WASHINGTON – Catheter-directed clot lysis and thrombectomy with creation of a bypass shunt is a reasonable alternative to prolonged anticoagulation for treating patients with portal vein thrombosis (PVT) based on the accumulated reported experience since 1993 using this percutaneous treatment.

Use of a transjugular intrahepatic portosystemic shunt (TIPS) for treating portal vein thrombosis (PVT) “is feasible and effective in achieving a significant and sustainable reduction in clot burden with a low risk of major complications,” Nelson Valentin, MD, said at the annual Digestive Disease Week.^® “TIPS should be considered a viable treatment option for patients with PVT,” said Dr. Valentin, a gastroenterology fellow at Mount Sinai Beth Israel hospital in New York.

Mitchel L. Zoler/MDedge News

“There is sufficient evidence from these reports to at least consider TIPS as an adjunct to anticoagulation or perhaps as primary therapy,” especially for patients with PVT who have a contraindication for anticoagulation, Dr. Valentin said in an interview. Standard anticoagulation for PVT would today involve acute treatment with a low-molecular-weight heparin followed by oral anticoagulation for a total treatment time of at least 6 months and continued for a year or longer in some patients. A recently published review of reported experience using anticoagulation to treat PVT found a complete recanalization rate of 41% and a complete or partial rate of 66%, which suggests that TIPS is at least as effective, although Dr. Valentin cautioned that no reported study has directly compared the two alternative approaches. A study designed to make this direct comparison is warranted by the reported results using TIPS, Dr. Valentin said. And the experience with TIPS positions it as an option for patients who do not respond to anticoagulation or would prefer an alternative to prolonged anticoagulation.

One factor currently limiting use of TIPS, which is usually performed by an interventional radiologist, is that the procedure is technically demanding, with a limited number of operators with the expertise to perform it. If TIPS became more widely accepted as an option for treating PVT, then the pool of interventionalists experienced with performing the procedure would grow, Dr. Valentin noted.

[email protected]

On Twitter @mitchelzoler

SOURCE: Valentin N et al. Digestive Disease Week, Presentation 361.

WASHINGTON – Catheter-directed clot lysis and thrombectomy with creation of a bypass shunt is a reasonable alternative to prolonged anticoagulation for treating patients with portal vein thrombosis (PVT) based on the accumulated reported experience since 1993 using this percutaneous treatment.

Use of a transjugular intrahepatic portosystemic shunt (TIPS) for treating portal vein thrombosis (PVT) “is feasible and effective in achieving a significant and sustainable reduction in clot burden with a low risk of major complications,” Nelson Valentin, MD, said at the annual Digestive Disease Week.^® “TIPS should be considered a viable treatment option for patients with PVT,” said Dr. Valentin, a gastroenterology fellow at Mount Sinai Beth Israel hospital in New York.

Mitchel L. Zoler/MDedge News

“There is sufficient evidence from these reports to at least consider TIPS as an adjunct to anticoagulation or perhaps as primary therapy,” especially for patients with PVT who have a contraindication for anticoagulation, Dr. Valentin said in an interview. Standard anticoagulation for PVT would today involve acute treatment with a low-molecular-weight heparin followed by oral anticoagulation for a total treatment time of at least 6 months and continued for a year or longer in some patients. A recently published review of reported experience using anticoagulation to treat PVT found a complete recanalization rate of 41% and a complete or partial rate of 66%, which suggests that TIPS is at least as effective, although Dr. Valentin cautioned that no reported study has directly compared the two alternative approaches. A study designed to make this direct comparison is warranted by the reported results using TIPS, Dr. Valentin said. And the experience with TIPS positions it as an option for patients who do not respond to anticoagulation or would prefer an alternative to prolonged anticoagulation.

One factor currently limiting use of TIPS, which is usually performed by an interventional radiologist, is that the procedure is technically demanding, with a limited number of operators with the expertise to perform it. If TIPS became more widely accepted as an option for treating PVT, then the pool of interventionalists experienced with performing the procedure would grow, Dr. Valentin noted.

[email protected]

On Twitter @mitchelzoler

SOURCE: Valentin N et al. Digestive Disease Week, Presentation 361.

WASHINGTON – Catheter-directed clot lysis and thrombectomy with creation of a bypass shunt is a reasonable alternative to prolonged anticoagulation for treating patients with portal vein thrombosis (PVT) based on the accumulated reported experience since 1993 using this percutaneous treatment.

Use of a transjugular intrahepatic portosystemic shunt (TIPS) for treating portal vein thrombosis (PVT) “is feasible and effective in achieving a significant and sustainable reduction in clot burden with a low risk of major complications,” Nelson Valentin, MD, said at the annual Digestive Disease Week.^® “TIPS should be considered a viable treatment option for patients with PVT,” said Dr. Valentin, a gastroenterology fellow at Mount Sinai Beth Israel hospital in New York.

Mitchel L. Zoler/MDedge News

“There is sufficient evidence from these reports to at least consider TIPS as an adjunct to anticoagulation or perhaps as primary therapy,” especially for patients with PVT who have a contraindication for anticoagulation, Dr. Valentin said in an interview. Standard anticoagulation for PVT would today involve acute treatment with a low-molecular-weight heparin followed by oral anticoagulation for a total treatment time of at least 6 months and continued for a year or longer in some patients. A recently published review of reported experience using anticoagulation to treat PVT found a complete recanalization rate of 41% and a complete or partial rate of 66%, which suggests that TIPS is at least as effective, although Dr. Valentin cautioned that no reported study has directly compared the two alternative approaches. A study designed to make this direct comparison is warranted by the reported results using TIPS, Dr. Valentin said. And the experience with TIPS positions it as an option for patients who do not respond to anticoagulation or would prefer an alternative to prolonged anticoagulation.

One factor currently limiting use of TIPS, which is usually performed by an interventional radiologist, is that the procedure is technically demanding, with a limited number of operators with the expertise to perform it. If TIPS became more widely accepted as an option for treating PVT, then the pool of interventionalists experienced with performing the procedure would grow, Dr. Valentin noted.

[email protected]

On Twitter @mitchelzoler

SOURCE: Valentin N et al. Digestive Disease Week, Presentation 361.

The SVS is recruiting volunteers to serve on a new Task Force on the Future of Vascular Surgery, which will examine a number of critical trends shaping the specialty. President-elect Michael Makaroun, MD, will chair the new group. Learn more, including how to volunteer, here.

The SVS is recruiting volunteers to serve on a new Task Force on the Future of Vascular Surgery, which will examine a number of critical trends shaping the specialty. President-elect Michael Makaroun, MD, will chair the new group. Learn more, including how to volunteer, here.

The SVS is recruiting volunteers to serve on a new Task Force on the Future of Vascular Surgery, which will examine a number of critical trends shaping the specialty. President-elect Michael Makaroun, MD, will chair the new group. Learn more, including how to volunteer, here.

Help build the Vascular Annual Meeting’ new “Ask the Experts” sessions. The four small-group sessions will focus on common issues in vascular disease — coding, aortic care for occlusive disease, hemodialysis and PAD — with an expert reviewing a member's prior case. Members are invited to submit a case on these topics, briefly describing the case and providing a brief history and physical exam of the patient, the results and any additional issues they want to discuss during the program. Sessions will be held daily, Wednesday through Saturday. Submit a case here.

Help build the Vascular Annual Meeting’ new “Ask the Experts” sessions. The four small-group sessions will focus on common issues in vascular disease — coding, aortic care for occlusive disease, hemodialysis and PAD — with an expert reviewing a member's prior case. Members are invited to submit a case on these topics, briefly describing the case and providing a brief history and physical exam of the patient, the results and any additional issues they want to discuss during the program. Sessions will be held daily, Wednesday through Saturday. Submit a case here.

Help build the Vascular Annual Meeting’ new “Ask the Experts” sessions. The four small-group sessions will focus on common issues in vascular disease — coding, aortic care for occlusive disease, hemodialysis and PAD — with an expert reviewing a member's prior case. Members are invited to submit a case on these topics, briefly describing the case and providing a brief history and physical exam of the patient, the results and any additional issues they want to discuss during the program. Sessions will be held daily, Wednesday through Saturday. Submit a case here.

Don’t miss the vascular surgery world’s headline event! Join colleagues and friends in Boston for this year’s Vascular Annual Meeting, June 20 to 23. Scientific sessions are June 21-23 and the Exhibit Hall is open June 21 to 22. Click here to register. To get a full schedule and begin creating your own personal agenda, complete with marking sessions as favorites, see the VAM Planner.

Don’t miss the vascular surgery world’s headline event! Join colleagues and friends in Boston for this year’s Vascular Annual Meeting, June 20 to 23. Scientific sessions are June 21-23 and the Exhibit Hall is open June 21 to 22. Click here to register. To get a full schedule and begin creating your own personal agenda, complete with marking sessions as favorites, see the VAM Planner.

Don’t miss the vascular surgery world’s headline event! Join colleagues and friends in Boston for this year’s Vascular Annual Meeting, June 20 to 23. Scientific sessions are June 21-23 and the Exhibit Hall is open June 21 to 22. Click here to register. To get a full schedule and begin creating your own personal agenda, complete with marking sessions as favorites, see the VAM Planner.

CHICAGO – Denosumab may be preferable to bisphosphonates in myeloma patients in specific scenarios, G. David Roodman, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

“We use denosumab in patients with compromised renal function,” said Dr. Roodman, director of the Division of Hematology-Oncology at Indiana University, Indianapolis, noting one such scenario. That use of denosumab echoes recently published ASCO guidelines on bone-modifying therapy.

Andrew D. Bowser/MDedge News

The addition of denosumab was based in part on results of a recent randomized phase 3 trial that comprised 1,718 myeloma patients who were treated with either denosumab or zoledronic acid.

The primary endpoint, time to first on-study skeletal-related event, was evaluated after 676 skeletal-related events had accrued on study. The investigators found no difference in time to first event (hazard ratio [HR], 0.98; 95% confidence interval, 0.85-1.14; P = 0.82).

Likewise, the secondary endpoint of overall survival showed no difference between arms (HR, 0.90; 95% CI, 0.70-1.16), though an exploratory analysis did suggest denosumab was superior on the endpoint of progression-free survival (HR, 0.82; 95% CI, 0.68-0.99).

The ASCO guidelines also recommend that clinicians consider less-frequent dosing in patients with responsive or stable disease. That recommendation is based on results of two studies of less-frequent dosing prompted by concerns over the risk of osteonecrosis of the jaw, an uncommon but potentially serious complication associated with bone-modifying agents.

Both studies suggested every-3-months dosing of zoledronic acid could be effective. However, Dr. Roodman noted that both studies had limitations that need to be considered, including small numbers of myeloma patients, limited duration of therapy studied, and a high dropout rate in the case of one study. Due to those limitations, “it’s very difficult to draw conclusions about this today,” Dr. Roodman said.

Dr. Roodman reported that he had a consulting or advisory role with Amgen.

CHICAGO – Denosumab may be preferable to bisphosphonates in myeloma patients in specific scenarios, G. David Roodman, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

“We use denosumab in patients with compromised renal function,” said Dr. Roodman, director of the Division of Hematology-Oncology at Indiana University, Indianapolis, noting one such scenario. That use of denosumab echoes recently published ASCO guidelines on bone-modifying therapy.

Andrew D. Bowser/MDedge News

The addition of denosumab was based in part on results of a recent randomized phase 3 trial that comprised 1,718 myeloma patients who were treated with either denosumab or zoledronic acid.

The primary endpoint, time to first on-study skeletal-related event, was evaluated after 676 skeletal-related events had accrued on study. The investigators found no difference in time to first event (hazard ratio [HR], 0.98; 95% confidence interval, 0.85-1.14; P = 0.82).

Likewise, the secondary endpoint of overall survival showed no difference between arms (HR, 0.90; 95% CI, 0.70-1.16), though an exploratory analysis did suggest denosumab was superior on the endpoint of progression-free survival (HR, 0.82; 95% CI, 0.68-0.99).

The ASCO guidelines also recommend that clinicians consider less-frequent dosing in patients with responsive or stable disease. That recommendation is based on results of two studies of less-frequent dosing prompted by concerns over the risk of osteonecrosis of the jaw, an uncommon but potentially serious complication associated with bone-modifying agents.

Both studies suggested every-3-months dosing of zoledronic acid could be effective. However, Dr. Roodman noted that both studies had limitations that need to be considered, including small numbers of myeloma patients, limited duration of therapy studied, and a high dropout rate in the case of one study. Due to those limitations, “it’s very difficult to draw conclusions about this today,” Dr. Roodman said.

Dr. Roodman reported that he had a consulting or advisory role with Amgen.

CHICAGO – Denosumab may be preferable to bisphosphonates in myeloma patients in specific scenarios, G. David Roodman, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

“We use denosumab in patients with compromised renal function,” said Dr. Roodman, director of the Division of Hematology-Oncology at Indiana University, Indianapolis, noting one such scenario. That use of denosumab echoes recently published ASCO guidelines on bone-modifying therapy.

Andrew D. Bowser/MDedge News

The addition of denosumab was based in part on results of a recent randomized phase 3 trial that comprised 1,718 myeloma patients who were treated with either denosumab or zoledronic acid.

The primary endpoint, time to first on-study skeletal-related event, was evaluated after 676 skeletal-related events had accrued on study. The investigators found no difference in time to first event (hazard ratio [HR], 0.98; 95% confidence interval, 0.85-1.14; P = 0.82).

Likewise, the secondary endpoint of overall survival showed no difference between arms (HR, 0.90; 95% CI, 0.70-1.16), though an exploratory analysis did suggest denosumab was superior on the endpoint of progression-free survival (HR, 0.82; 95% CI, 0.68-0.99).

The ASCO guidelines also recommend that clinicians consider less-frequent dosing in patients with responsive or stable disease. That recommendation is based on results of two studies of less-frequent dosing prompted by concerns over the risk of osteonecrosis of the jaw, an uncommon but potentially serious complication associated with bone-modifying agents.

Both studies suggested every-3-months dosing of zoledronic acid could be effective. However, Dr. Roodman noted that both studies had limitations that need to be considered, including small numbers of myeloma patients, limited duration of therapy studied, and a high dropout rate in the case of one study. Due to those limitations, “it’s very difficult to draw conclusions about this today,” Dr. Roodman said.

Dr. Roodman reported that he had a consulting or advisory role with Amgen.

Citation: Fejzo MS, Sazonova OV, Fah Sathirapongsasuti J, et al. Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nature Communications. 2018;9:1178.

Citation: Fejzo MS, Sazonova OV, Fah Sathirapongsasuti J, et al. Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nature Communications. 2018;9:1178.

Citation: Fejzo MS, Sazonova OV, Fah Sathirapongsasuti J, et al. Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nature Communications. 2018;9:1178.

CHICAGO – Matched targeted therapy improved long-term survival in patients with advanced cancer, according to findings from a retrospective analysis of molecularly profiled patients.

Of 3,743 patients tested as part of IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy), 1,307 (34.9%) had at least one targetable molecular alteration. Of those, 711 (54.4%) received either matched targeted therapy that was being tested in a clinical trial or – in a small number of cases – therapy with an approved treatment used off label, and 596 (45.6%) received nonmatched therapy, Apostolia-Maria Tsimberidou, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.

The objective response rates in 697 evaluable matched therapy patients was 16.2% versus 5.4% in 571 evaluable nonmatched patients, and stable disease for at least 6 months occurred in 18.7% and 14.7% of patients, respectively, for an overall disease control rate of 34.9% versus 20.1%, said Dr. Tsimberidou, a professor at the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival in those who received matched versus nonmatched therapy was 4.0 months and 2.8 months, respectively (hazard ratio, 0.67), and median overall survival was 9.3 and 7.3 months, respectively (HR, 0.72), she said.

The 3-year overall survival rate was 15% versus 7%, respectively, and 10-year survival was 6% and 1%, respectively.

Patients included in IMPACT had a mean age of 57 years, and 39% were men. They were heavily pretreated (mean number of prior therapies was 4); only 2.8% of patients had no prior treatment. Cancers included gastrointestinal (24.2%), gynecologic (19.4%), breast (13.5%), melanoma (11.9%) and lung (8.7%).

In this video interview, Dr. Tsimberidou describes the rationale, methodology, and findings of IMPACT, including the use of a prognostic scoring system developed as part of the study to predict overall survival based on baseline characteristics, such as baseline p13K/AKT/mTOR pathway molecular alterations, which were shown on multivariate analysis in IMPACT to predict shorter overall survival versus other alterations. Other predictors of shorter survival included liver metastases, elevated lactate dehydrogenase levels, poor functional status, low albumin levels, elevated platelet counts, and age of 60 years or older.

SOURCE: Tsimberidou AM et al. ASCO 2018, Abstract LBA 2553.

CHICAGO – Matched targeted therapy improved long-term survival in patients with advanced cancer, according to findings from a retrospective analysis of molecularly profiled patients.

Of 3,743 patients tested as part of IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy), 1,307 (34.9%) had at least one targetable molecular alteration. Of those, 711 (54.4%) received either matched targeted therapy that was being tested in a clinical trial or – in a small number of cases – therapy with an approved treatment used off label, and 596 (45.6%) received nonmatched therapy, Apostolia-Maria Tsimberidou, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.

The objective response rates in 697 evaluable matched therapy patients was 16.2% versus 5.4% in 571 evaluable nonmatched patients, and stable disease for at least 6 months occurred in 18.7% and 14.7% of patients, respectively, for an overall disease control rate of 34.9% versus 20.1%, said Dr. Tsimberidou, a professor at the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival in those who received matched versus nonmatched therapy was 4.0 months and 2.8 months, respectively (hazard ratio, 0.67), and median overall survival was 9.3 and 7.3 months, respectively (HR, 0.72), she said.

The 3-year overall survival rate was 15% versus 7%, respectively, and 10-year survival was 6% and 1%, respectively.

Patients included in IMPACT had a mean age of 57 years, and 39% were men. They were heavily pretreated (mean number of prior therapies was 4); only 2.8% of patients had no prior treatment. Cancers included gastrointestinal (24.2%), gynecologic (19.4%), breast (13.5%), melanoma (11.9%) and lung (8.7%).

In this video interview, Dr. Tsimberidou describes the rationale, methodology, and findings of IMPACT, including the use of a prognostic scoring system developed as part of the study to predict overall survival based on baseline characteristics, such as baseline p13K/AKT/mTOR pathway molecular alterations, which were shown on multivariate analysis in IMPACT to predict shorter overall survival versus other alterations. Other predictors of shorter survival included liver metastases, elevated lactate dehydrogenase levels, poor functional status, low albumin levels, elevated platelet counts, and age of 60 years or older.

SOURCE: Tsimberidou AM et al. ASCO 2018, Abstract LBA 2553.

CHICAGO – Matched targeted therapy improved long-term survival in patients with advanced cancer, according to findings from a retrospective analysis of molecularly profiled patients.

Of 3,743 patients tested as part of IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy), 1,307 (34.9%) had at least one targetable molecular alteration. Of those, 711 (54.4%) received either matched targeted therapy that was being tested in a clinical trial or – in a small number of cases – therapy with an approved treatment used off label, and 596 (45.6%) received nonmatched therapy, Apostolia-Maria Tsimberidou, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.

The objective response rates in 697 evaluable matched therapy patients was 16.2% versus 5.4% in 571 evaluable nonmatched patients, and stable disease for at least 6 months occurred in 18.7% and 14.7% of patients, respectively, for an overall disease control rate of 34.9% versus 20.1%, said Dr. Tsimberidou, a professor at the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival in those who received matched versus nonmatched therapy was 4.0 months and 2.8 months, respectively (hazard ratio, 0.67), and median overall survival was 9.3 and 7.3 months, respectively (HR, 0.72), she said.

The 3-year overall survival rate was 15% versus 7%, respectively, and 10-year survival was 6% and 1%, respectively.

Patients included in IMPACT had a mean age of 57 years, and 39% were men. They were heavily pretreated (mean number of prior therapies was 4); only 2.8% of patients had no prior treatment. Cancers included gastrointestinal (24.2%), gynecologic (19.4%), breast (13.5%), melanoma (11.9%) and lung (8.7%).

In this video interview, Dr. Tsimberidou describes the rationale, methodology, and findings of IMPACT, including the use of a prognostic scoring system developed as part of the study to predict overall survival based on baseline characteristics, such as baseline p13K/AKT/mTOR pathway molecular alterations, which were shown on multivariate analysis in IMPACT to predict shorter overall survival versus other alterations. Other predictors of shorter survival included liver metastases, elevated lactate dehydrogenase levels, poor functional status, low albumin levels, elevated platelet counts, and age of 60 years or older.

SOURCE: Tsimberidou AM et al. ASCO 2018, Abstract LBA 2553.

CHICAGO – Pembrolizumab (Keytruda) as first-line treatment of advanced non–small-cell lung cancer (NSCLC) offered longer overall survival with better tolerability compared with chemotherapy, results of the Keynote-042 phase 3 randomized trial show.

Among 1,274 patients with advanced, previously untreated NSCLC with expression of the PD-L1 on 1% or more of tumor cells, median overall survival after a median follow-up of 12.8 months was 16.7 months for patients treated with pembrolizumab monotherapy, compared with 12.1 months for patients treated with either paclitaxel or pemetrexed plus carboplatin, reported lead author Gilberto Lopes, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami.

Neil Osterweil/MDedge News

‘A true milestone’

ASCO expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, said at the briefing that “this study represents a true milestone for the field, because now, for the first time, we can say that among non–small-cell lung cancer patients receiving first-line therapy, the vast majority can receive immunotherapy with pembrolizumab instead of chemotherapy.”

He noted that an earlier study, Keynote-024, showed that pembrolizumab significantly improved progression-free survival in patients with tumors expressing PD-L1 on at least 50% of cells compared with standard platinum-based chemotherapy (10.3 vs. 6 months).

Neil Osterweil/MDedge News

As noted before, the primary endpoint of overall survival among all patients with a TPS of 1% or greater was met, with respective median overall survival in the pembrolizumab vs. chemotherapy groups of 16.7 vs. 12.1 months, translating into a hazard ratio favoring pembrolizumab of 0.81 (P = .0018). Respective hazard ratios for the TPS 20% or greater and TPS 50% or greater groups were 0.77 (P = .0020), and 0.69 (P = .0003).

At 12.8 months of median follow-up, 13% of patients assigned to pembrolizumab were still on the drug, and 4.3% of patients were receiving maintenance pemetrexed.

Treatment-related adverse events of any grade occurred in 399 of 636 patients assigned to pembrolizumab (62.7%), vs. 553 of 615 patients assigned to chemotherapy (89.9%).

Grade 3 or greater events occurred in 17.8% vs. 41% of patients, respectively, There were 13 deaths related to therapy in the pembrolizumab arm (2.0%), and 14 in the chemotherapy arm (2.3%).

Adverse events leading to discontinuation were similar between the groups, at 9% and 9.4%, respectively.

There were more immune-mediated adverse events in the pembrolizumab arm (27.8% vs. 7.2%), and of these, grade 3 or greater events occurred in 8% vs. 1.5% of patients, respectively.

There was one immune-mediated death, from pneumonitis, in the immunotherapy arm; there were no deaths related to immune-mediated side effects in the chemotherapy arm.

“I really view this as a ‘double whammy’ for patients,” Dr. Heymach said at the briefing. “Often advances in survival for our lung cancer patients come at the cost of significant toxicities. Here, by contrast, not only are patients living longer and having a much higher likelihood of prolonged survival in years, often instead of months, but they’re also receiving a treatment that has substantially less toxicity across virtually all measures, and this really impacts the day-to-day life of these patients.”

Leena Gandhi, MD, PhD, of the Perlmutter Cancer Center at New York University, the invited discussant at the plenary, agreed that pembrolizumab improves survival, compared with chemotherapy patients with PD-L1 expression levels greater than 1%, but noted that most of the benefit – as also seen in Keynote-024 – was in those patients whose tumors had high levels of PD-L1 expression.

She emphasized that although PD-L1 is an imperfect biomarker, it should still be used to help select patients for therapy, and may be complementary with tumor mutational burden for more precise treatment selection.

“What we know, and what this study adds to, is that PD-L1 really does define a patient population that could receive benefit from pembrolizumab over chemotherapy. Patients with low or no PD-L1 expression likely should get some type of combination therapy,” she said.

“I do think this study extends what we’ve seen from other recent studies, which is that chemotherapy alone is no longer a first-line standard of care in non–small-cell lung cancer,” she added.

Merck funded the study. Dr. Lopes disclosed institutional research funding from Merck Sharp & Dohme, EMD Serono, and AstraZeneca. Dr. Heymach disclosed stock/ownership in Bio-Tree and Cardinal Spine, a consulting or advisory role for Abbvie, ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Genentech, Medivation, Novartis, Oncomed, and Synta, and institutional research funding from AstraZeneca. Dr. Gandhi reported having no relevant disclosures.

SOURCE: Lobes G et al. ASCO 2018, abstract LBA4.

CHICAGO – Pembrolizumab (Keytruda) as first-line treatment of advanced non–small-cell lung cancer (NSCLC) offered longer overall survival with better tolerability compared with chemotherapy, results of the Keynote-042 phase 3 randomized trial show.

Among 1,274 patients with advanced, previously untreated NSCLC with expression of the PD-L1 on 1% or more of tumor cells, median overall survival after a median follow-up of 12.8 months was 16.7 months for patients treated with pembrolizumab monotherapy, compared with 12.1 months for patients treated with either paclitaxel or pemetrexed plus carboplatin, reported lead author Gilberto Lopes, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami.

Neil Osterweil/MDedge News

‘A true milestone’

ASCO expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, said at the briefing that “this study represents a true milestone for the field, because now, for the first time, we can say that among non–small-cell lung cancer patients receiving first-line therapy, the vast majority can receive immunotherapy with pembrolizumab instead of chemotherapy.”

He noted that an earlier study, Keynote-024, showed that pembrolizumab significantly improved progression-free survival in patients with tumors expressing PD-L1 on at least 50% of cells compared with standard platinum-based chemotherapy (10.3 vs. 6 months).

Neil Osterweil/MDedge News

As noted before, the primary endpoint of overall survival among all patients with a TPS of 1% or greater was met, with respective median overall survival in the pembrolizumab vs. chemotherapy groups of 16.7 vs. 12.1 months, translating into a hazard ratio favoring pembrolizumab of 0.81 (P = .0018). Respective hazard ratios for the TPS 20% or greater and TPS 50% or greater groups were 0.77 (P = .0020), and 0.69 (P = .0003).

At 12.8 months of median follow-up, 13% of patients assigned to pembrolizumab were still on the drug, and 4.3% of patients were receiving maintenance pemetrexed.

Treatment-related adverse events of any grade occurred in 399 of 636 patients assigned to pembrolizumab (62.7%), vs. 553 of 615 patients assigned to chemotherapy (89.9%).

Grade 3 or greater events occurred in 17.8% vs. 41% of patients, respectively, There were 13 deaths related to therapy in the pembrolizumab arm (2.0%), and 14 in the chemotherapy arm (2.3%).

Adverse events leading to discontinuation were similar between the groups, at 9% and 9.4%, respectively.

There were more immune-mediated adverse events in the pembrolizumab arm (27.8% vs. 7.2%), and of these, grade 3 or greater events occurred in 8% vs. 1.5% of patients, respectively.

There was one immune-mediated death, from pneumonitis, in the immunotherapy arm; there were no deaths related to immune-mediated side effects in the chemotherapy arm.

“I really view this as a ‘double whammy’ for patients,” Dr. Heymach said at the briefing. “Often advances in survival for our lung cancer patients come at the cost of significant toxicities. Here, by contrast, not only are patients living longer and having a much higher likelihood of prolonged survival in years, often instead of months, but they’re also receiving a treatment that has substantially less toxicity across virtually all measures, and this really impacts the day-to-day life of these patients.”

Leena Gandhi, MD, PhD, of the Perlmutter Cancer Center at New York University, the invited discussant at the plenary, agreed that pembrolizumab improves survival, compared with chemotherapy patients with PD-L1 expression levels greater than 1%, but noted that most of the benefit – as also seen in Keynote-024 – was in those patients whose tumors had high levels of PD-L1 expression.

She emphasized that although PD-L1 is an imperfect biomarker, it should still be used to help select patients for therapy, and may be complementary with tumor mutational burden for more precise treatment selection.

“What we know, and what this study adds to, is that PD-L1 really does define a patient population that could receive benefit from pembrolizumab over chemotherapy. Patients with low or no PD-L1 expression likely should get some type of combination therapy,” she said.

“I do think this study extends what we’ve seen from other recent studies, which is that chemotherapy alone is no longer a first-line standard of care in non–small-cell lung cancer,” she added.

Merck funded the study. Dr. Lopes disclosed institutional research funding from Merck Sharp & Dohme, EMD Serono, and AstraZeneca. Dr. Heymach disclosed stock/ownership in Bio-Tree and Cardinal Spine, a consulting or advisory role for Abbvie, ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Genentech, Medivation, Novartis, Oncomed, and Synta, and institutional research funding from AstraZeneca. Dr. Gandhi reported having no relevant disclosures.

SOURCE: Lobes G et al. ASCO 2018, abstract LBA4.

CHICAGO – Pembrolizumab (Keytruda) as first-line treatment of advanced non–small-cell lung cancer (NSCLC) offered longer overall survival with better tolerability compared with chemotherapy, results of the Keynote-042 phase 3 randomized trial show.

Among 1,274 patients with advanced, previously untreated NSCLC with expression of the PD-L1 on 1% or more of tumor cells, median overall survival after a median follow-up of 12.8 months was 16.7 months for patients treated with pembrolizumab monotherapy, compared with 12.1 months for patients treated with either paclitaxel or pemetrexed plus carboplatin, reported lead author Gilberto Lopes, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami.

Neil Osterweil/MDedge News

‘A true milestone’

ASCO expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, said at the briefing that “this study represents a true milestone for the field, because now, for the first time, we can say that among non–small-cell lung cancer patients receiving first-line therapy, the vast majority can receive immunotherapy with pembrolizumab instead of chemotherapy.”

He noted that an earlier study, Keynote-024, showed that pembrolizumab significantly improved progression-free survival in patients with tumors expressing PD-L1 on at least 50% of cells compared with standard platinum-based chemotherapy (10.3 vs. 6 months).

Neil Osterweil/MDedge News

As noted before, the primary endpoint of overall survival among all patients with a TPS of 1% or greater was met, with respective median overall survival in the pembrolizumab vs. chemotherapy groups of 16.7 vs. 12.1 months, translating into a hazard ratio favoring pembrolizumab of 0.81 (P = .0018). Respective hazard ratios for the TPS 20% or greater and TPS 50% or greater groups were 0.77 (P = .0020), and 0.69 (P = .0003).

At 12.8 months of median follow-up, 13% of patients assigned to pembrolizumab were still on the drug, and 4.3% of patients were receiving maintenance pemetrexed.

Treatment-related adverse events of any grade occurred in 399 of 636 patients assigned to pembrolizumab (62.7%), vs. 553 of 615 patients assigned to chemotherapy (89.9%).

Grade 3 or greater events occurred in 17.8% vs. 41% of patients, respectively, There were 13 deaths related to therapy in the pembrolizumab arm (2.0%), and 14 in the chemotherapy arm (2.3%).

Adverse events leading to discontinuation were similar between the groups, at 9% and 9.4%, respectively.

There were more immune-mediated adverse events in the pembrolizumab arm (27.8% vs. 7.2%), and of these, grade 3 or greater events occurred in 8% vs. 1.5% of patients, respectively.

There was one immune-mediated death, from pneumonitis, in the immunotherapy arm; there were no deaths related to immune-mediated side effects in the chemotherapy arm.

“I really view this as a ‘double whammy’ for patients,” Dr. Heymach said at the briefing. “Often advances in survival for our lung cancer patients come at the cost of significant toxicities. Here, by contrast, not only are patients living longer and having a much higher likelihood of prolonged survival in years, often instead of months, but they’re also receiving a treatment that has substantially less toxicity across virtually all measures, and this really impacts the day-to-day life of these patients.”

Leena Gandhi, MD, PhD, of the Perlmutter Cancer Center at New York University, the invited discussant at the plenary, agreed that pembrolizumab improves survival, compared with chemotherapy patients with PD-L1 expression levels greater than 1%, but noted that most of the benefit – as also seen in Keynote-024 – was in those patients whose tumors had high levels of PD-L1 expression.

She emphasized that although PD-L1 is an imperfect biomarker, it should still be used to help select patients for therapy, and may be complementary with tumor mutational burden for more precise treatment selection.

“What we know, and what this study adds to, is that PD-L1 really does define a patient population that could receive benefit from pembrolizumab over chemotherapy. Patients with low or no PD-L1 expression likely should get some type of combination therapy,” she said.

“I do think this study extends what we’ve seen from other recent studies, which is that chemotherapy alone is no longer a first-line standard of care in non–small-cell lung cancer,” she added.

Merck funded the study. Dr. Lopes disclosed institutional research funding from Merck Sharp & Dohme, EMD Serono, and AstraZeneca. Dr. Heymach disclosed stock/ownership in Bio-Tree and Cardinal Spine, a consulting or advisory role for Abbvie, ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Genentech, Medivation, Novartis, Oncomed, and Synta, and institutional research funding from AstraZeneca. Dr. Gandhi reported having no relevant disclosures.

SOURCE: Lobes G et al. ASCO 2018, abstract LBA4.

AIDS, the Vietnam War, whatever your preferred scale for measuring horrific events, the numbers from the opioid crisis are as grave or worse. And, once again, it is the young who are dying. How we got to this point is an unbelievable story of corporate greed, government incompetence, regulatory commission overreach, and, unfortunately, physician ignorance.

Every one of us has contributed to this tragedy, and most of us still do. There are some easy first steps surgeons can take, but first let’s review the mistakes made that drove our country into addiction.

BackyardProduction/Thinkstock

In 1995, as their patent on MS Contin was set to expire, Purdue Pharma gained Food and Drug Administration approval for OxyContin (“contin” is pharma talk for continuous). At this time, opioids generally were considered to be dangerous and mainly prescribed for cancer or end-of-life patients. Purdue representatives began an aggressive marketing campaign to break out of this niche. They were aided in this pursuit by the FDA, which wrote in the package insert that iatrogenic addiction was rare and the delayed absorption of OxyContin “is believed to reduce the abuse liability of a drug.” These statements were made without the backing of any clinical trials. But with an on-label statement of reduced addiction risk, representatives could sell OxyContin based on a diminished potential for abuse.

In addition to oncologists, the drug was now marketed to rheumatologists, primary care physicians, and surgeons. OxyContin, therefore, broke through the cancer barrier and became one of the most widely prescribed painkillers in the United States. While generating billions in profits, OxyContin also would become one of the most abused drugs in history.

There were several issues with OxyContin that led to its widespread misuse. The preparation contained up to 160 mg of oxycodone per pill, 16 times more than the strongest Percocet formulary. The tablet also could easily be crushed, overcoming the delayed-release formulation. Because of the FDA insert, sales representatives were free to report an addiction risk of less than 1%, which they did. Widely.

But what science backed this claim? The study referenced was not a study at all. The citation was a one-paragraph, five-sentence letter to the editor published by the New England Journal of Medicine in 1980. In it, the authors briefly described their experience with inpatient opioid therapy. No reference was made to outpatient opioid prescriptions. Still, this letter has been scientifically cited more than 600 times, with a spike starting in 1995, the year OxyContin was released. Even as thousands of Americans were dying each year from opioid use, the “study” continued to be offered as proof of a low risk of addiction. As recently as 2014, the letter was cited in the journal OncoTargets and Therapy to support the statement, “In reality, medical opioid addiction is very rare.”

Maybe if we knew our history we could avoid repeating it. Previously, the drug diacetylmorphine was introduced as a safe, nonaddictive substitute for morphine by Bayer Pharmaceutical in the late 1890s. Diacetylmorphine is better known by its trademarked name, Heroin.

In 1996, the American Pain Society and the American Academy of Pain Medicine formed a committee to issue a joint statement that advocated opioid use for chronic pain and again stating a low risk of addiction. The committee was chaired by J. David Haddox, DDS, MD, a paid speaker (and later executive) for Purdue Pharma. The American Pain Society also launched a campaign to treat pain more aggressively. “Pain is the fifth vital sign” became a far-reaching strategy, which was adopted by the Department of Veterans Affairs and, ultimately, nearly every hospital in the country. The campaign was so successful that, in 2001, the Joint Commission required hospitals to:

• Assess pain in every patient.
• Record the results.
• Provide treatment for the pain.
• Reassess the effectiveness of the treatment.
• Teach staff how to manage pain.

The Joint Commission is not alone in creating opioid-friendly regulations. The Hospital Consumer Assessment of Healthcare Providers and Systems surveys patients after hospital stays. Several of the questions include pain management. One asks the patient whether the hospital staff did “everything they could” to assist with the patient’s pain. The satisfaction scores from these surveys are directly tied to hospital payments.

In 1998, the Federation of State Medical Boards published a statement reassuring doctors that they would not be punished for prescribing even large amounts of opioids if it were in the course of medical treatment. In 2004, the FSMB went further, stating that medical boards should consider “undertreatment of pain” to be a “departure from an acceptable standard of practice,” suggesting that state medical boards should sanction doctors who undertreated pain. According to a report by Catan et al. in the Wall Street Journal, this policy was drawn up with help from Dr. Haddox, who is now a senior executive with Purdue. The FSMB also would later disclose nearly $2 million in funding from opioid manufacturers.

These regulatory groups created widespread legal and financial pressure for doctors to diagnose and quickly treat pain in every patient. But what resources did we have to do this swiftly and effectively? Opioid prescriptions soared. There were 116 million opioid prescriptions issued in 1999; by 2013, it was 207 million. Annually, there are now more opioid prescriptions filled in the United States than there are people. Overdose deaths rose 500% between 1999 and 2016. Last year, there were more than 42,000 opioid-related mortalities in the United States. Like an untended fire, the crisis now spreads unabated.

What about vascular surgeons? Few of us prescribe OxyContin. Surely the 30 Percocets we give out after surgery are safe? In reality, Percocet contains oxycodone, the same opioid found in OxyContin, and therefore, carries a high risk of addiction. Norco, Vicodin, and Lortab all contain the opioid hydrocodone. Some studies have shown a higher risk of addiction with oxycodone, but all opioids carry a significant danger of abuse and dependence. As surgeons, we came into to this crisis with little or no training. This made us susceptible to bad science, bad-faith marketing, and bad ideas from regulatory commissions. Most of us learned how to prescribe postop opioids during the “hidden curriculum” of our third and fourth years of medical school: In other words, the residents taught us. Much like learning sex education on the streets, your mileage may vary. It is no wonder that a 2016 JAMA Internal Medicine news release found that simply having surgery was a risk factor for developing an opioid addiction. Surgeons don’t have an evidence-based plan to treat postoperative pain with opioids. About 6.5% of patients are still taking “postop” opioids 3-6 months after minor surgery; the numbers are about the same for major surgery (5.9%). Therefore, it is unlikely that pain is driving this chronic use.

Richard J. Barth Jr., MD, of Dartmouth-Hitchcock Medical Center in Lebanon, N.H., has studied opioid use following surgery extensively. He found there is a wide variety in surgeons’ opioid-prescribing habits and most of us overprescribe. In one study, 72% of the prescribed pills after surgery were not taken. He recommends the following guideline for opioid prescriptions after inpatient surgical procedures: If the patient took no opioids the day before discharge, no script is needed. For patients taking 1-3 pills the day before discharge, 15 pills are given; and for those taking 4 or more pills, a script for 30 is given.

As vascular surgeons, we must break out of our bubble and address our contributions to this crisis. It is past time to look at our own habits. Overprescribing is dangerous; the excess pills often are found by abusers, sold, or used recreationally by others in the household. Some patients take all of the pills simply because that is what the doctor prescribed; to the patient, he or she is merely following the doctor’s orders, and therefore not engaging in a risky behavior.

As vascular surgeons, there are several steps we can take immediately to reduce our contributions to the opioid epidemic and protect our patients:

• Always use the lowest effective dose of opioids and dramatically reduce the number of pills in your postop scripts. Fewer than 15 pills will cover most surgeries we perform.
• New data show that acetaminophen combined with ibuprofen works better for acute pain than acetaminophen combined with an opioid. Increase your use of nonnarcotic pain medications.
• Counsel your patients on the risk of addiction. If you plan to issue a script with only a few pills or nonnarcotics, let them know why in advance.
• Use caution when prescribing opioids to patients with anxiety or depression. The risk of addiction is much higher in these patients because of the anxiolytic and antidepressant qualities that opioids have.
• Avoid opioids in patients taking benzodiazepines, which can exacerbate the risk of respiratory depression and death.
• Help patients safely dispose of unused opioids.
• Use drug-monitoring programs whenever available.
• Use opioids for acute pain only. We do not have the training to manage long-term use.

Meanwhile, OxyContin still is available and sold exclusively by Purdue Pharma. Before its patent expired, Purdue altered the formulation to make it harder to abuse when crushing the tablets. They then lobbied the FDA to block generic production of the original formula because it was “unsafe.” Though Purdue (under Mundipharma) now markets this original version in South America, Europe, and Asia.

Many lawsuits have been brought against Purdue. Even with such high-profile lawyers as Rudy Giuliani and Eric Holder, Purdue has paid more than $600 million in fines and pleaded guilty to marketing OxyContin with “the intent to defraud or mislead.” Three Purdue executives have pleaded guilty to criminal misdemeanor charges.

In 2015, the FDA approved marketing OxyContin to children as young as age 11 years..

To address their role in the opioid crisis, the Joint Commission issued a statement on April 18, 2016. It was not a master class in self-awareness; the statement claimed that it is a “misconception” that Joint Commission standards pushed doctors to prescribe opioids. Yet, according to a Class Action complaint (Kenova v. JCAHO), in a 2001 monograph published by the Joint Commission (and funded by Purdue Pharma), they wrote “Some clinicians have inaccurate and exaggerated concerns about addiction, tolerance, and risk of death. This attitude prevails despite the fact that there is no evidence that addiction is a significant issue when persons are given opioids for pain control.”

In 2016, the AMA passed a resolution to drop pain as a vital sign. They also urged the Joint Commission to stop requiring hospitals to ask patients about the quality of their pain care. The American College of Surgeons has started an education initiative to help surgeons and patients learn about opioids and surgery (funded by Pacira Pharmaceuticals, makers of EXPAREL, an injectable long-lasting local anesthetic). In a March 2016 statement in the New England Journal of Medicine, Centers for Disease Control and Prevention representatives said of opioids “We know of no other medication routinely used for a nonfatal condition that kills patients so frequently.” As vascular surgeons, we are long overdue for a self-assessment. It is now time to change our practices and habits to help end this national addiction.

Dr. Sheahan is the Claude C. Craighead Jr. Professor and chair, division of vascular and endovascular surgery, Louisiana State University Health Sciences Center, New Orleans.

Resources

1. Hill M et al. Guideline for discharge opioid prescriptions after inpatient general surgical procedures. J Am Coll Surg. In Press.

2. Kenova v. JCAHO Class Action Complaint. United States District Court for the Southern District of West Virginia.

3. Mandell BF. The fifth vital sign: a complex story of politics and patient care. Cleveland Clinic Journal of Medicine 2016 Jun:83:400.

4. Leung PT et al. A 1980 letter on the risk of opioid addiction. New England Journal of Medicine 2017;376:2194-5.

5. www.jointcommission.org/joint_commission_statement_on_pain_management

6. www.cdc.gov/drugoverdose/epidemic/index.html

7. Catan T et al. A pain-drug champion has second thoughts. Wall Street Journal. Dec. 17, 2012 (updated online version).

8. Federation of State Medical Boards news release. www.fsmb.org/globalassets/advocacy/news-releases/2014/rems-grant-press-release-jan2014-final.pdf

9. Chou R et al. American Pain Society – American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009;10:113-130.

10. Van Zee A. The promotion and marketing of OxyContin: Commercial triumph, public health tragedy. Am J Public Health 2009;99:221-7.

11. Keefe, PR. The family that built an empire of pain. The New Yorker. October 30, 2017.

AIDS, the Vietnam War, whatever your preferred scale for measuring horrific events, the numbers from the opioid crisis are as grave or worse. And, once again, it is the young who are dying. How we got to this point is an unbelievable story of corporate greed, government incompetence, regulatory commission overreach, and, unfortunately, physician ignorance.

Every one of us has contributed to this tragedy, and most of us still do. There are some easy first steps surgeons can take, but first let’s review the mistakes made that drove our country into addiction.

BackyardProduction/Thinkstock

In 1995, as their patent on MS Contin was set to expire, Purdue Pharma gained Food and Drug Administration approval for OxyContin (“contin” is pharma talk for continuous). At this time, opioids generally were considered to be dangerous and mainly prescribed for cancer or end-of-life patients. Purdue representatives began an aggressive marketing campaign to break out of this niche. They were aided in this pursuit by the FDA, which wrote in the package insert that iatrogenic addiction was rare and the delayed absorption of OxyContin “is believed to reduce the abuse liability of a drug.” These statements were made without the backing of any clinical trials. But with an on-label statement of reduced addiction risk, representatives could sell OxyContin based on a diminished potential for abuse.

In addition to oncologists, the drug was now marketed to rheumatologists, primary care physicians, and surgeons. OxyContin, therefore, broke through the cancer barrier and became one of the most widely prescribed painkillers in the United States. While generating billions in profits, OxyContin also would become one of the most abused drugs in history.

There were several issues with OxyContin that led to its widespread misuse. The preparation contained up to 160 mg of oxycodone per pill, 16 times more than the strongest Percocet formulary. The tablet also could easily be crushed, overcoming the delayed-release formulation. Because of the FDA insert, sales representatives were free to report an addiction risk of less than 1%, which they did. Widely.

But what science backed this claim? The study referenced was not a study at all. The citation was a one-paragraph, five-sentence letter to the editor published by the New England Journal of Medicine in 1980. In it, the authors briefly described their experience with inpatient opioid therapy. No reference was made to outpatient opioid prescriptions. Still, this letter has been scientifically cited more than 600 times, with a spike starting in 1995, the year OxyContin was released. Even as thousands of Americans were dying each year from opioid use, the “study” continued to be offered as proof of a low risk of addiction. As recently as 2014, the letter was cited in the journal OncoTargets and Therapy to support the statement, “In reality, medical opioid addiction is very rare.”

Maybe if we knew our history we could avoid repeating it. Previously, the drug diacetylmorphine was introduced as a safe, nonaddictive substitute for morphine by Bayer Pharmaceutical in the late 1890s. Diacetylmorphine is better known by its trademarked name, Heroin.

In 1996, the American Pain Society and the American Academy of Pain Medicine formed a committee to issue a joint statement that advocated opioid use for chronic pain and again stating a low risk of addiction. The committee was chaired by J. David Haddox, DDS, MD, a paid speaker (and later executive) for Purdue Pharma. The American Pain Society also launched a campaign to treat pain more aggressively. “Pain is the fifth vital sign” became a far-reaching strategy, which was adopted by the Department of Veterans Affairs and, ultimately, nearly every hospital in the country. The campaign was so successful that, in 2001, the Joint Commission required hospitals to:

• Assess pain in every patient.
• Record the results.
• Provide treatment for the pain.
• Reassess the effectiveness of the treatment.
• Teach staff how to manage pain.

The Joint Commission is not alone in creating opioid-friendly regulations. The Hospital Consumer Assessment of Healthcare Providers and Systems surveys patients after hospital stays. Several of the questions include pain management. One asks the patient whether the hospital staff did “everything they could” to assist with the patient’s pain. The satisfaction scores from these surveys are directly tied to hospital payments.

In 1998, the Federation of State Medical Boards published a statement reassuring doctors that they would not be punished for prescribing even large amounts of opioids if it were in the course of medical treatment. In 2004, the FSMB went further, stating that medical boards should consider “undertreatment of pain” to be a “departure from an acceptable standard of practice,” suggesting that state medical boards should sanction doctors who undertreated pain. According to a report by Catan et al. in the Wall Street Journal, this policy was drawn up with help from Dr. Haddox, who is now a senior executive with Purdue. The FSMB also would later disclose nearly $2 million in funding from opioid manufacturers.

These regulatory groups created widespread legal and financial pressure for doctors to diagnose and quickly treat pain in every patient. But what resources did we have to do this swiftly and effectively? Opioid prescriptions soared. There were 116 million opioid prescriptions issued in 1999; by 2013, it was 207 million. Annually, there are now more opioid prescriptions filled in the United States than there are people. Overdose deaths rose 500% between 1999 and 2016. Last year, there were more than 42,000 opioid-related mortalities in the United States. Like an untended fire, the crisis now spreads unabated.

What about vascular surgeons? Few of us prescribe OxyContin. Surely the 30 Percocets we give out after surgery are safe? In reality, Percocet contains oxycodone, the same opioid found in OxyContin, and therefore, carries a high risk of addiction. Norco, Vicodin, and Lortab all contain the opioid hydrocodone. Some studies have shown a higher risk of addiction with oxycodone, but all opioids carry a significant danger of abuse and dependence. As surgeons, we came into to this crisis with little or no training. This made us susceptible to bad science, bad-faith marketing, and bad ideas from regulatory commissions. Most of us learned how to prescribe postop opioids during the “hidden curriculum” of our third and fourth years of medical school: In other words, the residents taught us. Much like learning sex education on the streets, your mileage may vary. It is no wonder that a 2016 JAMA Internal Medicine news release found that simply having surgery was a risk factor for developing an opioid addiction. Surgeons don’t have an evidence-based plan to treat postoperative pain with opioids. About 6.5% of patients are still taking “postop” opioids 3-6 months after minor surgery; the numbers are about the same for major surgery (5.9%). Therefore, it is unlikely that pain is driving this chronic use.

Richard J. Barth Jr., MD, of Dartmouth-Hitchcock Medical Center in Lebanon, N.H., has studied opioid use following surgery extensively. He found there is a wide variety in surgeons’ opioid-prescribing habits and most of us overprescribe. In one study, 72% of the prescribed pills after surgery were not taken. He recommends the following guideline for opioid prescriptions after inpatient surgical procedures: If the patient took no opioids the day before discharge, no script is needed. For patients taking 1-3 pills the day before discharge, 15 pills are given; and for those taking 4 or more pills, a script for 30 is given.

As vascular surgeons, we must break out of our bubble and address our contributions to this crisis. It is past time to look at our own habits. Overprescribing is dangerous; the excess pills often are found by abusers, sold, or used recreationally by others in the household. Some patients take all of the pills simply because that is what the doctor prescribed; to the patient, he or she is merely following the doctor’s orders, and therefore not engaging in a risky behavior.

As vascular surgeons, there are several steps we can take immediately to reduce our contributions to the opioid epidemic and protect our patients:

• Always use the lowest effective dose of opioids and dramatically reduce the number of pills in your postop scripts. Fewer than 15 pills will cover most surgeries we perform.
• New data show that acetaminophen combined with ibuprofen works better for acute pain than acetaminophen combined with an opioid. Increase your use of nonnarcotic pain medications.
• Counsel your patients on the risk of addiction. If you plan to issue a script with only a few pills or nonnarcotics, let them know why in advance.
• Use caution when prescribing opioids to patients with anxiety or depression. The risk of addiction is much higher in these patients because of the anxiolytic and antidepressant qualities that opioids have.
• Avoid opioids in patients taking benzodiazepines, which can exacerbate the risk of respiratory depression and death.
• Help patients safely dispose of unused opioids.
• Use drug-monitoring programs whenever available.
• Use opioids for acute pain only. We do not have the training to manage long-term use.

Meanwhile, OxyContin still is available and sold exclusively by Purdue Pharma. Before its patent expired, Purdue altered the formulation to make it harder to abuse when crushing the tablets. They then lobbied the FDA to block generic production of the original formula because it was “unsafe.” Though Purdue (under Mundipharma) now markets this original version in South America, Europe, and Asia.

Many lawsuits have been brought against Purdue. Even with such high-profile lawyers as Rudy Giuliani and Eric Holder, Purdue has paid more than $600 million in fines and pleaded guilty to marketing OxyContin with “the intent to defraud or mislead.” Three Purdue executives have pleaded guilty to criminal misdemeanor charges.

In 2015, the FDA approved marketing OxyContin to children as young as age 11 years..

To address their role in the opioid crisis, the Joint Commission issued a statement on April 18, 2016. It was not a master class in self-awareness; the statement claimed that it is a “misconception” that Joint Commission standards pushed doctors to prescribe opioids. Yet, according to a Class Action complaint (Kenova v. JCAHO), in a 2001 monograph published by the Joint Commission (and funded by Purdue Pharma), they wrote “Some clinicians have inaccurate and exaggerated concerns about addiction, tolerance, and risk of death. This attitude prevails despite the fact that there is no evidence that addiction is a significant issue when persons are given opioids for pain control.”

In 2016, the AMA passed a resolution to drop pain as a vital sign. They also urged the Joint Commission to stop requiring hospitals to ask patients about the quality of their pain care. The American College of Surgeons has started an education initiative to help surgeons and patients learn about opioids and surgery (funded by Pacira Pharmaceuticals, makers of EXPAREL, an injectable long-lasting local anesthetic). In a March 2016 statement in the New England Journal of Medicine, Centers for Disease Control and Prevention representatives said of opioids “We know of no other medication routinely used for a nonfatal condition that kills patients so frequently.” As vascular surgeons, we are long overdue for a self-assessment. It is now time to change our practices and habits to help end this national addiction.

Dr. Sheahan is the Claude C. Craighead Jr. Professor and chair, division of vascular and endovascular surgery, Louisiana State University Health Sciences Center, New Orleans.

Resources

1. Hill M et al. Guideline for discharge opioid prescriptions after inpatient general surgical procedures. J Am Coll Surg. In Press.

2. Kenova v. JCAHO Class Action Complaint. United States District Court for the Southern District of West Virginia.

3. Mandell BF. The fifth vital sign: a complex story of politics and patient care. Cleveland Clinic Journal of Medicine 2016 Jun:83:400.

4. Leung PT et al. A 1980 letter on the risk of opioid addiction. New England Journal of Medicine 2017;376:2194-5.

5. www.jointcommission.org/joint_commission_statement_on_pain_management

6. www.cdc.gov/drugoverdose/epidemic/index.html

7. Catan T et al. A pain-drug champion has second thoughts. Wall Street Journal. Dec. 17, 2012 (updated online version).

8. Federation of State Medical Boards news release. www.fsmb.org/globalassets/advocacy/news-releases/2014/rems-grant-press-release-jan2014-final.pdf

9. Chou R et al. American Pain Society – American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009;10:113-130.

10. Van Zee A. The promotion and marketing of OxyContin: Commercial triumph, public health tragedy. Am J Public Health 2009;99:221-7.

11. Keefe, PR. The family that built an empire of pain. The New Yorker. October 30, 2017.

AIDS, the Vietnam War, whatever your preferred scale for measuring horrific events, the numbers from the opioid crisis are as grave or worse. And, once again, it is the young who are dying. How we got to this point is an unbelievable story of corporate greed, government incompetence, regulatory commission overreach, and, unfortunately, physician ignorance.

Every one of us has contributed to this tragedy, and most of us still do. There are some easy first steps surgeons can take, but first let’s review the mistakes made that drove our country into addiction.

BackyardProduction/Thinkstock

In 1995, as their patent on MS Contin was set to expire, Purdue Pharma gained Food and Drug Administration approval for OxyContin (“contin” is pharma talk for continuous). At this time, opioids generally were considered to be dangerous and mainly prescribed for cancer or end-of-life patients. Purdue representatives began an aggressive marketing campaign to break out of this niche. They were aided in this pursuit by the FDA, which wrote in the package insert that iatrogenic addiction was rare and the delayed absorption of OxyContin “is believed to reduce the abuse liability of a drug.” These statements were made without the backing of any clinical trials. But with an on-label statement of reduced addiction risk, representatives could sell OxyContin based on a diminished potential for abuse.

In addition to oncologists, the drug was now marketed to rheumatologists, primary care physicians, and surgeons. OxyContin, therefore, broke through the cancer barrier and became one of the most widely prescribed painkillers in the United States. While generating billions in profits, OxyContin also would become one of the most abused drugs in history.

There were several issues with OxyContin that led to its widespread misuse. The preparation contained up to 160 mg of oxycodone per pill, 16 times more than the strongest Percocet formulary. The tablet also could easily be crushed, overcoming the delayed-release formulation. Because of the FDA insert, sales representatives were free to report an addiction risk of less than 1%, which they did. Widely.

But what science backed this claim? The study referenced was not a study at all. The citation was a one-paragraph, five-sentence letter to the editor published by the New England Journal of Medicine in 1980. In it, the authors briefly described their experience with inpatient opioid therapy. No reference was made to outpatient opioid prescriptions. Still, this letter has been scientifically cited more than 600 times, with a spike starting in 1995, the year OxyContin was released. Even as thousands of Americans were dying each year from opioid use, the “study” continued to be offered as proof of a low risk of addiction. As recently as 2014, the letter was cited in the journal OncoTargets and Therapy to support the statement, “In reality, medical opioid addiction is very rare.”

Maybe if we knew our history we could avoid repeating it. Previously, the drug diacetylmorphine was introduced as a safe, nonaddictive substitute for morphine by Bayer Pharmaceutical in the late 1890s. Diacetylmorphine is better known by its trademarked name, Heroin.

In 1996, the American Pain Society and the American Academy of Pain Medicine formed a committee to issue a joint statement that advocated opioid use for chronic pain and again stating a low risk of addiction. The committee was chaired by J. David Haddox, DDS, MD, a paid speaker (and later executive) for Purdue Pharma. The American Pain Society also launched a campaign to treat pain more aggressively. “Pain is the fifth vital sign” became a far-reaching strategy, which was adopted by the Department of Veterans Affairs and, ultimately, nearly every hospital in the country. The campaign was so successful that, in 2001, the Joint Commission required hospitals to:

• Assess pain in every patient.
• Record the results.
• Provide treatment for the pain.
• Reassess the effectiveness of the treatment.
• Teach staff how to manage pain.

The Joint Commission is not alone in creating opioid-friendly regulations. The Hospital Consumer Assessment of Healthcare Providers and Systems surveys patients after hospital stays. Several of the questions include pain management. One asks the patient whether the hospital staff did “everything they could” to assist with the patient’s pain. The satisfaction scores from these surveys are directly tied to hospital payments.

In 1998, the Federation of State Medical Boards published a statement reassuring doctors that they would not be punished for prescribing even large amounts of opioids if it were in the course of medical treatment. In 2004, the FSMB went further, stating that medical boards should consider “undertreatment of pain” to be a “departure from an acceptable standard of practice,” suggesting that state medical boards should sanction doctors who undertreated pain. According to a report by Catan et al. in the Wall Street Journal, this policy was drawn up with help from Dr. Haddox, who is now a senior executive with Purdue. The FSMB also would later disclose nearly $2 million in funding from opioid manufacturers.

These regulatory groups created widespread legal and financial pressure for doctors to diagnose and quickly treat pain in every patient. But what resources did we have to do this swiftly and effectively? Opioid prescriptions soared. There were 116 million opioid prescriptions issued in 1999; by 2013, it was 207 million. Annually, there are now more opioid prescriptions filled in the United States than there are people. Overdose deaths rose 500% between 1999 and 2016. Last year, there were more than 42,000 opioid-related mortalities in the United States. Like an untended fire, the crisis now spreads unabated.

What about vascular surgeons? Few of us prescribe OxyContin. Surely the 30 Percocets we give out after surgery are safe? In reality, Percocet contains oxycodone, the same opioid found in OxyContin, and therefore, carries a high risk of addiction. Norco, Vicodin, and Lortab all contain the opioid hydrocodone. Some studies have shown a higher risk of addiction with oxycodone, but all opioids carry a significant danger of abuse and dependence. As surgeons, we came into to this crisis with little or no training. This made us susceptible to bad science, bad-faith marketing, and bad ideas from regulatory commissions. Most of us learned how to prescribe postop opioids during the “hidden curriculum” of our third and fourth years of medical school: In other words, the residents taught us. Much like learning sex education on the streets, your mileage may vary. It is no wonder that a 2016 JAMA Internal Medicine news release found that simply having surgery was a risk factor for developing an opioid addiction. Surgeons don’t have an evidence-based plan to treat postoperative pain with opioids. About 6.5% of patients are still taking “postop” opioids 3-6 months after minor surgery; the numbers are about the same for major surgery (5.9%). Therefore, it is unlikely that pain is driving this chronic use.

Richard J. Barth Jr., MD, of Dartmouth-Hitchcock Medical Center in Lebanon, N.H., has studied opioid use following surgery extensively. He found there is a wide variety in surgeons’ opioid-prescribing habits and most of us overprescribe. In one study, 72% of the prescribed pills after surgery were not taken. He recommends the following guideline for opioid prescriptions after inpatient surgical procedures: If the patient took no opioids the day before discharge, no script is needed. For patients taking 1-3 pills the day before discharge, 15 pills are given; and for those taking 4 or more pills, a script for 30 is given.

As vascular surgeons, we must break out of our bubble and address our contributions to this crisis. It is past time to look at our own habits. Overprescribing is dangerous; the excess pills often are found by abusers, sold, or used recreationally by others in the household. Some patients take all of the pills simply because that is what the doctor prescribed; to the patient, he or she is merely following the doctor’s orders, and therefore not engaging in a risky behavior.

As vascular surgeons, there are several steps we can take immediately to reduce our contributions to the opioid epidemic and protect our patients:

• Always use the lowest effective dose of opioids and dramatically reduce the number of pills in your postop scripts. Fewer than 15 pills will cover most surgeries we perform.
• New data show that acetaminophen combined with ibuprofen works better for acute pain than acetaminophen combined with an opioid. Increase your use of nonnarcotic pain medications.
• Counsel your patients on the risk of addiction. If you plan to issue a script with only a few pills or nonnarcotics, let them know why in advance.
• Use caution when prescribing opioids to patients with anxiety or depression. The risk of addiction is much higher in these patients because of the anxiolytic and antidepressant qualities that opioids have.
• Avoid opioids in patients taking benzodiazepines, which can exacerbate the risk of respiratory depression and death.
• Help patients safely dispose of unused opioids.
• Use drug-monitoring programs whenever available.
• Use opioids for acute pain only. We do not have the training to manage long-term use.

Meanwhile, OxyContin still is available and sold exclusively by Purdue Pharma. Before its patent expired, Purdue altered the formulation to make it harder to abuse when crushing the tablets. They then lobbied the FDA to block generic production of the original formula because it was “unsafe.” Though Purdue (under Mundipharma) now markets this original version in South America, Europe, and Asia.

Many lawsuits have been brought against Purdue. Even with such high-profile lawyers as Rudy Giuliani and Eric Holder, Purdue has paid more than $600 million in fines and pleaded guilty to marketing OxyContin with “the intent to defraud or mislead.” Three Purdue executives have pleaded guilty to criminal misdemeanor charges.

In 2015, the FDA approved marketing OxyContin to children as young as age 11 years..

To address their role in the opioid crisis, the Joint Commission issued a statement on April 18, 2016. It was not a master class in self-awareness; the statement claimed that it is a “misconception” that Joint Commission standards pushed doctors to prescribe opioids. Yet, according to a Class Action complaint (Kenova v. JCAHO), in a 2001 monograph published by the Joint Commission (and funded by Purdue Pharma), they wrote “Some clinicians have inaccurate and exaggerated concerns about addiction, tolerance, and risk of death. This attitude prevails despite the fact that there is no evidence that addiction is a significant issue when persons are given opioids for pain control.”

In 2016, the AMA passed a resolution to drop pain as a vital sign. They also urged the Joint Commission to stop requiring hospitals to ask patients about the quality of their pain care. The American College of Surgeons has started an education initiative to help surgeons and patients learn about opioids and surgery (funded by Pacira Pharmaceuticals, makers of EXPAREL, an injectable long-lasting local anesthetic). In a March 2016 statement in the New England Journal of Medicine, Centers for Disease Control and Prevention representatives said of opioids “We know of no other medication routinely used for a nonfatal condition that kills patients so frequently.” As vascular surgeons, we are long overdue for a self-assessment. It is now time to change our practices and habits to help end this national addiction.

Dr. Sheahan is the Claude C. Craighead Jr. Professor and chair, division of vascular and endovascular surgery, Louisiana State University Health Sciences Center, New Orleans.

Resources

1. Hill M et al. Guideline for discharge opioid prescriptions after inpatient general surgical procedures. J Am Coll Surg. In Press.

2. Kenova v. JCAHO Class Action Complaint. United States District Court for the Southern District of West Virginia.

3. Mandell BF. The fifth vital sign: a complex story of politics and patient care. Cleveland Clinic Journal of Medicine 2016 Jun:83:400.

4. Leung PT et al. A 1980 letter on the risk of opioid addiction. New England Journal of Medicine 2017;376:2194-5.

5. www.jointcommission.org/joint_commission_statement_on_pain_management

6. www.cdc.gov/drugoverdose/epidemic/index.html

7. Catan T et al. A pain-drug champion has second thoughts. Wall Street Journal. Dec. 17, 2012 (updated online version).

8. Federation of State Medical Boards news release. www.fsmb.org/globalassets/advocacy/news-releases/2014/rems-grant-press-release-jan2014-final.pdf

9. Chou R et al. American Pain Society – American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009;10:113-130.

10. Van Zee A. The promotion and marketing of OxyContin: Commercial triumph, public health tragedy. Am J Public Health 2009;99:221-7.

11. Keefe, PR. The family that built an empire of pain. The New Yorker. October 30, 2017.

The Insomnia Severity Index might be the most effective screening tool at identifying insomnia among outpatients with mental disorders, according to a study published in Sleep Medicine.

The cross-sectional study compared six self-administered sleep measures – the Pittsburgh Sleep Quality Index, Insomnia Severity Index (ISI), Epworth Sleepiness Scale, Flinders Fatigue Scale, Functional Outcomes of Sleep Questionnaire, and Dysfunctional Beliefs and Attitudes about Sleep scale – in 400 psychiatric outpatients.

Of those, the Insomnia Severity Index was the most accurate way to discriminate between cases of insomnia and noncases according to both the DSM-5 and ICD-10 criteria. In fact, the Insomnia Severity Index was the only scale that was able to discriminate both with good accuracy.

The area under the curve for the ISI was 0.88 for the ICD definition, and 0.82 for the DSM-5 criteria. Researchers found that the best sensitivity and specificity for the ISI was achieved using cutoff scores of less than or equal to 14 for ICD-10 insomnia and less than or equal to 11 for DSM-5 insomnia.

A cutoff of 14 or above for the ISI yielded a sensitivity of 81.3%, specificity of 80.9%, positive predictive value of 66.7%, and negative predictive value of 90.2%.

The Pittsburgh Sleep Quality Index was found to have good accuracy in discriminating between cases and noncases using the ICD-10 criteria, but only had fair accuracy for the DSM-5 criteria. However, it was slightly better than the ISI at detecting insomnia cases, according to the DSM-5 criteria, in people with either bipolar affective or anxiety disorders.

The Flinders Fatigue Scale, Functional Outcomes of Sleep Questionnaire, and Dysfunctional Beliefs and Attitudes about Sleep scale all showed fair accuracy for the ICD-10 criteria but low accuracy for the DSM-5 criteria, while the Epworth Sleepiness Scale had low accuracy for the ICD-10 criteria and was nondiscriminatory for the DSM-5 criteria.

SOURCE: Seow LSE et al. Sleep Med. 2018 Jan;41:86-93.
 

The Insomnia Severity Index might be the most effective screening tool at identifying insomnia among outpatients with mental disorders, according to a study published in Sleep Medicine.

The cross-sectional study compared six self-administered sleep measures – the Pittsburgh Sleep Quality Index, Insomnia Severity Index (ISI), Epworth Sleepiness Scale, Flinders Fatigue Scale, Functional Outcomes of Sleep Questionnaire, and Dysfunctional Beliefs and Attitudes about Sleep scale – in 400 psychiatric outpatients.

Of those, the Insomnia Severity Index was the most accurate way to discriminate between cases of insomnia and noncases according to both the DSM-5 and ICD-10 criteria. In fact, the Insomnia Severity Index was the only scale that was able to discriminate both with good accuracy.

The area under the curve for the ISI was 0.88 for the ICD definition, and 0.82 for the DSM-5 criteria. Researchers found that the best sensitivity and specificity for the ISI was achieved using cutoff scores of less than or equal to 14 for ICD-10 insomnia and less than or equal to 11 for DSM-5 insomnia.

A cutoff of 14 or above for the ISI yielded a sensitivity of 81.3%, specificity of 80.9%, positive predictive value of 66.7%, and negative predictive value of 90.2%.

The Pittsburgh Sleep Quality Index was found to have good accuracy in discriminating between cases and noncases using the ICD-10 criteria, but only had fair accuracy for the DSM-5 criteria. However, it was slightly better than the ISI at detecting insomnia cases, according to the DSM-5 criteria, in people with either bipolar affective or anxiety disorders.

The Flinders Fatigue Scale, Functional Outcomes of Sleep Questionnaire, and Dysfunctional Beliefs and Attitudes about Sleep scale all showed fair accuracy for the ICD-10 criteria but low accuracy for the DSM-5 criteria, while the Epworth Sleepiness Scale had low accuracy for the ICD-10 criteria and was nondiscriminatory for the DSM-5 criteria.

SOURCE: Seow LSE et al. Sleep Med. 2018 Jan;41:86-93.
 

The Insomnia Severity Index might be the most effective screening tool at identifying insomnia among outpatients with mental disorders, according to a study published in Sleep Medicine.

The cross-sectional study compared six self-administered sleep measures – the Pittsburgh Sleep Quality Index, Insomnia Severity Index (ISI), Epworth Sleepiness Scale, Flinders Fatigue Scale, Functional Outcomes of Sleep Questionnaire, and Dysfunctional Beliefs and Attitudes about Sleep scale – in 400 psychiatric outpatients.

Of those, the Insomnia Severity Index was the most accurate way to discriminate between cases of insomnia and noncases according to both the DSM-5 and ICD-10 criteria. In fact, the Insomnia Severity Index was the only scale that was able to discriminate both with good accuracy.

The area under the curve for the ISI was 0.88 for the ICD definition, and 0.82 for the DSM-5 criteria. Researchers found that the best sensitivity and specificity for the ISI was achieved using cutoff scores of less than or equal to 14 for ICD-10 insomnia and less than or equal to 11 for DSM-5 insomnia.

A cutoff of 14 or above for the ISI yielded a sensitivity of 81.3%, specificity of 80.9%, positive predictive value of 66.7%, and negative predictive value of 90.2%.

The Pittsburgh Sleep Quality Index was found to have good accuracy in discriminating between cases and noncases using the ICD-10 criteria, but only had fair accuracy for the DSM-5 criteria. However, it was slightly better than the ISI at detecting insomnia cases, according to the DSM-5 criteria, in people with either bipolar affective or anxiety disorders.

The Flinders Fatigue Scale, Functional Outcomes of Sleep Questionnaire, and Dysfunctional Beliefs and Attitudes about Sleep scale all showed fair accuracy for the ICD-10 criteria but low accuracy for the DSM-5 criteria, while the Epworth Sleepiness Scale had low accuracy for the ICD-10 criteria and was nondiscriminatory for the DSM-5 criteria.

SOURCE: Seow LSE et al. Sleep Med. 2018 Jan;41:86-93.