Study Overview

Objective. The objectives of this study were to (1) quantify the frequency of preoperative advance care planning (ACP) discussion and documentation for older adults undergoing major surgery in a national sample, and (2) characterize how surgical patients and their family members considered ACP after postoperative complications.

Design. A secondary analysis of data from a multisite randomized clinical trial testing the effects of a question prompt list intervention (a Question Problem List [QPL] brochure with 11 questions) given to patients aged 60 years or older undergoing high-risk surgery on preoperative communication with their surgeons.

Setting and participants. This multisite randomized controlled trial involved 5 study sites that encompassed distinct US geographic areas, including University of Wisconsin Hospital and Clinics (UWHC), Madison; the University of California, San Francisco, Medical Center (UCSF); Oregon Health & Science University (OHSU), Portland; the University Hospital of Rutgers New Jersey Medical School (Rutgers), Newark; and the Brigham and Women’s Hospital (BWH), Boston, Massachusetts. The study enrolled 40 surgeons who routinely performed high-risk oncological or vascular surgery via purposeful sampling; patients aged 60 years or older with at least 1 comorbidity and an oncological or vascular problem that were treatable with high-risk surgery; and 1 invited family member per enrolled patient to participate in open-ended interviews postsurgery. High-risk surgery was defined as an operation that has a 30-day in-hospital mortality rate greater than or equal to 1%. Data were collected from June 1, 2016, to November 30, 2018.

Main outcome measures. The frequency of preoperative discussions and documentation of ACP was determined. For patients who had major surgery, any mention of ACP (ie, mention of advance directive [AD], health care power of attorney, or preference for limitations of life-sustaining treatments) by the surgeon, patient or family member during the audio recorded, transcribed, and coded preoperative consultation was counted. The presence of a written AD in the medical record at the time of the initial consultation, filed between the consultation and the date of surgery, or added postoperatively, was recorded using a standardized abstraction form. Postoperative treatments administered and complications experienced within 6 weeks after surgery were recorded. Open-ended interviews with patients who experienced significant postoperative complications (eg, prolonged hospitalization > 8 days, intensive care unit stay > 3 days) and their family members were conducted 6 weeks after surgery. Information ascertained during interviews focused on treatment decisions, postoperative experiences, and interpersonal relationships among patients, families, and clinicians. Transcripts of these interviews were then subjected to qualitative content analysis.

Main results. A total of 446 patients were enrolled in the primary study. Of these patients, 213 (122 men [57%]; 91 women [43%]; mean [SD] age, 72 [7] years) underwent major surgery. Only 13 (6.1%) of those who had major surgery had any discussion related to ACP in the preoperative consultation. In this cohort, 141 (66%) patients did not have an AD on file before undergoing major surgery. The presence of AD was not associated with age (60-69 years, 26 [31%]; 70-79 years, 31 [33%]; ≥ 80 years, 15 [42%]; P = .55), number of comorbidities (1, 35 [32%]; 2, 18 [33%]; ≥ 3, 19 [40%]; P = .62), or type of procedure (oncological, 53 [32%]; vascular, 19 [42%]; P = .22). Moreover, there was no difference in preoperative communication about ACP or documentation of an AD for patients who were mailed a QPL brochure compared to those who received usual care (intervention, 38 [35%]; usual care, 34 [33%]; P = .77). Rates of AD documentation were associated with individual study sites with BWH and UWHC having higher rates of documentation (20 [50%] and 27 [44%], respectively) compared to OHSU, UCSF, or Rutgers (7 [17%], 17 [35%], and 1 [5%], respectively). Analysis from the interviews indicated that patients and families felt unprepared for serious surgical complications and had varied interpretations of ACP. Patients with complications were enthusiastic about ACP but did not think it was important to discuss their preferences for life-sustaining treatments with their surgeon preoperatively.

Conclusion. Although surgeons and patients report that they believe ACP is important, preoperative discussion of patient preferences rarely occurs. This study found that the frequency of ACP discussions or AD documentations among older patients undergoing high-risk oncologic or vascular surgery was low. Interventions that are aimed to increase rates of preoperative ACP discussions should be implemented to help prepare patients and their families for difficult decisions in the setting of serious surgical complications and could help decrease postoperative conflicts that result from unclear patient care goals.

Commentary

Surgeons and patients approach surgical interventions with optimistic outlooks while simultaneously preparing for unintended adverse outcomes. For patients, preoperative ACP discussions ease the burden on their families and ensure their wishes and care goals are communicated. For surgeons, these discussions inform them how best to support the values of the patient. Therefore, it is unsurprising that preoperative ACP is viewed favorably by both groups. Given the consensus that ACP is important in the care of older adults undergoing high-risk surgery, one would assume that preoperative ACP discussion is a standard of practice among surgeons and their aging patients. However, in a secondary analysis of a randomized control trial testing a patient-mediated intervention to improve preoperative communication, Kalbfell et al¹ showed that ACP discussions rarely take place prior to major surgery in older adults. This finding highlights the significant discrepancy between the belief that ACP is important, and the actual rate that it is practiced, in older patients undergoing high-risk surgery. This discordance is highly concerning because it suggests that surgeons who provide care to a very vulnerable subset of older patients may overlook an essential aspect of preoperative care and therefore lack a thorough and thoughtful understanding of the patient’s care goals. In practice, this omission can pose significant challenges associated with the surgeon and family’s decisions to use postoperative life-sustaining interventions or to manage unforeseen complications should a patient become unable to make medical decisions.

The barriers to conducting successful ACP discussions between surgeons and patients are multifactorial. Kalbfell et al¹ highlighted several of these barriers, including lack of patient efficacy, physician attitudes, and institutional values in older adults who require major surgeries. The inadequacy of patient efficacy in preoperative ACP is illustrated by findings from the primary, multisite trial of QPL intervention conducted by Schwarze et al. Interestingly, the authors found that patients who did not receive QPL brochure had no ACP discussions, and that QPL implementation did not significantly improve discussion rates despite its intent to encourage these discussions.² Possible explanations for this lack of engagement might be a lack of health literacy or patient efficacy in the study population. Qualitative data from the current study provided further evidence to support these explanations. For instance, some patients provided limited or incomplete information about their wishes for health care management while others felt it was unnecessary to have ACP discussions unless complications arose.¹ However, the latter example counters the purpose of ACP which is to enable patients to make plans about future health care and not reactive to a medical complication or emergency.

Surgeons bear a large responsibility in providing treatments that are consistent with the care goals of the patient. Thus, surgeons play a crucial role in engaging, guiding, and facilitating ACP discussions with patients. This role is even more critical when patients are unable or unwilling to initiate care goal discussions. Physician attitudes towards ACP, therefore, greatly influence the effectiveness of these discussions. In a study of self-administered surveys by vascular, neurologic, and cardiothoracic surgeons, greater than 90% of respondents viewed postoperative life-supporting therapy as necessary, and 54% would decline to operate on patients with an AD limiting life-supporting therapy.³ Moreover, the same study showed that 52% of respondents reported discussing AD before surgery, a figure that exceeded the actual rates at which ACP discussions occur in many other studies. In the current study, Kalbfell et al¹ also found that surgeons viewed ACP discussions largely in the context of AD creation and declined to investigate the full scope of patient preferences. These findings, when combined with other studies that indicate an incomplete understanding of ACP in some surgeons, suggest that not all physicians are able or willing to navigate these sometimes lengthy and difficult conversations with patients. This gap in practice provides opportunities for training in surgical specialties that center on optimizing preoperative ACP discussions to meet the care needs of older patients.

Institutional value and culture are important factors that impact physician behavior and the practice of ACP discussion. In the current study, the authors reported that the majority of ACP discussions were held by a minority of surgeons and that different institutions and study sites had vastly different rates of ACP documentation.¹ These results are further supported by findings of large variations between physicians and hospitals in ACP reporting in hospitalized frail older adults.⁴ These variations in practices at different institutions suggest that it is possible to improve rates of preoperative ACP discussion. Reasons for these differences need to be further investigated in order to identify strategies, resources, or trainings required by medical institutions to support surgeons to carry out ACP discussions with patients undergoing high-risk surgeries.

The study conducted by Kalbfell et al¹ has several strengths. For example, it included Spanish-speaking patients and the use of a Spanish version of the QPL intervention to account for cultural differences. The study also included multiple surgical specialties and institutions and captured a large and national sample, thus making its findings more generalizable. However, the lack of data on the duration of preoperative consultation visits in patients who completed ACP discussions poses a limitation to this study. This is relevant because surgeon availability to engage in lengthy ACP discussions may be limited due to busy clinical schedules. Additional data on the duration of preoperative visits inclusive of a thoughtfully conducted ACP discussion could help to modify clinical workflow to facilitate its uptake in surgical practices.

Applications for Clinical Practice

The findings from the current study indicate that patients and surgeons agree that preoperative ACP discussions are beneficial to the clinical care of older adults before high-risk surgeries. However, these important conversations do not occur frequently. Surgeons and health care institutions need to identify strategies to initiate, facilitate, and optimize productive preoperative ACP discussions to provide patient-centered care in vulnerable older surgical patients.

Financial disclosures: None.

Study Overview

Objective. The objectives of this study were to (1) quantify the frequency of preoperative advance care planning (ACP) discussion and documentation for older adults undergoing major surgery in a national sample, and (2) characterize how surgical patients and their family members considered ACP after postoperative complications.

Design. A secondary analysis of data from a multisite randomized clinical trial testing the effects of a question prompt list intervention (a Question Problem List [QPL] brochure with 11 questions) given to patients aged 60 years or older undergoing high-risk surgery on preoperative communication with their surgeons.

Setting and participants. This multisite randomized controlled trial involved 5 study sites that encompassed distinct US geographic areas, including University of Wisconsin Hospital and Clinics (UWHC), Madison; the University of California, San Francisco, Medical Center (UCSF); Oregon Health & Science University (OHSU), Portland; the University Hospital of Rutgers New Jersey Medical School (Rutgers), Newark; and the Brigham and Women’s Hospital (BWH), Boston, Massachusetts. The study enrolled 40 surgeons who routinely performed high-risk oncological or vascular surgery via purposeful sampling; patients aged 60 years or older with at least 1 comorbidity and an oncological or vascular problem that were treatable with high-risk surgery; and 1 invited family member per enrolled patient to participate in open-ended interviews postsurgery. High-risk surgery was defined as an operation that has a 30-day in-hospital mortality rate greater than or equal to 1%. Data were collected from June 1, 2016, to November 30, 2018.

Main outcome measures. The frequency of preoperative discussions and documentation of ACP was determined. For patients who had major surgery, any mention of ACP (ie, mention of advance directive [AD], health care power of attorney, or preference for limitations of life-sustaining treatments) by the surgeon, patient or family member during the audio recorded, transcribed, and coded preoperative consultation was counted. The presence of a written AD in the medical record at the time of the initial consultation, filed between the consultation and the date of surgery, or added postoperatively, was recorded using a standardized abstraction form. Postoperative treatments administered and complications experienced within 6 weeks after surgery were recorded. Open-ended interviews with patients who experienced significant postoperative complications (eg, prolonged hospitalization > 8 days, intensive care unit stay > 3 days) and their family members were conducted 6 weeks after surgery. Information ascertained during interviews focused on treatment decisions, postoperative experiences, and interpersonal relationships among patients, families, and clinicians. Transcripts of these interviews were then subjected to qualitative content analysis.

Main results. A total of 446 patients were enrolled in the primary study. Of these patients, 213 (122 men [57%]; 91 women [43%]; mean [SD] age, 72 [7] years) underwent major surgery. Only 13 (6.1%) of those who had major surgery had any discussion related to ACP in the preoperative consultation. In this cohort, 141 (66%) patients did not have an AD on file before undergoing major surgery. The presence of AD was not associated with age (60-69 years, 26 [31%]; 70-79 years, 31 [33%]; ≥ 80 years, 15 [42%]; P = .55), number of comorbidities (1, 35 [32%]; 2, 18 [33%]; ≥ 3, 19 [40%]; P = .62), or type of procedure (oncological, 53 [32%]; vascular, 19 [42%]; P = .22). Moreover, there was no difference in preoperative communication about ACP or documentation of an AD for patients who were mailed a QPL brochure compared to those who received usual care (intervention, 38 [35%]; usual care, 34 [33%]; P = .77). Rates of AD documentation were associated with individual study sites with BWH and UWHC having higher rates of documentation (20 [50%] and 27 [44%], respectively) compared to OHSU, UCSF, or Rutgers (7 [17%], 17 [35%], and 1 [5%], respectively). Analysis from the interviews indicated that patients and families felt unprepared for serious surgical complications and had varied interpretations of ACP. Patients with complications were enthusiastic about ACP but did not think it was important to discuss their preferences for life-sustaining treatments with their surgeon preoperatively.

Conclusion. Although surgeons and patients report that they believe ACP is important, preoperative discussion of patient preferences rarely occurs. This study found that the frequency of ACP discussions or AD documentations among older patients undergoing high-risk oncologic or vascular surgery was low. Interventions that are aimed to increase rates of preoperative ACP discussions should be implemented to help prepare patients and their families for difficult decisions in the setting of serious surgical complications and could help decrease postoperative conflicts that result from unclear patient care goals.

Commentary

Surgeons and patients approach surgical interventions with optimistic outlooks while simultaneously preparing for unintended adverse outcomes. For patients, preoperative ACP discussions ease the burden on their families and ensure their wishes and care goals are communicated. For surgeons, these discussions inform them how best to support the values of the patient. Therefore, it is unsurprising that preoperative ACP is viewed favorably by both groups. Given the consensus that ACP is important in the care of older adults undergoing high-risk surgery, one would assume that preoperative ACP discussion is a standard of practice among surgeons and their aging patients. However, in a secondary analysis of a randomized control trial testing a patient-mediated intervention to improve preoperative communication, Kalbfell et al¹ showed that ACP discussions rarely take place prior to major surgery in older adults. This finding highlights the significant discrepancy between the belief that ACP is important, and the actual rate that it is practiced, in older patients undergoing high-risk surgery. This discordance is highly concerning because it suggests that surgeons who provide care to a very vulnerable subset of older patients may overlook an essential aspect of preoperative care and therefore lack a thorough and thoughtful understanding of the patient’s care goals. In practice, this omission can pose significant challenges associated with the surgeon and family’s decisions to use postoperative life-sustaining interventions or to manage unforeseen complications should a patient become unable to make medical decisions.

The barriers to conducting successful ACP discussions between surgeons and patients are multifactorial. Kalbfell et al¹ highlighted several of these barriers, including lack of patient efficacy, physician attitudes, and institutional values in older adults who require major surgeries. The inadequacy of patient efficacy in preoperative ACP is illustrated by findings from the primary, multisite trial of QPL intervention conducted by Schwarze et al. Interestingly, the authors found that patients who did not receive QPL brochure had no ACP discussions, and that QPL implementation did not significantly improve discussion rates despite its intent to encourage these discussions.² Possible explanations for this lack of engagement might be a lack of health literacy or patient efficacy in the study population. Qualitative data from the current study provided further evidence to support these explanations. For instance, some patients provided limited or incomplete information about their wishes for health care management while others felt it was unnecessary to have ACP discussions unless complications arose.¹ However, the latter example counters the purpose of ACP which is to enable patients to make plans about future health care and not reactive to a medical complication or emergency.

Surgeons bear a large responsibility in providing treatments that are consistent with the care goals of the patient. Thus, surgeons play a crucial role in engaging, guiding, and facilitating ACP discussions with patients. This role is even more critical when patients are unable or unwilling to initiate care goal discussions. Physician attitudes towards ACP, therefore, greatly influence the effectiveness of these discussions. In a study of self-administered surveys by vascular, neurologic, and cardiothoracic surgeons, greater than 90% of respondents viewed postoperative life-supporting therapy as necessary, and 54% would decline to operate on patients with an AD limiting life-supporting therapy.³ Moreover, the same study showed that 52% of respondents reported discussing AD before surgery, a figure that exceeded the actual rates at which ACP discussions occur in many other studies. In the current study, Kalbfell et al¹ also found that surgeons viewed ACP discussions largely in the context of AD creation and declined to investigate the full scope of patient preferences. These findings, when combined with other studies that indicate an incomplete understanding of ACP in some surgeons, suggest that not all physicians are able or willing to navigate these sometimes lengthy and difficult conversations with patients. This gap in practice provides opportunities for training in surgical specialties that center on optimizing preoperative ACP discussions to meet the care needs of older patients.

Institutional value and culture are important factors that impact physician behavior and the practice of ACP discussion. In the current study, the authors reported that the majority of ACP discussions were held by a minority of surgeons and that different institutions and study sites had vastly different rates of ACP documentation.¹ These results are further supported by findings of large variations between physicians and hospitals in ACP reporting in hospitalized frail older adults.⁴ These variations in practices at different institutions suggest that it is possible to improve rates of preoperative ACP discussion. Reasons for these differences need to be further investigated in order to identify strategies, resources, or trainings required by medical institutions to support surgeons to carry out ACP discussions with patients undergoing high-risk surgeries.

The study conducted by Kalbfell et al¹ has several strengths. For example, it included Spanish-speaking patients and the use of a Spanish version of the QPL intervention to account for cultural differences. The study also included multiple surgical specialties and institutions and captured a large and national sample, thus making its findings more generalizable. However, the lack of data on the duration of preoperative consultation visits in patients who completed ACP discussions poses a limitation to this study. This is relevant because surgeon availability to engage in lengthy ACP discussions may be limited due to busy clinical schedules. Additional data on the duration of preoperative visits inclusive of a thoughtfully conducted ACP discussion could help to modify clinical workflow to facilitate its uptake in surgical practices.

Applications for Clinical Practice

The findings from the current study indicate that patients and surgeons agree that preoperative ACP discussions are beneficial to the clinical care of older adults before high-risk surgeries. However, these important conversations do not occur frequently. Surgeons and health care institutions need to identify strategies to initiate, facilitate, and optimize productive preoperative ACP discussions to provide patient-centered care in vulnerable older surgical patients.

Financial disclosures: None.

Study Overview

Objective. The objectives of this study were to (1) quantify the frequency of preoperative advance care planning (ACP) discussion and documentation for older adults undergoing major surgery in a national sample, and (2) characterize how surgical patients and their family members considered ACP after postoperative complications.

Design. A secondary analysis of data from a multisite randomized clinical trial testing the effects of a question prompt list intervention (a Question Problem List [QPL] brochure with 11 questions) given to patients aged 60 years or older undergoing high-risk surgery on preoperative communication with their surgeons.

Setting and participants. This multisite randomized controlled trial involved 5 study sites that encompassed distinct US geographic areas, including University of Wisconsin Hospital and Clinics (UWHC), Madison; the University of California, San Francisco, Medical Center (UCSF); Oregon Health & Science University (OHSU), Portland; the University Hospital of Rutgers New Jersey Medical School (Rutgers), Newark; and the Brigham and Women’s Hospital (BWH), Boston, Massachusetts. The study enrolled 40 surgeons who routinely performed high-risk oncological or vascular surgery via purposeful sampling; patients aged 60 years or older with at least 1 comorbidity and an oncological or vascular problem that were treatable with high-risk surgery; and 1 invited family member per enrolled patient to participate in open-ended interviews postsurgery. High-risk surgery was defined as an operation that has a 30-day in-hospital mortality rate greater than or equal to 1%. Data were collected from June 1, 2016, to November 30, 2018.

Main outcome measures. The frequency of preoperative discussions and documentation of ACP was determined. For patients who had major surgery, any mention of ACP (ie, mention of advance directive [AD], health care power of attorney, or preference for limitations of life-sustaining treatments) by the surgeon, patient or family member during the audio recorded, transcribed, and coded preoperative consultation was counted. The presence of a written AD in the medical record at the time of the initial consultation, filed between the consultation and the date of surgery, or added postoperatively, was recorded using a standardized abstraction form. Postoperative treatments administered and complications experienced within 6 weeks after surgery were recorded. Open-ended interviews with patients who experienced significant postoperative complications (eg, prolonged hospitalization > 8 days, intensive care unit stay > 3 days) and their family members were conducted 6 weeks after surgery. Information ascertained during interviews focused on treatment decisions, postoperative experiences, and interpersonal relationships among patients, families, and clinicians. Transcripts of these interviews were then subjected to qualitative content analysis.

Main results. A total of 446 patients were enrolled in the primary study. Of these patients, 213 (122 men [57%]; 91 women [43%]; mean [SD] age, 72 [7] years) underwent major surgery. Only 13 (6.1%) of those who had major surgery had any discussion related to ACP in the preoperative consultation. In this cohort, 141 (66%) patients did not have an AD on file before undergoing major surgery. The presence of AD was not associated with age (60-69 years, 26 [31%]; 70-79 years, 31 [33%]; ≥ 80 years, 15 [42%]; P = .55), number of comorbidities (1, 35 [32%]; 2, 18 [33%]; ≥ 3, 19 [40%]; P = .62), or type of procedure (oncological, 53 [32%]; vascular, 19 [42%]; P = .22). Moreover, there was no difference in preoperative communication about ACP or documentation of an AD for patients who were mailed a QPL brochure compared to those who received usual care (intervention, 38 [35%]; usual care, 34 [33%]; P = .77). Rates of AD documentation were associated with individual study sites with BWH and UWHC having higher rates of documentation (20 [50%] and 27 [44%], respectively) compared to OHSU, UCSF, or Rutgers (7 [17%], 17 [35%], and 1 [5%], respectively). Analysis from the interviews indicated that patients and families felt unprepared for serious surgical complications and had varied interpretations of ACP. Patients with complications were enthusiastic about ACP but did not think it was important to discuss their preferences for life-sustaining treatments with their surgeon preoperatively.

Conclusion. Although surgeons and patients report that they believe ACP is important, preoperative discussion of patient preferences rarely occurs. This study found that the frequency of ACP discussions or AD documentations among older patients undergoing high-risk oncologic or vascular surgery was low. Interventions that are aimed to increase rates of preoperative ACP discussions should be implemented to help prepare patients and their families for difficult decisions in the setting of serious surgical complications and could help decrease postoperative conflicts that result from unclear patient care goals.

Commentary

Surgeons and patients approach surgical interventions with optimistic outlooks while simultaneously preparing for unintended adverse outcomes. For patients, preoperative ACP discussions ease the burden on their families and ensure their wishes and care goals are communicated. For surgeons, these discussions inform them how best to support the values of the patient. Therefore, it is unsurprising that preoperative ACP is viewed favorably by both groups. Given the consensus that ACP is important in the care of older adults undergoing high-risk surgery, one would assume that preoperative ACP discussion is a standard of practice among surgeons and their aging patients. However, in a secondary analysis of a randomized control trial testing a patient-mediated intervention to improve preoperative communication, Kalbfell et al¹ showed that ACP discussions rarely take place prior to major surgery in older adults. This finding highlights the significant discrepancy between the belief that ACP is important, and the actual rate that it is practiced, in older patients undergoing high-risk surgery. This discordance is highly concerning because it suggests that surgeons who provide care to a very vulnerable subset of older patients may overlook an essential aspect of preoperative care and therefore lack a thorough and thoughtful understanding of the patient’s care goals. In practice, this omission can pose significant challenges associated with the surgeon and family’s decisions to use postoperative life-sustaining interventions or to manage unforeseen complications should a patient become unable to make medical decisions.

The barriers to conducting successful ACP discussions between surgeons and patients are multifactorial. Kalbfell et al¹ highlighted several of these barriers, including lack of patient efficacy, physician attitudes, and institutional values in older adults who require major surgeries. The inadequacy of patient efficacy in preoperative ACP is illustrated by findings from the primary, multisite trial of QPL intervention conducted by Schwarze et al. Interestingly, the authors found that patients who did not receive QPL brochure had no ACP discussions, and that QPL implementation did not significantly improve discussion rates despite its intent to encourage these discussions.² Possible explanations for this lack of engagement might be a lack of health literacy or patient efficacy in the study population. Qualitative data from the current study provided further evidence to support these explanations. For instance, some patients provided limited or incomplete information about their wishes for health care management while others felt it was unnecessary to have ACP discussions unless complications arose.¹ However, the latter example counters the purpose of ACP which is to enable patients to make plans about future health care and not reactive to a medical complication or emergency.

Surgeons bear a large responsibility in providing treatments that are consistent with the care goals of the patient. Thus, surgeons play a crucial role in engaging, guiding, and facilitating ACP discussions with patients. This role is even more critical when patients are unable or unwilling to initiate care goal discussions. Physician attitudes towards ACP, therefore, greatly influence the effectiveness of these discussions. In a study of self-administered surveys by vascular, neurologic, and cardiothoracic surgeons, greater than 90% of respondents viewed postoperative life-supporting therapy as necessary, and 54% would decline to operate on patients with an AD limiting life-supporting therapy.³ Moreover, the same study showed that 52% of respondents reported discussing AD before surgery, a figure that exceeded the actual rates at which ACP discussions occur in many other studies. In the current study, Kalbfell et al¹ also found that surgeons viewed ACP discussions largely in the context of AD creation and declined to investigate the full scope of patient preferences. These findings, when combined with other studies that indicate an incomplete understanding of ACP in some surgeons, suggest that not all physicians are able or willing to navigate these sometimes lengthy and difficult conversations with patients. This gap in practice provides opportunities for training in surgical specialties that center on optimizing preoperative ACP discussions to meet the care needs of older patients.

Institutional value and culture are important factors that impact physician behavior and the practice of ACP discussion. In the current study, the authors reported that the majority of ACP discussions were held by a minority of surgeons and that different institutions and study sites had vastly different rates of ACP documentation.¹ These results are further supported by findings of large variations between physicians and hospitals in ACP reporting in hospitalized frail older adults.⁴ These variations in practices at different institutions suggest that it is possible to improve rates of preoperative ACP discussion. Reasons for these differences need to be further investigated in order to identify strategies, resources, or trainings required by medical institutions to support surgeons to carry out ACP discussions with patients undergoing high-risk surgeries.

The study conducted by Kalbfell et al¹ has several strengths. For example, it included Spanish-speaking patients and the use of a Spanish version of the QPL intervention to account for cultural differences. The study also included multiple surgical specialties and institutions and captured a large and national sample, thus making its findings more generalizable. However, the lack of data on the duration of preoperative consultation visits in patients who completed ACP discussions poses a limitation to this study. This is relevant because surgeon availability to engage in lengthy ACP discussions may be limited due to busy clinical schedules. Additional data on the duration of preoperative visits inclusive of a thoughtfully conducted ACP discussion could help to modify clinical workflow to facilitate its uptake in surgical practices.

Applications for Clinical Practice

The findings from the current study indicate that patients and surgeons agree that preoperative ACP discussions are beneficial to the clinical care of older adults before high-risk surgeries. However, these important conversations do not occur frequently. Surgeons and health care institutions need to identify strategies to initiate, facilitate, and optimize productive preoperative ACP discussions to provide patient-centered care in vulnerable older surgical patients.

Financial disclosures: None.

Patients in their 90s with cancer tolerated immunotherapy well with few serious adverse effects, and they lived for an average of 1.6 years after treatment, a small new study within the US Department of Veterans Affairs (VA) health system reports.

Only 6.3% of 48 patients who were treated with immune checkpoint inhibitors experienced the most severe types of side effects – grade III/IV events – and a total of 27% had any adverse effects, according to the report, which was presented at the 2021 annual meeting of the Association of VA Hematology/Oncology (AVAHO) being held virtually and inperson in Denver Colorado, September 24 to September 26, 2021.

“Our project should help give confidence to oncologists treating the elderly,” said Andrew Joseph Benefield, MD, a hematology/oncology fellow at Wake Forest Baptist Medical Center, in an interview. “Immunotherapy can be given safely and likely effectively in select individuals over the age of 90 with good performance status.”

Benefield and colleagues launched their study to gain insight into a little-studied area: How does cancer treatment affects nonagenarians? “I think many oncologists have been in a situation where they encounter an individual over the age of 90 years who has a good performance status, and they've wondered if immunotherapy would be helpful and safe, particularly given our knowledge of waning immune strength as people age,” he said.

The researchers retrospectively tracked patients with cancer who were at least 90 years old from 2016 to 2017 and were treated with immune checkpoint inhibitors. Most were fit or fairly fit with Eastern Cooperative Oncology Group (ECOG) physical performance scales of 0 or 1 (n = 26), and nearly all had cancer in stage IV (n = 42). Melanoma was the most common type of cancer (n = 19), followed by non-small-cell lung cancer (n = 15). Patients were treated with an average of 12.2 cycles.

“In general, we saw that treatment was well-tolerated,” Dr. Benefield said. “We also noted that a trend toward better long-term survival outcomes in individuals with very good performance status at the start of treatment. We hope to parse this out more as we add more data to our data-set, as the numbers are still too small for confident direct comparison.”

Dr. Benefield said he has treated a limited number of patients in their 90s who were highly physical fit for their age and “very eager” to be treated. “They wanted to do anything they could to maintain their lifestyle,” he said. “In my experience, aggressive supportive care and close monitoring for developing toxicities has been most helpful.”

The researchers don’t know the causes of death of many of the patients, and it’s not clear how they fared in their final days. Still, Dr. Benefield said, “extending someone's life by more than 1 year with relatively low risk of adverse effects is reasonable.”

Oncologist Melisa Wong, MD, MAS, of the University of California, San Francisco, reviewed the study and said in an interview that it “a valuable description of outcomes for nonagenarians receiving immunotherapy in the VA healthcare system.” As she noted, “many other studies of immunotherapy among older adults focus on patients aged 65 or 70 and older while very few focus on octogenarians or nonagenarians.”

The findings suggest that “it is important to move beyond chronological age and assess patients’ physiologic age through a geriatric assessment,” she said. “Geriatric assessment-derived risk scores have been shown to predict chemotherapy toxicity for older adults and research to develop similar tools for immunotherapy are ongoing.”

However, she cautioned that older patients may become suffer so much from the most common side effect of immunotherapy -- fatigue – that “their independence is at stake.”

“Some of these patient choose to stop immunotherapy because the side effects aren’t worth it anymore,” she said. “The challenge for oncologists is not knowing in advance which patients will fall into each of these categories.”

She added that her geriatric oncology research focuses on improving risk stratification for older adults, such as those who are at least 70 with lung adenocarcinoma.

Oncologist Grant R. Williams, MD, MSPH, director of the Cancer & Aging Program at the University of Alabama at Birmingham, agreed in an interview that comprehensive geriatric assessments are important to guide treatment in the oldest adults. “In addition, it is important to elicit the goals of treatment as well,” he said. “For older adults that are fit or at least pre-frail and desire aggressive treatment, immunotherapy is a very reasonable approach, particularly when patients are closely monitored for side effects.”

No study funding is reported. The authors report no disclosures. Dr. Wong discloses an immediate family member is an employee and stock holder of Genentech. Dr. Williams has no disclosures.

Patients in their 90s with cancer tolerated immunotherapy well with few serious adverse effects, and they lived for an average of 1.6 years after treatment, a small new study within the US Department of Veterans Affairs (VA) health system reports.

Only 6.3% of 48 patients who were treated with immune checkpoint inhibitors experienced the most severe types of side effects – grade III/IV events – and a total of 27% had any adverse effects, according to the report, which was presented at the 2021 annual meeting of the Association of VA Hematology/Oncology (AVAHO) being held virtually and inperson in Denver Colorado, September 24 to September 26, 2021.

“Our project should help give confidence to oncologists treating the elderly,” said Andrew Joseph Benefield, MD, a hematology/oncology fellow at Wake Forest Baptist Medical Center, in an interview. “Immunotherapy can be given safely and likely effectively in select individuals over the age of 90 with good performance status.”

Benefield and colleagues launched their study to gain insight into a little-studied area: How does cancer treatment affects nonagenarians? “I think many oncologists have been in a situation where they encounter an individual over the age of 90 years who has a good performance status, and they've wondered if immunotherapy would be helpful and safe, particularly given our knowledge of waning immune strength as people age,” he said.

The researchers retrospectively tracked patients with cancer who were at least 90 years old from 2016 to 2017 and were treated with immune checkpoint inhibitors. Most were fit or fairly fit with Eastern Cooperative Oncology Group (ECOG) physical performance scales of 0 or 1 (n = 26), and nearly all had cancer in stage IV (n = 42). Melanoma was the most common type of cancer (n = 19), followed by non-small-cell lung cancer (n = 15). Patients were treated with an average of 12.2 cycles.

“In general, we saw that treatment was well-tolerated,” Dr. Benefield said. “We also noted that a trend toward better long-term survival outcomes in individuals with very good performance status at the start of treatment. We hope to parse this out more as we add more data to our data-set, as the numbers are still too small for confident direct comparison.”

Dr. Benefield said he has treated a limited number of patients in their 90s who were highly physical fit for their age and “very eager” to be treated. “They wanted to do anything they could to maintain their lifestyle,” he said. “In my experience, aggressive supportive care and close monitoring for developing toxicities has been most helpful.”

The researchers don’t know the causes of death of many of the patients, and it’s not clear how they fared in their final days. Still, Dr. Benefield said, “extending someone's life by more than 1 year with relatively low risk of adverse effects is reasonable.”

Oncologist Melisa Wong, MD, MAS, of the University of California, San Francisco, reviewed the study and said in an interview that it “a valuable description of outcomes for nonagenarians receiving immunotherapy in the VA healthcare system.” As she noted, “many other studies of immunotherapy among older adults focus on patients aged 65 or 70 and older while very few focus on octogenarians or nonagenarians.”

The findings suggest that “it is important to move beyond chronological age and assess patients’ physiologic age through a geriatric assessment,” she said. “Geriatric assessment-derived risk scores have been shown to predict chemotherapy toxicity for older adults and research to develop similar tools for immunotherapy are ongoing.”

However, she cautioned that older patients may become suffer so much from the most common side effect of immunotherapy -- fatigue – that “their independence is at stake.”

“Some of these patient choose to stop immunotherapy because the side effects aren’t worth it anymore,” she said. “The challenge for oncologists is not knowing in advance which patients will fall into each of these categories.”

She added that her geriatric oncology research focuses on improving risk stratification for older adults, such as those who are at least 70 with lung adenocarcinoma.

Oncologist Grant R. Williams, MD, MSPH, director of the Cancer & Aging Program at the University of Alabama at Birmingham, agreed in an interview that comprehensive geriatric assessments are important to guide treatment in the oldest adults. “In addition, it is important to elicit the goals of treatment as well,” he said. “For older adults that are fit or at least pre-frail and desire aggressive treatment, immunotherapy is a very reasonable approach, particularly when patients are closely monitored for side effects.”

No study funding is reported. The authors report no disclosures. Dr. Wong discloses an immediate family member is an employee and stock holder of Genentech. Dr. Williams has no disclosures.

Patients in their 90s with cancer tolerated immunotherapy well with few serious adverse effects, and they lived for an average of 1.6 years after treatment, a small new study within the US Department of Veterans Affairs (VA) health system reports.

Only 6.3% of 48 patients who were treated with immune checkpoint inhibitors experienced the most severe types of side effects – grade III/IV events – and a total of 27% had any adverse effects, according to the report, which was presented at the 2021 annual meeting of the Association of VA Hematology/Oncology (AVAHO) being held virtually and inperson in Denver Colorado, September 24 to September 26, 2021.

“Our project should help give confidence to oncologists treating the elderly,” said Andrew Joseph Benefield, MD, a hematology/oncology fellow at Wake Forest Baptist Medical Center, in an interview. “Immunotherapy can be given safely and likely effectively in select individuals over the age of 90 with good performance status.”

Benefield and colleagues launched their study to gain insight into a little-studied area: How does cancer treatment affects nonagenarians? “I think many oncologists have been in a situation where they encounter an individual over the age of 90 years who has a good performance status, and they've wondered if immunotherapy would be helpful and safe, particularly given our knowledge of waning immune strength as people age,” he said.

The researchers retrospectively tracked patients with cancer who were at least 90 years old from 2016 to 2017 and were treated with immune checkpoint inhibitors. Most were fit or fairly fit with Eastern Cooperative Oncology Group (ECOG) physical performance scales of 0 or 1 (n = 26), and nearly all had cancer in stage IV (n = 42). Melanoma was the most common type of cancer (n = 19), followed by non-small-cell lung cancer (n = 15). Patients were treated with an average of 12.2 cycles.

“In general, we saw that treatment was well-tolerated,” Dr. Benefield said. “We also noted that a trend toward better long-term survival outcomes in individuals with very good performance status at the start of treatment. We hope to parse this out more as we add more data to our data-set, as the numbers are still too small for confident direct comparison.”

Dr. Benefield said he has treated a limited number of patients in their 90s who were highly physical fit for their age and “very eager” to be treated. “They wanted to do anything they could to maintain their lifestyle,” he said. “In my experience, aggressive supportive care and close monitoring for developing toxicities has been most helpful.”

The researchers don’t know the causes of death of many of the patients, and it’s not clear how they fared in their final days. Still, Dr. Benefield said, “extending someone's life by more than 1 year with relatively low risk of adverse effects is reasonable.”

Oncologist Melisa Wong, MD, MAS, of the University of California, San Francisco, reviewed the study and said in an interview that it “a valuable description of outcomes for nonagenarians receiving immunotherapy in the VA healthcare system.” As she noted, “many other studies of immunotherapy among older adults focus on patients aged 65 or 70 and older while very few focus on octogenarians or nonagenarians.”

The findings suggest that “it is important to move beyond chronological age and assess patients’ physiologic age through a geriatric assessment,” she said. “Geriatric assessment-derived risk scores have been shown to predict chemotherapy toxicity for older adults and research to develop similar tools for immunotherapy are ongoing.”

However, she cautioned that older patients may become suffer so much from the most common side effect of immunotherapy -- fatigue – that “their independence is at stake.”

“Some of these patient choose to stop immunotherapy because the side effects aren’t worth it anymore,” she said. “The challenge for oncologists is not knowing in advance which patients will fall into each of these categories.”

She added that her geriatric oncology research focuses on improving risk stratification for older adults, such as those who are at least 70 with lung adenocarcinoma.

Oncologist Grant R. Williams, MD, MSPH, director of the Cancer & Aging Program at the University of Alabama at Birmingham, agreed in an interview that comprehensive geriatric assessments are important to guide treatment in the oldest adults. “In addition, it is important to elicit the goals of treatment as well,” he said. “For older adults that are fit or at least pre-frail and desire aggressive treatment, immunotherapy is a very reasonable approach, particularly when patients are closely monitored for side effects.”

No study funding is reported. The authors report no disclosures. Dr. Wong discloses an immediate family member is an employee and stock holder of Genentech. Dr. Williams has no disclosures.

George Froehle, PA, a primary care clinician at CentraCare in rural St. Cloud, Minn., has been prescribing the HIV prevention pill tenofovir disoproxil fumarate plus emtricitabine since it was marketed by the brand name Truvada and the Food and Drug Administration approved it in 2012. But recently, he’s been having conversations with patients about the new HIV prevention pill, tenofovir alafenamide plus emtricitabine (TAF/FTC, Descovy) as well.

“They may have a friend who has heard that Descovy is newer and safer,” Mr. Froehle said. But that’s not necessarily the case, at least according to lab values. A recent study in the journal Open Forum Infectious Diseases suggests that only between 1 in 10 and 1 in 3 switches to the new formulation of HIV pre-exposure prophylaxis (PrEP) are indicated by lab work – and that nearly half of people receiving a prescription for the new version had lab results actually contraindicating the switch.

This, combined with the lower cost of generic Truvada and the steep cost of Descovy, led study coauthor and HIV PrEP prescriber Douglas Krakower, MD, and colleagues to suggest that the generic version should be standard of care for all people on PrEP unless otherwise indicated.

This just “makes good sense,” Dr. Krakower, assistant professor of medicine at Harvard Medical School, Boston, told this news organization.

“It’s important to ultimately allow for patients and providers to have access to all of the PrEP options so they can choose the best option for each person,” he said. “But our data suggest that strategies to optimize the cost-effectiveness of PrEP prescribing, such as formulary interventions and education for patients and providers, could be beneficial – as long as there is an easy mechanism for patients and providers to override restrictions when there are clinical indications.”

Current PrEP guidelines from the Centers for Disease Control and Prevention don’t list a first-line or second-line treatment for PrEP. But recent guidance issued to insurance companies by the Biden administration specifically grants insurers permission to employ stepped formularies and cost sharing.

“Since the branded version of PrEP is not specified in the [U.S. Preventive Services Task Force] recommendation, plans and issuers may cover a generic version of PrEP without cost sharing and impose cost sharing on an equivalent branded version,” the rule, issued July 19, states. “However, plans and insurers must accommodate any individual for whom a particular PrEP medication [generic or brand name] would be medically inappropriate, as determined by the individual’s health care provider, by having a mechanism for waiving the otherwise applicable cost-sharing for the brand or nonpreferred brand version.”

Both drugs have been found to be 99% effective in stopping HIV acquisition in people at risk for it. Descovy is approved specifically for gay and bisexual men, transgender women, and anyone having anal sex. Ongoing studies are looking at the effectiveness of Descovy in people having vaginal sex. Generic Truvada has been approved for all people.
 

The biomarkers of switching

To be clear, both medicines are exceedingly safe, said lead author and epidemiologist Julia Marcus, PhD, MPH, associate professor at Harvard Medical School. Side effects have been mild and include nausea and diarrhea in the first month. What lab work tells clinicians is the potential for physiologic changes, but those changes don’t necessarily translate to clinical events.

“When I say harmful, I mean potentially harmful,” she said in an interview. “It’s really based on these incremental changes that maybe, in the long run, could be harmful.”

But she added that there are two types of damage from medicines: “There’s potential physiological damage, but there’s also potential financial damage.” While generic Truvada has a list price as low as $30 a bottle, Descovy has a list price of up to $2,000 a month. And the push for PrEP is growing. Recently, the head of the division of HIV/AIDS at the National Institute of Allergy and Infectious Diseases urged providers to get all their “HIV-negative, at-risk patients on PrEP tomorrow,” in light of the latest HIV vaccine failure.

So Dr. Marcus and team looked at data from the 2892 people who started taking PrEP in the year before the FDA approved Descovy in October 2019. Participants accessed PrEP through Fenway Health, a Boston-area health clinic serving a largely gay, lesbian, bisexual, transgender, and otherwise queer population, and the largest PrEP prescriber in New England. They then tracked which participants switched to Descovy and correlated the switches to lab work and CDC guidance for PrEP.

What they found was that just 11.9% of participants, or 343 people, switched to the newer formulation. That’s lower than the 27.2% who switched in nationally available data, which were released at a recent HIV conference. But when Dr. Krakower and colleagues looked at whether their PrEP prescriptions were appropriate based on the patients’ lab work, the findings were mixed.

On the one hand, they showed that 24 of those 343 people who switched to Descovy had creatinine clearance levels or bone mineral density measurements low enough to make the switch a good option. But that’s just 7% of all people who switched. They then ran a secondary model, in which they broadened the criteria for a switch from strictly those lab values to conditions that might indicate borderline kidney function, which could eventually lead to kidney damage. These included diagnoses of hypertension or diabetes, or borderline creatinine levels between 60 and 70 mL/minute.

“Even when we defined clinical indications as generously as we could, we still saw that only a minority had clinical indications for switching,” said “Most of the switching to TAF/FTC was potentially unnecessary, and some of it may have been harmful for people who had cardiovascular risk factors.”

That’s because although Descovy doesn’t affect renal and bone mineral markers, it does affect cholesterol levels and weight. Aftermarket and FDA data revealed a small but noticeable increase in statin use among people taking the new brand-name PrEP pill. When Marcus and colleagues looked for those biomarkers – total cholesterol greater than200, BMI of 30 or more, LDL cholesterol of more than 160 or HDL cholesterol of less than 40 – 14% of switches fit the criteria for contraindications for Descovy. That’s 10 times the rate of potential harm in switching as there was for those who stayed on the generic Truvada and would have been better served on Descovy. That came in at just 1.4%.

“There may be many reasons why patients or providers might choose to switch that we couldn’t document in our study,” she said. For instance, the newer formulation, Descovy, is a significantly smaller pill than the generic is. Or the perception of novelty might drive some switches.

“But I think we need qualitative work to understand how these decisions are being made,” she said in an interview. “It will be important to follow these patients to see what happens in terms of clinical outcomes.”

For his part, Mr. Froehle found the study intriguing. It reflects his own thinking around the value of the newer formulation. He also prescribes for people living with HIV. For them, the benefit of the new formulation of tenofovir present in Descovy has clear clinical relevance. After all, people living with HIV can be on their drug regimens for decades.

But people on PrEP aren’t likely to be on the pills as long, and so the real benefit of the newer, more expensive formulation is less clear. And he added that he’s already getting “pushback” from some insurance companies on the name-brand version, with companies asking for proof via lab values that a person has a history of kidney impairment or bone mineral density loss.

“It doesn’t happen a ton,” he said. “But it’s starting to happen, and normally it kind of builds from there.”

So when a patient comes in and asks specifically for Descovy, he usually will talk to them about it.

“If it’s what the patient wants and insurance covers it and it’s not unsafe for them to be on it, there might not be a reason to not prescribe Descovy,” said Mr. Froehle, who served as a sub-principal investigator for the DISCOVER clinical trial that showed the new PrEP was as effective as Truvada. “But now with Truvada being generic, we will talk about Truvada as being something we start up front because it may have a lower cost and it’s cheaper to the system. Then we can always switch to Descovy as needed.”

This study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Marcus reported receiving fees from Kaiser Permanente Northern California on a research grant from Gilead Sciences. Dr. Krakower reported having conducted research that was funded by Gilead Sciences and Merck, as well as honoraria for medical education content and presentations for Medscape Medical News, MED-IQ, and DKBMed and royalties from work conducted by UpToDate. Mr. Froehle reported receiving fees from Gilead Sciences in connection with a Gilead advisory board.

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

George Froehle, PA, a primary care clinician at CentraCare in rural St. Cloud, Minn., has been prescribing the HIV prevention pill tenofovir disoproxil fumarate plus emtricitabine since it was marketed by the brand name Truvada and the Food and Drug Administration approved it in 2012. But recently, he’s been having conversations with patients about the new HIV prevention pill, tenofovir alafenamide plus emtricitabine (TAF/FTC, Descovy) as well.

“They may have a friend who has heard that Descovy is newer and safer,” Mr. Froehle said. But that’s not necessarily the case, at least according to lab values. A recent study in the journal Open Forum Infectious Diseases suggests that only between 1 in 10 and 1 in 3 switches to the new formulation of HIV pre-exposure prophylaxis (PrEP) are indicated by lab work – and that nearly half of people receiving a prescription for the new version had lab results actually contraindicating the switch.

This, combined with the lower cost of generic Truvada and the steep cost of Descovy, led study coauthor and HIV PrEP prescriber Douglas Krakower, MD, and colleagues to suggest that the generic version should be standard of care for all people on PrEP unless otherwise indicated.

This just “makes good sense,” Dr. Krakower, assistant professor of medicine at Harvard Medical School, Boston, told this news organization.

“It’s important to ultimately allow for patients and providers to have access to all of the PrEP options so they can choose the best option for each person,” he said. “But our data suggest that strategies to optimize the cost-effectiveness of PrEP prescribing, such as formulary interventions and education for patients and providers, could be beneficial – as long as there is an easy mechanism for patients and providers to override restrictions when there are clinical indications.”

Current PrEP guidelines from the Centers for Disease Control and Prevention don’t list a first-line or second-line treatment for PrEP. But recent guidance issued to insurance companies by the Biden administration specifically grants insurers permission to employ stepped formularies and cost sharing.

“Since the branded version of PrEP is not specified in the [U.S. Preventive Services Task Force] recommendation, plans and issuers may cover a generic version of PrEP without cost sharing and impose cost sharing on an equivalent branded version,” the rule, issued July 19, states. “However, plans and insurers must accommodate any individual for whom a particular PrEP medication [generic or brand name] would be medically inappropriate, as determined by the individual’s health care provider, by having a mechanism for waiving the otherwise applicable cost-sharing for the brand or nonpreferred brand version.”

Both drugs have been found to be 99% effective in stopping HIV acquisition in people at risk for it. Descovy is approved specifically for gay and bisexual men, transgender women, and anyone having anal sex. Ongoing studies are looking at the effectiveness of Descovy in people having vaginal sex. Generic Truvada has been approved for all people.
 

The biomarkers of switching

To be clear, both medicines are exceedingly safe, said lead author and epidemiologist Julia Marcus, PhD, MPH, associate professor at Harvard Medical School. Side effects have been mild and include nausea and diarrhea in the first month. What lab work tells clinicians is the potential for physiologic changes, but those changes don’t necessarily translate to clinical events.

“When I say harmful, I mean potentially harmful,” she said in an interview. “It’s really based on these incremental changes that maybe, in the long run, could be harmful.”

But she added that there are two types of damage from medicines: “There’s potential physiological damage, but there’s also potential financial damage.” While generic Truvada has a list price as low as $30 a bottle, Descovy has a list price of up to $2,000 a month. And the push for PrEP is growing. Recently, the head of the division of HIV/AIDS at the National Institute of Allergy and Infectious Diseases urged providers to get all their “HIV-negative, at-risk patients on PrEP tomorrow,” in light of the latest HIV vaccine failure.

So Dr. Marcus and team looked at data from the 2892 people who started taking PrEP in the year before the FDA approved Descovy in October 2019. Participants accessed PrEP through Fenway Health, a Boston-area health clinic serving a largely gay, lesbian, bisexual, transgender, and otherwise queer population, and the largest PrEP prescriber in New England. They then tracked which participants switched to Descovy and correlated the switches to lab work and CDC guidance for PrEP.

What they found was that just 11.9% of participants, or 343 people, switched to the newer formulation. That’s lower than the 27.2% who switched in nationally available data, which were released at a recent HIV conference. But when Dr. Krakower and colleagues looked at whether their PrEP prescriptions were appropriate based on the patients’ lab work, the findings were mixed.

On the one hand, they showed that 24 of those 343 people who switched to Descovy had creatinine clearance levels or bone mineral density measurements low enough to make the switch a good option. But that’s just 7% of all people who switched. They then ran a secondary model, in which they broadened the criteria for a switch from strictly those lab values to conditions that might indicate borderline kidney function, which could eventually lead to kidney damage. These included diagnoses of hypertension or diabetes, or borderline creatinine levels between 60 and 70 mL/minute.

“Even when we defined clinical indications as generously as we could, we still saw that only a minority had clinical indications for switching,” said “Most of the switching to TAF/FTC was potentially unnecessary, and some of it may have been harmful for people who had cardiovascular risk factors.”

That’s because although Descovy doesn’t affect renal and bone mineral markers, it does affect cholesterol levels and weight. Aftermarket and FDA data revealed a small but noticeable increase in statin use among people taking the new brand-name PrEP pill. When Marcus and colleagues looked for those biomarkers – total cholesterol greater than200, BMI of 30 or more, LDL cholesterol of more than 160 or HDL cholesterol of less than 40 – 14% of switches fit the criteria for contraindications for Descovy. That’s 10 times the rate of potential harm in switching as there was for those who stayed on the generic Truvada and would have been better served on Descovy. That came in at just 1.4%.

“There may be many reasons why patients or providers might choose to switch that we couldn’t document in our study,” she said. For instance, the newer formulation, Descovy, is a significantly smaller pill than the generic is. Or the perception of novelty might drive some switches.

“But I think we need qualitative work to understand how these decisions are being made,” she said in an interview. “It will be important to follow these patients to see what happens in terms of clinical outcomes.”

For his part, Mr. Froehle found the study intriguing. It reflects his own thinking around the value of the newer formulation. He also prescribes for people living with HIV. For them, the benefit of the new formulation of tenofovir present in Descovy has clear clinical relevance. After all, people living with HIV can be on their drug regimens for decades.

But people on PrEP aren’t likely to be on the pills as long, and so the real benefit of the newer, more expensive formulation is less clear. And he added that he’s already getting “pushback” from some insurance companies on the name-brand version, with companies asking for proof via lab values that a person has a history of kidney impairment or bone mineral density loss.

“It doesn’t happen a ton,” he said. “But it’s starting to happen, and normally it kind of builds from there.”

So when a patient comes in and asks specifically for Descovy, he usually will talk to them about it.

“If it’s what the patient wants and insurance covers it and it’s not unsafe for them to be on it, there might not be a reason to not prescribe Descovy,” said Mr. Froehle, who served as a sub-principal investigator for the DISCOVER clinical trial that showed the new PrEP was as effective as Truvada. “But now with Truvada being generic, we will talk about Truvada as being something we start up front because it may have a lower cost and it’s cheaper to the system. Then we can always switch to Descovy as needed.”

This study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Marcus reported receiving fees from Kaiser Permanente Northern California on a research grant from Gilead Sciences. Dr. Krakower reported having conducted research that was funded by Gilead Sciences and Merck, as well as honoraria for medical education content and presentations for Medscape Medical News, MED-IQ, and DKBMed and royalties from work conducted by UpToDate. Mr. Froehle reported receiving fees from Gilead Sciences in connection with a Gilead advisory board.

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

George Froehle, PA, a primary care clinician at CentraCare in rural St. Cloud, Minn., has been prescribing the HIV prevention pill tenofovir disoproxil fumarate plus emtricitabine since it was marketed by the brand name Truvada and the Food and Drug Administration approved it in 2012. But recently, he’s been having conversations with patients about the new HIV prevention pill, tenofovir alafenamide plus emtricitabine (TAF/FTC, Descovy) as well.

“They may have a friend who has heard that Descovy is newer and safer,” Mr. Froehle said. But that’s not necessarily the case, at least according to lab values. A recent study in the journal Open Forum Infectious Diseases suggests that only between 1 in 10 and 1 in 3 switches to the new formulation of HIV pre-exposure prophylaxis (PrEP) are indicated by lab work – and that nearly half of people receiving a prescription for the new version had lab results actually contraindicating the switch.

This, combined with the lower cost of generic Truvada and the steep cost of Descovy, led study coauthor and HIV PrEP prescriber Douglas Krakower, MD, and colleagues to suggest that the generic version should be standard of care for all people on PrEP unless otherwise indicated.

This just “makes good sense,” Dr. Krakower, assistant professor of medicine at Harvard Medical School, Boston, told this news organization.

“It’s important to ultimately allow for patients and providers to have access to all of the PrEP options so they can choose the best option for each person,” he said. “But our data suggest that strategies to optimize the cost-effectiveness of PrEP prescribing, such as formulary interventions and education for patients and providers, could be beneficial – as long as there is an easy mechanism for patients and providers to override restrictions when there are clinical indications.”

Current PrEP guidelines from the Centers for Disease Control and Prevention don’t list a first-line or second-line treatment for PrEP. But recent guidance issued to insurance companies by the Biden administration specifically grants insurers permission to employ stepped formularies and cost sharing.

“Since the branded version of PrEP is not specified in the [U.S. Preventive Services Task Force] recommendation, plans and issuers may cover a generic version of PrEP without cost sharing and impose cost sharing on an equivalent branded version,” the rule, issued July 19, states. “However, plans and insurers must accommodate any individual for whom a particular PrEP medication [generic or brand name] would be medically inappropriate, as determined by the individual’s health care provider, by having a mechanism for waiving the otherwise applicable cost-sharing for the brand or nonpreferred brand version.”

Both drugs have been found to be 99% effective in stopping HIV acquisition in people at risk for it. Descovy is approved specifically for gay and bisexual men, transgender women, and anyone having anal sex. Ongoing studies are looking at the effectiveness of Descovy in people having vaginal sex. Generic Truvada has been approved for all people.
 

The biomarkers of switching

To be clear, both medicines are exceedingly safe, said lead author and epidemiologist Julia Marcus, PhD, MPH, associate professor at Harvard Medical School. Side effects have been mild and include nausea and diarrhea in the first month. What lab work tells clinicians is the potential for physiologic changes, but those changes don’t necessarily translate to clinical events.

“When I say harmful, I mean potentially harmful,” she said in an interview. “It’s really based on these incremental changes that maybe, in the long run, could be harmful.”

But she added that there are two types of damage from medicines: “There’s potential physiological damage, but there’s also potential financial damage.” While generic Truvada has a list price as low as $30 a bottle, Descovy has a list price of up to $2,000 a month. And the push for PrEP is growing. Recently, the head of the division of HIV/AIDS at the National Institute of Allergy and Infectious Diseases urged providers to get all their “HIV-negative, at-risk patients on PrEP tomorrow,” in light of the latest HIV vaccine failure.

So Dr. Marcus and team looked at data from the 2892 people who started taking PrEP in the year before the FDA approved Descovy in October 2019. Participants accessed PrEP through Fenway Health, a Boston-area health clinic serving a largely gay, lesbian, bisexual, transgender, and otherwise queer population, and the largest PrEP prescriber in New England. They then tracked which participants switched to Descovy and correlated the switches to lab work and CDC guidance for PrEP.

What they found was that just 11.9% of participants, or 343 people, switched to the newer formulation. That’s lower than the 27.2% who switched in nationally available data, which were released at a recent HIV conference. But when Dr. Krakower and colleagues looked at whether their PrEP prescriptions were appropriate based on the patients’ lab work, the findings were mixed.

On the one hand, they showed that 24 of those 343 people who switched to Descovy had creatinine clearance levels or bone mineral density measurements low enough to make the switch a good option. But that’s just 7% of all people who switched. They then ran a secondary model, in which they broadened the criteria for a switch from strictly those lab values to conditions that might indicate borderline kidney function, which could eventually lead to kidney damage. These included diagnoses of hypertension or diabetes, or borderline creatinine levels between 60 and 70 mL/minute.

“Even when we defined clinical indications as generously as we could, we still saw that only a minority had clinical indications for switching,” said “Most of the switching to TAF/FTC was potentially unnecessary, and some of it may have been harmful for people who had cardiovascular risk factors.”

That’s because although Descovy doesn’t affect renal and bone mineral markers, it does affect cholesterol levels and weight. Aftermarket and FDA data revealed a small but noticeable increase in statin use among people taking the new brand-name PrEP pill. When Marcus and colleagues looked for those biomarkers – total cholesterol greater than200, BMI of 30 or more, LDL cholesterol of more than 160 or HDL cholesterol of less than 40 – 14% of switches fit the criteria for contraindications for Descovy. That’s 10 times the rate of potential harm in switching as there was for those who stayed on the generic Truvada and would have been better served on Descovy. That came in at just 1.4%.

“There may be many reasons why patients or providers might choose to switch that we couldn’t document in our study,” she said. For instance, the newer formulation, Descovy, is a significantly smaller pill than the generic is. Or the perception of novelty might drive some switches.

“But I think we need qualitative work to understand how these decisions are being made,” she said in an interview. “It will be important to follow these patients to see what happens in terms of clinical outcomes.”

For his part, Mr. Froehle found the study intriguing. It reflects his own thinking around the value of the newer formulation. He also prescribes for people living with HIV. For them, the benefit of the new formulation of tenofovir present in Descovy has clear clinical relevance. After all, people living with HIV can be on their drug regimens for decades.

But people on PrEP aren’t likely to be on the pills as long, and so the real benefit of the newer, more expensive formulation is less clear. And he added that he’s already getting “pushback” from some insurance companies on the name-brand version, with companies asking for proof via lab values that a person has a history of kidney impairment or bone mineral density loss.

“It doesn’t happen a ton,” he said. “But it’s starting to happen, and normally it kind of builds from there.”

So when a patient comes in and asks specifically for Descovy, he usually will talk to them about it.

“If it’s what the patient wants and insurance covers it and it’s not unsafe for them to be on it, there might not be a reason to not prescribe Descovy,” said Mr. Froehle, who served as a sub-principal investigator for the DISCOVER clinical trial that showed the new PrEP was as effective as Truvada. “But now with Truvada being generic, we will talk about Truvada as being something we start up front because it may have a lower cost and it’s cheaper to the system. Then we can always switch to Descovy as needed.”

This study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Marcus reported receiving fees from Kaiser Permanente Northern California on a research grant from Gilead Sciences. Dr. Krakower reported having conducted research that was funded by Gilead Sciences and Merck, as well as honoraria for medical education content and presentations for Medscape Medical News, MED-IQ, and DKBMed and royalties from work conducted by UpToDate. Mr. Froehle reported receiving fees from Gilead Sciences in connection with a Gilead advisory board.

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

Two new cases of a mysterious virus have been reported by the Alaska Department of Health and Social Services. Both people were diagnosed after receiving urgent care in a Fairbanks-area clinic. One was a child with a sore on the left elbow, along with fever and swollen lymph nodes. And the other was an unrelated middle-aged woman with a pox mark on her leg, swollen lymph nodes, and joint pain. In both cases, symptoms improved within 3 weeks.

This isn’t the first time the so-called Alaskapox virus has been detected in the region. In 2015, a woman living near Fairbanks turned up at her doctor’s office with a single reddened pox-like mark on her upper arm and a feeling of fatigue.

Sampling of the pox mark showed that it was caused by a previously unidentified virus of the same family as smallpox and cowpox.

Five years later, another woman showed up with similar signs and symptoms, and her pox also proved to be the result of what public health experts started calling the Alaskapox virus.

In both cases, the women recovered completely.
 

Smallpox-like illness

Public health sleuths figured out that in three of the four cases, the patients lived in a home with a cat or cats, and one of these cats was known to hunt small animals.

Experts already knew that cats mingling in cow pastures and sickened by cattle virus had helped cowpox make the leap from bovines to humans. And just as in the case of cowpox, they suspected that cats might again be spreading this new virus to people, too.

All four of the infected people lived in sparsely populated areas amid forests. Officials laid animal traps where some of the affected people lived and identified the virus in several species of small wild animals.

The animals that turned up most often with Alaskapox were small mouse-like voles. The rodents with rounded muzzles are known for burrowing in the region. And scientists suspect the Alaskapox virus makes its way from these wild animals to humans through their pet cats or possibly by direct exposure outdoors.

None of the four people identified so far with Alaskapox knew each other or interacted, so officials also suspect that there are more cases going unrecognized, possibly because the symptoms are mild or nonexistent.

There are no documented cases of person-to-person transmission of Alaskapox, according to public health officials monitoring the small number of cases. But other pox viruses can spread by direct contact with skin lesions, so clinicians are recommending that people cover wounds with bandages. Three of the people with Alaskapox mistook their lesions at first for a bite from a spider or insect.

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

Two new cases of a mysterious virus have been reported by the Alaska Department of Health and Social Services. Both people were diagnosed after receiving urgent care in a Fairbanks-area clinic. One was a child with a sore on the left elbow, along with fever and swollen lymph nodes. And the other was an unrelated middle-aged woman with a pox mark on her leg, swollen lymph nodes, and joint pain. In both cases, symptoms improved within 3 weeks.

This isn’t the first time the so-called Alaskapox virus has been detected in the region. In 2015, a woman living near Fairbanks turned up at her doctor’s office with a single reddened pox-like mark on her upper arm and a feeling of fatigue.

Sampling of the pox mark showed that it was caused by a previously unidentified virus of the same family as smallpox and cowpox.

Five years later, another woman showed up with similar signs and symptoms, and her pox also proved to be the result of what public health experts started calling the Alaskapox virus.

In both cases, the women recovered completely.
 

Smallpox-like illness

Public health sleuths figured out that in three of the four cases, the patients lived in a home with a cat or cats, and one of these cats was known to hunt small animals.

Experts already knew that cats mingling in cow pastures and sickened by cattle virus had helped cowpox make the leap from bovines to humans. And just as in the case of cowpox, they suspected that cats might again be spreading this new virus to people, too.

All four of the infected people lived in sparsely populated areas amid forests. Officials laid animal traps where some of the affected people lived and identified the virus in several species of small wild animals.

The animals that turned up most often with Alaskapox were small mouse-like voles. The rodents with rounded muzzles are known for burrowing in the region. And scientists suspect the Alaskapox virus makes its way from these wild animals to humans through their pet cats or possibly by direct exposure outdoors.

None of the four people identified so far with Alaskapox knew each other or interacted, so officials also suspect that there are more cases going unrecognized, possibly because the symptoms are mild or nonexistent.

There are no documented cases of person-to-person transmission of Alaskapox, according to public health officials monitoring the small number of cases. But other pox viruses can spread by direct contact with skin lesions, so clinicians are recommending that people cover wounds with bandages. Three of the people with Alaskapox mistook their lesions at first for a bite from a spider or insect.

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

Two new cases of a mysterious virus have been reported by the Alaska Department of Health and Social Services. Both people were diagnosed after receiving urgent care in a Fairbanks-area clinic. One was a child with a sore on the left elbow, along with fever and swollen lymph nodes. And the other was an unrelated middle-aged woman with a pox mark on her leg, swollen lymph nodes, and joint pain. In both cases, symptoms improved within 3 weeks.

This isn’t the first time the so-called Alaskapox virus has been detected in the region. In 2015, a woman living near Fairbanks turned up at her doctor’s office with a single reddened pox-like mark on her upper arm and a feeling of fatigue.

Sampling of the pox mark showed that it was caused by a previously unidentified virus of the same family as smallpox and cowpox.

Five years later, another woman showed up with similar signs and symptoms, and her pox also proved to be the result of what public health experts started calling the Alaskapox virus.

In both cases, the women recovered completely.
 

Smallpox-like illness

Public health sleuths figured out that in three of the four cases, the patients lived in a home with a cat or cats, and one of these cats was known to hunt small animals.

Experts already knew that cats mingling in cow pastures and sickened by cattle virus had helped cowpox make the leap from bovines to humans. And just as in the case of cowpox, they suspected that cats might again be spreading this new virus to people, too.

All four of the infected people lived in sparsely populated areas amid forests. Officials laid animal traps where some of the affected people lived and identified the virus in several species of small wild animals.

The animals that turned up most often with Alaskapox were small mouse-like voles. The rodents with rounded muzzles are known for burrowing in the region. And scientists suspect the Alaskapox virus makes its way from these wild animals to humans through their pet cats or possibly by direct exposure outdoors.

None of the four people identified so far with Alaskapox knew each other or interacted, so officials also suspect that there are more cases going unrecognized, possibly because the symptoms are mild or nonexistent.

There are no documented cases of person-to-person transmission of Alaskapox, according to public health officials monitoring the small number of cases. But other pox viruses can spread by direct contact with skin lesions, so clinicians are recommending that people cover wounds with bandages. Three of the people with Alaskapox mistook their lesions at first for a bite from a spider or insect.

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

New evidence suggests a drug used to lower blood sugar levels may also help extend the duration of preterm pregnancies in women with preeclampsia.

The findings from a small clinical trial, published Sept. 23 in the BMJ, showed that pregnant women who received the diabetes medication metformin prolonged their pregnancy by a week compared to those who received a placebo. Although this finding was not statistically significant, researchers said they are “cautiously optimistic” about the treatment of preterm preeclampsia.

“We hope that it will encourage others to test not only metformin but also other promising therapeutic candidates to treat and prevent preeclampsia,” study author Catherine Cluver, MBChB, FCOG, PhD, associate professor in the department of obstetrics and gynecology at Stellenbosch University in South Africa, said in an interview.

Preeclampsia, a condition that occurs about 1 in 25 pregnancies in the United States, happens when a woman develops high blood pressure and protein in her urine, according to the Centers for Disease Control and Prevention.

Preterm preeclampsia is a severe variant affecting 0.5% of all pregnancies, or 10% of those with preeclampsia, researchers wrote in the study. The condition is associated with more maternal and neonatal death and increases their risks of developing an illness.

Dr. Cluver said that when a mother develops preeclampsia, the lining of her blood vessels, or the endothelium, is affected and there are specific proteins in the blood that increase. Dr. Cluver’s preclinical study found that metformin improved endothelial function and decreased these biomarkers in laboratory work.

“We therefore set out to see if metformin could be used to prolong gestation in preterm preeclampsia,” she said.

For the study, Dr. Cluver and colleagues performed a double-blind, placebo-controlled clinical trial to compare the prolongation of pregnancies among women who were at least 26 months pregnant with preterm preeclampsia. They were treated with either 3 grams of extended-release metformin (90 women), or a matching placebo (90 women).*

In the treatment group, the average time from the start of the study to delivery was 17.7 days, compared to 10.1 days in the placebo group. The median difference was 7.6 days.

The researchers also found that 40% of women in the metformin group reached 34 weeks’ gestation compared with 28% of those in the placebo group. Fewer women in the metformin group delivered because of fetal indications such as fetal distress or other issues – 33% vs. 44%. However, the researchers said those results were not statistically significant.

They said they were cautiously optimistic when they found that the median time for prolongation of pregnancy in the metformin group was 17.5 days compared with 7.9 days in the placebo group, findings that were statistically significant.

Some adverse effects participants experienced while taking metformin during their pregnancy included diarrhea and an increase in nausea.

Although the study is important in maternal-fetal medicine and is a novel approach to preterm preeclampsia, the findings weren’t strong enough, but they point to the need for further study, said Victor Klein, MD, MBA, CPHRM, a specialist in high-risk pregnancy who was not involved in the study.

“Even though they did have an improved outcome, it wasn’t strong enough. It wasn’t long enough to prove that the medicine was useful or efficacious,” said Dr. Klein, vice chairman of obstetrics and gynecology at North Shore University Hospital, New York.

Metformin is also used to treat gestational diabetes, which is an “advantage of repurposing the drug is that it is likely to be safe,” the researchers wrote. They said longer term follow-up data might be worthwhile in future trials.

None of the experts had conflicts of interest to disclose.

*This story was updated on 10/6/2021.

New evidence suggests a drug used to lower blood sugar levels may also help extend the duration of preterm pregnancies in women with preeclampsia.

The findings from a small clinical trial, published Sept. 23 in the BMJ, showed that pregnant women who received the diabetes medication metformin prolonged their pregnancy by a week compared to those who received a placebo. Although this finding was not statistically significant, researchers said they are “cautiously optimistic” about the treatment of preterm preeclampsia.

“We hope that it will encourage others to test not only metformin but also other promising therapeutic candidates to treat and prevent preeclampsia,” study author Catherine Cluver, MBChB, FCOG, PhD, associate professor in the department of obstetrics and gynecology at Stellenbosch University in South Africa, said in an interview.

Preeclampsia, a condition that occurs about 1 in 25 pregnancies in the United States, happens when a woman develops high blood pressure and protein in her urine, according to the Centers for Disease Control and Prevention.

Preterm preeclampsia is a severe variant affecting 0.5% of all pregnancies, or 10% of those with preeclampsia, researchers wrote in the study. The condition is associated with more maternal and neonatal death and increases their risks of developing an illness.

Dr. Cluver said that when a mother develops preeclampsia, the lining of her blood vessels, or the endothelium, is affected and there are specific proteins in the blood that increase. Dr. Cluver’s preclinical study found that metformin improved endothelial function and decreased these biomarkers in laboratory work.

“We therefore set out to see if metformin could be used to prolong gestation in preterm preeclampsia,” she said.

For the study, Dr. Cluver and colleagues performed a double-blind, placebo-controlled clinical trial to compare the prolongation of pregnancies among women who were at least 26 months pregnant with preterm preeclampsia. They were treated with either 3 grams of extended-release metformin (90 women), or a matching placebo (90 women).*

In the treatment group, the average time from the start of the study to delivery was 17.7 days, compared to 10.1 days in the placebo group. The median difference was 7.6 days.

The researchers also found that 40% of women in the metformin group reached 34 weeks’ gestation compared with 28% of those in the placebo group. Fewer women in the metformin group delivered because of fetal indications such as fetal distress or other issues – 33% vs. 44%. However, the researchers said those results were not statistically significant.

They said they were cautiously optimistic when they found that the median time for prolongation of pregnancy in the metformin group was 17.5 days compared with 7.9 days in the placebo group, findings that were statistically significant.

Some adverse effects participants experienced while taking metformin during their pregnancy included diarrhea and an increase in nausea.

Although the study is important in maternal-fetal medicine and is a novel approach to preterm preeclampsia, the findings weren’t strong enough, but they point to the need for further study, said Victor Klein, MD, MBA, CPHRM, a specialist in high-risk pregnancy who was not involved in the study.

“Even though they did have an improved outcome, it wasn’t strong enough. It wasn’t long enough to prove that the medicine was useful or efficacious,” said Dr. Klein, vice chairman of obstetrics and gynecology at North Shore University Hospital, New York.

Metformin is also used to treat gestational diabetes, which is an “advantage of repurposing the drug is that it is likely to be safe,” the researchers wrote. They said longer term follow-up data might be worthwhile in future trials.

None of the experts had conflicts of interest to disclose.

*This story was updated on 10/6/2021.

New evidence suggests a drug used to lower blood sugar levels may also help extend the duration of preterm pregnancies in women with preeclampsia.

The findings from a small clinical trial, published Sept. 23 in the BMJ, showed that pregnant women who received the diabetes medication metformin prolonged their pregnancy by a week compared to those who received a placebo. Although this finding was not statistically significant, researchers said they are “cautiously optimistic” about the treatment of preterm preeclampsia.

“We hope that it will encourage others to test not only metformin but also other promising therapeutic candidates to treat and prevent preeclampsia,” study author Catherine Cluver, MBChB, FCOG, PhD, associate professor in the department of obstetrics and gynecology at Stellenbosch University in South Africa, said in an interview.

Preeclampsia, a condition that occurs about 1 in 25 pregnancies in the United States, happens when a woman develops high blood pressure and protein in her urine, according to the Centers for Disease Control and Prevention.

Preterm preeclampsia is a severe variant affecting 0.5% of all pregnancies, or 10% of those with preeclampsia, researchers wrote in the study. The condition is associated with more maternal and neonatal death and increases their risks of developing an illness.

Dr. Cluver said that when a mother develops preeclampsia, the lining of her blood vessels, or the endothelium, is affected and there are specific proteins in the blood that increase. Dr. Cluver’s preclinical study found that metformin improved endothelial function and decreased these biomarkers in laboratory work.

“We therefore set out to see if metformin could be used to prolong gestation in preterm preeclampsia,” she said.

For the study, Dr. Cluver and colleagues performed a double-blind, placebo-controlled clinical trial to compare the prolongation of pregnancies among women who were at least 26 months pregnant with preterm preeclampsia. They were treated with either 3 grams of extended-release metformin (90 women), or a matching placebo (90 women).*

In the treatment group, the average time from the start of the study to delivery was 17.7 days, compared to 10.1 days in the placebo group. The median difference was 7.6 days.

The researchers also found that 40% of women in the metformin group reached 34 weeks’ gestation compared with 28% of those in the placebo group. Fewer women in the metformin group delivered because of fetal indications such as fetal distress or other issues – 33% vs. 44%. However, the researchers said those results were not statistically significant.

They said they were cautiously optimistic when they found that the median time for prolongation of pregnancy in the metformin group was 17.5 days compared with 7.9 days in the placebo group, findings that were statistically significant.

Some adverse effects participants experienced while taking metformin during their pregnancy included diarrhea and an increase in nausea.

Although the study is important in maternal-fetal medicine and is a novel approach to preterm preeclampsia, the findings weren’t strong enough, but they point to the need for further study, said Victor Klein, MD, MBA, CPHRM, a specialist in high-risk pregnancy who was not involved in the study.

“Even though they did have an improved outcome, it wasn’t strong enough. It wasn’t long enough to prove that the medicine was useful or efficacious,” said Dr. Klein, vice chairman of obstetrics and gynecology at North Shore University Hospital, New York.

Metformin is also used to treat gestational diabetes, which is an “advantage of repurposing the drug is that it is likely to be safe,” the researchers wrote. They said longer term follow-up data might be worthwhile in future trials.

None of the experts had conflicts of interest to disclose.

*This story was updated on 10/6/2021.

Although Guillain-Barré syndrome may rarely follow a recent infection with SARS-CoV-2, a strong relationship of GBS with the novel coronavirus is unlikely, say researchers with the International GBS Outcome Study (IGOS) consortium.

“Our study shows that COVID-19 may precede Guillain-Barré syndrome in rare cases, but the existence of a true association or causal relation still needs to be established,” Bart Jacobs, MD, PhD, department of neurology and immunology, Erasmus Medical Center and University Medical Center, both in Rotterdam, the Netherlands, said in a statement.

The study was published online in the journal Brain.
 

No uptick in pandemic cases

Since the beginning of the pandemic, there are reports of more than 90 GBS diagnoses following a possible COVID-19 infection. However, it remains unclear whether COVID-19 is another potential infectious trigger or whether the reported cases are coincidental.

To investigate further, Dr. Jacobs and the IGOS consortium reviewed 49 patients (median age, 56 years) with GBS who were added to their ongoing prospective observational cohort study between Jan. 30 and May 30, 2020.

The patients came from China, Denmark, France, Greece, Italy, Japan, the Netherlands, Spain, Switzerland, and the United Kingdom.

Of the 49 GBS patients, 8 (16%) had a confirmed and 3 (6%) had a probable SARS-CoV-2 infection; 15 had possible SARS-CoV-2 infection, 21 had no suspicion of SARS-CoV-2 infection, and 2 were “unclassifiable.”

Of the 11 patients with confirmed/probable SARS-CoV-2 infection, 9 had no serological evidence of any other recent preceding infection known to be associated with GBS.

The other two had serological evidence of a recent Campylobacter jejuni infection, which could have played a role in GBS onset, the researchers noted.

Most patients with a confirmed/probable SARS-CoV-2 infection had a sensorimotor GBS variant (73%), although Miller Fisher syndrome–GBS overlap (18%) and an ataxic variant (9%) were also found.

All patients with a confirmed/probable SARS-CoV-2 infection had a severe form of GBS. Common early neurologic features were facial weakness (64%), sensory deficits (82%), and autonomic dysfunction (64%), although not significantly different, compared with the other patients.

All eight patients who underwent nerve conduction study had a demyelinating subtype, which was more frequent than in the other GBS patients (47%; P = .012) as well as historical region and age-matched controls included in the IGOS cohort before the pandemic (52%, P = .016).

The median time from the onset of SARS-CoV-2 infection to neurologic symptoms was 16 days and ranged from 12 to 22 days. 
 

More research needed

The researchers noted that the 22% frequency of a preceding SARS-CoV-2 infection in this study population was “higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection.”

Importantly, however, they did not find more patients diagnosed with GBS during the first 4 months of the pandemic, compared with previous years, “suggesting that a strong association between SARS-CoV-2 and GBS is unlikely.”

“Should SARS-CoV-2 indeed be able to trigger GBS, our data are consistent with a postinfectious disease mechanism rather than direct viral invasion,” they noted, adding that the study was not designed to quantify a causative link between GBS and SARS-CoV-2. 

“An unbiased multicenter, international, case-control study is needed to determine whether there is an association or not,” they wrote.

The IGOS is financially supported by the GBS-CIDP Foundation International, Gain, Erasmus MC University Medical Center Rotterdam, Glasgow University, CSL Behring, Grifols, Annexon and Hansa Biopharma. Dr. Jacobs received grants from Grifols, CSL-Behring, Annexon, Prinses Beatrix Spierfonds, Hansa Biopharma, and GBS-CIDP Foundation International and is on the global medical advisory board of the GBS CIDP Foundation International.

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

Although Guillain-Barré syndrome may rarely follow a recent infection with SARS-CoV-2, a strong relationship of GBS with the novel coronavirus is unlikely, say researchers with the International GBS Outcome Study (IGOS) consortium.

“Our study shows that COVID-19 may precede Guillain-Barré syndrome in rare cases, but the existence of a true association or causal relation still needs to be established,” Bart Jacobs, MD, PhD, department of neurology and immunology, Erasmus Medical Center and University Medical Center, both in Rotterdam, the Netherlands, said in a statement.

The study was published online in the journal Brain.
 

No uptick in pandemic cases

Since the beginning of the pandemic, there are reports of more than 90 GBS diagnoses following a possible COVID-19 infection. However, it remains unclear whether COVID-19 is another potential infectious trigger or whether the reported cases are coincidental.

To investigate further, Dr. Jacobs and the IGOS consortium reviewed 49 patients (median age, 56 years) with GBS who were added to their ongoing prospective observational cohort study between Jan. 30 and May 30, 2020.

The patients came from China, Denmark, France, Greece, Italy, Japan, the Netherlands, Spain, Switzerland, and the United Kingdom.

Of the 49 GBS patients, 8 (16%) had a confirmed and 3 (6%) had a probable SARS-CoV-2 infection; 15 had possible SARS-CoV-2 infection, 21 had no suspicion of SARS-CoV-2 infection, and 2 were “unclassifiable.”

Of the 11 patients with confirmed/probable SARS-CoV-2 infection, 9 had no serological evidence of any other recent preceding infection known to be associated with GBS.

The other two had serological evidence of a recent Campylobacter jejuni infection, which could have played a role in GBS onset, the researchers noted.

Most patients with a confirmed/probable SARS-CoV-2 infection had a sensorimotor GBS variant (73%), although Miller Fisher syndrome–GBS overlap (18%) and an ataxic variant (9%) were also found.

All patients with a confirmed/probable SARS-CoV-2 infection had a severe form of GBS. Common early neurologic features were facial weakness (64%), sensory deficits (82%), and autonomic dysfunction (64%), although not significantly different, compared with the other patients.

All eight patients who underwent nerve conduction study had a demyelinating subtype, which was more frequent than in the other GBS patients (47%; P = .012) as well as historical region and age-matched controls included in the IGOS cohort before the pandemic (52%, P = .016).

The median time from the onset of SARS-CoV-2 infection to neurologic symptoms was 16 days and ranged from 12 to 22 days. 
 

More research needed

The researchers noted that the 22% frequency of a preceding SARS-CoV-2 infection in this study population was “higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection.”

Importantly, however, they did not find more patients diagnosed with GBS during the first 4 months of the pandemic, compared with previous years, “suggesting that a strong association between SARS-CoV-2 and GBS is unlikely.”

“Should SARS-CoV-2 indeed be able to trigger GBS, our data are consistent with a postinfectious disease mechanism rather than direct viral invasion,” they noted, adding that the study was not designed to quantify a causative link between GBS and SARS-CoV-2. 

“An unbiased multicenter, international, case-control study is needed to determine whether there is an association or not,” they wrote.

The IGOS is financially supported by the GBS-CIDP Foundation International, Gain, Erasmus MC University Medical Center Rotterdam, Glasgow University, CSL Behring, Grifols, Annexon and Hansa Biopharma. Dr. Jacobs received grants from Grifols, CSL-Behring, Annexon, Prinses Beatrix Spierfonds, Hansa Biopharma, and GBS-CIDP Foundation International and is on the global medical advisory board of the GBS CIDP Foundation International.

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

Although Guillain-Barré syndrome may rarely follow a recent infection with SARS-CoV-2, a strong relationship of GBS with the novel coronavirus is unlikely, say researchers with the International GBS Outcome Study (IGOS) consortium.

“Our study shows that COVID-19 may precede Guillain-Barré syndrome in rare cases, but the existence of a true association or causal relation still needs to be established,” Bart Jacobs, MD, PhD, department of neurology and immunology, Erasmus Medical Center and University Medical Center, both in Rotterdam, the Netherlands, said in a statement.

The study was published online in the journal Brain.
 

No uptick in pandemic cases

Since the beginning of the pandemic, there are reports of more than 90 GBS diagnoses following a possible COVID-19 infection. However, it remains unclear whether COVID-19 is another potential infectious trigger or whether the reported cases are coincidental.

To investigate further, Dr. Jacobs and the IGOS consortium reviewed 49 patients (median age, 56 years) with GBS who were added to their ongoing prospective observational cohort study between Jan. 30 and May 30, 2020.

The patients came from China, Denmark, France, Greece, Italy, Japan, the Netherlands, Spain, Switzerland, and the United Kingdom.

Of the 49 GBS patients, 8 (16%) had a confirmed and 3 (6%) had a probable SARS-CoV-2 infection; 15 had possible SARS-CoV-2 infection, 21 had no suspicion of SARS-CoV-2 infection, and 2 were “unclassifiable.”

Of the 11 patients with confirmed/probable SARS-CoV-2 infection, 9 had no serological evidence of any other recent preceding infection known to be associated with GBS.

The other two had serological evidence of a recent Campylobacter jejuni infection, which could have played a role in GBS onset, the researchers noted.

Most patients with a confirmed/probable SARS-CoV-2 infection had a sensorimotor GBS variant (73%), although Miller Fisher syndrome–GBS overlap (18%) and an ataxic variant (9%) were also found.

All patients with a confirmed/probable SARS-CoV-2 infection had a severe form of GBS. Common early neurologic features were facial weakness (64%), sensory deficits (82%), and autonomic dysfunction (64%), although not significantly different, compared with the other patients.

All eight patients who underwent nerve conduction study had a demyelinating subtype, which was more frequent than in the other GBS patients (47%; P = .012) as well as historical region and age-matched controls included in the IGOS cohort before the pandemic (52%, P = .016).

The median time from the onset of SARS-CoV-2 infection to neurologic symptoms was 16 days and ranged from 12 to 22 days. 
 

More research needed

The researchers noted that the 22% frequency of a preceding SARS-CoV-2 infection in this study population was “higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection.”

Importantly, however, they did not find more patients diagnosed with GBS during the first 4 months of the pandemic, compared with previous years, “suggesting that a strong association between SARS-CoV-2 and GBS is unlikely.”

“Should SARS-CoV-2 indeed be able to trigger GBS, our data are consistent with a postinfectious disease mechanism rather than direct viral invasion,” they noted, adding that the study was not designed to quantify a causative link between GBS and SARS-CoV-2. 

“An unbiased multicenter, international, case-control study is needed to determine whether there is an association or not,” they wrote.

The IGOS is financially supported by the GBS-CIDP Foundation International, Gain, Erasmus MC University Medical Center Rotterdam, Glasgow University, CSL Behring, Grifols, Annexon and Hansa Biopharma. Dr. Jacobs received grants from Grifols, CSL-Behring, Annexon, Prinses Beatrix Spierfonds, Hansa Biopharma, and GBS-CIDP Foundation International and is on the global medical advisory board of the GBS CIDP Foundation International.

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

Combination bevacizumab and osimertinib provided no progression-free survival benefit over osimertinib alone for the first-line treatment of advanced epidermal growth factor receptor (EGFR)–mutated nonsquamous non–small cell lung cancer (NSCLC) in patients in an open-label, phase 2 study.

Median progression-free survival (PFS) was 20.2 months in 61 patients in the osimertinib monotherapy arm and 22.1 months in 61 patients in the combination treatment arm (hazard ratio, 0.862), Hirotsugu Kenmotsu, MD, PhD, reported at the 2021 Congress of the European Society for Medical Oncology Sept. 18 (abstract LBA44).

“The study did not meet the primary endpoint,” said Dr. Kenmotsu of Shizuoka Cancer Center, Nagaizumi, Japan. “One-year progression-free survival was 63.7% and 73.8%, respectively.

However, subgroup analyses showed a trend toward improved PFS with combination bevacizumab and osimertinib in ever-smokers (HR, 0.481) and patients with Del19 mutations (HR, 0.622), he said.

Bevacizumab was also associated with a significant reduction in the risk of pneumonitis, an interstitial lung disease (ILD): Pneumonitis occurred in 18.3% of patients in the combination therapy arm, compared with 3.3% in the osimertinib monotherapy arm.

Study participants were untreated patients with advanced nonsquamous NSCLC harboring an EGFR-sensitizing mutation – either Del19 or L858R – without symptomatic brain metastases. They were enrolled between January 2018 and September 2018 and randomized to receive 80 mg of osimertinib daily, either alone or with 15 mg/kg of bevacizumab every 3 weeks.

The objective response rate was 82% in the combination therapy arm and 86% in osimertinib monotherapy arm, Dr. Kenmotsu said, adding that overall survival data are not yet mature.

Grade 3-4 adverse events occurred in 34 patients (56%) in the combination therapy arm and in 29 patients (48%) in the osimertinib monotherapy arm, he noted.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has been a standard first-line treatment for NSCLC harboring activating EGFR mutations, he explained, noting that prior studies have shown promise for improved PFS with the addition of antivascular endothelial growth factor inhibitors to first-generation EGFR TKIs in this population.

Although the current study failed to show efficacy of the combination therapy versus osimertinib monotherapy for improving PFS in nonsquamous NSCLC harboring EGFR mutation, ever-smokers and patients with exon 19 deletions might benefit from the combination therapy as first-line treatment, and the combination might also reduce the risk of osimertinib-related pneumonitis, Dr. Kenmotsu said.

The study is among those that address “really important questions in lung cancer today,” said invited discussant Natasha B. Leighl, MD, professor of medicine at the University of Toronto’s Princess Margaret Cancer Center.

“I certainly agree with the authors that this study is a negative trial and bevacizumab does not improve PFS over the standard of osimertinib alone,” she said, acknowledging that the study is the first randomized comparison of the two treatment approaches in the first-line setting. She also agreed with the authors that the subgroup findings are intriguing.

“But ... what is the biomarker?” she asked, referring to the “very interesting” finding of a possible bevacizumab benefit among ever-smokers. “I’m looking forward to more correlative studies to help define this further.”

The novel finding of a significantly reduced risk of pneumonitis with the addition of bevacizumab, on the other hand, is “extremely exciting,” she said, explaining that the combination therapy approach could “perhaps [be used] as a potential therapy for patients with TKI-induced ILD and no other options, or those at very high risk of ILD, for example, perhaps, post immunotherapy or in high-risk populations.”

This study was funded by AstraZeneca. Dr. Kenmotsu and Dr. Leigh each disclosed financial relationships with numerous pharmaceutical companies.

This article was updated Sept. 24, 2021.

[email protected]

Combination bevacizumab and osimertinib provided no progression-free survival benefit over osimertinib alone for the first-line treatment of advanced epidermal growth factor receptor (EGFR)–mutated nonsquamous non–small cell lung cancer (NSCLC) in patients in an open-label, phase 2 study.

Median progression-free survival (PFS) was 20.2 months in 61 patients in the osimertinib monotherapy arm and 22.1 months in 61 patients in the combination treatment arm (hazard ratio, 0.862), Hirotsugu Kenmotsu, MD, PhD, reported at the 2021 Congress of the European Society for Medical Oncology Sept. 18 (abstract LBA44).

“The study did not meet the primary endpoint,” said Dr. Kenmotsu of Shizuoka Cancer Center, Nagaizumi, Japan. “One-year progression-free survival was 63.7% and 73.8%, respectively.

However, subgroup analyses showed a trend toward improved PFS with combination bevacizumab and osimertinib in ever-smokers (HR, 0.481) and patients with Del19 mutations (HR, 0.622), he said.

Bevacizumab was also associated with a significant reduction in the risk of pneumonitis, an interstitial lung disease (ILD): Pneumonitis occurred in 18.3% of patients in the combination therapy arm, compared with 3.3% in the osimertinib monotherapy arm.

Study participants were untreated patients with advanced nonsquamous NSCLC harboring an EGFR-sensitizing mutation – either Del19 or L858R – without symptomatic brain metastases. They were enrolled between January 2018 and September 2018 and randomized to receive 80 mg of osimertinib daily, either alone or with 15 mg/kg of bevacizumab every 3 weeks.

The objective response rate was 82% in the combination therapy arm and 86% in osimertinib monotherapy arm, Dr. Kenmotsu said, adding that overall survival data are not yet mature.

Grade 3-4 adverse events occurred in 34 patients (56%) in the combination therapy arm and in 29 patients (48%) in the osimertinib monotherapy arm, he noted.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has been a standard first-line treatment for NSCLC harboring activating EGFR mutations, he explained, noting that prior studies have shown promise for improved PFS with the addition of antivascular endothelial growth factor inhibitors to first-generation EGFR TKIs in this population.

Although the current study failed to show efficacy of the combination therapy versus osimertinib monotherapy for improving PFS in nonsquamous NSCLC harboring EGFR mutation, ever-smokers and patients with exon 19 deletions might benefit from the combination therapy as first-line treatment, and the combination might also reduce the risk of osimertinib-related pneumonitis, Dr. Kenmotsu said.

The study is among those that address “really important questions in lung cancer today,” said invited discussant Natasha B. Leighl, MD, professor of medicine at the University of Toronto’s Princess Margaret Cancer Center.

“I certainly agree with the authors that this study is a negative trial and bevacizumab does not improve PFS over the standard of osimertinib alone,” she said, acknowledging that the study is the first randomized comparison of the two treatment approaches in the first-line setting. She also agreed with the authors that the subgroup findings are intriguing.

“But ... what is the biomarker?” she asked, referring to the “very interesting” finding of a possible bevacizumab benefit among ever-smokers. “I’m looking forward to more correlative studies to help define this further.”

The novel finding of a significantly reduced risk of pneumonitis with the addition of bevacizumab, on the other hand, is “extremely exciting,” she said, explaining that the combination therapy approach could “perhaps [be used] as a potential therapy for patients with TKI-induced ILD and no other options, or those at very high risk of ILD, for example, perhaps, post immunotherapy or in high-risk populations.”

This study was funded by AstraZeneca. Dr. Kenmotsu and Dr. Leigh each disclosed financial relationships with numerous pharmaceutical companies.

This article was updated Sept. 24, 2021.

[email protected]

Combination bevacizumab and osimertinib provided no progression-free survival benefit over osimertinib alone for the first-line treatment of advanced epidermal growth factor receptor (EGFR)–mutated nonsquamous non–small cell lung cancer (NSCLC) in patients in an open-label, phase 2 study.

Median progression-free survival (PFS) was 20.2 months in 61 patients in the osimertinib monotherapy arm and 22.1 months in 61 patients in the combination treatment arm (hazard ratio, 0.862), Hirotsugu Kenmotsu, MD, PhD, reported at the 2021 Congress of the European Society for Medical Oncology Sept. 18 (abstract LBA44).

“The study did not meet the primary endpoint,” said Dr. Kenmotsu of Shizuoka Cancer Center, Nagaizumi, Japan. “One-year progression-free survival was 63.7% and 73.8%, respectively.

However, subgroup analyses showed a trend toward improved PFS with combination bevacizumab and osimertinib in ever-smokers (HR, 0.481) and patients with Del19 mutations (HR, 0.622), he said.

Bevacizumab was also associated with a significant reduction in the risk of pneumonitis, an interstitial lung disease (ILD): Pneumonitis occurred in 18.3% of patients in the combination therapy arm, compared with 3.3% in the osimertinib monotherapy arm.

Study participants were untreated patients with advanced nonsquamous NSCLC harboring an EGFR-sensitizing mutation – either Del19 or L858R – without symptomatic brain metastases. They were enrolled between January 2018 and September 2018 and randomized to receive 80 mg of osimertinib daily, either alone or with 15 mg/kg of bevacizumab every 3 weeks.

The objective response rate was 82% in the combination therapy arm and 86% in osimertinib monotherapy arm, Dr. Kenmotsu said, adding that overall survival data are not yet mature.

Grade 3-4 adverse events occurred in 34 patients (56%) in the combination therapy arm and in 29 patients (48%) in the osimertinib monotherapy arm, he noted.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has been a standard first-line treatment for NSCLC harboring activating EGFR mutations, he explained, noting that prior studies have shown promise for improved PFS with the addition of antivascular endothelial growth factor inhibitors to first-generation EGFR TKIs in this population.

Although the current study failed to show efficacy of the combination therapy versus osimertinib monotherapy for improving PFS in nonsquamous NSCLC harboring EGFR mutation, ever-smokers and patients with exon 19 deletions might benefit from the combination therapy as first-line treatment, and the combination might also reduce the risk of osimertinib-related pneumonitis, Dr. Kenmotsu said.

The study is among those that address “really important questions in lung cancer today,” said invited discussant Natasha B. Leighl, MD, professor of medicine at the University of Toronto’s Princess Margaret Cancer Center.

“I certainly agree with the authors that this study is a negative trial and bevacizumab does not improve PFS over the standard of osimertinib alone,” she said, acknowledging that the study is the first randomized comparison of the two treatment approaches in the first-line setting. She also agreed with the authors that the subgroup findings are intriguing.

“But ... what is the biomarker?” she asked, referring to the “very interesting” finding of a possible bevacizumab benefit among ever-smokers. “I’m looking forward to more correlative studies to help define this further.”

The novel finding of a significantly reduced risk of pneumonitis with the addition of bevacizumab, on the other hand, is “extremely exciting,” she said, explaining that the combination therapy approach could “perhaps [be used] as a potential therapy for patients with TKI-induced ILD and no other options, or those at very high risk of ILD, for example, perhaps, post immunotherapy or in high-risk populations.”

This study was funded by AstraZeneca. Dr. Kenmotsu and Dr. Leigh each disclosed financial relationships with numerous pharmaceutical companies.

This article was updated Sept. 24, 2021.

[email protected]

The combination of nivolumab (Opdivo, Bristol Myers Squibb) and rucaparib (Rubraca, Clovis Oncology) demonstrated noteworthy activity among patients with metastatic prostate cancer harboring BRCA mutations, according to new research presented Sept. 18 (abstract 579MO) at the European Society for Medical Oncology Congress 2021.

The findings were specific to patients not yet been treated with chemotherapy and whose tumors were positive for homologous recombination deficiency (HRD). However, for patients whose tumors were negative for HRD, the clinical activity was limited, said Daniel P. Petrylak, MD, Yale University, New Haven, Conn., and lead investigator for the study called CheckMate 9KD (NCT03338790) .

The patients who were included in all CheckMate 9KD cohorts had no prior treatment with targeted T-cell co-stimulation or immune checkpoint pathways. They had metastatic castrate resistant prostate cancer with documented disease progression, ECOG performance status of 0-1, and tissue available for HRD testing.

Dr. Petrylak offered an updated analysis of cohort A2 with 71 patients (median age 73 years), all of whom had received 1-2 prior new hormonal therapies in the pre-chemotherapy setting. Patients who had received prior PARP inhibitors were ineligible, as were those who refused chemotherapy treatment.
 

ORR/PSA RR primary endpoints

Patients received nivolumab and rucaparib, nivolumab at 480 mg (q4 weeks up to 2 years) and rucaparib at 600 mg b.i.d., until disease progression or unacceptable toxicity. Objective response rate and PSA response rate (PSA-RR) were the primary endpoint, with overall survival as a secondary endpoint, along with time to objective response, duration of objective response, time to PSA progression, safety, and radiographic progression-free survival.

Median follow-up was 17.5 months with median treatment duration of 4.6 months in the nivolumab group and 5.5 months for rucaparib. At the time of the final database lock in March 2021, 65 patients (91.5%) had discontinued treatment, most often for disease progression (n = 43; 60.6%) or study drug toxicity (n = 8; 11.3%). Four patients (5.6%) remained on treatment.
 

Better responses for HRD and BRCA 1/2 positive

Stratifying response outcomes showed higher rates for patients who were HRD positive and BRCA1/2 positive for confirmed objective response rate (HRD+ 25.0%, BRCA 1/2+ 33.3%, HRD-/not evaluable 5.3%, all patients 15.4%) and for PSA response (HRD+ 41.9%, BRCA 1/2+ 84.6%, HRD-/not evaluable 14.3%, all patients 27.3%). Partial response rates were 33.3% for BRCA 1/2, 25.0% for HRD positive, 5.3% for HRD- and 15.4% for all patients. Radiographic progression-free survival was longer in the HRD positive group at a median of 10.9 months (95% CI 6.7-12.0), compared with 5.6 months (3.7-9.1) in the HRD-/not evaluable group. Overall survival was similar in the HRD negative group/not evaluable group at 19.0 months (8.2-22.1) and the HRD positive group at 22.7 months (14.1-NE).

Safety profile as expected

Treatment-related adverse events were reported for most patients (64/71, 90.1%), with grade 3-4 events in about half (50.7%). The most common event was grade 1-2 nausea (40.8%), with anemia at 32.4% and alanine aminotransferase (ALT) increases and fatigue both at 28.2%. Adverse events led to discontinuation in 23.9% of patients, with anemia and increased ALT leading both at 4.2%. Grade 3-4 adverse events led to discontinuation in 15.5% of patients. Investigators reported no treatment-related deaths. “The safety profile of nivolumab plus rucaparib was as expected based on the individual components with no new safety signals,” Dr. Petrylak said.

Longer follow-up is needed, Dr. Petrylak added, to better characterize the clinical benefits of adding nivolumab to rucaparib for this population.

Discussion moderator Guilia Baciarello, MD, Milan, asked how much nivolumab added to the rucaparib benefit. Dr. Petrylak responded, “We really can’t determine how much it’s adding because the single-agent data, particularly with the checkpoints, is generally very low. I can’t recall any published data with nivolumab as a single agent, but for example with pembrolizumab or atezolizumab in unselected patients it’s 5%-10%. So, we really can’t tell how much nivolumab added in the BRCA positive patients.”

Dr. Baciarello asked, “Will there be a nivolumab versus rucaparib trial in HRD positive patients?”

“I think that’s something that needs to be considered. I think we may also want to consider doing a broader phase II in that group of patients to really nail down the signal. That’s under discussion,” Dr. Petrylak said.

The study was funded by Bristol Myers Squibb. Dr. Petrylak disclosed numerous financial interests including personal and consulting fees.

This article was updated Sept. 24, 2021.

The combination of nivolumab (Opdivo, Bristol Myers Squibb) and rucaparib (Rubraca, Clovis Oncology) demonstrated noteworthy activity among patients with metastatic prostate cancer harboring BRCA mutations, according to new research presented Sept. 18 (abstract 579MO) at the European Society for Medical Oncology Congress 2021.

The findings were specific to patients not yet been treated with chemotherapy and whose tumors were positive for homologous recombination deficiency (HRD). However, for patients whose tumors were negative for HRD, the clinical activity was limited, said Daniel P. Petrylak, MD, Yale University, New Haven, Conn., and lead investigator for the study called CheckMate 9KD (NCT03338790) .

The patients who were included in all CheckMate 9KD cohorts had no prior treatment with targeted T-cell co-stimulation or immune checkpoint pathways. They had metastatic castrate resistant prostate cancer with documented disease progression, ECOG performance status of 0-1, and tissue available for HRD testing.

Dr. Petrylak offered an updated analysis of cohort A2 with 71 patients (median age 73 years), all of whom had received 1-2 prior new hormonal therapies in the pre-chemotherapy setting. Patients who had received prior PARP inhibitors were ineligible, as were those who refused chemotherapy treatment.
 

ORR/PSA RR primary endpoints

Patients received nivolumab and rucaparib, nivolumab at 480 mg (q4 weeks up to 2 years) and rucaparib at 600 mg b.i.d., until disease progression or unacceptable toxicity. Objective response rate and PSA response rate (PSA-RR) were the primary endpoint, with overall survival as a secondary endpoint, along with time to objective response, duration of objective response, time to PSA progression, safety, and radiographic progression-free survival.

Median follow-up was 17.5 months with median treatment duration of 4.6 months in the nivolumab group and 5.5 months for rucaparib. At the time of the final database lock in March 2021, 65 patients (91.5%) had discontinued treatment, most often for disease progression (n = 43; 60.6%) or study drug toxicity (n = 8; 11.3%). Four patients (5.6%) remained on treatment.
 

Better responses for HRD and BRCA 1/2 positive

Stratifying response outcomes showed higher rates for patients who were HRD positive and BRCA1/2 positive for confirmed objective response rate (HRD+ 25.0%, BRCA 1/2+ 33.3%, HRD-/not evaluable 5.3%, all patients 15.4%) and for PSA response (HRD+ 41.9%, BRCA 1/2+ 84.6%, HRD-/not evaluable 14.3%, all patients 27.3%). Partial response rates were 33.3% for BRCA 1/2, 25.0% for HRD positive, 5.3% for HRD- and 15.4% for all patients. Radiographic progression-free survival was longer in the HRD positive group at a median of 10.9 months (95% CI 6.7-12.0), compared with 5.6 months (3.7-9.1) in the HRD-/not evaluable group. Overall survival was similar in the HRD negative group/not evaluable group at 19.0 months (8.2-22.1) and the HRD positive group at 22.7 months (14.1-NE).

Safety profile as expected

Treatment-related adverse events were reported for most patients (64/71, 90.1%), with grade 3-4 events in about half (50.7%). The most common event was grade 1-2 nausea (40.8%), with anemia at 32.4% and alanine aminotransferase (ALT) increases and fatigue both at 28.2%. Adverse events led to discontinuation in 23.9% of patients, with anemia and increased ALT leading both at 4.2%. Grade 3-4 adverse events led to discontinuation in 15.5% of patients. Investigators reported no treatment-related deaths. “The safety profile of nivolumab plus rucaparib was as expected based on the individual components with no new safety signals,” Dr. Petrylak said.

Longer follow-up is needed, Dr. Petrylak added, to better characterize the clinical benefits of adding nivolumab to rucaparib for this population.

Discussion moderator Guilia Baciarello, MD, Milan, asked how much nivolumab added to the rucaparib benefit. Dr. Petrylak responded, “We really can’t determine how much it’s adding because the single-agent data, particularly with the checkpoints, is generally very low. I can’t recall any published data with nivolumab as a single agent, but for example with pembrolizumab or atezolizumab in unselected patients it’s 5%-10%. So, we really can’t tell how much nivolumab added in the BRCA positive patients.”

Dr. Baciarello asked, “Will there be a nivolumab versus rucaparib trial in HRD positive patients?”

“I think that’s something that needs to be considered. I think we may also want to consider doing a broader phase II in that group of patients to really nail down the signal. That’s under discussion,” Dr. Petrylak said.

The study was funded by Bristol Myers Squibb. Dr. Petrylak disclosed numerous financial interests including personal and consulting fees.

This article was updated Sept. 24, 2021.

The combination of nivolumab (Opdivo, Bristol Myers Squibb) and rucaparib (Rubraca, Clovis Oncology) demonstrated noteworthy activity among patients with metastatic prostate cancer harboring BRCA mutations, according to new research presented Sept. 18 (abstract 579MO) at the European Society for Medical Oncology Congress 2021.

The findings were specific to patients not yet been treated with chemotherapy and whose tumors were positive for homologous recombination deficiency (HRD). However, for patients whose tumors were negative for HRD, the clinical activity was limited, said Daniel P. Petrylak, MD, Yale University, New Haven, Conn., and lead investigator for the study called CheckMate 9KD (NCT03338790) .

The patients who were included in all CheckMate 9KD cohorts had no prior treatment with targeted T-cell co-stimulation or immune checkpoint pathways. They had metastatic castrate resistant prostate cancer with documented disease progression, ECOG performance status of 0-1, and tissue available for HRD testing.

Dr. Petrylak offered an updated analysis of cohort A2 with 71 patients (median age 73 years), all of whom had received 1-2 prior new hormonal therapies in the pre-chemotherapy setting. Patients who had received prior PARP inhibitors were ineligible, as were those who refused chemotherapy treatment.
 

ORR/PSA RR primary endpoints

Patients received nivolumab and rucaparib, nivolumab at 480 mg (q4 weeks up to 2 years) and rucaparib at 600 mg b.i.d., until disease progression or unacceptable toxicity. Objective response rate and PSA response rate (PSA-RR) were the primary endpoint, with overall survival as a secondary endpoint, along with time to objective response, duration of objective response, time to PSA progression, safety, and radiographic progression-free survival.

Median follow-up was 17.5 months with median treatment duration of 4.6 months in the nivolumab group and 5.5 months for rucaparib. At the time of the final database lock in March 2021, 65 patients (91.5%) had discontinued treatment, most often for disease progression (n = 43; 60.6%) or study drug toxicity (n = 8; 11.3%). Four patients (5.6%) remained on treatment.
 

Better responses for HRD and BRCA 1/2 positive

Stratifying response outcomes showed higher rates for patients who were HRD positive and BRCA1/2 positive for confirmed objective response rate (HRD+ 25.0%, BRCA 1/2+ 33.3%, HRD-/not evaluable 5.3%, all patients 15.4%) and for PSA response (HRD+ 41.9%, BRCA 1/2+ 84.6%, HRD-/not evaluable 14.3%, all patients 27.3%). Partial response rates were 33.3% for BRCA 1/2, 25.0% for HRD positive, 5.3% for HRD- and 15.4% for all patients. Radiographic progression-free survival was longer in the HRD positive group at a median of 10.9 months (95% CI 6.7-12.0), compared with 5.6 months (3.7-9.1) in the HRD-/not evaluable group. Overall survival was similar in the HRD negative group/not evaluable group at 19.0 months (8.2-22.1) and the HRD positive group at 22.7 months (14.1-NE).

Safety profile as expected

Treatment-related adverse events were reported for most patients (64/71, 90.1%), with grade 3-4 events in about half (50.7%). The most common event was grade 1-2 nausea (40.8%), with anemia at 32.4% and alanine aminotransferase (ALT) increases and fatigue both at 28.2%. Adverse events led to discontinuation in 23.9% of patients, with anemia and increased ALT leading both at 4.2%. Grade 3-4 adverse events led to discontinuation in 15.5% of patients. Investigators reported no treatment-related deaths. “The safety profile of nivolumab plus rucaparib was as expected based on the individual components with no new safety signals,” Dr. Petrylak said.

Longer follow-up is needed, Dr. Petrylak added, to better characterize the clinical benefits of adding nivolumab to rucaparib for this population.

Discussion moderator Guilia Baciarello, MD, Milan, asked how much nivolumab added to the rucaparib benefit. Dr. Petrylak responded, “We really can’t determine how much it’s adding because the single-agent data, particularly with the checkpoints, is generally very low. I can’t recall any published data with nivolumab as a single agent, but for example with pembrolizumab or atezolizumab in unselected patients it’s 5%-10%. So, we really can’t tell how much nivolumab added in the BRCA positive patients.”

Dr. Baciarello asked, “Will there be a nivolumab versus rucaparib trial in HRD positive patients?”

“I think that’s something that needs to be considered. I think we may also want to consider doing a broader phase II in that group of patients to really nail down the signal. That’s under discussion,” Dr. Petrylak said.

The study was funded by Bristol Myers Squibb. Dr. Petrylak disclosed numerous financial interests including personal and consulting fees.

This article was updated Sept. 24, 2021.

Withholding mycophenolate around the time of vaccination against SARS-CoV-2 proved safe and augmented the humoral response to vaccination among a group of patients at one center who were taking the immunosuppressive drug for a variety of rheumatic and musculoskeletal diseases (RMDs).

Previous studies have shown that use of mycophenolate attenuates the humoral response to SARS-CoV-2 vaccination, and the most up-to-date recommendations from the American College of Rheumatology on SARS-CoV-2 vaccination in patients with RMDs advise that mycophenolate should be withheld for a week after receiving the vaccine.

To understand better how withholding mycophenolate would affect immune response to SARS-CoV-2 vaccination, rheumatology fellow Caoilfhionn M. Connolly, MD, and coauthors at Johns Hopkins University, Baltimore, described in their report – published online Sept. 23, 2021, in Annals of the Rheumatic Diseases – how they compared the immune responses to vaccination in 24 patients who withheld mycophenolate and 171 patients who did not stop taking it. All but 1 of the 24 patients who withheld mycophenolate were female, with a median age of 51 years, and they had mostly systemic lupus erythematosus (6 patients), myositis (5), scleroderma (4), or overlap connective tissue disease (4). Three patients received the Janssen/Johnson & Johnson vaccine; all others received either the two-dose Moderna or Pfizer/BioNTech mRNA series.

At a median of 32 days after vaccination, all but two of the patients (92%) who withheld mycophenolate had detectable antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, compared with 65% of those who continued the drug (P = .01). This calculated to patients who withheld the drug as having nearly sixfold higher odds for a positive antibody response (odds ratio, 5.8; 95% CI, 1.3-25.5; P = .02). The association remained statistically significant in an logistic regression analysis that was adjusted for age, sex, race, vaccine type, and use of rituximab and glucocorticoids.

The withholding group also had significantly higher median anti-RBD immunoglobulin titers than did the group that continued therapy (125 vs. 7 U/L; P = .004).

Two patients who reported a flare of their underlying disease during the perivaccination period were treated with topical and oral glucocorticoids.

The patients who withdrew mycophenolate had taken it with twice daily dosing at a median total daily dose of 2,000 mg. They ended up withholding a median of 20 doses around the time of vaccination, with 54% withholding before, 38% both before and after, and 8% only after vaccination.

The researchers said that the conclusions that can be drawn from the study were limited by its small sample size, which “did not allow for evaluation of optimal duration of withholding therapy,” and also its “nonrandomized design, lack of data on cellular response, and limited information on dosing of other immunosuppressive agents.”

Three of the authors disclosed receiving consulting and speaking honoraria from Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallincrodt, and Thermo Fisher Scientific. A fourth author has received consulting fees from Janssen, Boehringer Ingelheim, Mallinckrodt, EMD Serono, Allogene, and ArgenX.

[email protected]

Withholding mycophenolate around the time of vaccination against SARS-CoV-2 proved safe and augmented the humoral response to vaccination among a group of patients at one center who were taking the immunosuppressive drug for a variety of rheumatic and musculoskeletal diseases (RMDs).

Previous studies have shown that use of mycophenolate attenuates the humoral response to SARS-CoV-2 vaccination, and the most up-to-date recommendations from the American College of Rheumatology on SARS-CoV-2 vaccination in patients with RMDs advise that mycophenolate should be withheld for a week after receiving the vaccine.

To understand better how withholding mycophenolate would affect immune response to SARS-CoV-2 vaccination, rheumatology fellow Caoilfhionn M. Connolly, MD, and coauthors at Johns Hopkins University, Baltimore, described in their report – published online Sept. 23, 2021, in Annals of the Rheumatic Diseases – how they compared the immune responses to vaccination in 24 patients who withheld mycophenolate and 171 patients who did not stop taking it. All but 1 of the 24 patients who withheld mycophenolate were female, with a median age of 51 years, and they had mostly systemic lupus erythematosus (6 patients), myositis (5), scleroderma (4), or overlap connective tissue disease (4). Three patients received the Janssen/Johnson & Johnson vaccine; all others received either the two-dose Moderna or Pfizer/BioNTech mRNA series.

At a median of 32 days after vaccination, all but two of the patients (92%) who withheld mycophenolate had detectable antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, compared with 65% of those who continued the drug (P = .01). This calculated to patients who withheld the drug as having nearly sixfold higher odds for a positive antibody response (odds ratio, 5.8; 95% CI, 1.3-25.5; P = .02). The association remained statistically significant in an logistic regression analysis that was adjusted for age, sex, race, vaccine type, and use of rituximab and glucocorticoids.

The withholding group also had significantly higher median anti-RBD immunoglobulin titers than did the group that continued therapy (125 vs. 7 U/L; P = .004).

Two patients who reported a flare of their underlying disease during the perivaccination period were treated with topical and oral glucocorticoids.

The patients who withdrew mycophenolate had taken it with twice daily dosing at a median total daily dose of 2,000 mg. They ended up withholding a median of 20 doses around the time of vaccination, with 54% withholding before, 38% both before and after, and 8% only after vaccination.

The researchers said that the conclusions that can be drawn from the study were limited by its small sample size, which “did not allow for evaluation of optimal duration of withholding therapy,” and also its “nonrandomized design, lack of data on cellular response, and limited information on dosing of other immunosuppressive agents.”

Three of the authors disclosed receiving consulting and speaking honoraria from Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallincrodt, and Thermo Fisher Scientific. A fourth author has received consulting fees from Janssen, Boehringer Ingelheim, Mallinckrodt, EMD Serono, Allogene, and ArgenX.

[email protected]

Withholding mycophenolate around the time of vaccination against SARS-CoV-2 proved safe and augmented the humoral response to vaccination among a group of patients at one center who were taking the immunosuppressive drug for a variety of rheumatic and musculoskeletal diseases (RMDs).

Previous studies have shown that use of mycophenolate attenuates the humoral response to SARS-CoV-2 vaccination, and the most up-to-date recommendations from the American College of Rheumatology on SARS-CoV-2 vaccination in patients with RMDs advise that mycophenolate should be withheld for a week after receiving the vaccine.

To understand better how withholding mycophenolate would affect immune response to SARS-CoV-2 vaccination, rheumatology fellow Caoilfhionn M. Connolly, MD, and coauthors at Johns Hopkins University, Baltimore, described in their report – published online Sept. 23, 2021, in Annals of the Rheumatic Diseases – how they compared the immune responses to vaccination in 24 patients who withheld mycophenolate and 171 patients who did not stop taking it. All but 1 of the 24 patients who withheld mycophenolate were female, with a median age of 51 years, and they had mostly systemic lupus erythematosus (6 patients), myositis (5), scleroderma (4), or overlap connective tissue disease (4). Three patients received the Janssen/Johnson & Johnson vaccine; all others received either the two-dose Moderna or Pfizer/BioNTech mRNA series.

At a median of 32 days after vaccination, all but two of the patients (92%) who withheld mycophenolate had detectable antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, compared with 65% of those who continued the drug (P = .01). This calculated to patients who withheld the drug as having nearly sixfold higher odds for a positive antibody response (odds ratio, 5.8; 95% CI, 1.3-25.5; P = .02). The association remained statistically significant in an logistic regression analysis that was adjusted for age, sex, race, vaccine type, and use of rituximab and glucocorticoids.

The withholding group also had significantly higher median anti-RBD immunoglobulin titers than did the group that continued therapy (125 vs. 7 U/L; P = .004).

Two patients who reported a flare of their underlying disease during the perivaccination period were treated with topical and oral glucocorticoids.

The patients who withdrew mycophenolate had taken it with twice daily dosing at a median total daily dose of 2,000 mg. They ended up withholding a median of 20 doses around the time of vaccination, with 54% withholding before, 38% both before and after, and 8% only after vaccination.

The researchers said that the conclusions that can be drawn from the study were limited by its small sample size, which “did not allow for evaluation of optimal duration of withholding therapy,” and also its “nonrandomized design, lack of data on cellular response, and limited information on dosing of other immunosuppressive agents.”

Three of the authors disclosed receiving consulting and speaking honoraria from Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallincrodt, and Thermo Fisher Scientific. A fourth author has received consulting fees from Janssen, Boehringer Ingelheim, Mallinckrodt, EMD Serono, Allogene, and ArgenX.

[email protected]

Older age, higher subjective disease activity, and exercising for more than 120 minutes per week were three factors linked to patients with ankylosing spondylitis (AS) who switched from their original tumor necrosis factor inhibitor (TNFi) treatment within 2 years in a U.S.-based study.

Data from the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) also found that higher levels of inflammation, but not radiographic disease, were linked to patients changing from one TNFi to another, or to an interleukin (IL)-17 inhibitor or Janus kinase (JAK) inhibitor.

“Different factors were associated in AS patients who switch from their initial TNF inhibitor to another TNF inhibitor, IL-17 inhibitor, or JAK inhibitor within 2 years versus after 2 years of treatment,” John D. Reveille, MD, professor and vice chair of rheumatology and clinical immunogenetics with McGovern Medical School at UTHealth Houston, said at the 12th International Congress on Spondyloarthritides.

“We’re currently looking at different approaches to analyzing these data. And, certainly, this needs need to be looked at in other cohorts,” Dr. Reveille said.

PSOAS is a prospective observational cohort study that has been looking at predictors of AS severity for almost 20 years. Started in 2002, the study has routinely collected a whole host of data on various demographic and disease-related factors.

The reasoning behind the current analysis of PSOAS data was that a relatively recent study based on a commercial claims database had found that many patients with AS do not remain on their initial TNFi 2 years after initiation. So, Dr. Reveille and associates decided to look at the factors that could be influencing whether patients who started a TNFi would remain on their original drug in the PSOAS cohort.

In all, 533 patients from the PSOAS cohort who had at least 2 years of follow-up were included in the analysis. The majority (n = 496) were treated with a TNFi, 34 had received an IL-17 inhibitor, and 3 had received a JAK inhibitor.

Of the 496 patients treated with a TNFi, almost 70% (n = 344) persisted with this treatment for the duration of the study. Of those that switched to another TNFi or IL-17 or JAK inhibitor treatment, 20% (n = 101) did so within 2 years and the remaining 10% (n = 51) after 2 years.

Multinominal logistic regression modeling revealed a number of different factors that were associated with switching within 2 years versus switching after 2 years.

Compared to patients who persisted with treatment throughout the study period, patients who switched from their original TNFi within 2 years were more likely to be older (odds ratio [OR], 2.0 for ≥ 40 vs. < 40 years; P = .002), have a higher Bath Ankylosing Spondyloarthritis Disease Activity Index (BASDAI) score at baseline (OR, 1.73 for ≥ 4 vs. < 4; P = .03), higher C-reactive protein levels (OR, 1.94 for ≥ 0.8 mg/dL vs. < 0.8 mg/dL, P = .004), and greater weekly duration of exercise (OR, 1.95 for ≥ 120 minutes per week vs. < 120; P <.001).

Switchers also were less likely to have severe radiographic disease at baseline, as determined by the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS, OR, 0.63; P = .03), and less likely to be current smokers (OR, 0.69; P < .001).

Factors associated with switching after 2 years versus persisting with treatment were higher baseline BASDAI (OR, 2.31; P = .01), exercising more than 120 minutes per week (OR, 1.66; P = .03), and having more comorbidities (OR, 1.63 for ≥ 2 vs. < 2, P = .04).

However, patients who switched after 2 years were less likely to be depressed (OR, 0.35; P = .002) or to have a longer baseline disease duration (OR, 0.27 for ≥ 20 years vs. < 20 years P < .001).

The association observed between switching within 2 years and lower likelihood of currently smoking was a “little bit puzzling,” one delegate said after Dr. Reveille’s presentation. “The opposite has been shown in the literature, and current smokers seem to be refractory to TNF inhibitor therapy,” the delegate observed.

“I was confounded when I saw the data,” Dr. Reveille acknowledged. Because this was an observational study, this finding needs more investigation, he agreed. “Interestingly, we have seen this negative association with some other parameters, too,” he added.

The HLA-B27 carrier and radiographic status were carefully checked, so there should not be a problem with the diagnosis, Dr. Reveille reassured. Further analyses of the findings are now warranted.

Funding for the study was provided by the U.S. Department of Health and Human Services, the National Institutes of Health, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Additional funding was received from the Spondyloarthritis Association of America and Eli Lilly.

Dr. Reveille made no personal disclosures; a coauthor of the abstract was an employee of Eli Lilly.

Older age, higher subjective disease activity, and exercising for more than 120 minutes per week were three factors linked to patients with ankylosing spondylitis (AS) who switched from their original tumor necrosis factor inhibitor (TNFi) treatment within 2 years in a U.S.-based study.

Data from the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) also found that higher levels of inflammation, but not radiographic disease, were linked to patients changing from one TNFi to another, or to an interleukin (IL)-17 inhibitor or Janus kinase (JAK) inhibitor.

“Different factors were associated in AS patients who switch from their initial TNF inhibitor to another TNF inhibitor, IL-17 inhibitor, or JAK inhibitor within 2 years versus after 2 years of treatment,” John D. Reveille, MD, professor and vice chair of rheumatology and clinical immunogenetics with McGovern Medical School at UTHealth Houston, said at the 12th International Congress on Spondyloarthritides.

“We’re currently looking at different approaches to analyzing these data. And, certainly, this needs need to be looked at in other cohorts,” Dr. Reveille said.

PSOAS is a prospective observational cohort study that has been looking at predictors of AS severity for almost 20 years. Started in 2002, the study has routinely collected a whole host of data on various demographic and disease-related factors.

The reasoning behind the current analysis of PSOAS data was that a relatively recent study based on a commercial claims database had found that many patients with AS do not remain on their initial TNFi 2 years after initiation. So, Dr. Reveille and associates decided to look at the factors that could be influencing whether patients who started a TNFi would remain on their original drug in the PSOAS cohort.

In all, 533 patients from the PSOAS cohort who had at least 2 years of follow-up were included in the analysis. The majority (n = 496) were treated with a TNFi, 34 had received an IL-17 inhibitor, and 3 had received a JAK inhibitor.

Of the 496 patients treated with a TNFi, almost 70% (n = 344) persisted with this treatment for the duration of the study. Of those that switched to another TNFi or IL-17 or JAK inhibitor treatment, 20% (n = 101) did so within 2 years and the remaining 10% (n = 51) after 2 years.

Multinominal logistic regression modeling revealed a number of different factors that were associated with switching within 2 years versus switching after 2 years.

Compared to patients who persisted with treatment throughout the study period, patients who switched from their original TNFi within 2 years were more likely to be older (odds ratio [OR], 2.0 for ≥ 40 vs. < 40 years; P = .002), have a higher Bath Ankylosing Spondyloarthritis Disease Activity Index (BASDAI) score at baseline (OR, 1.73 for ≥ 4 vs. < 4; P = .03), higher C-reactive protein levels (OR, 1.94 for ≥ 0.8 mg/dL vs. < 0.8 mg/dL, P = .004), and greater weekly duration of exercise (OR, 1.95 for ≥ 120 minutes per week vs. < 120; P <.001).

Switchers also were less likely to have severe radiographic disease at baseline, as determined by the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS, OR, 0.63; P = .03), and less likely to be current smokers (OR, 0.69; P < .001).

Factors associated with switching after 2 years versus persisting with treatment were higher baseline BASDAI (OR, 2.31; P = .01), exercising more than 120 minutes per week (OR, 1.66; P = .03), and having more comorbidities (OR, 1.63 for ≥ 2 vs. < 2, P = .04).

However, patients who switched after 2 years were less likely to be depressed (OR, 0.35; P = .002) or to have a longer baseline disease duration (OR, 0.27 for ≥ 20 years vs. < 20 years P < .001).

The association observed between switching within 2 years and lower likelihood of currently smoking was a “little bit puzzling,” one delegate said after Dr. Reveille’s presentation. “The opposite has been shown in the literature, and current smokers seem to be refractory to TNF inhibitor therapy,” the delegate observed.

“I was confounded when I saw the data,” Dr. Reveille acknowledged. Because this was an observational study, this finding needs more investigation, he agreed. “Interestingly, we have seen this negative association with some other parameters, too,” he added.

The HLA-B27 carrier and radiographic status were carefully checked, so there should not be a problem with the diagnosis, Dr. Reveille reassured. Further analyses of the findings are now warranted.

Funding for the study was provided by the U.S. Department of Health and Human Services, the National Institutes of Health, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Additional funding was received from the Spondyloarthritis Association of America and Eli Lilly.

Dr. Reveille made no personal disclosures; a coauthor of the abstract was an employee of Eli Lilly.

Older age, higher subjective disease activity, and exercising for more than 120 minutes per week were three factors linked to patients with ankylosing spondylitis (AS) who switched from their original tumor necrosis factor inhibitor (TNFi) treatment within 2 years in a U.S.-based study.

Data from the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) also found that higher levels of inflammation, but not radiographic disease, were linked to patients changing from one TNFi to another, or to an interleukin (IL)-17 inhibitor or Janus kinase (JAK) inhibitor.

“Different factors were associated in AS patients who switch from their initial TNF inhibitor to another TNF inhibitor, IL-17 inhibitor, or JAK inhibitor within 2 years versus after 2 years of treatment,” John D. Reveille, MD, professor and vice chair of rheumatology and clinical immunogenetics with McGovern Medical School at UTHealth Houston, said at the 12th International Congress on Spondyloarthritides.

“We’re currently looking at different approaches to analyzing these data. And, certainly, this needs need to be looked at in other cohorts,” Dr. Reveille said.

PSOAS is a prospective observational cohort study that has been looking at predictors of AS severity for almost 20 years. Started in 2002, the study has routinely collected a whole host of data on various demographic and disease-related factors.

The reasoning behind the current analysis of PSOAS data was that a relatively recent study based on a commercial claims database had found that many patients with AS do not remain on their initial TNFi 2 years after initiation. So, Dr. Reveille and associates decided to look at the factors that could be influencing whether patients who started a TNFi would remain on their original drug in the PSOAS cohort.

In all, 533 patients from the PSOAS cohort who had at least 2 years of follow-up were included in the analysis. The majority (n = 496) were treated with a TNFi, 34 had received an IL-17 inhibitor, and 3 had received a JAK inhibitor.

Of the 496 patients treated with a TNFi, almost 70% (n = 344) persisted with this treatment for the duration of the study. Of those that switched to another TNFi or IL-17 or JAK inhibitor treatment, 20% (n = 101) did so within 2 years and the remaining 10% (n = 51) after 2 years.

Multinominal logistic regression modeling revealed a number of different factors that were associated with switching within 2 years versus switching after 2 years.

Compared to patients who persisted with treatment throughout the study period, patients who switched from their original TNFi within 2 years were more likely to be older (odds ratio [OR], 2.0 for ≥ 40 vs. < 40 years; P = .002), have a higher Bath Ankylosing Spondyloarthritis Disease Activity Index (BASDAI) score at baseline (OR, 1.73 for ≥ 4 vs. < 4; P = .03), higher C-reactive protein levels (OR, 1.94 for ≥ 0.8 mg/dL vs. < 0.8 mg/dL, P = .004), and greater weekly duration of exercise (OR, 1.95 for ≥ 120 minutes per week vs. < 120; P <.001).

Switchers also were less likely to have severe radiographic disease at baseline, as determined by the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS, OR, 0.63; P = .03), and less likely to be current smokers (OR, 0.69; P < .001).

Factors associated with switching after 2 years versus persisting with treatment were higher baseline BASDAI (OR, 2.31; P = .01), exercising more than 120 minutes per week (OR, 1.66; P = .03), and having more comorbidities (OR, 1.63 for ≥ 2 vs. < 2, P = .04).

However, patients who switched after 2 years were less likely to be depressed (OR, 0.35; P = .002) or to have a longer baseline disease duration (OR, 0.27 for ≥ 20 years vs. < 20 years P < .001).

The association observed between switching within 2 years and lower likelihood of currently smoking was a “little bit puzzling,” one delegate said after Dr. Reveille’s presentation. “The opposite has been shown in the literature, and current smokers seem to be refractory to TNF inhibitor therapy,” the delegate observed.

“I was confounded when I saw the data,” Dr. Reveille acknowledged. Because this was an observational study, this finding needs more investigation, he agreed. “Interestingly, we have seen this negative association with some other parameters, too,” he added.

The HLA-B27 carrier and radiographic status were carefully checked, so there should not be a problem with the diagnosis, Dr. Reveille reassured. Further analyses of the findings are now warranted.

Funding for the study was provided by the U.S. Department of Health and Human Services, the National Institutes of Health, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Additional funding was received from the Spondyloarthritis Association of America and Eli Lilly.

Dr. Reveille made no personal disclosures; a coauthor of the abstract was an employee of Eli Lilly.