be higher in Medicare beneficiaries, and according to one estimate, in 2030 and beyond nearly 75% of diagnosed myeloma patients will be aged 64 to 84 years, an increase from nearly 66% today.⁷ Changing demographics, increasing oral therapy options, and patient convenience demand attention to providing prescription drug coverage to all Medicare beneficiaries. This study lends support to that demand.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To investigate the relationship between prescription drug coverage, receipt of active myeloma therapy, and overall survival (OS) among Medicare beneficiaries with multiple myeloma.

Design. Case-control and retrospective cohort archival data research.

Setting and participants. Authors examined SEER-Medicare registry and extracted patients with histologically confirmed multiple myeloma diagnosed in the period 2006 to 2011. Availability of complete Medicare part A/B claims from 1 year before diagnosis until December 2013 was required for analysis. Patients with Medicare advantage or managed care plans did not have claims data available and hence were excluded. Beneficiaries with a diagnosis of diffuse large B-cell lymphoma (DLBCL), who typically receive parenteral drugs for lymphoma therapy, were used as a control cohort.

Main outcome measures. Association between prescription drug coverage status and OS was the primary outcome measure of interest. Authors reported 3-year restricted survival time (RMST) ratios to compare OS among the beneficiaries with different prescription drug coverages. Receipt of active myeloma therapy among beneficiaries was also studied. Relative risk, adjusting for patient and disease-related characteristics, was reported to examine receipt of active myeloma therapy.

Results. Records of 9755 Medicare beneficiaries were evaluated. Of these, 1460 (15%) had no prescription coverage at diagnosis, 3283 (34%) had part D plan prescription benefits, 3607 (37%) had sponsored prescription coverage through an employer, federal employer, or veterans plan, and 1405 (14%) had a Medicaid prescription plan. Beneficiaries without coverage had fewer comorbidities, including anemia, neuropathy, or renal disease, than those with part D prescription coverage or Medicaid. Of those without any prescription drug coverage, 41% obtained prescription plan coverage after diagnosis of myeloma by the following January. Conversely, only 19% of patients with DLBCL and no coverage obtained a prescription plan.

Patients with myeloma were followed for 4.9 years and median survival was 2.3 years, with a 3-year OS rate of 43.1% (95% confidence interval [CI], 42.1%-44.1%). Relative to the group without coverage, survival was 16% longer in the Medicare part D group and sponsored plan group (RMST 1.16; 95% CI, 1.12-1.21). Medicaid/Medicare dual beneficiaries had worse OS in both myeloma and DLBCL consistent with poor performance status and unfavorable baseline comorbidities. However, among patients with myeloma, Medicaid/Medicare dual beneficiaries had better survival (RMST 1.08; 95% CI, 1.03-1.13) compared to the group without coverage. There was no difference in OS for those with or without prescription drug coverage in the DLBCL cohort.

There were significant differences in treatment of myeloma based on types of prescription drug coverage. Due to increasing use of bortezomib following its approval by the U.S. Food and Drug Administration (FDA), parenteral chemotherapy use doubled from 24% to 48% from 2006 to 2011, and utility of active myeloma care increased from 88% to 91%. Medicare part D plan enrollees were 6% more likely to receive active myeloma care, and both Medicaid group and sponsored plan group beneficiaries were equally likely to receive active myeloma care compared to beneficiaries without prescription coverage. Medicaid enrollees were less likely to receive parenteral therapy.

Conclusion. Medicare beneficiaries with prescription drug coverage and multiple myeloma are more likely to receive myeloma therapy and have longer OS compared to those without prescription drug coverage.

Commentary

First-line therapy of multiple myeloma has evolved over the past 2 decades. Parenteral agents such as vincristine, adriamycin, dexamethasone, and cyclophosphamide and oral therapy with melphalan and prednisone were the mainstay of treatment in the past. In the past decade, the arrival of oral therapy using thalidomide or lenalidomide and parenteral therapy using bortezomib has increased OS in patients with myeloma. Most recently, a combination of lenalidomide, bortezomib, and dexamethasone has emerged as one of the frontline therapies of choice.¹ Incorporation of bortezomib or an oral immunomodulatory drug is almost universal in first-line therapy.

Oral antineoplastic therapy is increasingly being approved by the FDA and being utilized in the community. During the period 2016-2018, more than half the new FDA-approved oncology drugs were in oral formulation.² As such, access to these agents is crucial in cancer therapy. The cost of oral therapy in patients without prescription drug coverage is sometimes more than $10,000 per month, which represents a significant impediment to its adoption. Forty-three states and Washington, DC, have enacted drug parity laws that require patients to pay no more for an oral cancer treatment than they would for an infusion. However, currently there is no such federal law, and Medicare beneficiaries must participate either through part D, state Medicaid, or a sponsored program to obtain prescription drug coverage. Despite being enrolled in part D, many beneficiaries fall into the “doughnut hole” (the requirement of Part D beneficiaries with high prescription drug expenses to pay more once the total cost of their medicines reaches a certain threshold) for prescription drugs at the time of need. From 2019 onward, enrollees will see significant, yet sometimes still insufficient, coverage benefits due to ending of the doughnut hole.³ Only a very limited number of oral chemotherapy agents are covered through Medicare part B, and of those covered, only oral melphalan is used for myeloma.

The authors have acknowledged multiple limitations of their investigation, including possible unobserved clinical differences between beneficiaries. SEER-Medicare registry has limitations in obtaining individual level data and may not contain specific results of cytogenetics, laboratory risk markers, and response to therapy, which are important to determine overall outcome. A prospective evaluation may be more suitable to assess these variables independently or through a multivariate analysis in determining receipt of therapy on OS, although such a study is currently not feasible.

The indicator of active myeloma care was defined as 2 or more outpatient physician visits or receipt of parenteral chemotherapy. This definition is somewhat suboptimal, as often patients with myeloma are under surveillance and may not necessarily be receiving active treatment. Moreover, the exact prescription pattern of lenalidomide, the most active first-line oral therapy, could not be captured from this retrospective registry review. Therefore, definitive conclusions regarding use of lenalidomide and thalidomide and receipt of therapy in this population cannot be made.

A significant improvement in OS has been established using maintenance lenalidomide following high-dose chemotherapy and stem cell transplantation.⁴ Only 5% of this study population received stem cell transplantation. This may be due to a median age of 77 years at diagnosis in the group studied, higher than the 66 to 70 years previously published.⁵ Stem cell transplantation is now commonly being used even in the older population. The 3-year survival of 83% following stem cell transplantation in myeloma patients aged 75 to 84 years was nearly identical to that of the younger population.⁶ Since stem cell transplantation is feasible in older Medicare beneficiaries and maintenance lenalidomide for 2 years following transplant improves survival, the option of providing maintenance therapy with oral lenalidomide must be made available to Medicare beneficiaries. Due to a very limited use of transplantation in this study, the impact of oral lenalidomide maintenance in OS cannot be judged.

Of the patients reviewed in this study, 6% had a listed diagnosis of plasmacytoma. These individuals typically are treated with radiation therapy only. It is unclear if these patients also received any systemic myeloma therapy or if they ever progressed to myeloma. Availability of prescription drug coverage may not be relevant to this group. Also, the authors reported that part D participants were less likely to receive classic cytotoxic chemotherapy. This may be somewhat irrelevant in Medicare beneficiaries with a median age of 77 years for current practice, as frontline induction with old classic cytotoxic chemotherapy is less commonly used in this population.

Investigators have appropriately recognized a lack of ability to discern whether inferior survival in the group without prescription drug coverage was the result of not receiving therapy at all or inability to receive oral immunomodulatory drugs. There would have been little reason for not proceeding to parenteral therapy. As noted, 41% of beneficiaries without coverage at diagnosis subsequently obtained coverage but continued to have significantly worse survival. Cause of death, including whether related to myeloma, was not reported. The authors suggest that early separation of survival curves could therefore be reflective of suboptimal first-line therapy that lacked oral immunomodulatory drugs. During the study period 2006-2011, first-line use of lenalidomide was common.

Median survival of patients with myeloma in this study was only 27 months. According to the American Cancer Society, in 2018 median survival for stage I myeloma has not been reached, stage II myeloma is 83 months, and stage III myeloma is 43 months. A robust and dynamic landscape in myeloma therapy prevents a clear attribution to individual agents, whether oral or parenteral, in improving OS. Thus, 3-year RMST, while appropriate for 2006-2011, may not be relevant today.

Applications for Clinical Practice

The oncology community routinely encounters difficulty in initiating therapy using oral agents rapidly after diagnosis of myeloma. The retrospective data analyzed in the current study suggests that delay in initiating or unavailability of oral agents may adversely impact OS. The common approach of initiating parenteral therapy while awaiting approvals from payers or charity programs and subsequently adding oral therapy when available has not been studied in assessing OS. The oncology community should initiate plans to obtain prescription drug coverage through either Medicare part D, Medicaid, a sponsored plan, or financial assistance charity programs as soon as possible after diagnosis of myeloma. Moreover, continuation of these prescription drug plans should be strongly considered throughout the course of myeloma, as subsequent lines of treatment will quite likely involve other active and approved oral agents, such as pomalidomide, ixazomib, and panobinostat, besides other supportive therapy.

One of the mechanisms to obtain prescription drug coverage includes enrollment in state Medicaid programs for those who are eligible. Currently, 17 states have not yet adopted Medicaid expansion under the Affordable Care Act. Expansion of Medicaid in these states could increase availability of prescription drug benefits. In this study, 15.8% of Medicare and Medicaid dual enrollees with access to oral agents at low or no cost did not receive myeloma care, slightly higher than the 13.1% with no prescription drug coverage. Lower utilization in this population may be explained based on differences in comorbidities or socioeconomic conditions rather than availability of a prescription plan.

The incidence of myeloma is expected to be higher in Medicare beneficiaries, and according to one estimate, in 2030 and beyond nearly 75% of diagnosed myeloma patients will be aged 64 to 84 years, an increase from nearly 66% today.⁷ Changing demographics, increasing oral therapy options, and patient convenience demand attention to providing prescription drug coverage to all Medicare beneficiaries. This study lends support to that demand.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Editor's Note

Gastroenterologists are becoming increasingly involved in the management of obesity. While prior therapy for obesity was mainly based on lifestyle changes, medication, or surgery, the new and exciting field of endoscopic bariatric and metabolic therapies has recently garnered incredible attention and momentum.

In this quarter’s In Focus article, brought to you by The New Gastroenterologist, Pichamol Jirapinyo and Christopher Thompson (Brigham and Women’s Hospital) provide an outstanding overview of the gastric and small bowel endoscopic interventions that are either already approved for use in obesity or currently being studied. This field is moving incredibly fast, and knowledge and understanding of these endoscopic therapies for obesity will undoubtedly be important for our field.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Obesity is a rising pandemic. As of 2016, 93.3 million U.S. adults had obesity, representing 39.8% of our adult population.¹ It is estimated that approximately $147 billion is spent annually on caring for patients with obesity. Traditionally, the management of obesity includes lifestyle therapy (diet and exercise), pharmacotherapy (six Food and Drug Administration–approved medications for obesity), and bariatric surgery (sleeve gastrectomy [SG] and Roux-en-Y gastric bypass [RYGB]). Nevertheless, intensive lifestyle intervention and pharmacotherapy are associated with approximately 3.1%-6.6% total weight loss (TWL),^2-7 and bariatric surgery is associated with 20%-33.3% TWL.⁸ However, less than 2% of patients who are eligible for bariatric surgery elect to undergo surgery, leaving a large proportion of patients with obesity untreated or undertreated.⁹

Copyright Elsevier and AGA Institute (2017)

Endoscopic bariatric and metabolic therapies (EBMTs) encompass an emerging field for the treatment of obesity. In general, EBMTs are associated with greater weight loss than are lifestyle intervention and pharmacotherapy, but with a less- invasive risk profile than bariatric surgery. EBMTs may be divided into two general categories – gastric and small bowel interventions (Figure 1 and Table 1). Gastric EBMTs are effective at treating obesity, while small bowel EBMTs are effective at treating metabolic diseases with a variable weight loss profile depending on the device.^10,11

Of note, a variety of study designs (including retrospective series, prospective series, and randomized trials with and without shams) have been employed, which can affect outcomes. Therefore, weight loss comparisons among studies are challenging and should be considered in this context.
 

Gastric interventions

Currently, there are three types of EBMTs that are FDA approved and used for the treatment of obesity. These include intragastric balloons (IGBs), plications and suturing, and aspiration therapy (AT). Other technologies that are under investigation also will be briefly covered.

Intragastric balloons

An intragastric balloon is a space-occupying device that is placed in the stomach. The mechanism of action of IGBs involves delaying gastric emptying, which leads to increased satiety.¹² There are several types of IGBs available worldwide differing in techniques of placement and removal (endoscopic versus fluoroscopic versus swallowable), materials used to fill the balloon (fluid-filled versus air-filled), and the number of balloons placed (single versus duo versus three-balloon). At the time of this writing, three IGBs are approved by the FDA (Orbera, ReShape, and Obalon), all for patients with body mass indexes of 30-40 kg/m², and two others are in the process of obtaining FDA approval (Spatz and Elipse).

Orbera gastric balloon (Apollo Endosurgery, Austin, Tex.) is a single fluid-filled IGB that is endoscopically placed and removed at 6 months. The balloon is filled with 400-700 cc of saline with or without methylene blue (to identify leakage or rupture). Recently, Orbera365, which allows the balloon to stay for 12 months instead of 6 months, has become available in Europe; however, it is yet to be approved in the United States. The U.S. pivotal trial (Orbera trial) including 255 subjects (125 Orbera arm versus 130 non-sham control arm) demonstrated 10.2% TWL in the Orbera group compared with 3.3% TWL in the control group at 6 months based on intention-to-treat (ITT) analysis. This difference persisted at 12 months (6 months after explantation) with 7.6% TWL for the Orbera group versus 3.1% TWL for the control group.^13,14

ReShape integrated dual balloon system (ReShape Lifesciences, San Clemente, Calif.) consists of two connected fluid-filled balloons that are endoscopically placed and removed at 6 months. Each balloon is filled with 375-450 cc of saline mixed with methylene blue. The U.S. pivotal trial (REDUCE trial) including 326 subjects (187 ReShape arm versus 139 sham arm) demonstrated 6.8% TWL in the ReShape group compared with 3.3% TWL in the sham group at 6 months based on ITT analysis.^15,16

Obalon balloon system (Obalon Therapeutics, Carlsbad, Calif.) is a swallowable, gas-filled balloon system that requires endoscopy only for removal. During placement, a capsule is swallowed under fluoroscopic guidance. The balloon is then inflated with 250 cc of nitrogen mix gas prior to tube detachment. Up to three balloons may be swallowed sequentially at 1-month intervals. At 6 months from the first balloon placement, all balloons are removed endoscopically. The U.S. pivotal trial (SMART trial) including 366 subjects (185 Obalon arm versus 181 sham capsule arm) demonstrated 6.6% TWL in the Obalon group compared with 3.4% TWL in the sham group at 6 months based on ITT analysis.^17,18

Two other balloons that are currently under investigation in the United States are the Spatz3 adjustable balloon system (Spatz Medical, Great Neck, N.Y.) and Elipse balloon (Allurion Technologies, Wellesley, Mass.). The Spatz3 is a fluid-filled balloon that is placed and removed endoscopically. It consists of a single balloon and a connecting tube that allows volume adjustment for control of symptoms and possible augmentation of weight loss. The U.S. pivotal trial was recently completed and the data are being reviewed by the FDA. The Elipse is a swallowable fluid-filled balloon that does not require endoscopy for placement or removal. At 4 months, the balloon releases fluid allowing it to empty and pass naturally. The U.S. pivotal trial (ENLIGHTEN trial) is currently underway.

A meta-analysis of randomized controlled trials revealed improvement in most metabolic parameters (diastolic blood pressure, fasting glucose, hemoglobin A_1c, and waist circumference) following IGB compared with controls.¹⁹ Nausea and vomiting are seen in approximately 30% and should be addressed appropriately. Pooled serious adverse event (SAE) rate was 1.5%, which included migration, perforation, and death. Since 2016, 14 deaths have been reported according to the FDA MAUDE database. Corporate response was that over 295,000 balloons had been distributed worldwide with a mortality rate of less than 0.01%.²⁰
 

Plication and suturing

Currently, there are two endoscopic devices that are approved for the general indication of tissue apposition. These include the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, Calif.) and the Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Tex.). These devices are used to remodel the stomach to create a sleeve-like structure to induce weight loss.

The IOP system consists of a transport, which is a 54-Fr flexible endoscope. It consists of four working channels that accommodate a G-Prox (for tissue approximation), a G-Lix (for tissue grasping), and an ultrathin endoscope (for visualization). In April 2008, Horgan performed the first-in-human primary obesity surgery endoluminal (POSE) procedure in Argentina. The procedure involves the use of the IOP system to place plications primarily in the fundus to modify gastric accommodation.²¹ The U.S. pivotal trial (ESSENTIAL trial) including 332 subjects (221 POSE arm versus 111 sham arm) demonstrated 5.0% TWL in the POSE group compared with 1.4% in the sham group at 12 months based on ITT analysis.²² A European multicenter randomized controlled trial (MILEPOST trial) including 44 subjects (34 POSE arm versus 10 non-sham control arm) demonstrated 13.0% TWL in the POSE group compared with 5.3% TWL in the control group at 12 months.²³ A recent meta-analysis including five studies with 586 subjects showed pooled weight loss of 13.2% at 12-15 months following POSE with a pooled serious adverse event rate of 3.2%.²⁴ These included extraluminal bleeding, minor bleeding at the suture site, hepatic abscess, chest pain, nausea, vomiting, and abdominal pain. A distal POSE procedure with a new plication pattern focusing on the gastric body to augment the effect on gastric emptying has also been described.²⁵

The Overstitch is an endoscopic suturing device that is mounted on a double-channel endoscope. At the tip of the scope, there is a curved suture arm and an anchor exchange that allow the needle to pass back and forth to perform full-thickness bites. The tissue helix may also be placed through the second channel to grasp tissue. In April 2012, Thompson performed the first-in-human endoscopic sutured/sleeve gastroplasty (ESG) procedure in India, which was published together with cases performed in Panama and the Dominican Republic.^26-28 This procedure involves the use of the Overstitch device to place several sets of running sutures along the greater curvature of the stomach to create a sleeve-like structure. It is thought to delay gastric emptying and therefore increase satiety.²⁹ The largest multicenter retrospective study including 248 patients demonstrated 18.6% TWL at 2 years with 2% SAE rate including perigastric fluid collections, extraluminal hemorrhage, pulmonary embolism, pneumoperitoneum, and pneumothorax.³⁰

Aspiration therapy

Aspiration therapy (AT; Aspire Bariatrics, King of Prussia, Pa.) allows patients to remove 25%-30% of ingested calories at approximately 30 minutes after meals. AT consists of an A-tube, which is a 26-Fr gastrostomy tube with a 15-cm fenestrated drainage catheter placed endoscopically via a standard pull technique. At 1-2 weeks after A-tube placement, the tube is cut down to the skin and connected to the port prior to aspiration. AT is approved for patients with a BMI of 35-55 kg/m².³¹ The U.S. pivotal trial (PATHWAY trial) including 207 subjects (137 AT arm versus 70 non-sham control arm) demonstrated 12.1% TWL in the AT group compared to 3.5% in the control group at 12 months based on ITT analysis. The SAE rate was 3.6% including severe abdominal pain, peritonitis, prepyloric ulcer, and A-tube replacement due to skin-port malfunction.³²

Transpyloric shuttle

The transpyloric shuttle (TPS; BAROnova, Goleta, Calif.) consists of a spherical bulb that is attached to a smaller cylindrical bulb by a flexible tether. It is placed and removed endoscopically at 6 months. TPS resides across the pylorus creating intermittent obstruction that may result in delayed gastric emptying. A pilot study including 20 patients demonstrated 14.5% TWL at 6 months.³³ The U.S. pivotal trial (ENDObesity II trial) was recently completed and the data are being reviewed by the FDA.

Revision for weight regain following bariatric surgery

Weight regain is common following RYGB^34,35 and can be associated with dilation of the gastrojejunal anastomosis (GJA).³⁶ Several procedures have been developed to treat this condition by focusing on reduction of GJA size and are available in the United States (Figure 2). These procedures have level I evidence supporting their use and include transoral outlet reduction (TORe) and restorative obesity surgery endoluminal (ROSE).³⁷ TORe involves the use of the Overstitch to place sutures at the GJA. At 1 year, patients had 8.4% TWL with improvement in comorbidities.³⁸ Weight loss remained significant up to 3-5 years.^39,40 The modern ROSE procedure utilizes the IOP system to place plications at the GJA and distal gastric pouch following argon plasma coagulation (APC). A small series showed 12.4% TWL at 6 months.⁴¹ APC is also currently being investigated as a standalone therapy for weight regain in this population.

Small bowel interventions

There are several small bowel interventions, with different mechanisms of action, available internationally. Many of these are under investigation in the United States; however, none are currently FDA approved.

Duodenal-jejunal bypass liner

Duodenal-jejunal bypass liner (DJBL; GI Dynamics, Boston, Mass.) is a 60-cm fluoropolymer liner that is endoscopically placed and removed at 12 months. It is anchored at the duodenal bulb and ends at the jejunum. By excluding direct contact between chyme and the proximal small bowel, DJBL is thought to work via foregut mechanism where there is less inhibition of the incretin effect (greater increase in insulin secretion following oral glucose administration compared to intravenous glucose administration due to gut-derived factors that enhance insulin secretion) leading to improved insulin resistance. In addition, the enteral transit of chyme and bile is altered suggesting the possible role of the hindgut mechanism. The previous U.S. pivotal trial (ENDO trial) met efficacy endpoints. However, the study was stopped early by the company because of a hepatic abscess rate of 3.5%, all of which were treated conservatively.⁴² A new U.S. pivotal study is currently planned. A meta-analysis of 17 published studies, all of which were from outside the United States, demonstrated a significant decrease in hemoglobin A_1c of 1.3% and 18.9% TWL at 1 year following implantation in patients with obesity with concomitant diabetes.⁴³
 

Duodenal mucosal resurfacing

Duodenal mucosal resurfacing (Fractyl, Lexington, Mass.) involves saline lifting of the duodenal mucosa circumferentially prior to thermal ablation using an inflated balloon filled with heated water. It is hypothesized that this may reset the diseased duodenal enteroendocrine cells leading to restoration of the incretin effect. A pilot study including 39 patients with poorly controlled diabetes demonstrated a decrease in hemoglobin A_1c of 1.2%. The SAE rate was 7.7% including duodenal stenosis, all of which were treated with balloon dilation.⁴⁴ The U.S. pivotal trial is currently planned.

Gastroduodenal-jejunal bypass

Gastroduodenal-jejunal bypass (ValenTx., Hopkins, Minn.) is a 120-cm sleeve that is anchored at the gastroesophageal junction to create the anatomic changes of RYGB. It is placed and removed endoscopically with laparoscopic assistance. A pilot study including 12 patients demonstrated 35.9% excess weight loss at 12 months. Two out of 12 patients had early device removal due to intolerance and they were not included in the weight loss analysis.⁴⁵

Incisionless magnetic anastomosis system

The incisionless magnetic anastomosis system (GI Windows, West Bridgewater, Mass.) consists of self-assembling magnets that are deployed under fluoroscopic guidance through the working channel of colonoscopes to form magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is formed and the coupled magnets pass spontaneously. A pilot study including 10 patients showed 14.6% TWL and a decrease in hemoglobin A_1c of 1.9% (for patients with diabetes) at 1 year.⁴⁶ A randomized study outside the United States is currently underway.

Summary

Endoscopic bariatric and metabolic therapies are emerging as first-line treatments for obesity in many populations. They can serve as a gap therapy for patients who do not qualify for surgery, but also may have a specific role in the treatment of metabolic comorbidities. This field will continue to develop and improve with the introduction of personalized medicine leading to better patient selection, and newer combination therapies. It is time for gastroenterologists to become more involved in the management of this challenging condition.

Dr. Jirapinyo is an advanced and bariatric endoscopy fellow, Brigham and Women’s Hospital, Harvard Medical School, Boston; Dr. Thompson is director of therapeutic endoscopy, Brigham and Women’s Hospital, and associate professor of medicine, Harvard Medical School. Dr. Jirapinyo has served as a consultant for GI Dynamics and holds royalties for Endosim. Dr. Thompson has contracted research for Aspire Bariatrics, USGI Medical, Spatz, and Apollo Endosurgery; has served as a consultant for Boston Scientific, Covidien, USGI Medical, Olympus, and Fractyl; holds stocks and royalties for GI Windows and Endosim, and has served as an expert reviewer for GI Dynamics.
 

References

1. CDC. From https://www.cdc.gov/obesity/data/adult.html. Accessed on 11 September 2018.

2. Aronne LJ et al. Obesity. 2013;21:2163-71.

3. Torgerson JS et al. Diabetes Care. 2004;27:155-61.

4. Allison DB et al. Obesity. 2012;20:330-42.

5. Smith SR et al. N Engl J Med. 2010;363:245-56.

6. Apovian CM et al. Obesity. 2013;21:935-43.

7. Pi-Sunyer X et al. N Engl J Med. 2015;373:11-22.

8. Colguitt JL et al. Cochrane Database Syst Rev. 2014;8(8):CD003641.

9. Ponce J et al. Surg Obes Relat Dis. 2015;11(6):1199-200.

10. Jirapinyo P, Thompson CC et al. Clin Gastroenterol Hepatol. 2017;15(5):619-30.

11. Sullivan S et al.Gastroenterology. 2017;152(7):1791-801.

12. Gomez V et al. Obesity. 2016;24(9):1849-53.

13. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ORBERA Intragastric Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140008b.pdf. 2015:1-32.

14. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;81:AB147.

15. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ReShape Integrated Dual Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140012b.pdf. 2015:1-43.

16. Ponce J et al. Surg Obes Relat Dis. 2015;11:874-81.

17. Food and Drug Administration. Summary and effectiveness data (SSED): Obalon Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160001b.pdf. 2016:1-46.

18. Sullivan S et al. Gastroenterology. 2016;150:S1267.

19. Popov VB et al. Am J Gastroenterol. 2017;112:429-39.

20. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;82(3):425-38.

21. Espinos JC et al. Obes Surg. 2013;23(9):1375-83.

22. Sullivan S et al. Obesity. 2017;25:294-301.

23. Miller K et al. Obesity Surg. 2017;27(2):310-22.

24. Jirapinyo P et al. Gastrointest Endosc. 2018;87(6):AB604-AB605.

25. Jirapinyo P, Thompson CC. Video GIE. 2018;3(10):296-300.

26. Campos J et al. SAGES 2013 Presentation. Baltimore, MD. 19 April 2013.

27. Kumar N et al. Gastroenterology. 2014;146(5):S571-2.

28. Kumar N et al. Surg Endosc. 2018;32(4):2159-64.

29. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2017;15:37-43.

30. Lopez-Nava G et al. Obes Surg. 2017;27(10):2649-55.

31. Food and Drug Administration. Summary of safety and effectiveness (SSED): AspireAssist. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150024b.pdf. FDA,ed,2016:1-36.

32. Thompson CC et al. Am J Gastroenterol. 2017;112:447-57.

33. SAGES abstract archives. SAGES. Available from: http://www.sages.org/meetings/annual-meeting/abstracts-archive/first-clinical-experience-with-the-transpyloric-shuttle-tpsr-device-a-non-surgical-endoscopic treatment-for-obesity-results-from-a-3-month-and-6-month-study. Accessed Sept. 12, 2018.

34. Sjostrom L et al. N Engl J Med. 2007;357:741-52.

35. Adams TD et al. N Engl J Med. 2017;377:1143-55.

36. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2011;9:228-33.

37. Thompson CC et al. Gastroenterology. 2013;145(1):129-37.

38. Jirapinyo P et al. Endoscopy. 2018;50(4):371-7.

39. Kumar N, Thompson CC. Gastrointest Endosc. 2016;83(4):776-9.

40. Jirapinyo P et al. Gastrointest Endosc. 2017;85(5):AB93-94.

41. Jirapinyo P, Thompson CC et al. Comparison of a novel plication technique to suturing for endoscopic outlet reduction for the treatment of weight regain after Roux-en-Y gastric bypass. Obesity Week 2018. Poster presentation.

42. Kaplan LM et al. EndoBarrier therapy is associated with glycemic improvement, weight loss and safety issues in patients with obesity and type 2 diabetes on oral anti-hyperglycemic agents (The ENDO Trial). In: Oral Presentation at the 76th American Diabetes Association (ADA) Annual Meeting: 2016 June 10-14: New Orleans. Abstract number 362-LB.

43. Jirapinyo P et al. Diabetes Care. 2018;41(5):1106-15.

44. Rajagopalan H et al. Diabetes Care. 2016;39(12):2254-61.

45. Sandler BJ et al. Surgical Endosc. 2015;29:3298-303.

46. Machytka E et al. Gastrointest Endosc. 2017;86(5):904-12.

Editor's Note

Gastroenterologists are becoming increasingly involved in the management of obesity. While prior therapy for obesity was mainly based on lifestyle changes, medication, or surgery, the new and exciting field of endoscopic bariatric and metabolic therapies has recently garnered incredible attention and momentum.

In this quarter’s In Focus article, brought to you by The New Gastroenterologist, Pichamol Jirapinyo and Christopher Thompson (Brigham and Women’s Hospital) provide an outstanding overview of the gastric and small bowel endoscopic interventions that are either already approved for use in obesity or currently being studied. This field is moving incredibly fast, and knowledge and understanding of these endoscopic therapies for obesity will undoubtedly be important for our field.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Obesity is a rising pandemic. As of 2016, 93.3 million U.S. adults had obesity, representing 39.8% of our adult population.¹ It is estimated that approximately $147 billion is spent annually on caring for patients with obesity. Traditionally, the management of obesity includes lifestyle therapy (diet and exercise), pharmacotherapy (six Food and Drug Administration–approved medications for obesity), and bariatric surgery (sleeve gastrectomy [SG] and Roux-en-Y gastric bypass [RYGB]). Nevertheless, intensive lifestyle intervention and pharmacotherapy are associated with approximately 3.1%-6.6% total weight loss (TWL),^2-7 and bariatric surgery is associated with 20%-33.3% TWL.⁸ However, less than 2% of patients who are eligible for bariatric surgery elect to undergo surgery, leaving a large proportion of patients with obesity untreated or undertreated.⁹

Copyright Elsevier and AGA Institute (2017)

Endoscopic bariatric and metabolic therapies (EBMTs) encompass an emerging field for the treatment of obesity. In general, EBMTs are associated with greater weight loss than are lifestyle intervention and pharmacotherapy, but with a less- invasive risk profile than bariatric surgery. EBMTs may be divided into two general categories – gastric and small bowel interventions (Figure 1 and Table 1). Gastric EBMTs are effective at treating obesity, while small bowel EBMTs are effective at treating metabolic diseases with a variable weight loss profile depending on the device.^10,11

Of note, a variety of study designs (including retrospective series, prospective series, and randomized trials with and without shams) have been employed, which can affect outcomes. Therefore, weight loss comparisons among studies are challenging and should be considered in this context.
 

Gastric interventions

Currently, there are three types of EBMTs that are FDA approved and used for the treatment of obesity. These include intragastric balloons (IGBs), plications and suturing, and aspiration therapy (AT). Other technologies that are under investigation also will be briefly covered.

Intragastric balloons

An intragastric balloon is a space-occupying device that is placed in the stomach. The mechanism of action of IGBs involves delaying gastric emptying, which leads to increased satiety.¹² There are several types of IGBs available worldwide differing in techniques of placement and removal (endoscopic versus fluoroscopic versus swallowable), materials used to fill the balloon (fluid-filled versus air-filled), and the number of balloons placed (single versus duo versus three-balloon). At the time of this writing, three IGBs are approved by the FDA (Orbera, ReShape, and Obalon), all for patients with body mass indexes of 30-40 kg/m², and two others are in the process of obtaining FDA approval (Spatz and Elipse).

Orbera gastric balloon (Apollo Endosurgery, Austin, Tex.) is a single fluid-filled IGB that is endoscopically placed and removed at 6 months. The balloon is filled with 400-700 cc of saline with or without methylene blue (to identify leakage or rupture). Recently, Orbera365, which allows the balloon to stay for 12 months instead of 6 months, has become available in Europe; however, it is yet to be approved in the United States. The U.S. pivotal trial (Orbera trial) including 255 subjects (125 Orbera arm versus 130 non-sham control arm) demonstrated 10.2% TWL in the Orbera group compared with 3.3% TWL in the control group at 6 months based on intention-to-treat (ITT) analysis. This difference persisted at 12 months (6 months after explantation) with 7.6% TWL for the Orbera group versus 3.1% TWL for the control group.^13,14

ReShape integrated dual balloon system (ReShape Lifesciences, San Clemente, Calif.) consists of two connected fluid-filled balloons that are endoscopically placed and removed at 6 months. Each balloon is filled with 375-450 cc of saline mixed with methylene blue. The U.S. pivotal trial (REDUCE trial) including 326 subjects (187 ReShape arm versus 139 sham arm) demonstrated 6.8% TWL in the ReShape group compared with 3.3% TWL in the sham group at 6 months based on ITT analysis.^15,16

Obalon balloon system (Obalon Therapeutics, Carlsbad, Calif.) is a swallowable, gas-filled balloon system that requires endoscopy only for removal. During placement, a capsule is swallowed under fluoroscopic guidance. The balloon is then inflated with 250 cc of nitrogen mix gas prior to tube detachment. Up to three balloons may be swallowed sequentially at 1-month intervals. At 6 months from the first balloon placement, all balloons are removed endoscopically. The U.S. pivotal trial (SMART trial) including 366 subjects (185 Obalon arm versus 181 sham capsule arm) demonstrated 6.6% TWL in the Obalon group compared with 3.4% TWL in the sham group at 6 months based on ITT analysis.^17,18

Two other balloons that are currently under investigation in the United States are the Spatz3 adjustable balloon system (Spatz Medical, Great Neck, N.Y.) and Elipse balloon (Allurion Technologies, Wellesley, Mass.). The Spatz3 is a fluid-filled balloon that is placed and removed endoscopically. It consists of a single balloon and a connecting tube that allows volume adjustment for control of symptoms and possible augmentation of weight loss. The U.S. pivotal trial was recently completed and the data are being reviewed by the FDA. The Elipse is a swallowable fluid-filled balloon that does not require endoscopy for placement or removal. At 4 months, the balloon releases fluid allowing it to empty and pass naturally. The U.S. pivotal trial (ENLIGHTEN trial) is currently underway.

A meta-analysis of randomized controlled trials revealed improvement in most metabolic parameters (diastolic blood pressure, fasting glucose, hemoglobin A_1c, and waist circumference) following IGB compared with controls.¹⁹ Nausea and vomiting are seen in approximately 30% and should be addressed appropriately. Pooled serious adverse event (SAE) rate was 1.5%, which included migration, perforation, and death. Since 2016, 14 deaths have been reported according to the FDA MAUDE database. Corporate response was that over 295,000 balloons had been distributed worldwide with a mortality rate of less than 0.01%.²⁰
 

Plication and suturing

Currently, there are two endoscopic devices that are approved for the general indication of tissue apposition. These include the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, Calif.) and the Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Tex.). These devices are used to remodel the stomach to create a sleeve-like structure to induce weight loss.

The IOP system consists of a transport, which is a 54-Fr flexible endoscope. It consists of four working channels that accommodate a G-Prox (for tissue approximation), a G-Lix (for tissue grasping), and an ultrathin endoscope (for visualization). In April 2008, Horgan performed the first-in-human primary obesity surgery endoluminal (POSE) procedure in Argentina. The procedure involves the use of the IOP system to place plications primarily in the fundus to modify gastric accommodation.²¹ The U.S. pivotal trial (ESSENTIAL trial) including 332 subjects (221 POSE arm versus 111 sham arm) demonstrated 5.0% TWL in the POSE group compared with 1.4% in the sham group at 12 months based on ITT analysis.²² A European multicenter randomized controlled trial (MILEPOST trial) including 44 subjects (34 POSE arm versus 10 non-sham control arm) demonstrated 13.0% TWL in the POSE group compared with 5.3% TWL in the control group at 12 months.²³ A recent meta-analysis including five studies with 586 subjects showed pooled weight loss of 13.2% at 12-15 months following POSE with a pooled serious adverse event rate of 3.2%.²⁴ These included extraluminal bleeding, minor bleeding at the suture site, hepatic abscess, chest pain, nausea, vomiting, and abdominal pain. A distal POSE procedure with a new plication pattern focusing on the gastric body to augment the effect on gastric emptying has also been described.²⁵

The Overstitch is an endoscopic suturing device that is mounted on a double-channel endoscope. At the tip of the scope, there is a curved suture arm and an anchor exchange that allow the needle to pass back and forth to perform full-thickness bites. The tissue helix may also be placed through the second channel to grasp tissue. In April 2012, Thompson performed the first-in-human endoscopic sutured/sleeve gastroplasty (ESG) procedure in India, which was published together with cases performed in Panama and the Dominican Republic.^26-28 This procedure involves the use of the Overstitch device to place several sets of running sutures along the greater curvature of the stomach to create a sleeve-like structure. It is thought to delay gastric emptying and therefore increase satiety.²⁹ The largest multicenter retrospective study including 248 patients demonstrated 18.6% TWL at 2 years with 2% SAE rate including perigastric fluid collections, extraluminal hemorrhage, pulmonary embolism, pneumoperitoneum, and pneumothorax.³⁰

Aspiration therapy

Aspiration therapy (AT; Aspire Bariatrics, King of Prussia, Pa.) allows patients to remove 25%-30% of ingested calories at approximately 30 minutes after meals. AT consists of an A-tube, which is a 26-Fr gastrostomy tube with a 15-cm fenestrated drainage catheter placed endoscopically via a standard pull technique. At 1-2 weeks after A-tube placement, the tube is cut down to the skin and connected to the port prior to aspiration. AT is approved for patients with a BMI of 35-55 kg/m².³¹ The U.S. pivotal trial (PATHWAY trial) including 207 subjects (137 AT arm versus 70 non-sham control arm) demonstrated 12.1% TWL in the AT group compared to 3.5% in the control group at 12 months based on ITT analysis. The SAE rate was 3.6% including severe abdominal pain, peritonitis, prepyloric ulcer, and A-tube replacement due to skin-port malfunction.³²

Transpyloric shuttle

The transpyloric shuttle (TPS; BAROnova, Goleta, Calif.) consists of a spherical bulb that is attached to a smaller cylindrical bulb by a flexible tether. It is placed and removed endoscopically at 6 months. TPS resides across the pylorus creating intermittent obstruction that may result in delayed gastric emptying. A pilot study including 20 patients demonstrated 14.5% TWL at 6 months.³³ The U.S. pivotal trial (ENDObesity II trial) was recently completed and the data are being reviewed by the FDA.

Revision for weight regain following bariatric surgery

Weight regain is common following RYGB^34,35 and can be associated with dilation of the gastrojejunal anastomosis (GJA).³⁶ Several procedures have been developed to treat this condition by focusing on reduction of GJA size and are available in the United States (Figure 2). These procedures have level I evidence supporting their use and include transoral outlet reduction (TORe) and restorative obesity surgery endoluminal (ROSE).³⁷ TORe involves the use of the Overstitch to place sutures at the GJA. At 1 year, patients had 8.4% TWL with improvement in comorbidities.³⁸ Weight loss remained significant up to 3-5 years.^39,40 The modern ROSE procedure utilizes the IOP system to place plications at the GJA and distal gastric pouch following argon plasma coagulation (APC). A small series showed 12.4% TWL at 6 months.⁴¹ APC is also currently being investigated as a standalone therapy for weight regain in this population.

Small bowel interventions

There are several small bowel interventions, with different mechanisms of action, available internationally. Many of these are under investigation in the United States; however, none are currently FDA approved.

Duodenal-jejunal bypass liner

Duodenal-jejunal bypass liner (DJBL; GI Dynamics, Boston, Mass.) is a 60-cm fluoropolymer liner that is endoscopically placed and removed at 12 months. It is anchored at the duodenal bulb and ends at the jejunum. By excluding direct contact between chyme and the proximal small bowel, DJBL is thought to work via foregut mechanism where there is less inhibition of the incretin effect (greater increase in insulin secretion following oral glucose administration compared to intravenous glucose administration due to gut-derived factors that enhance insulin secretion) leading to improved insulin resistance. In addition, the enteral transit of chyme and bile is altered suggesting the possible role of the hindgut mechanism. The previous U.S. pivotal trial (ENDO trial) met efficacy endpoints. However, the study was stopped early by the company because of a hepatic abscess rate of 3.5%, all of which were treated conservatively.⁴² A new U.S. pivotal study is currently planned. A meta-analysis of 17 published studies, all of which were from outside the United States, demonstrated a significant decrease in hemoglobin A_1c of 1.3% and 18.9% TWL at 1 year following implantation in patients with obesity with concomitant diabetes.⁴³
 

Duodenal mucosal resurfacing

Duodenal mucosal resurfacing (Fractyl, Lexington, Mass.) involves saline lifting of the duodenal mucosa circumferentially prior to thermal ablation using an inflated balloon filled with heated water. It is hypothesized that this may reset the diseased duodenal enteroendocrine cells leading to restoration of the incretin effect. A pilot study including 39 patients with poorly controlled diabetes demonstrated a decrease in hemoglobin A_1c of 1.2%. The SAE rate was 7.7% including duodenal stenosis, all of which were treated with balloon dilation.⁴⁴ The U.S. pivotal trial is currently planned.

Gastroduodenal-jejunal bypass

Gastroduodenal-jejunal bypass (ValenTx., Hopkins, Minn.) is a 120-cm sleeve that is anchored at the gastroesophageal junction to create the anatomic changes of RYGB. It is placed and removed endoscopically with laparoscopic assistance. A pilot study including 12 patients demonstrated 35.9% excess weight loss at 12 months. Two out of 12 patients had early device removal due to intolerance and they were not included in the weight loss analysis.⁴⁵

Incisionless magnetic anastomosis system

The incisionless magnetic anastomosis system (GI Windows, West Bridgewater, Mass.) consists of self-assembling magnets that are deployed under fluoroscopic guidance through the working channel of colonoscopes to form magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is formed and the coupled magnets pass spontaneously. A pilot study including 10 patients showed 14.6% TWL and a decrease in hemoglobin A_1c of 1.9% (for patients with diabetes) at 1 year.⁴⁶ A randomized study outside the United States is currently underway.

Summary

Endoscopic bariatric and metabolic therapies are emerging as first-line treatments for obesity in many populations. They can serve as a gap therapy for patients who do not qualify for surgery, but also may have a specific role in the treatment of metabolic comorbidities. This field will continue to develop and improve with the introduction of personalized medicine leading to better patient selection, and newer combination therapies. It is time for gastroenterologists to become more involved in the management of this challenging condition.

Dr. Jirapinyo is an advanced and bariatric endoscopy fellow, Brigham and Women’s Hospital, Harvard Medical School, Boston; Dr. Thompson is director of therapeutic endoscopy, Brigham and Women’s Hospital, and associate professor of medicine, Harvard Medical School. Dr. Jirapinyo has served as a consultant for GI Dynamics and holds royalties for Endosim. Dr. Thompson has contracted research for Aspire Bariatrics, USGI Medical, Spatz, and Apollo Endosurgery; has served as a consultant for Boston Scientific, Covidien, USGI Medical, Olympus, and Fractyl; holds stocks and royalties for GI Windows and Endosim, and has served as an expert reviewer for GI Dynamics.
 

References

1. CDC. From https://www.cdc.gov/obesity/data/adult.html. Accessed on 11 September 2018.

2. Aronne LJ et al. Obesity. 2013;21:2163-71.

3. Torgerson JS et al. Diabetes Care. 2004;27:155-61.

4. Allison DB et al. Obesity. 2012;20:330-42.

5. Smith SR et al. N Engl J Med. 2010;363:245-56.

6. Apovian CM et al. Obesity. 2013;21:935-43.

7. Pi-Sunyer X et al. N Engl J Med. 2015;373:11-22.

8. Colguitt JL et al. Cochrane Database Syst Rev. 2014;8(8):CD003641.

9. Ponce J et al. Surg Obes Relat Dis. 2015;11(6):1199-200.

10. Jirapinyo P, Thompson CC et al. Clin Gastroenterol Hepatol. 2017;15(5):619-30.

11. Sullivan S et al.Gastroenterology. 2017;152(7):1791-801.

12. Gomez V et al. Obesity. 2016;24(9):1849-53.

13. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ORBERA Intragastric Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140008b.pdf. 2015:1-32.

14. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;81:AB147.

15. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ReShape Integrated Dual Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140012b.pdf. 2015:1-43.

16. Ponce J et al. Surg Obes Relat Dis. 2015;11:874-81.

17. Food and Drug Administration. Summary and effectiveness data (SSED): Obalon Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160001b.pdf. 2016:1-46.

18. Sullivan S et al. Gastroenterology. 2016;150:S1267.

19. Popov VB et al. Am J Gastroenterol. 2017;112:429-39.

20. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;82(3):425-38.

21. Espinos JC et al. Obes Surg. 2013;23(9):1375-83.

22. Sullivan S et al. Obesity. 2017;25:294-301.

23. Miller K et al. Obesity Surg. 2017;27(2):310-22.

24. Jirapinyo P et al. Gastrointest Endosc. 2018;87(6):AB604-AB605.

25. Jirapinyo P, Thompson CC. Video GIE. 2018;3(10):296-300.

26. Campos J et al. SAGES 2013 Presentation. Baltimore, MD. 19 April 2013.

27. Kumar N et al. Gastroenterology. 2014;146(5):S571-2.

28. Kumar N et al. Surg Endosc. 2018;32(4):2159-64.

29. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2017;15:37-43.

30. Lopez-Nava G et al. Obes Surg. 2017;27(10):2649-55.

31. Food and Drug Administration. Summary of safety and effectiveness (SSED): AspireAssist. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150024b.pdf. FDA,ed,2016:1-36.

32. Thompson CC et al. Am J Gastroenterol. 2017;112:447-57.

33. SAGES abstract archives. SAGES. Available from: http://www.sages.org/meetings/annual-meeting/abstracts-archive/first-clinical-experience-with-the-transpyloric-shuttle-tpsr-device-a-non-surgical-endoscopic treatment-for-obesity-results-from-a-3-month-and-6-month-study. Accessed Sept. 12, 2018.

34. Sjostrom L et al. N Engl J Med. 2007;357:741-52.

35. Adams TD et al. N Engl J Med. 2017;377:1143-55.

36. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2011;9:228-33.

37. Thompson CC et al. Gastroenterology. 2013;145(1):129-37.

38. Jirapinyo P et al. Endoscopy. 2018;50(4):371-7.

39. Kumar N, Thompson CC. Gastrointest Endosc. 2016;83(4):776-9.

40. Jirapinyo P et al. Gastrointest Endosc. 2017;85(5):AB93-94.

41. Jirapinyo P, Thompson CC et al. Comparison of a novel plication technique to suturing for endoscopic outlet reduction for the treatment of weight regain after Roux-en-Y gastric bypass. Obesity Week 2018. Poster presentation.

42. Kaplan LM et al. EndoBarrier therapy is associated with glycemic improvement, weight loss and safety issues in patients with obesity and type 2 diabetes on oral anti-hyperglycemic agents (The ENDO Trial). In: Oral Presentation at the 76th American Diabetes Association (ADA) Annual Meeting: 2016 June 10-14: New Orleans. Abstract number 362-LB.

43. Jirapinyo P et al. Diabetes Care. 2018;41(5):1106-15.

44. Rajagopalan H et al. Diabetes Care. 2016;39(12):2254-61.

45. Sandler BJ et al. Surgical Endosc. 2015;29:3298-303.

46. Machytka E et al. Gastrointest Endosc. 2017;86(5):904-12.

Editor's Note

Gastroenterologists are becoming increasingly involved in the management of obesity. While prior therapy for obesity was mainly based on lifestyle changes, medication, or surgery, the new and exciting field of endoscopic bariatric and metabolic therapies has recently garnered incredible attention and momentum.

In this quarter’s In Focus article, brought to you by The New Gastroenterologist, Pichamol Jirapinyo and Christopher Thompson (Brigham and Women’s Hospital) provide an outstanding overview of the gastric and small bowel endoscopic interventions that are either already approved for use in obesity or currently being studied. This field is moving incredibly fast, and knowledge and understanding of these endoscopic therapies for obesity will undoubtedly be important for our field.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Obesity is a rising pandemic. As of 2016, 93.3 million U.S. adults had obesity, representing 39.8% of our adult population.¹ It is estimated that approximately $147 billion is spent annually on caring for patients with obesity. Traditionally, the management of obesity includes lifestyle therapy (diet and exercise), pharmacotherapy (six Food and Drug Administration–approved medications for obesity), and bariatric surgery (sleeve gastrectomy [SG] and Roux-en-Y gastric bypass [RYGB]). Nevertheless, intensive lifestyle intervention and pharmacotherapy are associated with approximately 3.1%-6.6% total weight loss (TWL),^2-7 and bariatric surgery is associated with 20%-33.3% TWL.⁸ However, less than 2% of patients who are eligible for bariatric surgery elect to undergo surgery, leaving a large proportion of patients with obesity untreated or undertreated.⁹

Copyright Elsevier and AGA Institute (2017)

Endoscopic bariatric and metabolic therapies (EBMTs) encompass an emerging field for the treatment of obesity. In general, EBMTs are associated with greater weight loss than are lifestyle intervention and pharmacotherapy, but with a less- invasive risk profile than bariatric surgery. EBMTs may be divided into two general categories – gastric and small bowel interventions (Figure 1 and Table 1). Gastric EBMTs are effective at treating obesity, while small bowel EBMTs are effective at treating metabolic diseases with a variable weight loss profile depending on the device.^10,11

Of note, a variety of study designs (including retrospective series, prospective series, and randomized trials with and without shams) have been employed, which can affect outcomes. Therefore, weight loss comparisons among studies are challenging and should be considered in this context.
 

Gastric interventions

Currently, there are three types of EBMTs that are FDA approved and used for the treatment of obesity. These include intragastric balloons (IGBs), plications and suturing, and aspiration therapy (AT). Other technologies that are under investigation also will be briefly covered.

Intragastric balloons

An intragastric balloon is a space-occupying device that is placed in the stomach. The mechanism of action of IGBs involves delaying gastric emptying, which leads to increased satiety.¹² There are several types of IGBs available worldwide differing in techniques of placement and removal (endoscopic versus fluoroscopic versus swallowable), materials used to fill the balloon (fluid-filled versus air-filled), and the number of balloons placed (single versus duo versus three-balloon). At the time of this writing, three IGBs are approved by the FDA (Orbera, ReShape, and Obalon), all for patients with body mass indexes of 30-40 kg/m², and two others are in the process of obtaining FDA approval (Spatz and Elipse).

Orbera gastric balloon (Apollo Endosurgery, Austin, Tex.) is a single fluid-filled IGB that is endoscopically placed and removed at 6 months. The balloon is filled with 400-700 cc of saline with or without methylene blue (to identify leakage or rupture). Recently, Orbera365, which allows the balloon to stay for 12 months instead of 6 months, has become available in Europe; however, it is yet to be approved in the United States. The U.S. pivotal trial (Orbera trial) including 255 subjects (125 Orbera arm versus 130 non-sham control arm) demonstrated 10.2% TWL in the Orbera group compared with 3.3% TWL in the control group at 6 months based on intention-to-treat (ITT) analysis. This difference persisted at 12 months (6 months after explantation) with 7.6% TWL for the Orbera group versus 3.1% TWL for the control group.^13,14

ReShape integrated dual balloon system (ReShape Lifesciences, San Clemente, Calif.) consists of two connected fluid-filled balloons that are endoscopically placed and removed at 6 months. Each balloon is filled with 375-450 cc of saline mixed with methylene blue. The U.S. pivotal trial (REDUCE trial) including 326 subjects (187 ReShape arm versus 139 sham arm) demonstrated 6.8% TWL in the ReShape group compared with 3.3% TWL in the sham group at 6 months based on ITT analysis.^15,16

Obalon balloon system (Obalon Therapeutics, Carlsbad, Calif.) is a swallowable, gas-filled balloon system that requires endoscopy only for removal. During placement, a capsule is swallowed under fluoroscopic guidance. The balloon is then inflated with 250 cc of nitrogen mix gas prior to tube detachment. Up to three balloons may be swallowed sequentially at 1-month intervals. At 6 months from the first balloon placement, all balloons are removed endoscopically. The U.S. pivotal trial (SMART trial) including 366 subjects (185 Obalon arm versus 181 sham capsule arm) demonstrated 6.6% TWL in the Obalon group compared with 3.4% TWL in the sham group at 6 months based on ITT analysis.^17,18

Two other balloons that are currently under investigation in the United States are the Spatz3 adjustable balloon system (Spatz Medical, Great Neck, N.Y.) and Elipse balloon (Allurion Technologies, Wellesley, Mass.). The Spatz3 is a fluid-filled balloon that is placed and removed endoscopically. It consists of a single balloon and a connecting tube that allows volume adjustment for control of symptoms and possible augmentation of weight loss. The U.S. pivotal trial was recently completed and the data are being reviewed by the FDA. The Elipse is a swallowable fluid-filled balloon that does not require endoscopy for placement or removal. At 4 months, the balloon releases fluid allowing it to empty and pass naturally. The U.S. pivotal trial (ENLIGHTEN trial) is currently underway.

A meta-analysis of randomized controlled trials revealed improvement in most metabolic parameters (diastolic blood pressure, fasting glucose, hemoglobin A_1c, and waist circumference) following IGB compared with controls.¹⁹ Nausea and vomiting are seen in approximately 30% and should be addressed appropriately. Pooled serious adverse event (SAE) rate was 1.5%, which included migration, perforation, and death. Since 2016, 14 deaths have been reported according to the FDA MAUDE database. Corporate response was that over 295,000 balloons had been distributed worldwide with a mortality rate of less than 0.01%.²⁰
 

Plication and suturing

Currently, there are two endoscopic devices that are approved for the general indication of tissue apposition. These include the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, Calif.) and the Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Tex.). These devices are used to remodel the stomach to create a sleeve-like structure to induce weight loss.

The IOP system consists of a transport, which is a 54-Fr flexible endoscope. It consists of four working channels that accommodate a G-Prox (for tissue approximation), a G-Lix (for tissue grasping), and an ultrathin endoscope (for visualization). In April 2008, Horgan performed the first-in-human primary obesity surgery endoluminal (POSE) procedure in Argentina. The procedure involves the use of the IOP system to place plications primarily in the fundus to modify gastric accommodation.²¹ The U.S. pivotal trial (ESSENTIAL trial) including 332 subjects (221 POSE arm versus 111 sham arm) demonstrated 5.0% TWL in the POSE group compared with 1.4% in the sham group at 12 months based on ITT analysis.²² A European multicenter randomized controlled trial (MILEPOST trial) including 44 subjects (34 POSE arm versus 10 non-sham control arm) demonstrated 13.0% TWL in the POSE group compared with 5.3% TWL in the control group at 12 months.²³ A recent meta-analysis including five studies with 586 subjects showed pooled weight loss of 13.2% at 12-15 months following POSE with a pooled serious adverse event rate of 3.2%.²⁴ These included extraluminal bleeding, minor bleeding at the suture site, hepatic abscess, chest pain, nausea, vomiting, and abdominal pain. A distal POSE procedure with a new plication pattern focusing on the gastric body to augment the effect on gastric emptying has also been described.²⁵

The Overstitch is an endoscopic suturing device that is mounted on a double-channel endoscope. At the tip of the scope, there is a curved suture arm and an anchor exchange that allow the needle to pass back and forth to perform full-thickness bites. The tissue helix may also be placed through the second channel to grasp tissue. In April 2012, Thompson performed the first-in-human endoscopic sutured/sleeve gastroplasty (ESG) procedure in India, which was published together with cases performed in Panama and the Dominican Republic.^26-28 This procedure involves the use of the Overstitch device to place several sets of running sutures along the greater curvature of the stomach to create a sleeve-like structure. It is thought to delay gastric emptying and therefore increase satiety.²⁹ The largest multicenter retrospective study including 248 patients demonstrated 18.6% TWL at 2 years with 2% SAE rate including perigastric fluid collections, extraluminal hemorrhage, pulmonary embolism, pneumoperitoneum, and pneumothorax.³⁰

Aspiration therapy

Aspiration therapy (AT; Aspire Bariatrics, King of Prussia, Pa.) allows patients to remove 25%-30% of ingested calories at approximately 30 minutes after meals. AT consists of an A-tube, which is a 26-Fr gastrostomy tube with a 15-cm fenestrated drainage catheter placed endoscopically via a standard pull technique. At 1-2 weeks after A-tube placement, the tube is cut down to the skin and connected to the port prior to aspiration. AT is approved for patients with a BMI of 35-55 kg/m².³¹ The U.S. pivotal trial (PATHWAY trial) including 207 subjects (137 AT arm versus 70 non-sham control arm) demonstrated 12.1% TWL in the AT group compared to 3.5% in the control group at 12 months based on ITT analysis. The SAE rate was 3.6% including severe abdominal pain, peritonitis, prepyloric ulcer, and A-tube replacement due to skin-port malfunction.³²

Transpyloric shuttle

The transpyloric shuttle (TPS; BAROnova, Goleta, Calif.) consists of a spherical bulb that is attached to a smaller cylindrical bulb by a flexible tether. It is placed and removed endoscopically at 6 months. TPS resides across the pylorus creating intermittent obstruction that may result in delayed gastric emptying. A pilot study including 20 patients demonstrated 14.5% TWL at 6 months.³³ The U.S. pivotal trial (ENDObesity II trial) was recently completed and the data are being reviewed by the FDA.

Revision for weight regain following bariatric surgery

Weight regain is common following RYGB^34,35 and can be associated with dilation of the gastrojejunal anastomosis (GJA).³⁶ Several procedures have been developed to treat this condition by focusing on reduction of GJA size and are available in the United States (Figure 2). These procedures have level I evidence supporting their use and include transoral outlet reduction (TORe) and restorative obesity surgery endoluminal (ROSE).³⁷ TORe involves the use of the Overstitch to place sutures at the GJA. At 1 year, patients had 8.4% TWL with improvement in comorbidities.³⁸ Weight loss remained significant up to 3-5 years.^39,40 The modern ROSE procedure utilizes the IOP system to place plications at the GJA and distal gastric pouch following argon plasma coagulation (APC). A small series showed 12.4% TWL at 6 months.⁴¹ APC is also currently being investigated as a standalone therapy for weight regain in this population.

Small bowel interventions

There are several small bowel interventions, with different mechanisms of action, available internationally. Many of these are under investigation in the United States; however, none are currently FDA approved.

Duodenal-jejunal bypass liner

Duodenal-jejunal bypass liner (DJBL; GI Dynamics, Boston, Mass.) is a 60-cm fluoropolymer liner that is endoscopically placed and removed at 12 months. It is anchored at the duodenal bulb and ends at the jejunum. By excluding direct contact between chyme and the proximal small bowel, DJBL is thought to work via foregut mechanism where there is less inhibition of the incretin effect (greater increase in insulin secretion following oral glucose administration compared to intravenous glucose administration due to gut-derived factors that enhance insulin secretion) leading to improved insulin resistance. In addition, the enteral transit of chyme and bile is altered suggesting the possible role of the hindgut mechanism. The previous U.S. pivotal trial (ENDO trial) met efficacy endpoints. However, the study was stopped early by the company because of a hepatic abscess rate of 3.5%, all of which were treated conservatively.⁴² A new U.S. pivotal study is currently planned. A meta-analysis of 17 published studies, all of which were from outside the United States, demonstrated a significant decrease in hemoglobin A_1c of 1.3% and 18.9% TWL at 1 year following implantation in patients with obesity with concomitant diabetes.⁴³
 

Duodenal mucosal resurfacing

Duodenal mucosal resurfacing (Fractyl, Lexington, Mass.) involves saline lifting of the duodenal mucosa circumferentially prior to thermal ablation using an inflated balloon filled with heated water. It is hypothesized that this may reset the diseased duodenal enteroendocrine cells leading to restoration of the incretin effect. A pilot study including 39 patients with poorly controlled diabetes demonstrated a decrease in hemoglobin A_1c of 1.2%. The SAE rate was 7.7% including duodenal stenosis, all of which were treated with balloon dilation.⁴⁴ The U.S. pivotal trial is currently planned.

Gastroduodenal-jejunal bypass

Gastroduodenal-jejunal bypass (ValenTx., Hopkins, Minn.) is a 120-cm sleeve that is anchored at the gastroesophageal junction to create the anatomic changes of RYGB. It is placed and removed endoscopically with laparoscopic assistance. A pilot study including 12 patients demonstrated 35.9% excess weight loss at 12 months. Two out of 12 patients had early device removal due to intolerance and they were not included in the weight loss analysis.⁴⁵

Incisionless magnetic anastomosis system

The incisionless magnetic anastomosis system (GI Windows, West Bridgewater, Mass.) consists of self-assembling magnets that are deployed under fluoroscopic guidance through the working channel of colonoscopes to form magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is formed and the coupled magnets pass spontaneously. A pilot study including 10 patients showed 14.6% TWL and a decrease in hemoglobin A_1c of 1.9% (for patients with diabetes) at 1 year.⁴⁶ A randomized study outside the United States is currently underway.

Summary

Endoscopic bariatric and metabolic therapies are emerging as first-line treatments for obesity in many populations. They can serve as a gap therapy for patients who do not qualify for surgery, but also may have a specific role in the treatment of metabolic comorbidities. This field will continue to develop and improve with the introduction of personalized medicine leading to better patient selection, and newer combination therapies. It is time for gastroenterologists to become more involved in the management of this challenging condition.

Dr. Jirapinyo is an advanced and bariatric endoscopy fellow, Brigham and Women’s Hospital, Harvard Medical School, Boston; Dr. Thompson is director of therapeutic endoscopy, Brigham and Women’s Hospital, and associate professor of medicine, Harvard Medical School. Dr. Jirapinyo has served as a consultant for GI Dynamics and holds royalties for Endosim. Dr. Thompson has contracted research for Aspire Bariatrics, USGI Medical, Spatz, and Apollo Endosurgery; has served as a consultant for Boston Scientific, Covidien, USGI Medical, Olympus, and Fractyl; holds stocks and royalties for GI Windows and Endosim, and has served as an expert reviewer for GI Dynamics.
 

References

1. CDC. From https://www.cdc.gov/obesity/data/adult.html. Accessed on 11 September 2018.

2. Aronne LJ et al. Obesity. 2013;21:2163-71.

3. Torgerson JS et al. Diabetes Care. 2004;27:155-61.

4. Allison DB et al. Obesity. 2012;20:330-42.

5. Smith SR et al. N Engl J Med. 2010;363:245-56.

6. Apovian CM et al. Obesity. 2013;21:935-43.

7. Pi-Sunyer X et al. N Engl J Med. 2015;373:11-22.

8. Colguitt JL et al. Cochrane Database Syst Rev. 2014;8(8):CD003641.

9. Ponce J et al. Surg Obes Relat Dis. 2015;11(6):1199-200.

10. Jirapinyo P, Thompson CC et al. Clin Gastroenterol Hepatol. 2017;15(5):619-30.

11. Sullivan S et al.Gastroenterology. 2017;152(7):1791-801.

12. Gomez V et al. Obesity. 2016;24(9):1849-53.

13. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ORBERA Intragastric Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140008b.pdf. 2015:1-32.

14. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;81:AB147.

15. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ReShape Integrated Dual Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140012b.pdf. 2015:1-43.

16. Ponce J et al. Surg Obes Relat Dis. 2015;11:874-81.

17. Food and Drug Administration. Summary and effectiveness data (SSED): Obalon Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160001b.pdf. 2016:1-46.

18. Sullivan S et al. Gastroenterology. 2016;150:S1267.

19. Popov VB et al. Am J Gastroenterol. 2017;112:429-39.

20. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;82(3):425-38.

21. Espinos JC et al. Obes Surg. 2013;23(9):1375-83.

22. Sullivan S et al. Obesity. 2017;25:294-301.

23. Miller K et al. Obesity Surg. 2017;27(2):310-22.

24. Jirapinyo P et al. Gastrointest Endosc. 2018;87(6):AB604-AB605.

25. Jirapinyo P, Thompson CC. Video GIE. 2018;3(10):296-300.

26. Campos J et al. SAGES 2013 Presentation. Baltimore, MD. 19 April 2013.

27. Kumar N et al. Gastroenterology. 2014;146(5):S571-2.

28. Kumar N et al. Surg Endosc. 2018;32(4):2159-64.

29. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2017;15:37-43.

30. Lopez-Nava G et al. Obes Surg. 2017;27(10):2649-55.

31. Food and Drug Administration. Summary of safety and effectiveness (SSED): AspireAssist. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150024b.pdf. FDA,ed,2016:1-36.

32. Thompson CC et al. Am J Gastroenterol. 2017;112:447-57.

33. SAGES abstract archives. SAGES. Available from: http://www.sages.org/meetings/annual-meeting/abstracts-archive/first-clinical-experience-with-the-transpyloric-shuttle-tpsr-device-a-non-surgical-endoscopic treatment-for-obesity-results-from-a-3-month-and-6-month-study. Accessed Sept. 12, 2018.

34. Sjostrom L et al. N Engl J Med. 2007;357:741-52.

35. Adams TD et al. N Engl J Med. 2017;377:1143-55.

36. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2011;9:228-33.

37. Thompson CC et al. Gastroenterology. 2013;145(1):129-37.

38. Jirapinyo P et al. Endoscopy. 2018;50(4):371-7.

39. Kumar N, Thompson CC. Gastrointest Endosc. 2016;83(4):776-9.

40. Jirapinyo P et al. Gastrointest Endosc. 2017;85(5):AB93-94.

41. Jirapinyo P, Thompson CC et al. Comparison of a novel plication technique to suturing for endoscopic outlet reduction for the treatment of weight regain after Roux-en-Y gastric bypass. Obesity Week 2018. Poster presentation.

42. Kaplan LM et al. EndoBarrier therapy is associated with glycemic improvement, weight loss and safety issues in patients with obesity and type 2 diabetes on oral anti-hyperglycemic agents (The ENDO Trial). In: Oral Presentation at the 76th American Diabetes Association (ADA) Annual Meeting: 2016 June 10-14: New Orleans. Abstract number 362-LB.

43. Jirapinyo P et al. Diabetes Care. 2018;41(5):1106-15.

44. Rajagopalan H et al. Diabetes Care. 2016;39(12):2254-61.

45. Sandler BJ et al. Surgical Endosc. 2015;29:3298-303.

46. Machytka E et al. Gastrointest Endosc. 2017;86(5):904-12.

Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.

In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.

Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.

Patho/Wikimedia Commons/CC BY-SA 3.0

SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.

Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.

In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.

Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.

Patho/Wikimedia Commons/CC BY-SA 3.0

SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.

Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.

In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.

Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.

Patho/Wikimedia Commons/CC BY-SA 3.0

SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.

Cervical cancer was more likely to recur and overall survival was lower among patients who underwent minimally invasive vs. open abdominal radical hysterectomy, based on findings from the randomized, controlled phase 3 Laparoscopic Approach to Cervical Cancer (LACC) trial of more than 600 women.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The alarming findings, which led to early study termination, also were supported by results from a second population-based study. Both studies were published concurrently in the Oct. 31 issue of the New England Journal of Medicine.

The disease-free survival at 4.5 years among 319 patients who underwent minimally invasive surgery in the LACC trial was 86.0% vs. 96.5% in 312 patients who underwent open surgery, Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395).

At 3 years, the disease-free survival rates were 91.2% in the minimally invasive surgery group and 97.1% in open surgery group (hazard ratio for disease recurrence or death from cervical cancer, 3.74).

The differences between the groups persisted after adjustment for age, body mass index, disease stage, lymphovascular invasion, and lymph-node involvement. In the minimally invasive surgery group, the findings were comparable for those who underwent laparoscopic vs. robot-assisted surgery, the investigators found.

Further, at 3 years, overall survival was 93.8% vs. 99.0% (HR for death from any cause, 6.00), death from cervical cancer was 4.4% vs. 0.6% (HR, 6.56), and the rate of locoregional recurrence-free survival was 94.3 vs. 98.3 (HR, 4.26) in the minimally invasive and open surgery groups, respectively.

Study participants were women with a mean age of 46 years with stage IA1, IA2, or IB1 cervical cancer, with most (91.9%) having IB1 disease, and either squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. They were recruited from 33 centers worldwide between June 2008 and June 2017. Most of those assigned to minimally invasive surgery underwent laparoscopic surgery (84.4%), and the remaining patients underwent robot-assisted surgery.

The treatment groups were balanced with respect to baseline characteristics, they noted.

The minimally invasive approach is widely used given that guidelines from the National Comprehensive Cancer Network and European Society of Gynecological Oncology consider both surgical approaches acceptable, and since retrospective studies suggest laparoscopic radical hysterectomy is associated with lower complication rates and comparable outcomes. However, there are limited prospective data regarding survival outcomes in early stage disease with the two approaches, the researchers said.

“Our results call into question the findings in the literature suggesting that minimally invasive radical hysterectomy is associated with no difference in oncologic outcomes as compared with the open approach,” they wrote, noting that a number of factors may explain the differences, such as concurrent vs. sequential analyses in the current studies vs. prior studies (in sequential analyses, earlier procedures may have been performed under broader indications and less clearly defined radiotherapy guidelines), and the possibility that “routine use of a uterine manipulator might increase the propensity for tumor spillage” in minimally invasive surgery.

Strengths of the study include its prospective, randomized, international multicenter design and inclusion of a per-protocol analysis that was consistent with the intention-to-treat analysis, and limitations include the fact that intended enrollment wasn’t reached because of the “safety alert raised by the data and safety monitoring committee on the basis of the higher recurrence and death in the minimally invasive surgery groups,” as well as the inability to generalize the results to patients with low-risk disease as there was lack of power to evaluate outcomes in that context.

Justin Chura, MD, director of gynecologic oncology and robotic surgery at Cancer Treatment Center of America’s Eastern Regional Medical Center in Philadelphia, said in an interview, “The results of the study by Ramirez et al. are certainly disappointing for those among us who are advocates of minimally invasive surgery (MIS). In my own practice, I transitioned to minimally invasive radical hysterectomy approximately 10 years ago. Now that approach has to be reconsidered. While there are likely subsets of patients who will still benefit from a MIS approach without worsening oncologic outcomes, we do not have robust data to reliably identify those patients. 

“One factor that warrants further investigation is the use of a uterine manipulator. While I do not use a manipulator out of personal preference (one less step in the operating room), the idea of placing a device through the tumor or adjacent to it, has biologic plausibility in terms of displacing tumor cells into lymphatic channels,” he said. “Until we have more data, an open approach appears to be preferred.”*

Dr. Ramirez and Dr. Melamed each reported having no relevant disclosures. Dr. Salani and Dr. Chura are members of the Ob.Gyn. News editorial board, but reported having no other relevant disclosures.* 

[email protected]

SOURCE: Ramirez P. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.

*This article was updated 11/9/2018.

Cervical cancer was more likely to recur and overall survival was lower among patients who underwent minimally invasive vs. open abdominal radical hysterectomy, based on findings from the randomized, controlled phase 3 Laparoscopic Approach to Cervical Cancer (LACC) trial of more than 600 women.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The alarming findings, which led to early study termination, also were supported by results from a second population-based study. Both studies were published concurrently in the Oct. 31 issue of the New England Journal of Medicine.

The disease-free survival at 4.5 years among 319 patients who underwent minimally invasive surgery in the LACC trial was 86.0% vs. 96.5% in 312 patients who underwent open surgery, Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395).

At 3 years, the disease-free survival rates were 91.2% in the minimally invasive surgery group and 97.1% in open surgery group (hazard ratio for disease recurrence or death from cervical cancer, 3.74).

The differences between the groups persisted after adjustment for age, body mass index, disease stage, lymphovascular invasion, and lymph-node involvement. In the minimally invasive surgery group, the findings were comparable for those who underwent laparoscopic vs. robot-assisted surgery, the investigators found.

Further, at 3 years, overall survival was 93.8% vs. 99.0% (HR for death from any cause, 6.00), death from cervical cancer was 4.4% vs. 0.6% (HR, 6.56), and the rate of locoregional recurrence-free survival was 94.3 vs. 98.3 (HR, 4.26) in the minimally invasive and open surgery groups, respectively.

Study participants were women with a mean age of 46 years with stage IA1, IA2, or IB1 cervical cancer, with most (91.9%) having IB1 disease, and either squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. They were recruited from 33 centers worldwide between June 2008 and June 2017. Most of those assigned to minimally invasive surgery underwent laparoscopic surgery (84.4%), and the remaining patients underwent robot-assisted surgery.

The treatment groups were balanced with respect to baseline characteristics, they noted.

The minimally invasive approach is widely used given that guidelines from the National Comprehensive Cancer Network and European Society of Gynecological Oncology consider both surgical approaches acceptable, and since retrospective studies suggest laparoscopic radical hysterectomy is associated with lower complication rates and comparable outcomes. However, there are limited prospective data regarding survival outcomes in early stage disease with the two approaches, the researchers said.

“Our results call into question the findings in the literature suggesting that minimally invasive radical hysterectomy is associated with no difference in oncologic outcomes as compared with the open approach,” they wrote, noting that a number of factors may explain the differences, such as concurrent vs. sequential analyses in the current studies vs. prior studies (in sequential analyses, earlier procedures may have been performed under broader indications and less clearly defined radiotherapy guidelines), and the possibility that “routine use of a uterine manipulator might increase the propensity for tumor spillage” in minimally invasive surgery.

Strengths of the study include its prospective, randomized, international multicenter design and inclusion of a per-protocol analysis that was consistent with the intention-to-treat analysis, and limitations include the fact that intended enrollment wasn’t reached because of the “safety alert raised by the data and safety monitoring committee on the basis of the higher recurrence and death in the minimally invasive surgery groups,” as well as the inability to generalize the results to patients with low-risk disease as there was lack of power to evaluate outcomes in that context.

Justin Chura, MD, director of gynecologic oncology and robotic surgery at Cancer Treatment Center of America’s Eastern Regional Medical Center in Philadelphia, said in an interview, “The results of the study by Ramirez et al. are certainly disappointing for those among us who are advocates of minimally invasive surgery (MIS). In my own practice, I transitioned to minimally invasive radical hysterectomy approximately 10 years ago. Now that approach has to be reconsidered. While there are likely subsets of patients who will still benefit from a MIS approach without worsening oncologic outcomes, we do not have robust data to reliably identify those patients. 

“One factor that warrants further investigation is the use of a uterine manipulator. While I do not use a manipulator out of personal preference (one less step in the operating room), the idea of placing a device through the tumor or adjacent to it, has biologic plausibility in terms of displacing tumor cells into lymphatic channels,” he said. “Until we have more data, an open approach appears to be preferred.”*

Dr. Ramirez and Dr. Melamed each reported having no relevant disclosures. Dr. Salani and Dr. Chura are members of the Ob.Gyn. News editorial board, but reported having no other relevant disclosures.* 

[email protected]

SOURCE: Ramirez P. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.

*This article was updated 11/9/2018.

Cervical cancer was more likely to recur and overall survival was lower among patients who underwent minimally invasive vs. open abdominal radical hysterectomy, based on findings from the randomized, controlled phase 3 Laparoscopic Approach to Cervical Cancer (LACC) trial of more than 600 women.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The alarming findings, which led to early study termination, also were supported by results from a second population-based study. Both studies were published concurrently in the Oct. 31 issue of the New England Journal of Medicine.

The disease-free survival at 4.5 years among 319 patients who underwent minimally invasive surgery in the LACC trial was 86.0% vs. 96.5% in 312 patients who underwent open surgery, Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395).

At 3 years, the disease-free survival rates were 91.2% in the minimally invasive surgery group and 97.1% in open surgery group (hazard ratio for disease recurrence or death from cervical cancer, 3.74).

The differences between the groups persisted after adjustment for age, body mass index, disease stage, lymphovascular invasion, and lymph-node involvement. In the minimally invasive surgery group, the findings were comparable for those who underwent laparoscopic vs. robot-assisted surgery, the investigators found.

Further, at 3 years, overall survival was 93.8% vs. 99.0% (HR for death from any cause, 6.00), death from cervical cancer was 4.4% vs. 0.6% (HR, 6.56), and the rate of locoregional recurrence-free survival was 94.3 vs. 98.3 (HR, 4.26) in the minimally invasive and open surgery groups, respectively.

Study participants were women with a mean age of 46 years with stage IA1, IA2, or IB1 cervical cancer, with most (91.9%) having IB1 disease, and either squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. They were recruited from 33 centers worldwide between June 2008 and June 2017. Most of those assigned to minimally invasive surgery underwent laparoscopic surgery (84.4%), and the remaining patients underwent robot-assisted surgery.

The treatment groups were balanced with respect to baseline characteristics, they noted.

The minimally invasive approach is widely used given that guidelines from the National Comprehensive Cancer Network and European Society of Gynecological Oncology consider both surgical approaches acceptable, and since retrospective studies suggest laparoscopic radical hysterectomy is associated with lower complication rates and comparable outcomes. However, there are limited prospective data regarding survival outcomes in early stage disease with the two approaches, the researchers said.

“Our results call into question the findings in the literature suggesting that minimally invasive radical hysterectomy is associated with no difference in oncologic outcomes as compared with the open approach,” they wrote, noting that a number of factors may explain the differences, such as concurrent vs. sequential analyses in the current studies vs. prior studies (in sequential analyses, earlier procedures may have been performed under broader indications and less clearly defined radiotherapy guidelines), and the possibility that “routine use of a uterine manipulator might increase the propensity for tumor spillage” in minimally invasive surgery.

Strengths of the study include its prospective, randomized, international multicenter design and inclusion of a per-protocol analysis that was consistent with the intention-to-treat analysis, and limitations include the fact that intended enrollment wasn’t reached because of the “safety alert raised by the data and safety monitoring committee on the basis of the higher recurrence and death in the minimally invasive surgery groups,” as well as the inability to generalize the results to patients with low-risk disease as there was lack of power to evaluate outcomes in that context.

Justin Chura, MD, director of gynecologic oncology and robotic surgery at Cancer Treatment Center of America’s Eastern Regional Medical Center in Philadelphia, said in an interview, “The results of the study by Ramirez et al. are certainly disappointing for those among us who are advocates of minimally invasive surgery (MIS). In my own practice, I transitioned to minimally invasive radical hysterectomy approximately 10 years ago. Now that approach has to be reconsidered. While there are likely subsets of patients who will still benefit from a MIS approach without worsening oncologic outcomes, we do not have robust data to reliably identify those patients. 

“One factor that warrants further investigation is the use of a uterine manipulator. While I do not use a manipulator out of personal preference (one less step in the operating room), the idea of placing a device through the tumor or adjacent to it, has biologic plausibility in terms of displacing tumor cells into lymphatic channels,” he said. “Until we have more data, an open approach appears to be preferred.”*

Dr. Ramirez and Dr. Melamed each reported having no relevant disclosures. Dr. Salani and Dr. Chura are members of the Ob.Gyn. News editorial board, but reported having no other relevant disclosures.* 

[email protected]

SOURCE: Ramirez P. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.

*This article was updated 11/9/2018.

A macrophage-activating immune checkpoint inhibitor, combined with rituximab therapy, was safe and produced durable complete responses in patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study.

Courtesy Stanford Medicine

Mainly low-grade toxic effects were seen on treatment with Hu5F9-G4 (5F9) and rituximab, which induced responses in more than half of patients, of which more than one-third were complete responses, the study investigators reported.

Most of the responses were ongoing at the time of data cutoff, suggesting durable responses with the combination of rituximab and 5F9 – a humanized monoclonal antibody that blocks CD47, an antiphagocytic or “do not eat me” signal overexpressed by most cancers, Ranjana Advani, MD, of Stanford (Calif.) University, and her coauthors wrote.

“The macrophage-mediated activity of 5F9 plus rituximab may serve as an effective new immunotherapy for stimulating the innate immune system,” Dr. Advani and her colleagues reported in the New England Journal of Medicine.

The study included 22 patients, including 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma, who had received a median of four prior therapies. Almost all of the non-Hodgkin lymphomas (21, or 95%) were refractory to rituximab.

All patients received intravenous 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10-30 mg/kg in three dose-escalation cohorts, given until disease progression or lack of clinical benefit. Intravenous rituximab at 375 mg/m² weekly was started on the second week of the first cycle, and then monthly for cycles 2 through 6.

“Substantial antitumor activity” was seen with this chemotherapy-free regimen in a group of heavily pretreated, largely rituximab-refractory patients, Dr. Advani and her coauthors wrote in their report.

The objective response rate was 50%, including a 36% complete response rate in the intent-to-treat analysis. For DLBCL, the rates of objective and complete responses were 40% and 33%, while for follicular lymphoma, they were 71% and 43%.

The median duration of response was not reached in either disease cohort with a median follow-up of 6.2 months for DLBCL and 8.1 months for follicular lymphoma. Of the 11 patients who responded, 10 (91%) were still in response at the time of data cutoff. “Longer follow-up is needed,” the investigators wrote.

Most adverse events were seen within the first few weeks of treatment and mainly included anemia and infusion-related reactions. The anemia was an expected, on-target effect of 5F9 because of selective clearance of older red cells, which was predictable, transient, and mitigated by the maintenance dosing strategy employed in this phase 1b trial.

“As red cells age, they lose CD47 expression and gain expression of prophagocytic signals, leading to homeostatic clearance,” they wrote.

The activity of 5F9 and rituximab is “synergistic” based on the results of previous, preclinical investigations in models of lymphoma, Dr. Advani and her coauthors added.

A phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell non-Hodgkin lymphoma is ongoing, according to their report.

The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.

SOURCE: Advani R et al. N Engl J Med. 2018;379:1711-21.

A macrophage-activating immune checkpoint inhibitor, combined with rituximab therapy, was safe and produced durable complete responses in patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study.

Courtesy Stanford Medicine

Mainly low-grade toxic effects were seen on treatment with Hu5F9-G4 (5F9) and rituximab, which induced responses in more than half of patients, of which more than one-third were complete responses, the study investigators reported.

Most of the responses were ongoing at the time of data cutoff, suggesting durable responses with the combination of rituximab and 5F9 – a humanized monoclonal antibody that blocks CD47, an antiphagocytic or “do not eat me” signal overexpressed by most cancers, Ranjana Advani, MD, of Stanford (Calif.) University, and her coauthors wrote.

“The macrophage-mediated activity of 5F9 plus rituximab may serve as an effective new immunotherapy for stimulating the innate immune system,” Dr. Advani and her colleagues reported in the New England Journal of Medicine.

The study included 22 patients, including 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma, who had received a median of four prior therapies. Almost all of the non-Hodgkin lymphomas (21, or 95%) were refractory to rituximab.

All patients received intravenous 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10-30 mg/kg in three dose-escalation cohorts, given until disease progression or lack of clinical benefit. Intravenous rituximab at 375 mg/m² weekly was started on the second week of the first cycle, and then monthly for cycles 2 through 6.

“Substantial antitumor activity” was seen with this chemotherapy-free regimen in a group of heavily pretreated, largely rituximab-refractory patients, Dr. Advani and her coauthors wrote in their report.

The objective response rate was 50%, including a 36% complete response rate in the intent-to-treat analysis. For DLBCL, the rates of objective and complete responses were 40% and 33%, while for follicular lymphoma, they were 71% and 43%.

The median duration of response was not reached in either disease cohort with a median follow-up of 6.2 months for DLBCL and 8.1 months for follicular lymphoma. Of the 11 patients who responded, 10 (91%) were still in response at the time of data cutoff. “Longer follow-up is needed,” the investigators wrote.

Most adverse events were seen within the first few weeks of treatment and mainly included anemia and infusion-related reactions. The anemia was an expected, on-target effect of 5F9 because of selective clearance of older red cells, which was predictable, transient, and mitigated by the maintenance dosing strategy employed in this phase 1b trial.

“As red cells age, they lose CD47 expression and gain expression of prophagocytic signals, leading to homeostatic clearance,” they wrote.

The activity of 5F9 and rituximab is “synergistic” based on the results of previous, preclinical investigations in models of lymphoma, Dr. Advani and her coauthors added.

A phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell non-Hodgkin lymphoma is ongoing, according to their report.

The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.

SOURCE: Advani R et al. N Engl J Med. 2018;379:1711-21.

A macrophage-activating immune checkpoint inhibitor, combined with rituximab therapy, was safe and produced durable complete responses in patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study.

Courtesy Stanford Medicine

Mainly low-grade toxic effects were seen on treatment with Hu5F9-G4 (5F9) and rituximab, which induced responses in more than half of patients, of which more than one-third were complete responses, the study investigators reported.

Most of the responses were ongoing at the time of data cutoff, suggesting durable responses with the combination of rituximab and 5F9 – a humanized monoclonal antibody that blocks CD47, an antiphagocytic or “do not eat me” signal overexpressed by most cancers, Ranjana Advani, MD, of Stanford (Calif.) University, and her coauthors wrote.

“The macrophage-mediated activity of 5F9 plus rituximab may serve as an effective new immunotherapy for stimulating the innate immune system,” Dr. Advani and her colleagues reported in the New England Journal of Medicine.

The study included 22 patients, including 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma, who had received a median of four prior therapies. Almost all of the non-Hodgkin lymphomas (21, or 95%) were refractory to rituximab.

All patients received intravenous 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10-30 mg/kg in three dose-escalation cohorts, given until disease progression or lack of clinical benefit. Intravenous rituximab at 375 mg/m² weekly was started on the second week of the first cycle, and then monthly for cycles 2 through 6.

“Substantial antitumor activity” was seen with this chemotherapy-free regimen in a group of heavily pretreated, largely rituximab-refractory patients, Dr. Advani and her coauthors wrote in their report.

The objective response rate was 50%, including a 36% complete response rate in the intent-to-treat analysis. For DLBCL, the rates of objective and complete responses were 40% and 33%, while for follicular lymphoma, they were 71% and 43%.

The median duration of response was not reached in either disease cohort with a median follow-up of 6.2 months for DLBCL and 8.1 months for follicular lymphoma. Of the 11 patients who responded, 10 (91%) were still in response at the time of data cutoff. “Longer follow-up is needed,” the investigators wrote.

Most adverse events were seen within the first few weeks of treatment and mainly included anemia and infusion-related reactions. The anemia was an expected, on-target effect of 5F9 because of selective clearance of older red cells, which was predictable, transient, and mitigated by the maintenance dosing strategy employed in this phase 1b trial.

“As red cells age, they lose CD47 expression and gain expression of prophagocytic signals, leading to homeostatic clearance,” they wrote.

The activity of 5F9 and rituximab is “synergistic” based on the results of previous, preclinical investigations in models of lymphoma, Dr. Advani and her coauthors added.

A phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell non-Hodgkin lymphoma is ongoing, according to their report.

The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.

SOURCE: Advani R et al. N Engl J Med. 2018;379:1711-21.

While adjuvant axitinib failed to improve disease-free survival in a recent phase 3 renal cell carcinoma (RCC) trial, the highest-risk subgroup appeared to benefit, according to a report on the study.

The phase 3 ATLAS trial was stopped early because of a lack of benefit for axitinib versus placebo in the study, which included patients with locoregional RCC at risk of recurrence after nephrectomy.

However, a prespecified analysis showed that axitinib reduced risk of disease-free survival events by about one-third in the highest-risk subset of patients, according to investigator David I. Quinn, MD, USC Norris Comprehensive Cancer Center, Los Angeles, and colleagues.

That finding tracks with results of the earlier S-TRAC trial, in which patients at high risk of tumor recurrence after nephrectomy had significantly longer disease-free survival with sunitinib versus placebo, Dr. Quinn and coauthors said.

“Taken together, these results support that patients at highest risk for RCC recurrence benefit from adjuvant treatment,” they wrote in Annals of Oncology.

In the ATLAS trial, Dr. Quinn and coinvestigators at 137 centers in eight countries enrolled 724 adults with newly diagnosed renal cell carcinoma (greater than or equal to pT2 and/or N+, any Fuhrman grade) with Eastern Cooperative Oncology Group status of 0 or 1 and prior nephrectomy.

Patients were randomly assigned to oral, twice-daily axitinib 5 mg or placebo for up to 3 years of treatment, and at least 1 year of treatment provided there was no recurrence, substantial toxicity, or withdrawal of consent.

For the primary endpoint, disease-free survival per independent review committee assessment, the hazard ratio was 0.870 (95% confidence interval, 0.660-1.147; P = .3211), according to the report. Disease-free survival as rated by investigators showed a somewhat larger but still not statistically significant reduction in risk of an event, Dr. Quinn and colleagues said.

However, in the prespecified subgroup analyses, the patients at highest risk (pT3 with Fuhrman grade greater than or equal to 3 or pT4 and/or N+, any T, any Fuhrman grade) had a reduction of risk with hazard ratios of 0.735 per independent review committee (P = .0704) and 0.641 per investigator (P = .0051).

The ATLAS study was designed before results of the S-TRAC study were known, and so patients at lower risk of recurrence were included, said Dr. Quinn and coauthors.

Ongoing trials are looking at sorafenib, everolimus, and immune checkpoint inhibitors in the adjuvant RCC setting, they noted in their discussion of ATLAS, S-TRAC, and other investigations.

Results from these trials may provide clarification on the future of adjuvant treatment for RCC, and whether angiogenesis inhibition is the key mechanism to obtain a reduction in risk of relapse after nephrectomy,” they said.

The study was sponsored by Pfizer and SFJ Pharmaceuticals. Dr. Quinn reported providing advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca, and Astellas. Coauthors reported disclosures related to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer, and Roche, among others.

SOURCE: Quinn DI et al. Ann Oncol. 2018 Oct 20. doi: 10.1093/annonc/mdy454.

While adjuvant axitinib failed to improve disease-free survival in a recent phase 3 renal cell carcinoma (RCC) trial, the highest-risk subgroup appeared to benefit, according to a report on the study.

The phase 3 ATLAS trial was stopped early because of a lack of benefit for axitinib versus placebo in the study, which included patients with locoregional RCC at risk of recurrence after nephrectomy.

However, a prespecified analysis showed that axitinib reduced risk of disease-free survival events by about one-third in the highest-risk subset of patients, according to investigator David I. Quinn, MD, USC Norris Comprehensive Cancer Center, Los Angeles, and colleagues.

That finding tracks with results of the earlier S-TRAC trial, in which patients at high risk of tumor recurrence after nephrectomy had significantly longer disease-free survival with sunitinib versus placebo, Dr. Quinn and coauthors said.

“Taken together, these results support that patients at highest risk for RCC recurrence benefit from adjuvant treatment,” they wrote in Annals of Oncology.

In the ATLAS trial, Dr. Quinn and coinvestigators at 137 centers in eight countries enrolled 724 adults with newly diagnosed renal cell carcinoma (greater than or equal to pT2 and/or N+, any Fuhrman grade) with Eastern Cooperative Oncology Group status of 0 or 1 and prior nephrectomy.

Patients were randomly assigned to oral, twice-daily axitinib 5 mg or placebo for up to 3 years of treatment, and at least 1 year of treatment provided there was no recurrence, substantial toxicity, or withdrawal of consent.

For the primary endpoint, disease-free survival per independent review committee assessment, the hazard ratio was 0.870 (95% confidence interval, 0.660-1.147; P = .3211), according to the report. Disease-free survival as rated by investigators showed a somewhat larger but still not statistically significant reduction in risk of an event, Dr. Quinn and colleagues said.

However, in the prespecified subgroup analyses, the patients at highest risk (pT3 with Fuhrman grade greater than or equal to 3 or pT4 and/or N+, any T, any Fuhrman grade) had a reduction of risk with hazard ratios of 0.735 per independent review committee (P = .0704) and 0.641 per investigator (P = .0051).

The ATLAS study was designed before results of the S-TRAC study were known, and so patients at lower risk of recurrence were included, said Dr. Quinn and coauthors.

Ongoing trials are looking at sorafenib, everolimus, and immune checkpoint inhibitors in the adjuvant RCC setting, they noted in their discussion of ATLAS, S-TRAC, and other investigations.

Results from these trials may provide clarification on the future of adjuvant treatment for RCC, and whether angiogenesis inhibition is the key mechanism to obtain a reduction in risk of relapse after nephrectomy,” they said.

The study was sponsored by Pfizer and SFJ Pharmaceuticals. Dr. Quinn reported providing advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca, and Astellas. Coauthors reported disclosures related to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer, and Roche, among others.

SOURCE: Quinn DI et al. Ann Oncol. 2018 Oct 20. doi: 10.1093/annonc/mdy454.

While adjuvant axitinib failed to improve disease-free survival in a recent phase 3 renal cell carcinoma (RCC) trial, the highest-risk subgroup appeared to benefit, according to a report on the study.

The phase 3 ATLAS trial was stopped early because of a lack of benefit for axitinib versus placebo in the study, which included patients with locoregional RCC at risk of recurrence after nephrectomy.

However, a prespecified analysis showed that axitinib reduced risk of disease-free survival events by about one-third in the highest-risk subset of patients, according to investigator David I. Quinn, MD, USC Norris Comprehensive Cancer Center, Los Angeles, and colleagues.

That finding tracks with results of the earlier S-TRAC trial, in which patients at high risk of tumor recurrence after nephrectomy had significantly longer disease-free survival with sunitinib versus placebo, Dr. Quinn and coauthors said.

“Taken together, these results support that patients at highest risk for RCC recurrence benefit from adjuvant treatment,” they wrote in Annals of Oncology.

In the ATLAS trial, Dr. Quinn and coinvestigators at 137 centers in eight countries enrolled 724 adults with newly diagnosed renal cell carcinoma (greater than or equal to pT2 and/or N+, any Fuhrman grade) with Eastern Cooperative Oncology Group status of 0 or 1 and prior nephrectomy.

Patients were randomly assigned to oral, twice-daily axitinib 5 mg or placebo for up to 3 years of treatment, and at least 1 year of treatment provided there was no recurrence, substantial toxicity, or withdrawal of consent.

For the primary endpoint, disease-free survival per independent review committee assessment, the hazard ratio was 0.870 (95% confidence interval, 0.660-1.147; P = .3211), according to the report. Disease-free survival as rated by investigators showed a somewhat larger but still not statistically significant reduction in risk of an event, Dr. Quinn and colleagues said.

However, in the prespecified subgroup analyses, the patients at highest risk (pT3 with Fuhrman grade greater than or equal to 3 or pT4 and/or N+, any T, any Fuhrman grade) had a reduction of risk with hazard ratios of 0.735 per independent review committee (P = .0704) and 0.641 per investigator (P = .0051).

The ATLAS study was designed before results of the S-TRAC study were known, and so patients at lower risk of recurrence were included, said Dr. Quinn and coauthors.

Ongoing trials are looking at sorafenib, everolimus, and immune checkpoint inhibitors in the adjuvant RCC setting, they noted in their discussion of ATLAS, S-TRAC, and other investigations.

Results from these trials may provide clarification on the future of adjuvant treatment for RCC, and whether angiogenesis inhibition is the key mechanism to obtain a reduction in risk of relapse after nephrectomy,” they said.

The study was sponsored by Pfizer and SFJ Pharmaceuticals. Dr. Quinn reported providing advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca, and Astellas. Coauthors reported disclosures related to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer, and Roche, among others.

SOURCE: Quinn DI et al. Ann Oncol. 2018 Oct 20. doi: 10.1093/annonc/mdy454.

On Sept. 14 of this year, Apple executives took to the stage to tout the incredible benefits of their new Apple Watch Series 4. While impressively presented in typical Apple fashion, the watch appeared to be only an evolution – not a revolution – in wearable technology. Still, there were a few noteworthy aspects of the new model that seemed to shine a light on the direction of the industry as a whole, and these were all focused on health care.

Like products from FitBit, Garmin, and others, the new Apple Watch can monitor a user’s heart rate and notify if it goes too high or too low. In addition, the watch now includes “fall detection,” and can automatically call for help if its wearer has taken a spill and become unresponsive. Soon it will even be capable of recording a single-lead ECG and detecting atrial fibrillation. While this all sounds fantastic, it also raises an important question in the minds of many physicians (including us): What do we do with all of these new data?

Findings from a Digital Health Study published by the American Medical Association in 2016¹ reveal that most doctors are aware of growing advances in Mobile Health (mHealth). Interestingly, however, while 85% see potential advantages in mHealth, less than 30% have begun employing it in their practices. This speaks to an adoption divide and highlights the many barriers to overcome before we can bridge it.

First and foremost, providers need confidence in the accuracy of the monitoring equipment, and, thus far, that accuracy has been questionable. Heart rate measurement, for example, is a staple of all currently available fitness wearables, yet is replete with technological pitfalls. This is because most consumer devices rely on optical sensors to measure heart rate. While inexpensive and noninvasive, the accuracy of these sensors can be affected by the interference of sweat, movement, and even the patient’s skin conditions – so much so that FitBit is currently embroiled in a class action lawsuit² over the issue, in spite of providing disclaimers that a FitBit is “not a medical device.” To improve heart-monitoring capability, Apple has changed to a new sensor technology for this latest generation of Apple Watch. So far its accuracy has yet to be proven, and Apple’s delay in releasing the ECG features until “later this year” suggests there may still be bugs to work out.

Another significant concern raised by the onslaught of wearable health data is how to incorporate it into the electronic health record. Physicians care about efficient data integration, and, when asked in the aforementioned AMA study, physicians named this as their No. 1 functional requirement. EHR vendors have made some strides to allow patients to upload monitoring data directly through an online portal, but the large variety of available consumer devices has made standardizing this process difficult. Doctors have also made it clear that they want it to be straightforward to access and use the information provided by patients, and don’t want it to require special training. These are considerable challenges that will require collaboration between EHR vendors and wearable manufacturers to solve.

The introduction of additional players into the health care space also evokes questions of who owns this new health data set, and who is accountable for its integrity. If history is any indicator, device manufacturers will try their best to eschew any liability, and shift culpability onto patients and physicians. This is causing malpractice insurers to rethink policy coverage and forcing doctors to face a new reality of having “too much information.” While we are excited about the potential for better access to patient monitoring data, we agree that physicians need to understand where their responsibility for these data begins and ends.

Likewise, patients need to understand who has access to their personal health information, and how it’s being used. Privacy concerns will only become more evident as our society becomes ever more connected and as technologies become more invasive. The term “wearable” may soon become antiquated, as more products are coming to market that cross the skin barrier to collect samples directly from the blood or interstitial fluid. Devices such as Abbott’s new FreeStyle Libre continuous blood glucose monitor can be worn for weeks at a time, with its tiny sensor placed just under the skin. It constantly monitors trends in blood sugar and produces enough data points to determine the eating, sleeping, and activity habits of its wearer. This is all uploadable to Abbott’s servers, allowing patients and their providers to review it, thereby further expanding their personal health information footprint.

One encouraging aspect of the expansion mobile health technology is its organic, patient-led adoption. This is quite different from the epoch of electronic health records, which was motivated largely by government financial incentives and resulted in expensive, inefficient software. Patients are expressing a greater desire to take ownership of their health and have a growing interest in personal fitness. Also, the size of the consumer marketplace is forcing vendors to create competitive, high-value, and user-friendly mHealth devices. These products may seem to offer endless possibilities, but patients, vendors, and providers must fully acknowledge existing limitations in order to truly spark a revolution in wearable technology and actually improve patient care.

Dr. Notte is a family physician and clinical informaticist for Abington (Pa.) Memorial Hospital. He is a partner in EHR Practice Consultants, a firm that aids physicians in adopting electronic health records. Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Jefferson Health.

References

1. Digital Health Study: Physicians’ motivations and requirements for adopting digital clinical tools. (2016) American Medical Association.

2. Kate Mclellan et al. v. Fitbit Inc. Fitbit Heart Rate Monitors Fraud & Defects Lawsuit.

On Sept. 14 of this year, Apple executives took to the stage to tout the incredible benefits of their new Apple Watch Series 4. While impressively presented in typical Apple fashion, the watch appeared to be only an evolution – not a revolution – in wearable technology. Still, there were a few noteworthy aspects of the new model that seemed to shine a light on the direction of the industry as a whole, and these were all focused on health care.

Like products from FitBit, Garmin, and others, the new Apple Watch can monitor a user’s heart rate and notify if it goes too high or too low. In addition, the watch now includes “fall detection,” and can automatically call for help if its wearer has taken a spill and become unresponsive. Soon it will even be capable of recording a single-lead ECG and detecting atrial fibrillation. While this all sounds fantastic, it also raises an important question in the minds of many physicians (including us): What do we do with all of these new data?

Findings from a Digital Health Study published by the American Medical Association in 2016¹ reveal that most doctors are aware of growing advances in Mobile Health (mHealth). Interestingly, however, while 85% see potential advantages in mHealth, less than 30% have begun employing it in their practices. This speaks to an adoption divide and highlights the many barriers to overcome before we can bridge it.

First and foremost, providers need confidence in the accuracy of the monitoring equipment, and, thus far, that accuracy has been questionable. Heart rate measurement, for example, is a staple of all currently available fitness wearables, yet is replete with technological pitfalls. This is because most consumer devices rely on optical sensors to measure heart rate. While inexpensive and noninvasive, the accuracy of these sensors can be affected by the interference of sweat, movement, and even the patient’s skin conditions – so much so that FitBit is currently embroiled in a class action lawsuit² over the issue, in spite of providing disclaimers that a FitBit is “not a medical device.” To improve heart-monitoring capability, Apple has changed to a new sensor technology for this latest generation of Apple Watch. So far its accuracy has yet to be proven, and Apple’s delay in releasing the ECG features until “later this year” suggests there may still be bugs to work out.

Another significant concern raised by the onslaught of wearable health data is how to incorporate it into the electronic health record. Physicians care about efficient data integration, and, when asked in the aforementioned AMA study, physicians named this as their No. 1 functional requirement. EHR vendors have made some strides to allow patients to upload monitoring data directly through an online portal, but the large variety of available consumer devices has made standardizing this process difficult. Doctors have also made it clear that they want it to be straightforward to access and use the information provided by patients, and don’t want it to require special training. These are considerable challenges that will require collaboration between EHR vendors and wearable manufacturers to solve.

The introduction of additional players into the health care space also evokes questions of who owns this new health data set, and who is accountable for its integrity. If history is any indicator, device manufacturers will try their best to eschew any liability, and shift culpability onto patients and physicians. This is causing malpractice insurers to rethink policy coverage and forcing doctors to face a new reality of having “too much information.” While we are excited about the potential for better access to patient monitoring data, we agree that physicians need to understand where their responsibility for these data begins and ends.

Likewise, patients need to understand who has access to their personal health information, and how it’s being used. Privacy concerns will only become more evident as our society becomes ever more connected and as technologies become more invasive. The term “wearable” may soon become antiquated, as more products are coming to market that cross the skin barrier to collect samples directly from the blood or interstitial fluid. Devices such as Abbott’s new FreeStyle Libre continuous blood glucose monitor can be worn for weeks at a time, with its tiny sensor placed just under the skin. It constantly monitors trends in blood sugar and produces enough data points to determine the eating, sleeping, and activity habits of its wearer. This is all uploadable to Abbott’s servers, allowing patients and their providers to review it, thereby further expanding their personal health information footprint.

One encouraging aspect of the expansion mobile health technology is its organic, patient-led adoption. This is quite different from the epoch of electronic health records, which was motivated largely by government financial incentives and resulted in expensive, inefficient software. Patients are expressing a greater desire to take ownership of their health and have a growing interest in personal fitness. Also, the size of the consumer marketplace is forcing vendors to create competitive, high-value, and user-friendly mHealth devices. These products may seem to offer endless possibilities, but patients, vendors, and providers must fully acknowledge existing limitations in order to truly spark a revolution in wearable technology and actually improve patient care.

Dr. Notte is a family physician and clinical informaticist for Abington (Pa.) Memorial Hospital. He is a partner in EHR Practice Consultants, a firm that aids physicians in adopting electronic health records. Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Jefferson Health.

References

1. Digital Health Study: Physicians’ motivations and requirements for adopting digital clinical tools. (2016) American Medical Association.

2. Kate Mclellan et al. v. Fitbit Inc. Fitbit Heart Rate Monitors Fraud & Defects Lawsuit.

On Sept. 14 of this year, Apple executives took to the stage to tout the incredible benefits of their new Apple Watch Series 4. While impressively presented in typical Apple fashion, the watch appeared to be only an evolution – not a revolution – in wearable technology. Still, there were a few noteworthy aspects of the new model that seemed to shine a light on the direction of the industry as a whole, and these were all focused on health care.

Like products from FitBit, Garmin, and others, the new Apple Watch can monitor a user’s heart rate and notify if it goes too high or too low. In addition, the watch now includes “fall detection,” and can automatically call for help if its wearer has taken a spill and become unresponsive. Soon it will even be capable of recording a single-lead ECG and detecting atrial fibrillation. While this all sounds fantastic, it also raises an important question in the minds of many physicians (including us): What do we do with all of these new data?

Findings from a Digital Health Study published by the American Medical Association in 2016¹ reveal that most doctors are aware of growing advances in Mobile Health (mHealth). Interestingly, however, while 85% see potential advantages in mHealth, less than 30% have begun employing it in their practices. This speaks to an adoption divide and highlights the many barriers to overcome before we can bridge it.

First and foremost, providers need confidence in the accuracy of the monitoring equipment, and, thus far, that accuracy has been questionable. Heart rate measurement, for example, is a staple of all currently available fitness wearables, yet is replete with technological pitfalls. This is because most consumer devices rely on optical sensors to measure heart rate. While inexpensive and noninvasive, the accuracy of these sensors can be affected by the interference of sweat, movement, and even the patient’s skin conditions – so much so that FitBit is currently embroiled in a class action lawsuit² over the issue, in spite of providing disclaimers that a FitBit is “not a medical device.” To improve heart-monitoring capability, Apple has changed to a new sensor technology for this latest generation of Apple Watch. So far its accuracy has yet to be proven, and Apple’s delay in releasing the ECG features until “later this year” suggests there may still be bugs to work out.

Another significant concern raised by the onslaught of wearable health data is how to incorporate it into the electronic health record. Physicians care about efficient data integration, and, when asked in the aforementioned AMA study, physicians named this as their No. 1 functional requirement. EHR vendors have made some strides to allow patients to upload monitoring data directly through an online portal, but the large variety of available consumer devices has made standardizing this process difficult. Doctors have also made it clear that they want it to be straightforward to access and use the information provided by patients, and don’t want it to require special training. These are considerable challenges that will require collaboration between EHR vendors and wearable manufacturers to solve.

The introduction of additional players into the health care space also evokes questions of who owns this new health data set, and who is accountable for its integrity. If history is any indicator, device manufacturers will try their best to eschew any liability, and shift culpability onto patients and physicians. This is causing malpractice insurers to rethink policy coverage and forcing doctors to face a new reality of having “too much information.” While we are excited about the potential for better access to patient monitoring data, we agree that physicians need to understand where their responsibility for these data begins and ends.

Likewise, patients need to understand who has access to their personal health information, and how it’s being used. Privacy concerns will only become more evident as our society becomes ever more connected and as technologies become more invasive. The term “wearable” may soon become antiquated, as more products are coming to market that cross the skin barrier to collect samples directly from the blood or interstitial fluid. Devices such as Abbott’s new FreeStyle Libre continuous blood glucose monitor can be worn for weeks at a time, with its tiny sensor placed just under the skin. It constantly monitors trends in blood sugar and produces enough data points to determine the eating, sleeping, and activity habits of its wearer. This is all uploadable to Abbott’s servers, allowing patients and their providers to review it, thereby further expanding their personal health information footprint.

One encouraging aspect of the expansion mobile health technology is its organic, patient-led adoption. This is quite different from the epoch of electronic health records, which was motivated largely by government financial incentives and resulted in expensive, inefficient software. Patients are expressing a greater desire to take ownership of their health and have a growing interest in personal fitness. Also, the size of the consumer marketplace is forcing vendors to create competitive, high-value, and user-friendly mHealth devices. These products may seem to offer endless possibilities, but patients, vendors, and providers must fully acknowledge existing limitations in order to truly spark a revolution in wearable technology and actually improve patient care.

Dr. Notte is a family physician and clinical informaticist for Abington (Pa.) Memorial Hospital. He is a partner in EHR Practice Consultants, a firm that aids physicians in adopting electronic health records. Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Jefferson Health.

References

1. Digital Health Study: Physicians’ motivations and requirements for adopting digital clinical tools. (2016) American Medical Association.

2. Kate Mclellan et al. v. Fitbit Inc. Fitbit Heart Rate Monitors Fraud & Defects Lawsuit.

CASE Midlife woman with low libido causing distress

At her annual gynecologic visit, a 55-year-old woman notes that she has almost no interest in sex. In the past, her libido was good and relations were pleasurable. Since her mid-40s, she has noticed a gradual decline in libido and orgasmic response. Sexual frequency has declined from once or twice weekly to just a few times per month. She has been married for 25 years and describes the relationship as caring and strong. Her husband is healthy with a good libido; his intermittent erectile dysfunction is treated with a phosphodiesterase-5 inhibitor. The patient’s low libido is distressing, as the decline in sexual frequency is causing some conflict for the couple. She requests that her testosterone level be checked because she heard that treatment with testosterone cream will solve this problem.

Evaluating and treating low libido in menopausal women

Low libido is a very common sexual problem for women. When sexual problems are accompanied by distress, they are classified as sexual dysfunctions. Although ObGyns should discuss sexual concerns at every comprehensive visit, if the patient has no associated distress, treatment is not necessarily indicated. A woman with low libido or anorgasmia who is satisfied with her sex life and is not bothered by these issues does not require any intervention.

Currently, the only indication for testosterone therapy that is supported by clinical trial evidence is low sexual desire with associated distress, known as hypoactive sexual desire disorder (HSDD). Although other sexual problems also commonly occur in menopausal women, such as disorders of orgasm and pain, testosterone is not recommended for these problems. In addition, testosterone is not approved by the US Food and Drug Administration (FDA) for the treatment of female sexual dysfunction.

Routinely inquire about sexual functioning

Ask your patients about sexual concerns at every comprehensive visit. You can easily incorporate into the review of systems a general question, such as, “Do you have any sexual concerns?” If the patient does mention a sexual problem, schedule a separate visit (given appointment time constraints) to address it. History and physical examination information you gather during the comprehensive visit will be helpful in the subsequent problem-focused visit.

Taking a thorough history is key when addressing a patient’s sexual problems, since identifying possible etiologies guides treatment. Often, the cause of female sexual dysfunction is multifactorial and includes physiologic, psychologic, and relationship issues.

Explore potential causes, recommend standard therapies

Common causes of low libido in menopausal women include vasomotor symptoms, insomnia, urinary incontinence, cancer or another major medical problem, weight gain, poor body image, genitourinary syndrome of menopause (GSM) with dyspareunia, fatigue, stress, aging, relationship duration, lack of novelty, relationship conflict, and a partner’s sexual problems. Other common etiologies include depression, anxiety, and substance use disorders, as well as medications used to treat these disorders, including selective serotonin reuptake inhibitors (SSRIs).

Continue to: There are many effective therapies...

There are many effective therapies for low sexual desire to consider prior to initiating a trial of testosterone, which should be considered for HSDD only if the disorder persists after addressing all other possible contributing factors (TABLE 1).

Sex therapy, for example, provides information on sexual functioning and helps improve communication and mutual pleasure and satisfaction. Strongly encourage—if not require—a consultation with a sex therapist before prescribing testosterone for low libido. Any testosterone-derived improvement in sexual functioning will be enhanced by improved communication and additional strategies to achieve mutual pleasure.

Hormone therapy. Vasomotor symptoms, with their associated sleep disruption, fatigue, and reduced quality of life (QOL), often adversely impact sexual desire. Estrogen therapy does not appear to improve libido in otherwise asymptomatic women; however, in women with bothersome vasomotor symptoms treated with estrogen, sexual interest may increase as a result of improved sleep, fatigue, and overall QOL. The benefits of systemic hormone therapy generally outweigh its risks for most healthy women younger than age 60 who have bothersome hot flashes and night sweats.¹

Nonhormonal and other therapies. GSM with dyspareunia is a principal cause of sexual dysfunction in older women.² Many safe and effective treatments are available, including low-dose vaginal estrogen therapy, nonhormonal moisturizers and lubricants, ospemifene, vaginal dehydroepiandrosterone, and pelvic floor physical therapy.³ Urinary incontinence commonly occurs in midlife women and contributes to low libido.⁴

Lifestyle approaches. Address fatigue and stress by having the patient adjust her work and sleep schedules, obtain help with housework and meals, and engage in mind-body interventions, counseling, or yoga. Sexual function may benefit from yoga practice, likely as a result of the patient experiencing reduced stress and enhanced body image. Improving overall health and body image with regular exercise, optimal diet, and weight management may contribute to a more satisfying sex life after the onset of menopause.

Relationship refresh. Women’s sexual interest often declines with relationship duration, and both men and women who are in new relationships generally have increased libido, affirming the importance of novelty over the long term. Couples will benefit from “date nights,” weekends away from home, and trying novel positions, locations, and times for sex. Couple’s counseling may address relationship conflict.

Expert referral. Depression, anxiety, and substance use disorders are prevalent in menopausal women and contribute to sexual dysfunction. Effective therapy is available, although some pharmacologic treatments (including SSRIs) may be an additional cause of sexual dysfunction. In addition to recommending appropriate counseling and support, referring the patient to a psychopharmacologist with expertise in managing sexual adverse effects of medications may optimize care.

Continue to: Sexual function improves, but patient still wants to try testosterone

The patient returns for follow-up visits scheduled specifically to address her sexual concerns. Sex is more comfortable and pleasurable since initiating low-dose vaginal estrogen therapy. Having been on an SSRI since her mid-40s for mild depression, the patient switched to bupropion and notes improved libido and orgasmic response. She is exercising more regularly and working with a nutritionist to address a 15-lb weight gain after menopause. The couple saw a sex therapist and is communicating better about sex with more novelty in their repertoire. They are enjoying a regular date night. Although the patient’s sex life has improved with these interventions, she is still very interested in trying testosterone.

Testosterone’s effects on HSDD in menopausal women

After addressing the many factors that contribute to sexual disinterest, a trial of testosterone may be appropriate for a menopausal woman who continues to experience low libido with associated distress.

Testosterone levels decrease with aging in both men and women. Although testosterone levels decline by approximately 50% with bilateral oophorectomy, there is no decline in androgen levels with natural menopause.⁵ Testosterone circulates tightly bound to sex hormone–binding globulin (SHBG), so free or active testosterone will be reduced by oral estrogens, which increase SHBG levels.⁶ As most menopausal women will have a low testosterone level due to aging, measuring the testosterone level does not provide information about the etiology of the sexual problem.

Although some studies have identified an association between endogenous androgen levels and sexual function, the associations are modest and are of uncertain clinical significance.^7-9 Not surprisingly, other factors, such as physical and psychologic health and the quality of the relationship, often are reported as more important predictors of sexual satisfaction than androgen levels.¹⁰

While endogenous testosterone levels may not correlate with sexual function, clinical trials of carefully selected menopausal women with HSDD have shown that androgen treatment generally results in improved sexual function.¹¹ Studies demonstrate substantial improvements in sexual desire, orgasmic response, and frequency in menopausal women treated with high doses of intramuscular testosterone, which result in supraphysiologic androgen levels.^12,13 While it is interesting that women with testosterone levels in the male low range have sizeable increases in sexual desire and response, long-term use of high-dose testosterone would result in unacceptable androgenic adverse effects and risks.

Continue to: Testosterone in low doses...

Testosterone in low doses. It is more relevant to consider the impact on female sexual function of low doses of testosterone, which raise the reduced testosterone levels seen in older women to the higher levels seen in reproductive-aged women.

A series of double-blind, multicenter, randomized, placebo-controlled trials in menopausal women with HSDD examined the impact on sexual function of a transdermal testosterone patch (300 μg) that increased blood testosterone levels to the upper limit of normal for young women.^14-17 In these studies, compared with placebo, women using testosterone reported significant improvements in sexual desire, arousal, orgasmic response, frequency, and sexually related distress. Findings were consistent in surgically and naturally menopausal women, with and without the use of concurrent estrogen therapy. Improvements were clinically limited, however. On average, testosterone-treated women experienced 1 to 1.5 additional satisfying sexual events in a 4-week period compared with those treated with placebo. The percentage of women reporting a clinically meaningful benefit from treatment was significantly greater in women treated with testosterone (52%) compared with the placebo-treated women (31%).¹⁸ An appreciable placebo response was seen, typical of most studies of therapies for sexual dysfunction.

Safety concerns

Potential risks of testosterone treatment include acne, hirsutism, irreversible deepening of the voice, and adverse changes in lipids and liver function (TABLE 2).¹⁹ Adverse effects are dose dependent and are unlikely with physiologically dosed testosterone.

A 1-year study of testosterone patches in approximately 800 menopausal women with HSDD (with a subgroup of women followed for an additional year) provides the most comprehensive safety data available.¹⁷ Unwanted hair growth occurred more often in women receiving testosterone, without significant differences in blood biochemistry,hematologic parameters, carbohydrate metabolism, or lipids. Breast cancer was diagnosed in more women receiving testosterone than placebo. Although this finding may have been due to chance, the investigators concluded that long-term effects of testosterone treatment remain uncertain.

The FDA reviewed the data from the testosterone patch studies and determined that testosterone patches were effective for the treatment of HSDD in menopausal women, but more information was needed on long-term safety before approval could be granted. Another company then developed a testosterone gel product that produced similar blood levels as the testosterone patch. It was presumed that there would be similar efficacy; the principal goal of these studies was to examine long-term safety, particularly with respect to breast cancer and cardiovascular disease. Unexpectedly, although it raised testosterone blood levels to the upper limit of normal for young women, the testosterone gel product was no more effective than placebo.²⁰ The clinical trial was ended, with safety data never published.

Continue to: Availability of testosterone formulations

Currently, no androgen therapies are FDA approved for the treatment of female sexual dysfunction. Although the best evidence regarding testosterone efficacy and safety involves the use of testosterone patches (300 μg), appropriately dosed for women, these patches are not currently available. FDA-approved testosterone patches are approved for the treatment of male hypogonadism, but use of these patches in women is not recommended since they would result in very high circulating testosterone levels.

Testosterone subcutaneous implants, pellets, and intramuscular injections also are not recommended for women because of the risk of excessive dosing. Small trials of menopausal women taking oral estrogen with low sexual desire found that oral formulations of testosterone improved libido in this study population.²¹ The combination of esterified estrogens (0.625 mg) and methyltestosterone (1.25 mg) is available as a compounded, non-FDA approved product. Oral androgen formulations generally are not advised, due to potential adverse effects on lipids and liver function.²²

Compounded testosterone products. Ointments and creams may be compounded by prescription (TABLE 3). Product purity, dose, bioavailability, and quality typically are untested, and substantial variability exists between formulations and batches.²³ Applying 1% testosterone cream or gel (0.5 g/day) topically to the thigh or lower abdomen should increase the low testosterone levels typically seen in menopausal women to the higher levels seen in younger women.^24,25 Application to the vulva or vagina is not advised, as it may cause local irritation and is unpredictably absorbed.

Adapting male testosterone products. High-quality FDA-approved testosterone gel formulations are available for male hypogonadism. However, since women have approximately one-tenth the circulating testosterone levels of men, supraphysiologic dosing is a risk when these products are prescribed for women. Most testosterone products approved for men are provided in pumps or packets, and they are difficult to dose-adjust for women. Applying one-tenth the male dose of 1% testosterone gel (Testim), which comes in a resealable unit-dose tube, is an alternative to compounding. For men, the dose is 1 tube per day, so women should make 1 tube last for 10 days by using 3 to 4 drops of testosterone gel per day. Close physical contact must be avoided immediately after application, as topical hormone creams and gels are easily transferred to others. The safety and efficacy of compounded or dose-adjusted male testosterone products used in women are unknown.

Follow treated women closely. Women who elect to use transdermal testosterone therapy should be seen at 8 to 12 weeks to assess treatment response. Regular follow-up visits are required to assess response, satisfaction, and adverse effects, including acne and hirsutism. Since there may be little correlation between serum testosterone levels and the prescribed dose of a compounded testosterone product, testosterone levels should be measured regularly as a safety measure. The goal is to keep serum testosterone concentrations within the normal range for reproductive-aged women to reduce the likelihood of adverse effects. Testosterone levels should not be tested as an efficacy measure, however, as there is no testosterone level that will assure a satisfactory sex life.

CASE Conclusion

After a thorough discussion of high placebo response rates, potential adverse effects, unknown long-term risks, and off-label nature of testosterone use, the patient elects a trial of compounded 1% testosterone cream. Her clinician informs her of the limitations of compounded formulations and the need for regular testing of testosterone levels to prevent supraphysiologic dosing. At a follow-up visit 8 weeks later, she reports improved sexual desire and elects to continue treatment and monitoring. After using testosterone for 2 years, the patient is uncertain that she still is experiencing a significant benefit, stops testosterone treatment, and remains satisfied with her sex life.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Midlife woman with low libido causing distress

At her annual gynecologic visit, a 55-year-old woman notes that she has almost no interest in sex. In the past, her libido was good and relations were pleasurable. Since her mid-40s, she has noticed a gradual decline in libido and orgasmic response. Sexual frequency has declined from once or twice weekly to just a few times per month. She has been married for 25 years and describes the relationship as caring and strong. Her husband is healthy with a good libido; his intermittent erectile dysfunction is treated with a phosphodiesterase-5 inhibitor. The patient’s low libido is distressing, as the decline in sexual frequency is causing some conflict for the couple. She requests that her testosterone level be checked because she heard that treatment with testosterone cream will solve this problem.

Evaluating and treating low libido in menopausal women

Low libido is a very common sexual problem for women. When sexual problems are accompanied by distress, they are classified as sexual dysfunctions. Although ObGyns should discuss sexual concerns at every comprehensive visit, if the patient has no associated distress, treatment is not necessarily indicated. A woman with low libido or anorgasmia who is satisfied with her sex life and is not bothered by these issues does not require any intervention.

Currently, the only indication for testosterone therapy that is supported by clinical trial evidence is low sexual desire with associated distress, known as hypoactive sexual desire disorder (HSDD). Although other sexual problems also commonly occur in menopausal women, such as disorders of orgasm and pain, testosterone is not recommended for these problems. In addition, testosterone is not approved by the US Food and Drug Administration (FDA) for the treatment of female sexual dysfunction.

Routinely inquire about sexual functioning

Ask your patients about sexual concerns at every comprehensive visit. You can easily incorporate into the review of systems a general question, such as, “Do you have any sexual concerns?” If the patient does mention a sexual problem, schedule a separate visit (given appointment time constraints) to address it. History and physical examination information you gather during the comprehensive visit will be helpful in the subsequent problem-focused visit.

Taking a thorough history is key when addressing a patient’s sexual problems, since identifying possible etiologies guides treatment. Often, the cause of female sexual dysfunction is multifactorial and includes physiologic, psychologic, and relationship issues.

Explore potential causes, recommend standard therapies

Common causes of low libido in menopausal women include vasomotor symptoms, insomnia, urinary incontinence, cancer or another major medical problem, weight gain, poor body image, genitourinary syndrome of menopause (GSM) with dyspareunia, fatigue, stress, aging, relationship duration, lack of novelty, relationship conflict, and a partner’s sexual problems. Other common etiologies include depression, anxiety, and substance use disorders, as well as medications used to treat these disorders, including selective serotonin reuptake inhibitors (SSRIs).

Continue to: There are many effective therapies...

There are many effective therapies for low sexual desire to consider prior to initiating a trial of testosterone, which should be considered for HSDD only if the disorder persists after addressing all other possible contributing factors (TABLE 1).

Sex therapy, for example, provides information on sexual functioning and helps improve communication and mutual pleasure and satisfaction. Strongly encourage—if not require—a consultation with a sex therapist before prescribing testosterone for low libido. Any testosterone-derived improvement in sexual functioning will be enhanced by improved communication and additional strategies to achieve mutual pleasure.

Hormone therapy. Vasomotor symptoms, with their associated sleep disruption, fatigue, and reduced quality of life (QOL), often adversely impact sexual desire. Estrogen therapy does not appear to improve libido in otherwise asymptomatic women; however, in women with bothersome vasomotor symptoms treated with estrogen, sexual interest may increase as a result of improved sleep, fatigue, and overall QOL. The benefits of systemic hormone therapy generally outweigh its risks for most healthy women younger than age 60 who have bothersome hot flashes and night sweats.¹

Nonhormonal and other therapies. GSM with dyspareunia is a principal cause of sexual dysfunction in older women.² Many safe and effective treatments are available, including low-dose vaginal estrogen therapy, nonhormonal moisturizers and lubricants, ospemifene, vaginal dehydroepiandrosterone, and pelvic floor physical therapy.³ Urinary incontinence commonly occurs in midlife women and contributes to low libido.⁴

Lifestyle approaches. Address fatigue and stress by having the patient adjust her work and sleep schedules, obtain help with housework and meals, and engage in mind-body interventions, counseling, or yoga. Sexual function may benefit from yoga practice, likely as a result of the patient experiencing reduced stress and enhanced body image. Improving overall health and body image with regular exercise, optimal diet, and weight management may contribute to a more satisfying sex life after the onset of menopause.

Relationship refresh. Women’s sexual interest often declines with relationship duration, and both men and women who are in new relationships generally have increased libido, affirming the importance of novelty over the long term. Couples will benefit from “date nights,” weekends away from home, and trying novel positions, locations, and times for sex. Couple’s counseling may address relationship conflict.

Expert referral. Depression, anxiety, and substance use disorders are prevalent in menopausal women and contribute to sexual dysfunction. Effective therapy is available, although some pharmacologic treatments (including SSRIs) may be an additional cause of sexual dysfunction. In addition to recommending appropriate counseling and support, referring the patient to a psychopharmacologist with expertise in managing sexual adverse effects of medications may optimize care.

Continue to: Sexual function improves, but patient still wants to try testosterone

The patient returns for follow-up visits scheduled specifically to address her sexual concerns. Sex is more comfortable and pleasurable since initiating low-dose vaginal estrogen therapy. Having been on an SSRI since her mid-40s for mild depression, the patient switched to bupropion and notes improved libido and orgasmic response. She is exercising more regularly and working with a nutritionist to address a 15-lb weight gain after menopause. The couple saw a sex therapist and is communicating better about sex with more novelty in their repertoire. They are enjoying a regular date night. Although the patient’s sex life has improved with these interventions, she is still very interested in trying testosterone.

Testosterone’s effects on HSDD in menopausal women

After addressing the many factors that contribute to sexual disinterest, a trial of testosterone may be appropriate for a menopausal woman who continues to experience low libido with associated distress.

Testosterone levels decrease with aging in both men and women. Although testosterone levels decline by approximately 50% with bilateral oophorectomy, there is no decline in androgen levels with natural menopause.⁵ Testosterone circulates tightly bound to sex hormone–binding globulin (SHBG), so free or active testosterone will be reduced by oral estrogens, which increase SHBG levels.⁶ As most menopausal women will have a low testosterone level due to aging, measuring the testosterone level does not provide information about the etiology of the sexual problem.

Although some studies have identified an association between endogenous androgen levels and sexual function, the associations are modest and are of uncertain clinical significance.^7-9 Not surprisingly, other factors, such as physical and psychologic health and the quality of the relationship, often are reported as more important predictors of sexual satisfaction than androgen levels.¹⁰

While endogenous testosterone levels may not correlate with sexual function, clinical trials of carefully selected menopausal women with HSDD have shown that androgen treatment generally results in improved sexual function.¹¹ Studies demonstrate substantial improvements in sexual desire, orgasmic response, and frequency in menopausal women treated with high doses of intramuscular testosterone, which result in supraphysiologic androgen levels.^12,13 While it is interesting that women with testosterone levels in the male low range have sizeable increases in sexual desire and response, long-term use of high-dose testosterone would result in unacceptable androgenic adverse effects and risks.

Continue to: Testosterone in low doses...

Testosterone in low doses. It is more relevant to consider the impact on female sexual function of low doses of testosterone, which raise the reduced testosterone levels seen in older women to the higher levels seen in reproductive-aged women.

A series of double-blind, multicenter, randomized, placebo-controlled trials in menopausal women with HSDD examined the impact on sexual function of a transdermal testosterone patch (300 μg) that increased blood testosterone levels to the upper limit of normal for young women.^14-17 In these studies, compared with placebo, women using testosterone reported significant improvements in sexual desire, arousal, orgasmic response, frequency, and sexually related distress. Findings were consistent in surgically and naturally menopausal women, with and without the use of concurrent estrogen therapy. Improvements were clinically limited, however. On average, testosterone-treated women experienced 1 to 1.5 additional satisfying sexual events in a 4-week period compared with those treated with placebo. The percentage of women reporting a clinically meaningful benefit from treatment was significantly greater in women treated with testosterone (52%) compared with the placebo-treated women (31%).¹⁸ An appreciable placebo response was seen, typical of most studies of therapies for sexual dysfunction.

Safety concerns

Potential risks of testosterone treatment include acne, hirsutism, irreversible deepening of the voice, and adverse changes in lipids and liver function (TABLE 2).¹⁹ Adverse effects are dose dependent and are unlikely with physiologically dosed testosterone.

A 1-year study of testosterone patches in approximately 800 menopausal women with HSDD (with a subgroup of women followed for an additional year) provides the most comprehensive safety data available.¹⁷ Unwanted hair growth occurred more often in women receiving testosterone, without significant differences in blood biochemistry,hematologic parameters, carbohydrate metabolism, or lipids. Breast cancer was diagnosed in more women receiving testosterone than placebo. Although this finding may have been due to chance, the investigators concluded that long-term effects of testosterone treatment remain uncertain.

The FDA reviewed the data from the testosterone patch studies and determined that testosterone patches were effective for the treatment of HSDD in menopausal women, but more information was needed on long-term safety before approval could be granted. Another company then developed a testosterone gel product that produced similar blood levels as the testosterone patch. It was presumed that there would be similar efficacy; the principal goal of these studies was to examine long-term safety, particularly with respect to breast cancer and cardiovascular disease. Unexpectedly, although it raised testosterone blood levels to the upper limit of normal for young women, the testosterone gel product was no more effective than placebo.²⁰ The clinical trial was ended, with safety data never published.

Continue to: Availability of testosterone formulations

Currently, no androgen therapies are FDA approved for the treatment of female sexual dysfunction. Although the best evidence regarding testosterone efficacy and safety involves the use of testosterone patches (300 μg), appropriately dosed for women, these patches are not currently available. FDA-approved testosterone patches are approved for the treatment of male hypogonadism, but use of these patches in women is not recommended since they would result in very high circulating testosterone levels.

Testosterone subcutaneous implants, pellets, and intramuscular injections also are not recommended for women because of the risk of excessive dosing. Small trials of menopausal women taking oral estrogen with low sexual desire found that oral formulations of testosterone improved libido in this study population.²¹ The combination of esterified estrogens (0.625 mg) and methyltestosterone (1.25 mg) is available as a compounded, non-FDA approved product. Oral androgen formulations generally are not advised, due to potential adverse effects on lipids and liver function.²²

Compounded testosterone products. Ointments and creams may be compounded by prescription (TABLE 3). Product purity, dose, bioavailability, and quality typically are untested, and substantial variability exists between formulations and batches.²³ Applying 1% testosterone cream or gel (0.5 g/day) topically to the thigh or lower abdomen should increase the low testosterone levels typically seen in menopausal women to the higher levels seen in younger women.^24,25 Application to the vulva or vagina is not advised, as it may cause local irritation and is unpredictably absorbed.

Adapting male testosterone products. High-quality FDA-approved testosterone gel formulations are available for male hypogonadism. However, since women have approximately one-tenth the circulating testosterone levels of men, supraphysiologic dosing is a risk when these products are prescribed for women. Most testosterone products approved for men are provided in pumps or packets, and they are difficult to dose-adjust for women. Applying one-tenth the male dose of 1% testosterone gel (Testim), which comes in a resealable unit-dose tube, is an alternative to compounding. For men, the dose is 1 tube per day, so women should make 1 tube last for 10 days by using 3 to 4 drops of testosterone gel per day. Close physical contact must be avoided immediately after application, as topical hormone creams and gels are easily transferred to others. The safety and efficacy of compounded or dose-adjusted male testosterone products used in women are unknown.

Follow treated women closely. Women who elect to use transdermal testosterone therapy should be seen at 8 to 12 weeks to assess treatment response. Regular follow-up visits are required to assess response, satisfaction, and adverse effects, including acne and hirsutism. Since there may be little correlation between serum testosterone levels and the prescribed dose of a compounded testosterone product, testosterone levels should be measured regularly as a safety measure. The goal is to keep serum testosterone concentrations within the normal range for reproductive-aged women to reduce the likelihood of adverse effects. Testosterone levels should not be tested as an efficacy measure, however, as there is no testosterone level that will assure a satisfactory sex life.

CASE Conclusion

After a thorough discussion of high placebo response rates, potential adverse effects, unknown long-term risks, and off-label nature of testosterone use, the patient elects a trial of compounded 1% testosterone cream. Her clinician informs her of the limitations of compounded formulations and the need for regular testing of testosterone levels to prevent supraphysiologic dosing. At a follow-up visit 8 weeks later, she reports improved sexual desire and elects to continue treatment and monitoring. After using testosterone for 2 years, the patient is uncertain that she still is experiencing a significant benefit, stops testosterone treatment, and remains satisfied with her sex life.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Midlife woman with low libido causing distress

At her annual gynecologic visit, a 55-year-old woman notes that she has almost no interest in sex. In the past, her libido was good and relations were pleasurable. Since her mid-40s, she has noticed a gradual decline in libido and orgasmic response. Sexual frequency has declined from once or twice weekly to just a few times per month. She has been married for 25 years and describes the relationship as caring and strong. Her husband is healthy with a good libido; his intermittent erectile dysfunction is treated with a phosphodiesterase-5 inhibitor. The patient’s low libido is distressing, as the decline in sexual frequency is causing some conflict for the couple. She requests that her testosterone level be checked because she heard that treatment with testosterone cream will solve this problem.

Evaluating and treating low libido in menopausal women

Low libido is a very common sexual problem for women. When sexual problems are accompanied by distress, they are classified as sexual dysfunctions. Although ObGyns should discuss sexual concerns at every comprehensive visit, if the patient has no associated distress, treatment is not necessarily indicated. A woman with low libido or anorgasmia who is satisfied with her sex life and is not bothered by these issues does not require any intervention.

Currently, the only indication for testosterone therapy that is supported by clinical trial evidence is low sexual desire with associated distress, known as hypoactive sexual desire disorder (HSDD). Although other sexual problems also commonly occur in menopausal women, such as disorders of orgasm and pain, testosterone is not recommended for these problems. In addition, testosterone is not approved by the US Food and Drug Administration (FDA) for the treatment of female sexual dysfunction.

Routinely inquire about sexual functioning

Ask your patients about sexual concerns at every comprehensive visit. You can easily incorporate into the review of systems a general question, such as, “Do you have any sexual concerns?” If the patient does mention a sexual problem, schedule a separate visit (given appointment time constraints) to address it. History and physical examination information you gather during the comprehensive visit will be helpful in the subsequent problem-focused visit.

Taking a thorough history is key when addressing a patient’s sexual problems, since identifying possible etiologies guides treatment. Often, the cause of female sexual dysfunction is multifactorial and includes physiologic, psychologic, and relationship issues.

Explore potential causes, recommend standard therapies

Common causes of low libido in menopausal women include vasomotor symptoms, insomnia, urinary incontinence, cancer or another major medical problem, weight gain, poor body image, genitourinary syndrome of menopause (GSM) with dyspareunia, fatigue, stress, aging, relationship duration, lack of novelty, relationship conflict, and a partner’s sexual problems. Other common etiologies include depression, anxiety, and substance use disorders, as well as medications used to treat these disorders, including selective serotonin reuptake inhibitors (SSRIs).

Continue to: There are many effective therapies...

There are many effective therapies for low sexual desire to consider prior to initiating a trial of testosterone, which should be considered for HSDD only if the disorder persists after addressing all other possible contributing factors (TABLE 1).

Sex therapy, for example, provides information on sexual functioning and helps improve communication and mutual pleasure and satisfaction. Strongly encourage—if not require—a consultation with a sex therapist before prescribing testosterone for low libido. Any testosterone-derived improvement in sexual functioning will be enhanced by improved communication and additional strategies to achieve mutual pleasure.

Hormone therapy. Vasomotor symptoms, with their associated sleep disruption, fatigue, and reduced quality of life (QOL), often adversely impact sexual desire. Estrogen therapy does not appear to improve libido in otherwise asymptomatic women; however, in women with bothersome vasomotor symptoms treated with estrogen, sexual interest may increase as a result of improved sleep, fatigue, and overall QOL. The benefits of systemic hormone therapy generally outweigh its risks for most healthy women younger than age 60 who have bothersome hot flashes and night sweats.¹

Nonhormonal and other therapies. GSM with dyspareunia is a principal cause of sexual dysfunction in older women.² Many safe and effective treatments are available, including low-dose vaginal estrogen therapy, nonhormonal moisturizers and lubricants, ospemifene, vaginal dehydroepiandrosterone, and pelvic floor physical therapy.³ Urinary incontinence commonly occurs in midlife women and contributes to low libido.⁴

Lifestyle approaches. Address fatigue and stress by having the patient adjust her work and sleep schedules, obtain help with housework and meals, and engage in mind-body interventions, counseling, or yoga. Sexual function may benefit from yoga practice, likely as a result of the patient experiencing reduced stress and enhanced body image. Improving overall health and body image with regular exercise, optimal diet, and weight management may contribute to a more satisfying sex life after the onset of menopause.

Relationship refresh. Women’s sexual interest often declines with relationship duration, and both men and women who are in new relationships generally have increased libido, affirming the importance of novelty over the long term. Couples will benefit from “date nights,” weekends away from home, and trying novel positions, locations, and times for sex. Couple’s counseling may address relationship conflict.

Expert referral. Depression, anxiety, and substance use disorders are prevalent in menopausal women and contribute to sexual dysfunction. Effective therapy is available, although some pharmacologic treatments (including SSRIs) may be an additional cause of sexual dysfunction. In addition to recommending appropriate counseling and support, referring the patient to a psychopharmacologist with expertise in managing sexual adverse effects of medications may optimize care.

Continue to: Sexual function improves, but patient still wants to try testosterone

The patient returns for follow-up visits scheduled specifically to address her sexual concerns. Sex is more comfortable and pleasurable since initiating low-dose vaginal estrogen therapy. Having been on an SSRI since her mid-40s for mild depression, the patient switched to bupropion and notes improved libido and orgasmic response. She is exercising more regularly and working with a nutritionist to address a 15-lb weight gain after menopause. The couple saw a sex therapist and is communicating better about sex with more novelty in their repertoire. They are enjoying a regular date night. Although the patient’s sex life has improved with these interventions, she is still very interested in trying testosterone.

Testosterone’s effects on HSDD in menopausal women

After addressing the many factors that contribute to sexual disinterest, a trial of testosterone may be appropriate for a menopausal woman who continues to experience low libido with associated distress.

Testosterone levels decrease with aging in both men and women. Although testosterone levels decline by approximately 50% with bilateral oophorectomy, there is no decline in androgen levels with natural menopause.⁵ Testosterone circulates tightly bound to sex hormone–binding globulin (SHBG), so free or active testosterone will be reduced by oral estrogens, which increase SHBG levels.⁶ As most menopausal women will have a low testosterone level due to aging, measuring the testosterone level does not provide information about the etiology of the sexual problem.

Although some studies have identified an association between endogenous androgen levels and sexual function, the associations are modest and are of uncertain clinical significance.^7-9 Not surprisingly, other factors, such as physical and psychologic health and the quality of the relationship, often are reported as more important predictors of sexual satisfaction than androgen levels.¹⁰

While endogenous testosterone levels may not correlate with sexual function, clinical trials of carefully selected menopausal women with HSDD have shown that androgen treatment generally results in improved sexual function.¹¹ Studies demonstrate substantial improvements in sexual desire, orgasmic response, and frequency in menopausal women treated with high doses of intramuscular testosterone, which result in supraphysiologic androgen levels.^12,13 While it is interesting that women with testosterone levels in the male low range have sizeable increases in sexual desire and response, long-term use of high-dose testosterone would result in unacceptable androgenic adverse effects and risks.

Continue to: Testosterone in low doses...

Testosterone in low doses. It is more relevant to consider the impact on female sexual function of low doses of testosterone, which raise the reduced testosterone levels seen in older women to the higher levels seen in reproductive-aged women.

A series of double-blind, multicenter, randomized, placebo-controlled trials in menopausal women with HSDD examined the impact on sexual function of a transdermal testosterone patch (300 μg) that increased blood testosterone levels to the upper limit of normal for young women.^14-17 In these studies, compared with placebo, women using testosterone reported significant improvements in sexual desire, arousal, orgasmic response, frequency, and sexually related distress. Findings were consistent in surgically and naturally menopausal women, with and without the use of concurrent estrogen therapy. Improvements were clinically limited, however. On average, testosterone-treated women experienced 1 to 1.5 additional satisfying sexual events in a 4-week period compared with those treated with placebo. The percentage of women reporting a clinically meaningful benefit from treatment was significantly greater in women treated with testosterone (52%) compared with the placebo-treated women (31%).¹⁸ An appreciable placebo response was seen, typical of most studies of therapies for sexual dysfunction.

Safety concerns

Potential risks of testosterone treatment include acne, hirsutism, irreversible deepening of the voice, and adverse changes in lipids and liver function (TABLE 2).¹⁹ Adverse effects are dose dependent and are unlikely with physiologically dosed testosterone.

A 1-year study of testosterone patches in approximately 800 menopausal women with HSDD (with a subgroup of women followed for an additional year) provides the most comprehensive safety data available.¹⁷ Unwanted hair growth occurred more often in women receiving testosterone, without significant differences in blood biochemistry,hematologic parameters, carbohydrate metabolism, or lipids. Breast cancer was diagnosed in more women receiving testosterone than placebo. Although this finding may have been due to chance, the investigators concluded that long-term effects of testosterone treatment remain uncertain.

The FDA reviewed the data from the testosterone patch studies and determined that testosterone patches were effective for the treatment of HSDD in menopausal women, but more information was needed on long-term safety before approval could be granted. Another company then developed a testosterone gel product that produced similar blood levels as the testosterone patch. It was presumed that there would be similar efficacy; the principal goal of these studies was to examine long-term safety, particularly with respect to breast cancer and cardiovascular disease. Unexpectedly, although it raised testosterone blood levels to the upper limit of normal for young women, the testosterone gel product was no more effective than placebo.²⁰ The clinical trial was ended, with safety data never published.

Continue to: Availability of testosterone formulations

Currently, no androgen therapies are FDA approved for the treatment of female sexual dysfunction. Although the best evidence regarding testosterone efficacy and safety involves the use of testosterone patches (300 μg), appropriately dosed for women, these patches are not currently available. FDA-approved testosterone patches are approved for the treatment of male hypogonadism, but use of these patches in women is not recommended since they would result in very high circulating testosterone levels.

Testosterone subcutaneous implants, pellets, and intramuscular injections also are not recommended for women because of the risk of excessive dosing. Small trials of menopausal women taking oral estrogen with low sexual desire found that oral formulations of testosterone improved libido in this study population.²¹ The combination of esterified estrogens (0.625 mg) and methyltestosterone (1.25 mg) is available as a compounded, non-FDA approved product. Oral androgen formulations generally are not advised, due to potential adverse effects on lipids and liver function.²²

Compounded testosterone products. Ointments and creams may be compounded by prescription (TABLE 3). Product purity, dose, bioavailability, and quality typically are untested, and substantial variability exists between formulations and batches.²³ Applying 1% testosterone cream or gel (0.5 g/day) topically to the thigh or lower abdomen should increase the low testosterone levels typically seen in menopausal women to the higher levels seen in younger women.^24,25 Application to the vulva or vagina is not advised, as it may cause local irritation and is unpredictably absorbed.

Adapting male testosterone products. High-quality FDA-approved testosterone gel formulations are available for male hypogonadism. However, since women have approximately one-tenth the circulating testosterone levels of men, supraphysiologic dosing is a risk when these products are prescribed for women. Most testosterone products approved for men are provided in pumps or packets, and they are difficult to dose-adjust for women. Applying one-tenth the male dose of 1% testosterone gel (Testim), which comes in a resealable unit-dose tube, is an alternative to compounding. For men, the dose is 1 tube per day, so women should make 1 tube last for 10 days by using 3 to 4 drops of testosterone gel per day. Close physical contact must be avoided immediately after application, as topical hormone creams and gels are easily transferred to others. The safety and efficacy of compounded or dose-adjusted male testosterone products used in women are unknown.

Follow treated women closely. Women who elect to use transdermal testosterone therapy should be seen at 8 to 12 weeks to assess treatment response. Regular follow-up visits are required to assess response, satisfaction, and adverse effects, including acne and hirsutism. Since there may be little correlation between serum testosterone levels and the prescribed dose of a compounded testosterone product, testosterone levels should be measured regularly as a safety measure. The goal is to keep serum testosterone concentrations within the normal range for reproductive-aged women to reduce the likelihood of adverse effects. Testosterone levels should not be tested as an efficacy measure, however, as there is no testosterone level that will assure a satisfactory sex life.

CASE Conclusion

After a thorough discussion of high placebo response rates, potential adverse effects, unknown long-term risks, and off-label nature of testosterone use, the patient elects a trial of compounded 1% testosterone cream. Her clinician informs her of the limitations of compounded formulations and the need for regular testing of testosterone levels to prevent supraphysiologic dosing. At a follow-up visit 8 weeks later, she reports improved sexual desire and elects to continue treatment and monitoring. After using testosterone for 2 years, the patient is uncertain that she still is experiencing a significant benefit, stops testosterone treatment, and remains satisfied with her sex life.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

MUNICH – Revising the threshold for actionable high cardiovascular risk from the current 7.5% or greater risk of an event within 10 years as defined in American College of Cardiology/American Heart Association guidelines using the Atherosclerotic Cardiovascular Disease (ASCVD ) Risk Calculator to a 10% or greater 10-year risk would provide the optimal balance of sensitivity and specificity for discriminating future risk of cardiovascular events, according to Robert S. Rosenman, MD.

“I think this is very important from a public health policy perspective,” Dr. Rosenman, a cardiologist who is professor of medicine at Mount Sinai School of Medicine in New York, said at the annual congress of the European Society of Cardiology.

He elaborated: “This would eliminate 11.4 million people who are currently candidates for a statin but may not be getting the benefits of statin therapy. We feel that this information is actually quite important for the primary prevention population because there’s been a lot of pushback from our primary care physician colleagues about the overtreatment of low-risk individuals” under the current guidelines (Circulation. 2014 Jun 24;129[25 Suppl 2]:S49-73).

Dr. Rosenman and his coinvestigators conducted a secondary analysis of data on 21,343 adults in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study. All participants were free of a baseline history of heart disease or stroke. During a median 8.5 years of follow-up, 1,717 of them experienced adjudicated coronary heart disease or stroke events.

In multivariate analyses adjusted for standard cardiovascular risk factors, socioeconomic and demographic factors, and the use of statins and/or antihypertensive drugs, the higher the baseline 10-year predicted risk using the ACC/AHA ASCVD Risk Calculator based on the Pooled Cohort risk equations, the higher the incidence rate of cardiovascular events. No surprise there.

What was impressive, however, was that the optimal combination of sensitivity and specificity as captured in a statistic known as Youden’s index occurred at a 10-year predicted risk of 10%-12%. The biggest net improvement obtained through reclassification resulted from moving the threshold for elevated 10-year cardiovascular risk warranting statin therapy from 7.5% or greater to 10% or more, rather than using thresholds of 15% or 20%.

He cited data from the 2011-2014 National Health and Nutrition Examination Survey in support of his estimate that switching to a 10% threshold from the current 7.5% threshold would reduce the number of Americans deemed at high cardiovascular risk from 57.1 million to 45.8 million.

“This cutoff value of 10%, by the way, is the same cutoff value used in the recently published ACC/AHA guideline on hypertension. And it’s also the same cutoff value used for antiplatelet therapy in looking at the benefit/risk ratio. So this value of 10% is, I think, really the right number. Our study is the first effort that has been shown to validate that number, and it brings the cutoff values in the various guidelines in line,” the cardiologist observed.

Asked if these new findings are likely to result in a revision of the ACC/AHA cardiovascular risk assessment guidelines, Dr. Rosenman replied that the guidelines are under revision, with the draft update now circulating for comment. So the timing is dicey: His study is now in prepublication peer review, but hasn’t yet been published and thus may not carry persuasive weight.

“Hopefully, the guideline panel is going to make an adjustment to make the 10% figure in line with the blood pressure guidelines,” he said.

The new analysis of the REGARDS study was funded by a collaboration between Amgen, Mount Sinai School of Medicine, and the University of Alabama. Dr. Rosenman reported receiving research funding from and serving as an advisor to Amgen and a handful of other companies.
 

[email protected]

MUNICH – Revising the threshold for actionable high cardiovascular risk from the current 7.5% or greater risk of an event within 10 years as defined in American College of Cardiology/American Heart Association guidelines using the Atherosclerotic Cardiovascular Disease (ASCVD ) Risk Calculator to a 10% or greater 10-year risk would provide the optimal balance of sensitivity and specificity for discriminating future risk of cardiovascular events, according to Robert S. Rosenman, MD.

“I think this is very important from a public health policy perspective,” Dr. Rosenman, a cardiologist who is professor of medicine at Mount Sinai School of Medicine in New York, said at the annual congress of the European Society of Cardiology.

He elaborated: “This would eliminate 11.4 million people who are currently candidates for a statin but may not be getting the benefits of statin therapy. We feel that this information is actually quite important for the primary prevention population because there’s been a lot of pushback from our primary care physician colleagues about the overtreatment of low-risk individuals” under the current guidelines (Circulation. 2014 Jun 24;129[25 Suppl 2]:S49-73).

Dr. Rosenman and his coinvestigators conducted a secondary analysis of data on 21,343 adults in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study. All participants were free of a baseline history of heart disease or stroke. During a median 8.5 years of follow-up, 1,717 of them experienced adjudicated coronary heart disease or stroke events.

In multivariate analyses adjusted for standard cardiovascular risk factors, socioeconomic and demographic factors, and the use of statins and/or antihypertensive drugs, the higher the baseline 10-year predicted risk using the ACC/AHA ASCVD Risk Calculator based on the Pooled Cohort risk equations, the higher the incidence rate of cardiovascular events. No surprise there.

What was impressive, however, was that the optimal combination of sensitivity and specificity as captured in a statistic known as Youden’s index occurred at a 10-year predicted risk of 10%-12%. The biggest net improvement obtained through reclassification resulted from moving the threshold for elevated 10-year cardiovascular risk warranting statin therapy from 7.5% or greater to 10% or more, rather than using thresholds of 15% or 20%.

He cited data from the 2011-2014 National Health and Nutrition Examination Survey in support of his estimate that switching to a 10% threshold from the current 7.5% threshold would reduce the number of Americans deemed at high cardiovascular risk from 57.1 million to 45.8 million.

“This cutoff value of 10%, by the way, is the same cutoff value used in the recently published ACC/AHA guideline on hypertension. And it’s also the same cutoff value used for antiplatelet therapy in looking at the benefit/risk ratio. So this value of 10% is, I think, really the right number. Our study is the first effort that has been shown to validate that number, and it brings the cutoff values in the various guidelines in line,” the cardiologist observed.

Asked if these new findings are likely to result in a revision of the ACC/AHA cardiovascular risk assessment guidelines, Dr. Rosenman replied that the guidelines are under revision, with the draft update now circulating for comment. So the timing is dicey: His study is now in prepublication peer review, but hasn’t yet been published and thus may not carry persuasive weight.

“Hopefully, the guideline panel is going to make an adjustment to make the 10% figure in line with the blood pressure guidelines,” he said.

The new analysis of the REGARDS study was funded by a collaboration between Amgen, Mount Sinai School of Medicine, and the University of Alabama. Dr. Rosenman reported receiving research funding from and serving as an advisor to Amgen and a handful of other companies.
 

[email protected]

MUNICH – Revising the threshold for actionable high cardiovascular risk from the current 7.5% or greater risk of an event within 10 years as defined in American College of Cardiology/American Heart Association guidelines using the Atherosclerotic Cardiovascular Disease (ASCVD ) Risk Calculator to a 10% or greater 10-year risk would provide the optimal balance of sensitivity and specificity for discriminating future risk of cardiovascular events, according to Robert S. Rosenman, MD.

“I think this is very important from a public health policy perspective,” Dr. Rosenman, a cardiologist who is professor of medicine at Mount Sinai School of Medicine in New York, said at the annual congress of the European Society of Cardiology.

He elaborated: “This would eliminate 11.4 million people who are currently candidates for a statin but may not be getting the benefits of statin therapy. We feel that this information is actually quite important for the primary prevention population because there’s been a lot of pushback from our primary care physician colleagues about the overtreatment of low-risk individuals” under the current guidelines (Circulation. 2014 Jun 24;129[25 Suppl 2]:S49-73).

Dr. Rosenman and his coinvestigators conducted a secondary analysis of data on 21,343 adults in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study. All participants were free of a baseline history of heart disease or stroke. During a median 8.5 years of follow-up, 1,717 of them experienced adjudicated coronary heart disease or stroke events.

In multivariate analyses adjusted for standard cardiovascular risk factors, socioeconomic and demographic factors, and the use of statins and/or antihypertensive drugs, the higher the baseline 10-year predicted risk using the ACC/AHA ASCVD Risk Calculator based on the Pooled Cohort risk equations, the higher the incidence rate of cardiovascular events. No surprise there.

What was impressive, however, was that the optimal combination of sensitivity and specificity as captured in a statistic known as Youden’s index occurred at a 10-year predicted risk of 10%-12%. The biggest net improvement obtained through reclassification resulted from moving the threshold for elevated 10-year cardiovascular risk warranting statin therapy from 7.5% or greater to 10% or more, rather than using thresholds of 15% or 20%.

He cited data from the 2011-2014 National Health and Nutrition Examination Survey in support of his estimate that switching to a 10% threshold from the current 7.5% threshold would reduce the number of Americans deemed at high cardiovascular risk from 57.1 million to 45.8 million.

“This cutoff value of 10%, by the way, is the same cutoff value used in the recently published ACC/AHA guideline on hypertension. And it’s also the same cutoff value used for antiplatelet therapy in looking at the benefit/risk ratio. So this value of 10% is, I think, really the right number. Our study is the first effort that has been shown to validate that number, and it brings the cutoff values in the various guidelines in line,” the cardiologist observed.

Asked if these new findings are likely to result in a revision of the ACC/AHA cardiovascular risk assessment guidelines, Dr. Rosenman replied that the guidelines are under revision, with the draft update now circulating for comment. So the timing is dicey: His study is now in prepublication peer review, but hasn’t yet been published and thus may not carry persuasive weight.

“Hopefully, the guideline panel is going to make an adjustment to make the 10% figure in line with the blood pressure guidelines,” he said.

The new analysis of the REGARDS study was funded by a collaboration between Amgen, Mount Sinai School of Medicine, and the University of Alabama. Dr. Rosenman reported receiving research funding from and serving as an advisor to Amgen and a handful of other companies.
 

[email protected]