SILVER SPRING, MD. – With the unanimous support of a Food and Drug Administration advisory panel and a favorable review by the agency, a “biosimilar” version of filgrastim, the recombinant granulocyte colony-stimulating factor marketed as Neupogen, will likely become the first biosimilar product to be approved in the United States.

At a meeting on Jan. 7, the FDA’s Oncologic Drugs Advisory Committee voted 14-0 that the filgrastim biosimilar should be approved for the five indications approved for Neupogen in the United States, based on “the totality of the evidence,” which includes pharmacokinetic, pharmacodynamic, immunogenicity, and clinical data. With little debate, they agreed that other than minor differences in clinically inactive components, the biosimilar, currently referred to as “­EP2006,” was “highly similar” to the reference product, and that there were “no clinically meaningful differences” between EP2006 and Neupogen – the components of the definition of biosimilarity.

The meeting was considered historic, since this is the first biosimilar to be reviewed by an FDA advisory panel, and if approved, will be the first biosimilar to become available as a result of the Biologics Price Competition and Innovation Act of 2009, which was passed as part of the Affordable Care Act, creating “an abbreviated licensure pathway for biological products shown to be ‘biosimilar’ or ‘interchangeable’ with an FDA-licensed biological product,” according to the FDA.

Neupogen was approved by the FDA in 1991 and is marketed by Amgen. If approved, EP2006 would be the first biosimilar product to be approved in the United States, and, like generic drugs, is expected to provide a cheaper version of Neupogen. Sandoz, the generic pharmaceuticals arm of Novartis, plans to market the biosimilar as Zarxio in the United States. The filgrastim biosimilar was approved in 2009 in the European Union, where it is marketed as Zarzio, and it is now approved in more than 60 countries, with more than 7.5 million days of exposure, according to Sandoz.

Between 2009 and 2012, the use of filgrastim increased by 30% in Europe, and the biosimilar is now the most commonly prescribed version of filgrastim in Europe. The cost of filgrastim dropped substantially after approval because of the competition, company officials said.

EP2006 will be available in prefilled syringes containing 300 mcg/0.5 mL or 480 mcg/0.8 mL administered subcutaneously or intravenously, the same strengths as U.S.-approved Neupogen. For approval, Sandoz submitted eight studies, including two studies comparing EP2006 to U.S.-approved Neupogen conducted specifically for the U.S. approval, one of 28 healthy volunteers and another of 218 women with breast cancer, treated with myelosuppressive chemotherapy, evaluating the pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity (the breast cancer study also evaluated safety and efficacy). The remaining studies included studies in healthy volunteers and breast cancer patients, comparing the biosimilar to European-approved Neupogen, or single-arm studies.

At the meeting, Sigrid Balser, Ph.D., of the global clinical development department at Sandoz, said that in the U.S. study of healthy volunteers, there was a “high degree of similarity” between EP2006 and Neupogen in terms of the PD and PK results, and the absolute neutrophil count (ANC) and CD34+ cell responses. In the U.S. study of breast cancer patients, EP2006 and Neupogen were equivalent in terms of efficacy over the first chemotherapy cycle and had a similar safety profile over six chemotherapy cycles. There were no signs of immunogenicity associated with the biosimilar in the U.S. or European studies in patients with breast cancer or healthy volunteers.

Outside of the United States, more than 3,800 patients have been treated with Zarzio for various indications, including chemotherapy-induced neutropenia, hematopoietic stem cell mobilization, and severe chronic neutropenia, and have been monitored as part of postmarketing trials or routine pharmacovigilance. To date, there have been no signals of any differences in the safety profile of the filgrastim biosimilar, compared with Neupogen;no cases of immunogenicity; and safety and effectiveness has been “confirmed in clinical practice,” Dr. Balser added.

Based on the data, the FDA reviewers concluded that EP2006 is “highly similar to U.S.-licensed Neupogen, and that there are no clinically meaningful difference between the two products,” said Dr. Albert Deisseroth, medical officer and team leader in the division of hematology products, in the FDA’s office of hematology and oncology products.

“Clinically, they appear to really function pretty equally in terms of what you’re asking them to do,” said the panel chair, Dr. Deborah Armstrong, professor of oncology at Johns Hopkins University, Baltimore. The extensive use of the filgrastim biosimilar in other parts of the world provided evidence of “robust safety and efficacy,” which contributed to her support for approval, she added.

 

Cost is not allowed to be discussed during FDA panel meetings, and Sandoz did not specify any possible price of the biosimilar, but this issue was the “elephant in the room,” as one panelist pointed out. However, Dr. Louis Weiner, chairman of the department of oncology and director of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, who spoke on behalf of Sandoz at the meeting, said that the availability of the filgrastim biosimilar has “enormous promise in reducing cost and expanding access” to this treatment. Although it has “unquestioned clinical value,” he said that granulocyte colony-stimulating factor therapy is underused.

The five indications approved for Neupogen are to decrease the incidence of infection‚ as manifested by febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever; for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with acute myeloid leukemia; to reduce the duration of neutropenia and neutropenia-related clinical sequelae; for the mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and for chronic administration to reduce the incidence and duration of sequelae of neutropenia in symptomatic patients with congenital‚ cyclic‚ or idiopathic neutropenia.

The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of potential conflicts of interest related to the topic of the meeting. In some cases, a panelist may be given a waiver but not at this meeting. Dr. Weiner’s disclosure included being a consultant to Sandoz.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – With the unanimous support of a Food and Drug Administration advisory panel and a favorable review by the agency, a “biosimilar” version of filgrastim, the recombinant granulocyte colony-stimulating factor marketed as Neupogen, will likely become the first biosimilar product to be approved in the United States.

At a meeting on Jan. 7, the FDA’s Oncologic Drugs Advisory Committee voted 14-0 that the filgrastim biosimilar should be approved for the five indications approved for Neupogen in the United States, based on “the totality of the evidence,” which includes pharmacokinetic, pharmacodynamic, immunogenicity, and clinical data. With little debate, they agreed that other than minor differences in clinically inactive components, the biosimilar, currently referred to as “­EP2006,” was “highly similar” to the reference product, and that there were “no clinically meaningful differences” between EP2006 and Neupogen – the components of the definition of biosimilarity.

The meeting was considered historic, since this is the first biosimilar to be reviewed by an FDA advisory panel, and if approved, will be the first biosimilar to become available as a result of the Biologics Price Competition and Innovation Act of 2009, which was passed as part of the Affordable Care Act, creating “an abbreviated licensure pathway for biological products shown to be ‘biosimilar’ or ‘interchangeable’ with an FDA-licensed biological product,” according to the FDA.

Neupogen was approved by the FDA in 1991 and is marketed by Amgen. If approved, EP2006 would be the first biosimilar product to be approved in the United States, and, like generic drugs, is expected to provide a cheaper version of Neupogen. Sandoz, the generic pharmaceuticals arm of Novartis, plans to market the biosimilar as Zarxio in the United States. The filgrastim biosimilar was approved in 2009 in the European Union, where it is marketed as Zarzio, and it is now approved in more than 60 countries, with more than 7.5 million days of exposure, according to Sandoz.

Between 2009 and 2012, the use of filgrastim increased by 30% in Europe, and the biosimilar is now the most commonly prescribed version of filgrastim in Europe. The cost of filgrastim dropped substantially after approval because of the competition, company officials said.

EP2006 will be available in prefilled syringes containing 300 mcg/0.5 mL or 480 mcg/0.8 mL administered subcutaneously or intravenously, the same strengths as U.S.-approved Neupogen. For approval, Sandoz submitted eight studies, including two studies comparing EP2006 to U.S.-approved Neupogen conducted specifically for the U.S. approval, one of 28 healthy volunteers and another of 218 women with breast cancer, treated with myelosuppressive chemotherapy, evaluating the pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity (the breast cancer study also evaluated safety and efficacy). The remaining studies included studies in healthy volunteers and breast cancer patients, comparing the biosimilar to European-approved Neupogen, or single-arm studies.

At the meeting, Sigrid Balser, Ph.D., of the global clinical development department at Sandoz, said that in the U.S. study of healthy volunteers, there was a “high degree of similarity” between EP2006 and Neupogen in terms of the PD and PK results, and the absolute neutrophil count (ANC) and CD34+ cell responses. In the U.S. study of breast cancer patients, EP2006 and Neupogen were equivalent in terms of efficacy over the first chemotherapy cycle and had a similar safety profile over six chemotherapy cycles. There were no signs of immunogenicity associated with the biosimilar in the U.S. or European studies in patients with breast cancer or healthy volunteers.

Outside of the United States, more than 3,800 patients have been treated with Zarzio for various indications, including chemotherapy-induced neutropenia, hematopoietic stem cell mobilization, and severe chronic neutropenia, and have been monitored as part of postmarketing trials or routine pharmacovigilance. To date, there have been no signals of any differences in the safety profile of the filgrastim biosimilar, compared with Neupogen;no cases of immunogenicity; and safety and effectiveness has been “confirmed in clinical practice,” Dr. Balser added.

Based on the data, the FDA reviewers concluded that EP2006 is “highly similar to U.S.-licensed Neupogen, and that there are no clinically meaningful difference between the two products,” said Dr. Albert Deisseroth, medical officer and team leader in the division of hematology products, in the FDA’s office of hematology and oncology products.

“Clinically, they appear to really function pretty equally in terms of what you’re asking them to do,” said the panel chair, Dr. Deborah Armstrong, professor of oncology at Johns Hopkins University, Baltimore. The extensive use of the filgrastim biosimilar in other parts of the world provided evidence of “robust safety and efficacy,” which contributed to her support for approval, she added.

 

Cost is not allowed to be discussed during FDA panel meetings, and Sandoz did not specify any possible price of the biosimilar, but this issue was the “elephant in the room,” as one panelist pointed out. However, Dr. Louis Weiner, chairman of the department of oncology and director of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, who spoke on behalf of Sandoz at the meeting, said that the availability of the filgrastim biosimilar has “enormous promise in reducing cost and expanding access” to this treatment. Although it has “unquestioned clinical value,” he said that granulocyte colony-stimulating factor therapy is underused.

The five indications approved for Neupogen are to decrease the incidence of infection‚ as manifested by febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever; for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with acute myeloid leukemia; to reduce the duration of neutropenia and neutropenia-related clinical sequelae; for the mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and for chronic administration to reduce the incidence and duration of sequelae of neutropenia in symptomatic patients with congenital‚ cyclic‚ or idiopathic neutropenia.

The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of potential conflicts of interest related to the topic of the meeting. In some cases, a panelist may be given a waiver but not at this meeting. Dr. Weiner’s disclosure included being a consultant to Sandoz.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – With the unanimous support of a Food and Drug Administration advisory panel and a favorable review by the agency, a “biosimilar” version of filgrastim, the recombinant granulocyte colony-stimulating factor marketed as Neupogen, will likely become the first biosimilar product to be approved in the United States.

At a meeting on Jan. 7, the FDA’s Oncologic Drugs Advisory Committee voted 14-0 that the filgrastim biosimilar should be approved for the five indications approved for Neupogen in the United States, based on “the totality of the evidence,” which includes pharmacokinetic, pharmacodynamic, immunogenicity, and clinical data. With little debate, they agreed that other than minor differences in clinically inactive components, the biosimilar, currently referred to as “­EP2006,” was “highly similar” to the reference product, and that there were “no clinically meaningful differences” between EP2006 and Neupogen – the components of the definition of biosimilarity.

The meeting was considered historic, since this is the first biosimilar to be reviewed by an FDA advisory panel, and if approved, will be the first biosimilar to become available as a result of the Biologics Price Competition and Innovation Act of 2009, which was passed as part of the Affordable Care Act, creating “an abbreviated licensure pathway for biological products shown to be ‘biosimilar’ or ‘interchangeable’ with an FDA-licensed biological product,” according to the FDA.

Neupogen was approved by the FDA in 1991 and is marketed by Amgen. If approved, EP2006 would be the first biosimilar product to be approved in the United States, and, like generic drugs, is expected to provide a cheaper version of Neupogen. Sandoz, the generic pharmaceuticals arm of Novartis, plans to market the biosimilar as Zarxio in the United States. The filgrastim biosimilar was approved in 2009 in the European Union, where it is marketed as Zarzio, and it is now approved in more than 60 countries, with more than 7.5 million days of exposure, according to Sandoz.

Between 2009 and 2012, the use of filgrastim increased by 30% in Europe, and the biosimilar is now the most commonly prescribed version of filgrastim in Europe. The cost of filgrastim dropped substantially after approval because of the competition, company officials said.

EP2006 will be available in prefilled syringes containing 300 mcg/0.5 mL or 480 mcg/0.8 mL administered subcutaneously or intravenously, the same strengths as U.S.-approved Neupogen. For approval, Sandoz submitted eight studies, including two studies comparing EP2006 to U.S.-approved Neupogen conducted specifically for the U.S. approval, one of 28 healthy volunteers and another of 218 women with breast cancer, treated with myelosuppressive chemotherapy, evaluating the pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity (the breast cancer study also evaluated safety and efficacy). The remaining studies included studies in healthy volunteers and breast cancer patients, comparing the biosimilar to European-approved Neupogen, or single-arm studies.

At the meeting, Sigrid Balser, Ph.D., of the global clinical development department at Sandoz, said that in the U.S. study of healthy volunteers, there was a “high degree of similarity” between EP2006 and Neupogen in terms of the PD and PK results, and the absolute neutrophil count (ANC) and CD34+ cell responses. In the U.S. study of breast cancer patients, EP2006 and Neupogen were equivalent in terms of efficacy over the first chemotherapy cycle and had a similar safety profile over six chemotherapy cycles. There were no signs of immunogenicity associated with the biosimilar in the U.S. or European studies in patients with breast cancer or healthy volunteers.

Outside of the United States, more than 3,800 patients have been treated with Zarzio for various indications, including chemotherapy-induced neutropenia, hematopoietic stem cell mobilization, and severe chronic neutropenia, and have been monitored as part of postmarketing trials or routine pharmacovigilance. To date, there have been no signals of any differences in the safety profile of the filgrastim biosimilar, compared with Neupogen;no cases of immunogenicity; and safety and effectiveness has been “confirmed in clinical practice,” Dr. Balser added.

Based on the data, the FDA reviewers concluded that EP2006 is “highly similar to U.S.-licensed Neupogen, and that there are no clinically meaningful difference between the two products,” said Dr. Albert Deisseroth, medical officer and team leader in the division of hematology products, in the FDA’s office of hematology and oncology products.

“Clinically, they appear to really function pretty equally in terms of what you’re asking them to do,” said the panel chair, Dr. Deborah Armstrong, professor of oncology at Johns Hopkins University, Baltimore. The extensive use of the filgrastim biosimilar in other parts of the world provided evidence of “robust safety and efficacy,” which contributed to her support for approval, she added.

 

Cost is not allowed to be discussed during FDA panel meetings, and Sandoz did not specify any possible price of the biosimilar, but this issue was the “elephant in the room,” as one panelist pointed out. However, Dr. Louis Weiner, chairman of the department of oncology and director of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, who spoke on behalf of Sandoz at the meeting, said that the availability of the filgrastim biosimilar has “enormous promise in reducing cost and expanding access” to this treatment. Although it has “unquestioned clinical value,” he said that granulocyte colony-stimulating factor therapy is underused.

The five indications approved for Neupogen are to decrease the incidence of infection‚ as manifested by febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever; for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with acute myeloid leukemia; to reduce the duration of neutropenia and neutropenia-related clinical sequelae; for the mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and for chronic administration to reduce the incidence and duration of sequelae of neutropenia in symptomatic patients with congenital‚ cyclic‚ or idiopathic neutropenia.

The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of potential conflicts of interest related to the topic of the meeting. In some cases, a panelist may be given a waiver but not at this meeting. Dr. Weiner’s disclosure included being a consultant to Sandoz.

emechcatie@frontlinemedcom.com

Surgical repair remains the optimal method to treat a popliteal artery aneurysm.

Popliteal artery aneurysm, or PAA, is the most common peripheral aneurysm, but data on this disease are nonetheless limited. A report from the VASCUNET collaboration of registries showed that 1,471 repairs were performed among a population of 58 million people in eight countries, for a rate of 9.6 per million. Most (72%) were elective, and 78% were open repairs (Eur. J. Vasc. Endovasc. Surg. 2014;47:164-71).

Although the endovascular approach has been increasingly used since 2000, outcomes have varied considerably across studies.

A review of 163 relevant studies from more than 1,600 that have been published since 1994 showed extensive heterogeneity with respect to the inclusion of symptomatic vs. asymptomatic patients, emergent vs. elective cases, poor runoff vs. good runoff, types of stents used, and types of conduits used for open repair. This renders the validity of the meta-analysis of these studies uncertain.

However, based on the few studies with complete data concerning mortality, major adverse events, primary and secondary patency, and limb salvage – with separate analysis for elective and emergency repairs – it appears that the availability of the great saphenous vein (GSV) is an important determinant when deciding whether to perform an open repair, that the posterior approach is preferred (except in cases of aneurysms extending to the adductor canal or trifurcation vessels), and that elective open repair is associated with significantly better outcomes than endovascular repair on a number of measures.

For example, no difference was seen in mortality in 23 selected studies, but the 3-year primary patency was significantly better with open repair (85% vs. 58%), while the 3-year rate of major adverse events, including mortality, major amputation, graft thrombosis, and reintervention was lower (20% vs. 38%).

These findings were confirmed in a study of 149 elective repairs. In that series, major adverse events were significantly more common in endovascular vs. open cases (hazard ratio, 2.1), and poor runoff was associated with a higher risk of major adverse events regardless of the technique used (J. Vasc. Surg. 2014 60:631-8.e2).

A recent decision analysis model applied to patients with asymptomatic PAA also demonstrated that elective open repair with a GSV bypass is the preferred treatment for all outcomes, with stenting recommended in high-risk patient or those without a suitable vein (J. Vasc. Surg. 2014;59:651-62).

One concern with endovascular repair is the risk of stent fracture, particularly in younger more active patients as data suggest that the more active the individual, the greater the risk of stent fracture. In one study, the frequency of stent fracture in younger patients was 17%. This suggests that stenting is probably not the best technique to be used in active individuals.

The current data suggest that the best outcomes are achieved with elective open repair using the great saphenous vein. However, patency rates above 80% at 2 years have been reported recently for elective endovascular repair associated with dual antiplatelet therapy, thus it is possible that new stent grafts and best medical therapy could improve the results of endovascular repair.

Open repair also appears to be best in most emergent cases. In one meta-analysis of 11 studies involving 223 patients, graft thrombosis occurred in 8% of open cases vs. 53% of endovascular cases, patency at 6 months was 82% vs. 68%, and reintervention rates were 25% vs. 43% in open vs. endovascular cases, respectively.

Thrombolysis was associated with a significant improvement in 1-year primary graft patency rates compared with surgery alone, but this did not affect the amputation rate, and endovascular repair does not appear to improve the severe prognosis of acute ischemia in patients with PAA.

Despite the deceiving results of endovascular repair in those with acute ischemia, this technique could, however, be very useful in other emergent situations. For example, very old patients presenting with a ruptured PAA and a good runoff could benefit from an endovascular repair.

In summary, no level 1 evidence regarding open vs. endovascular repair for popliteal artery aneurysms can be obtained; most studies are retrospective and lack important characteristics. Based on the data that do exist, however, open repair with a vein bypass appears to be the best technique for most patients with PAA. Stenting should be reserved for high-risk and elderly asymptomatic patients. As for those with acute limb ischemia, no strong recommendation can be made based on the available data.

Dr. Jean-Baptiste Ricco is professor and chief of vascular surgery at the University of Poitiers, France. He reported having no disclosures. This and the accompanying perspective by Dr. Marone were based upon their live debate at the 2014 Vascular Annual Meeting.

 

Endovascular repair of PAA is an effective and durable treatment.

Outcomes following endovascular repair of PAA are at least equivalent to those following open repair with respect to patency and limb salvage in elective cases.

In the Swedish Vascular Registry – the largest report of open repair, representing 717 limbs treated with a mean follow-up of 7.2 years – the primary patency rate at 1 year for cases performed with a medial approach was 90% with vein conduit, and 72% with prosthetic conduit. For cases involving a posterior approach, the rates were 85% with vein conduit, and 81% with prosthetic conduit. The amputation rate was 9.6% at 1 year and 11% at last follow-up.

Furthermore, open surgical procedures are associated with a high wound complication rate. The average across studies is 7%, and was as high as 28% in some series. Open procedures are also associated with variable graft patency, continued aneurysm expansion (which occurred in a third of limbs treated with a medial approach in one series), and a significant amputation rate.

Data regarding endovascular PAA repair are encouraging. In the only prospective randomized trial to date, no significant difference was seen at 46 months with respect to primary patency (100% with open repair vs. 93.3% with endovascular repair), or limb salvage (100% for both).

Hospital length of stay, however, was significantly shorter with endovascular repair (7.7 days vs. 4.3 days), as was operative time (155 minutes vs. 75 minutes).

An update to that 2005 study (J. Vasc. Surg. 2005;42:185-93) showed no difference in patency at 72 months.

While there is a paucity of level 1 evidence (only 15 patients were included in each arm of that study), prospective cohort studies and institutional reviews also demonstrate the value of endovascular repair. Secondary patency at 1 and 3 years were 87% and 85%, respectively, in a 2013 study (Ann. Vasc. Surg. 2013;27:259-65), and the 1- and 2-year amputation rates were 2% and 3%, respectively.

In another series, 1-year primary patency was 92.9% with endovascular repair, compared with 83.3% with open repair, and 3-year patency was 63.7% vs. 77.8%. The differences were not statistically significant.

Length of stay was 3.9 days vs. 9.5 days. Eight wound infections and 2 hematomas occurred in the open repair patients, and two patients experienced enlargement requiring decompression.

The University of Pittsburgh experience with 50 endovascular repairs and 111 open repairs performed between 2004 and 2010 showed that morbidity was 14% vs. 32% for endovascular vs. open repair, and mortality was 2% vs. 3.6%, respectively, at 29-month follow-up. Wound infection rates were 2% and 16.2%, respectively, length of stay was 1 vs. 4 days, and reintervention and thrombosis rates did not differ significantly (12.2% vs. 10.8%, and 8 vs. 12 patients).

No significant differences were seen in aneurysm growth, primary assisted patency at 3 years, secondary patency at 3 years, or amputation rates at 1 year or 3 years.

A 2013 update also showed no differences in these outcomes.

In summary, endovascular repair of PAA is acceptable, with outcomes comparable to or better than open repair in elective cases. Long-term durability has been demonstrated, limb preservation is equivalent to open repair, and thrombotic complications are rare and can be treated successfully with re-intervention.

Furthermore, endovascular repair can be performed without the need for general anesthesia, lower morbidity can be expected perioperatively, hospital length of stay is shorter, and patients have a quicker return of functional status.

Dr. Luke Marone is a vascular surgeon at the University of Pittsburgh School of Medicine. He disclosed he is a consultant for Abiomed and Abbott.

Surgical repair remains the optimal method to treat a popliteal artery aneurysm.

Popliteal artery aneurysm, or PAA, is the most common peripheral aneurysm, but data on this disease are nonetheless limited. A report from the VASCUNET collaboration of registries showed that 1,471 repairs were performed among a population of 58 million people in eight countries, for a rate of 9.6 per million. Most (72%) were elective, and 78% were open repairs (Eur. J. Vasc. Endovasc. Surg. 2014;47:164-71).

Although the endovascular approach has been increasingly used since 2000, outcomes have varied considerably across studies.

A review of 163 relevant studies from more than 1,600 that have been published since 1994 showed extensive heterogeneity with respect to the inclusion of symptomatic vs. asymptomatic patients, emergent vs. elective cases, poor runoff vs. good runoff, types of stents used, and types of conduits used for open repair. This renders the validity of the meta-analysis of these studies uncertain.

However, based on the few studies with complete data concerning mortality, major adverse events, primary and secondary patency, and limb salvage – with separate analysis for elective and emergency repairs – it appears that the availability of the great saphenous vein (GSV) is an important determinant when deciding whether to perform an open repair, that the posterior approach is preferred (except in cases of aneurysms extending to the adductor canal or trifurcation vessels), and that elective open repair is associated with significantly better outcomes than endovascular repair on a number of measures.

For example, no difference was seen in mortality in 23 selected studies, but the 3-year primary patency was significantly better with open repair (85% vs. 58%), while the 3-year rate of major adverse events, including mortality, major amputation, graft thrombosis, and reintervention was lower (20% vs. 38%).

These findings were confirmed in a study of 149 elective repairs. In that series, major adverse events were significantly more common in endovascular vs. open cases (hazard ratio, 2.1), and poor runoff was associated with a higher risk of major adverse events regardless of the technique used (J. Vasc. Surg. 2014 60:631-8.e2).

A recent decision analysis model applied to patients with asymptomatic PAA also demonstrated that elective open repair with a GSV bypass is the preferred treatment for all outcomes, with stenting recommended in high-risk patient or those without a suitable vein (J. Vasc. Surg. 2014;59:651-62).

One concern with endovascular repair is the risk of stent fracture, particularly in younger more active patients as data suggest that the more active the individual, the greater the risk of stent fracture. In one study, the frequency of stent fracture in younger patients was 17%. This suggests that stenting is probably not the best technique to be used in active individuals.

The current data suggest that the best outcomes are achieved with elective open repair using the great saphenous vein. However, patency rates above 80% at 2 years have been reported recently for elective endovascular repair associated with dual antiplatelet therapy, thus it is possible that new stent grafts and best medical therapy could improve the results of endovascular repair.

Open repair also appears to be best in most emergent cases. In one meta-analysis of 11 studies involving 223 patients, graft thrombosis occurred in 8% of open cases vs. 53% of endovascular cases, patency at 6 months was 82% vs. 68%, and reintervention rates were 25% vs. 43% in open vs. endovascular cases, respectively.

Thrombolysis was associated with a significant improvement in 1-year primary graft patency rates compared with surgery alone, but this did not affect the amputation rate, and endovascular repair does not appear to improve the severe prognosis of acute ischemia in patients with PAA.

Despite the deceiving results of endovascular repair in those with acute ischemia, this technique could, however, be very useful in other emergent situations. For example, very old patients presenting with a ruptured PAA and a good runoff could benefit from an endovascular repair.

In summary, no level 1 evidence regarding open vs. endovascular repair for popliteal artery aneurysms can be obtained; most studies are retrospective and lack important characteristics. Based on the data that do exist, however, open repair with a vein bypass appears to be the best technique for most patients with PAA. Stenting should be reserved for high-risk and elderly asymptomatic patients. As for those with acute limb ischemia, no strong recommendation can be made based on the available data.

Dr. Jean-Baptiste Ricco is professor and chief of vascular surgery at the University of Poitiers, France. He reported having no disclosures. This and the accompanying perspective by Dr. Marone were based upon their live debate at the 2014 Vascular Annual Meeting.

 

Endovascular repair of PAA is an effective and durable treatment.

Outcomes following endovascular repair of PAA are at least equivalent to those following open repair with respect to patency and limb salvage in elective cases.

In the Swedish Vascular Registry – the largest report of open repair, representing 717 limbs treated with a mean follow-up of 7.2 years – the primary patency rate at 1 year for cases performed with a medial approach was 90% with vein conduit, and 72% with prosthetic conduit. For cases involving a posterior approach, the rates were 85% with vein conduit, and 81% with prosthetic conduit. The amputation rate was 9.6% at 1 year and 11% at last follow-up.

Furthermore, open surgical procedures are associated with a high wound complication rate. The average across studies is 7%, and was as high as 28% in some series. Open procedures are also associated with variable graft patency, continued aneurysm expansion (which occurred in a third of limbs treated with a medial approach in one series), and a significant amputation rate.

Data regarding endovascular PAA repair are encouraging. In the only prospective randomized trial to date, no significant difference was seen at 46 months with respect to primary patency (100% with open repair vs. 93.3% with endovascular repair), or limb salvage (100% for both).

Hospital length of stay, however, was significantly shorter with endovascular repair (7.7 days vs. 4.3 days), as was operative time (155 minutes vs. 75 minutes).

An update to that 2005 study (J. Vasc. Surg. 2005;42:185-93) showed no difference in patency at 72 months.

While there is a paucity of level 1 evidence (only 15 patients were included in each arm of that study), prospective cohort studies and institutional reviews also demonstrate the value of endovascular repair. Secondary patency at 1 and 3 years were 87% and 85%, respectively, in a 2013 study (Ann. Vasc. Surg. 2013;27:259-65), and the 1- and 2-year amputation rates were 2% and 3%, respectively.

In another series, 1-year primary patency was 92.9% with endovascular repair, compared with 83.3% with open repair, and 3-year patency was 63.7% vs. 77.8%. The differences were not statistically significant.

Length of stay was 3.9 days vs. 9.5 days. Eight wound infections and 2 hematomas occurred in the open repair patients, and two patients experienced enlargement requiring decompression.

The University of Pittsburgh experience with 50 endovascular repairs and 111 open repairs performed between 2004 and 2010 showed that morbidity was 14% vs. 32% for endovascular vs. open repair, and mortality was 2% vs. 3.6%, respectively, at 29-month follow-up. Wound infection rates were 2% and 16.2%, respectively, length of stay was 1 vs. 4 days, and reintervention and thrombosis rates did not differ significantly (12.2% vs. 10.8%, and 8 vs. 12 patients).

No significant differences were seen in aneurysm growth, primary assisted patency at 3 years, secondary patency at 3 years, or amputation rates at 1 year or 3 years.

A 2013 update also showed no differences in these outcomes.

In summary, endovascular repair of PAA is acceptable, with outcomes comparable to or better than open repair in elective cases. Long-term durability has been demonstrated, limb preservation is equivalent to open repair, and thrombotic complications are rare and can be treated successfully with re-intervention.

Furthermore, endovascular repair can be performed without the need for general anesthesia, lower morbidity can be expected perioperatively, hospital length of stay is shorter, and patients have a quicker return of functional status.

Dr. Luke Marone is a vascular surgeon at the University of Pittsburgh School of Medicine. He disclosed he is a consultant for Abiomed and Abbott.

Surgical repair remains the optimal method to treat a popliteal artery aneurysm.

Popliteal artery aneurysm, or PAA, is the most common peripheral aneurysm, but data on this disease are nonetheless limited. A report from the VASCUNET collaboration of registries showed that 1,471 repairs were performed among a population of 58 million people in eight countries, for a rate of 9.6 per million. Most (72%) were elective, and 78% were open repairs (Eur. J. Vasc. Endovasc. Surg. 2014;47:164-71).

Although the endovascular approach has been increasingly used since 2000, outcomes have varied considerably across studies.

A review of 163 relevant studies from more than 1,600 that have been published since 1994 showed extensive heterogeneity with respect to the inclusion of symptomatic vs. asymptomatic patients, emergent vs. elective cases, poor runoff vs. good runoff, types of stents used, and types of conduits used for open repair. This renders the validity of the meta-analysis of these studies uncertain.

However, based on the few studies with complete data concerning mortality, major adverse events, primary and secondary patency, and limb salvage – with separate analysis for elective and emergency repairs – it appears that the availability of the great saphenous vein (GSV) is an important determinant when deciding whether to perform an open repair, that the posterior approach is preferred (except in cases of aneurysms extending to the adductor canal or trifurcation vessels), and that elective open repair is associated with significantly better outcomes than endovascular repair on a number of measures.

For example, no difference was seen in mortality in 23 selected studies, but the 3-year primary patency was significantly better with open repair (85% vs. 58%), while the 3-year rate of major adverse events, including mortality, major amputation, graft thrombosis, and reintervention was lower (20% vs. 38%).

These findings were confirmed in a study of 149 elective repairs. In that series, major adverse events were significantly more common in endovascular vs. open cases (hazard ratio, 2.1), and poor runoff was associated with a higher risk of major adverse events regardless of the technique used (J. Vasc. Surg. 2014 60:631-8.e2).

A recent decision analysis model applied to patients with asymptomatic PAA also demonstrated that elective open repair with a GSV bypass is the preferred treatment for all outcomes, with stenting recommended in high-risk patient or those without a suitable vein (J. Vasc. Surg. 2014;59:651-62).

One concern with endovascular repair is the risk of stent fracture, particularly in younger more active patients as data suggest that the more active the individual, the greater the risk of stent fracture. In one study, the frequency of stent fracture in younger patients was 17%. This suggests that stenting is probably not the best technique to be used in active individuals.

The current data suggest that the best outcomes are achieved with elective open repair using the great saphenous vein. However, patency rates above 80% at 2 years have been reported recently for elective endovascular repair associated with dual antiplatelet therapy, thus it is possible that new stent grafts and best medical therapy could improve the results of endovascular repair.

Open repair also appears to be best in most emergent cases. In one meta-analysis of 11 studies involving 223 patients, graft thrombosis occurred in 8% of open cases vs. 53% of endovascular cases, patency at 6 months was 82% vs. 68%, and reintervention rates were 25% vs. 43% in open vs. endovascular cases, respectively.

Thrombolysis was associated with a significant improvement in 1-year primary graft patency rates compared with surgery alone, but this did not affect the amputation rate, and endovascular repair does not appear to improve the severe prognosis of acute ischemia in patients with PAA.

Despite the deceiving results of endovascular repair in those with acute ischemia, this technique could, however, be very useful in other emergent situations. For example, very old patients presenting with a ruptured PAA and a good runoff could benefit from an endovascular repair.

In summary, no level 1 evidence regarding open vs. endovascular repair for popliteal artery aneurysms can be obtained; most studies are retrospective and lack important characteristics. Based on the data that do exist, however, open repair with a vein bypass appears to be the best technique for most patients with PAA. Stenting should be reserved for high-risk and elderly asymptomatic patients. As for those with acute limb ischemia, no strong recommendation can be made based on the available data.

Dr. Jean-Baptiste Ricco is professor and chief of vascular surgery at the University of Poitiers, France. He reported having no disclosures. This and the accompanying perspective by Dr. Marone were based upon their live debate at the 2014 Vascular Annual Meeting.

 

Endovascular repair of PAA is an effective and durable treatment.

Outcomes following endovascular repair of PAA are at least equivalent to those following open repair with respect to patency and limb salvage in elective cases.

In the Swedish Vascular Registry – the largest report of open repair, representing 717 limbs treated with a mean follow-up of 7.2 years – the primary patency rate at 1 year for cases performed with a medial approach was 90% with vein conduit, and 72% with prosthetic conduit. For cases involving a posterior approach, the rates were 85% with vein conduit, and 81% with prosthetic conduit. The amputation rate was 9.6% at 1 year and 11% at last follow-up.

Furthermore, open surgical procedures are associated with a high wound complication rate. The average across studies is 7%, and was as high as 28% in some series. Open procedures are also associated with variable graft patency, continued aneurysm expansion (which occurred in a third of limbs treated with a medial approach in one series), and a significant amputation rate.

Data regarding endovascular PAA repair are encouraging. In the only prospective randomized trial to date, no significant difference was seen at 46 months with respect to primary patency (100% with open repair vs. 93.3% with endovascular repair), or limb salvage (100% for both).

Hospital length of stay, however, was significantly shorter with endovascular repair (7.7 days vs. 4.3 days), as was operative time (155 minutes vs. 75 minutes).

An update to that 2005 study (J. Vasc. Surg. 2005;42:185-93) showed no difference in patency at 72 months.

While there is a paucity of level 1 evidence (only 15 patients were included in each arm of that study), prospective cohort studies and institutional reviews also demonstrate the value of endovascular repair. Secondary patency at 1 and 3 years were 87% and 85%, respectively, in a 2013 study (Ann. Vasc. Surg. 2013;27:259-65), and the 1- and 2-year amputation rates were 2% and 3%, respectively.

In another series, 1-year primary patency was 92.9% with endovascular repair, compared with 83.3% with open repair, and 3-year patency was 63.7% vs. 77.8%. The differences were not statistically significant.

Length of stay was 3.9 days vs. 9.5 days. Eight wound infections and 2 hematomas occurred in the open repair patients, and two patients experienced enlargement requiring decompression.

The University of Pittsburgh experience with 50 endovascular repairs and 111 open repairs performed between 2004 and 2010 showed that morbidity was 14% vs. 32% for endovascular vs. open repair, and mortality was 2% vs. 3.6%, respectively, at 29-month follow-up. Wound infection rates were 2% and 16.2%, respectively, length of stay was 1 vs. 4 days, and reintervention and thrombosis rates did not differ significantly (12.2% vs. 10.8%, and 8 vs. 12 patients).

No significant differences were seen in aneurysm growth, primary assisted patency at 3 years, secondary patency at 3 years, or amputation rates at 1 year or 3 years.

A 2013 update also showed no differences in these outcomes.

In summary, endovascular repair of PAA is acceptable, with outcomes comparable to or better than open repair in elective cases. Long-term durability has been demonstrated, limb preservation is equivalent to open repair, and thrombotic complications are rare and can be treated successfully with re-intervention.

Furthermore, endovascular repair can be performed without the need for general anesthesia, lower morbidity can be expected perioperatively, hospital length of stay is shorter, and patients have a quicker return of functional status.

Dr. Luke Marone is a vascular surgeon at the University of Pittsburgh School of Medicine. He disclosed he is a consultant for Abiomed and Abbott.

SAN FRANCISCO—An investigational, humanized antibody fragment known as idarucizumab can reverse the anticoagulation effects of dabigatran, new research suggests.

In a small study, idarucizumab led to sustained reversal of dabigatran’s effects in healthy subjects, elderly volunteers, and participants with mild to moderate renal impairment.

Furthermore, dabigatran anticoagulation could be re-established 24 hours after the subjects had received idarucizumab.

Joachim Stangier, PhD, of Boehringer Ingelheim Pharma GmbH & Co KG in Biberach, Germany, presented these results at the 2014 ASH Annual Meeting as abstract 344*. Boehringer Ingelheim is the company developing idarucizumab.

Dr Stangier said idarucizumab binds dabigatran with high affinity, off-target binding is not expected, and no procoagulant effects have been observed with the drug.

In a previous study of healthy volunteers, idarucizumab provided immediate, complete, and sustained reversal of dabigatran’s anticoagulant effect. The effect was sustained when idarucizumab was given at 2 g and 4 g doses.

For the current study, Dr Stangier and his colleagues wanted to evaluate whether and to what extent doses of up to 5 g of idarucizumab would reverse the anticoagulant effects of dabigatran in healthy subjects, elderly participants, and renally impaired volunteers. The team also wanted to determine the effects of dabigatran given after subjects had received idarucizumab.

The study included 46 male and female subjects who were 45 to 80 years of age. Healthy subjects received dabigatran etexilate at 220 mg twice daily, and subjects with mild to moderate renal impairment received 150 mg twice daily, both over 4 days.

Subjects then received idarucizumab at 1 g, 2.5 g, 5 g, or 5 g given as 2 x 2.5 g 1 hour apart. They received these doses as 5-minute intravenous infusions 2 hours after their last dose of dabigatran.

The researchers found that dabigatran-prolonged clotting times—thrombin time, diluted thrombin time, ecarin clotting time, and activated partial thromboplastin time—were reversed to baseline immediately after the end of idarucizumab infusion.

And the team observed sustained reversal of dabigatran’s anticoagulant effects in all subjects.

The researchers then readministered dabigatran to healthy subjects 24 hours after idarucizumab treatment and to subjects who received placebo instead of idarucizumab.

Dabigatran-mediated anticoagulation was similar in subjects who received idarucizumab and those who received placebo. And anticoagulation was restored to levels comparable to initial levels.

Dr Stangier said there were no clinically relevant adverse events (AEs) related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. There were no AEs indicative of immunogenic reactions.

AEs and local tolerability reactions were similar for placebo and idarucizumab. And there was no relationship between the frequency of AEs and drug dose, gender, or renal function.

The researchers did observe a dose-dependent, transient increase in urine protein and low-weight proteins, but values returned to the normal range within 4 hours to 24 hours.

Based on these results, Dr Stangier said idarucizumab fulfills the requirements for a fast-acting and specific antidote to dabigatran with a favorable safety profile. Additional clinical testing of the antidote is ongoing.

*Information in the abstract differs from that presented.

SAN FRANCISCO—An investigational, humanized antibody fragment known as idarucizumab can reverse the anticoagulation effects of dabigatran, new research suggests.

In a small study, idarucizumab led to sustained reversal of dabigatran’s effects in healthy subjects, elderly volunteers, and participants with mild to moderate renal impairment.

Furthermore, dabigatran anticoagulation could be re-established 24 hours after the subjects had received idarucizumab.

Joachim Stangier, PhD, of Boehringer Ingelheim Pharma GmbH & Co KG in Biberach, Germany, presented these results at the 2014 ASH Annual Meeting as abstract 344*. Boehringer Ingelheim is the company developing idarucizumab.

Dr Stangier said idarucizumab binds dabigatran with high affinity, off-target binding is not expected, and no procoagulant effects have been observed with the drug.

In a previous study of healthy volunteers, idarucizumab provided immediate, complete, and sustained reversal of dabigatran’s anticoagulant effect. The effect was sustained when idarucizumab was given at 2 g and 4 g doses.

For the current study, Dr Stangier and his colleagues wanted to evaluate whether and to what extent doses of up to 5 g of idarucizumab would reverse the anticoagulant effects of dabigatran in healthy subjects, elderly participants, and renally impaired volunteers. The team also wanted to determine the effects of dabigatran given after subjects had received idarucizumab.

The study included 46 male and female subjects who were 45 to 80 years of age. Healthy subjects received dabigatran etexilate at 220 mg twice daily, and subjects with mild to moderate renal impairment received 150 mg twice daily, both over 4 days.

Subjects then received idarucizumab at 1 g, 2.5 g, 5 g, or 5 g given as 2 x 2.5 g 1 hour apart. They received these doses as 5-minute intravenous infusions 2 hours after their last dose of dabigatran.

The researchers found that dabigatran-prolonged clotting times—thrombin time, diluted thrombin time, ecarin clotting time, and activated partial thromboplastin time—were reversed to baseline immediately after the end of idarucizumab infusion.

And the team observed sustained reversal of dabigatran’s anticoagulant effects in all subjects.

The researchers then readministered dabigatran to healthy subjects 24 hours after idarucizumab treatment and to subjects who received placebo instead of idarucizumab.

Dabigatran-mediated anticoagulation was similar in subjects who received idarucizumab and those who received placebo. And anticoagulation was restored to levels comparable to initial levels.

Dr Stangier said there were no clinically relevant adverse events (AEs) related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. There were no AEs indicative of immunogenic reactions.

AEs and local tolerability reactions were similar for placebo and idarucizumab. And there was no relationship between the frequency of AEs and drug dose, gender, or renal function.

The researchers did observe a dose-dependent, transient increase in urine protein and low-weight proteins, but values returned to the normal range within 4 hours to 24 hours.

Based on these results, Dr Stangier said idarucizumab fulfills the requirements for a fast-acting and specific antidote to dabigatran with a favorable safety profile. Additional clinical testing of the antidote is ongoing.

*Information in the abstract differs from that presented.

SAN FRANCISCO—An investigational, humanized antibody fragment known as idarucizumab can reverse the anticoagulation effects of dabigatran, new research suggests.

In a small study, idarucizumab led to sustained reversal of dabigatran’s effects in healthy subjects, elderly volunteers, and participants with mild to moderate renal impairment.

Furthermore, dabigatran anticoagulation could be re-established 24 hours after the subjects had received idarucizumab.

Joachim Stangier, PhD, of Boehringer Ingelheim Pharma GmbH & Co KG in Biberach, Germany, presented these results at the 2014 ASH Annual Meeting as abstract 344*. Boehringer Ingelheim is the company developing idarucizumab.

Dr Stangier said idarucizumab binds dabigatran with high affinity, off-target binding is not expected, and no procoagulant effects have been observed with the drug.

In a previous study of healthy volunteers, idarucizumab provided immediate, complete, and sustained reversal of dabigatran’s anticoagulant effect. The effect was sustained when idarucizumab was given at 2 g and 4 g doses.

For the current study, Dr Stangier and his colleagues wanted to evaluate whether and to what extent doses of up to 5 g of idarucizumab would reverse the anticoagulant effects of dabigatran in healthy subjects, elderly participants, and renally impaired volunteers. The team also wanted to determine the effects of dabigatran given after subjects had received idarucizumab.

The study included 46 male and female subjects who were 45 to 80 years of age. Healthy subjects received dabigatran etexilate at 220 mg twice daily, and subjects with mild to moderate renal impairment received 150 mg twice daily, both over 4 days.

Subjects then received idarucizumab at 1 g, 2.5 g, 5 g, or 5 g given as 2 x 2.5 g 1 hour apart. They received these doses as 5-minute intravenous infusions 2 hours after their last dose of dabigatran.

The researchers found that dabigatran-prolonged clotting times—thrombin time, diluted thrombin time, ecarin clotting time, and activated partial thromboplastin time—were reversed to baseline immediately after the end of idarucizumab infusion.

And the team observed sustained reversal of dabigatran’s anticoagulant effects in all subjects.

The researchers then readministered dabigatran to healthy subjects 24 hours after idarucizumab treatment and to subjects who received placebo instead of idarucizumab.

Dabigatran-mediated anticoagulation was similar in subjects who received idarucizumab and those who received placebo. And anticoagulation was restored to levels comparable to initial levels.

Dr Stangier said there were no clinically relevant adverse events (AEs) related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. There were no AEs indicative of immunogenic reactions.

AEs and local tolerability reactions were similar for placebo and idarucizumab. And there was no relationship between the frequency of AEs and drug dose, gender, or renal function.

The researchers did observe a dose-dependent, transient increase in urine protein and low-weight proteins, but values returned to the normal range within 4 hours to 24 hours.

Based on these results, Dr Stangier said idarucizumab fulfills the requirements for a fast-acting and specific antidote to dabigatran with a favorable safety profile. Additional clinical testing of the antidote is ongoing.

*Information in the abstract differs from that presented.

The US Food and Drug Administration (FDA) has granted orphan designation to a cord blood product called NiCord for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and myelodysplastic syndromes (MDS).

NiCord consists of cells from a single cord blood unit cultured in nicotinamide—a vitamin B derivative—and cytokines that are typically used for expansion—thrombopoietin, interleukin 6, FLT3 ligand, and stem cell factor.

The FDA’s orphan drug designation for NiCord coincides with the positive opinion of the European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products regarding NiCord as a treatment for AML. Gamida Cell, the company developing NiCord, intends to file for orphan drug status with the EMA for other indications as well.

“Receipt of orphan drug status for NiCord in the US and Europe advances Gamida Cell’s commercialization plans a major step further, as both afford significant advantages,” said Yael Margolin, President and CEO of Gamida Cell.

Orphan drug designation provides various regulatory and economic benefits, including 7 years of market exclusivity upon product approval in the US and 10 years in the European Union.

Trials of NiCord

NiCord is currently being tested in a phase 1/2 study as an investigational therapeutic treatment for hematologic malignancies. In this study, NiCord is being used as the sole stem cell source.

In a previous study, presented at the 11th Annual International Cord Blood Symposium, researchers transplanted a NiCord unit and an unmanipulated cord blood unit in patients with ALL, AML, MDS, HL, or non-Hodgkin lymphoma.

A majority of patients in this small, phase 1/2 study achieved early platelet and neutrophil engraftment. And, in some patients, that engraftment persisted for 2 years.

Eight of the 11 patients enrolled achieved engraftment with the NiCord unit, and 2 engrafted with the unmanipulated cord blood unit. One patient had primary graft failure.

There were no adverse events attributable to the NiCord unit, but 4 patients developed grade 1-2 acute GVHD, and 1 patient developed limited chronic GVHD.

For more information on NiCord, visit the Gamida Cell website.

The US Food and Drug Administration (FDA) has granted orphan designation to a cord blood product called NiCord for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and myelodysplastic syndromes (MDS).

NiCord consists of cells from a single cord blood unit cultured in nicotinamide—a vitamin B derivative—and cytokines that are typically used for expansion—thrombopoietin, interleukin 6, FLT3 ligand, and stem cell factor.

The FDA’s orphan drug designation for NiCord coincides with the positive opinion of the European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products regarding NiCord as a treatment for AML. Gamida Cell, the company developing NiCord, intends to file for orphan drug status with the EMA for other indications as well.

“Receipt of orphan drug status for NiCord in the US and Europe advances Gamida Cell’s commercialization plans a major step further, as both afford significant advantages,” said Yael Margolin, President and CEO of Gamida Cell.

Orphan drug designation provides various regulatory and economic benefits, including 7 years of market exclusivity upon product approval in the US and 10 years in the European Union.

Trials of NiCord

NiCord is currently being tested in a phase 1/2 study as an investigational therapeutic treatment for hematologic malignancies. In this study, NiCord is being used as the sole stem cell source.

In a previous study, presented at the 11th Annual International Cord Blood Symposium, researchers transplanted a NiCord unit and an unmanipulated cord blood unit in patients with ALL, AML, MDS, HL, or non-Hodgkin lymphoma.

A majority of patients in this small, phase 1/2 study achieved early platelet and neutrophil engraftment. And, in some patients, that engraftment persisted for 2 years.

Eight of the 11 patients enrolled achieved engraftment with the NiCord unit, and 2 engrafted with the unmanipulated cord blood unit. One patient had primary graft failure.

There were no adverse events attributable to the NiCord unit, but 4 patients developed grade 1-2 acute GVHD, and 1 patient developed limited chronic GVHD.

For more information on NiCord, visit the Gamida Cell website.

The US Food and Drug Administration (FDA) has granted orphan designation to a cord blood product called NiCord for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and myelodysplastic syndromes (MDS).

NiCord consists of cells from a single cord blood unit cultured in nicotinamide—a vitamin B derivative—and cytokines that are typically used for expansion—thrombopoietin, interleukin 6, FLT3 ligand, and stem cell factor.

The FDA’s orphan drug designation for NiCord coincides with the positive opinion of the European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products regarding NiCord as a treatment for AML. Gamida Cell, the company developing NiCord, intends to file for orphan drug status with the EMA for other indications as well.

“Receipt of orphan drug status for NiCord in the US and Europe advances Gamida Cell’s commercialization plans a major step further, as both afford significant advantages,” said Yael Margolin, President and CEO of Gamida Cell.

Orphan drug designation provides various regulatory and economic benefits, including 7 years of market exclusivity upon product approval in the US and 10 years in the European Union.

Trials of NiCord

NiCord is currently being tested in a phase 1/2 study as an investigational therapeutic treatment for hematologic malignancies. In this study, NiCord is being used as the sole stem cell source.

In a previous study, presented at the 11th Annual International Cord Blood Symposium, researchers transplanted a NiCord unit and an unmanipulated cord blood unit in patients with ALL, AML, MDS, HL, or non-Hodgkin lymphoma.

A majority of patients in this small, phase 1/2 study achieved early platelet and neutrophil engraftment. And, in some patients, that engraftment persisted for 2 years.

Eight of the 11 patients enrolled achieved engraftment with the NiCord unit, and 2 engrafted with the unmanipulated cord blood unit. One patient had primary graft failure.

There were no adverse events attributable to the NiCord unit, but 4 patients developed grade 1-2 acute GVHD, and 1 patient developed limited chronic GVHD.

For more information on NiCord, visit the Gamida Cell website.

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, according to research published in Cell Metabolism.

Working with mice, researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of neutrophils.

“The link between these enzymes and neutrophils was a big surprise,” said study author Irfan J. Lodhi, PhD, of the Washington University School of Medicine in St. Louis.

“We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking.”

In the study, mice that couldn’t make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

“This may be a pathway to limit inflammation,” said study author Clay F. Semenkovich, MD, also of the Washington University School of Medicine.

“If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis.”

Dr Semenkovich said the enzymes specifically target neutrophils without affecting other immune cells, “so ether lipids appear to be a very precise target.”

The researchers also learned that inactivating the enzymes didn’t harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient’s neutrophil count would gradually rise, allowing the immune system to return to normal.

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, according to research published in Cell Metabolism.

Working with mice, researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of neutrophils.

“The link between these enzymes and neutrophils was a big surprise,” said study author Irfan J. Lodhi, PhD, of the Washington University School of Medicine in St. Louis.

“We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking.”

In the study, mice that couldn’t make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

“This may be a pathway to limit inflammation,” said study author Clay F. Semenkovich, MD, also of the Washington University School of Medicine.

“If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis.”

Dr Semenkovich said the enzymes specifically target neutrophils without affecting other immune cells, “so ether lipids appear to be a very precise target.”

The researchers also learned that inactivating the enzymes didn’t harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient’s neutrophil count would gradually rise, allowing the immune system to return to normal.

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, according to research published in Cell Metabolism.

Working with mice, researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of neutrophils.

“The link between these enzymes and neutrophils was a big surprise,” said study author Irfan J. Lodhi, PhD, of the Washington University School of Medicine in St. Louis.

“We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking.”

In the study, mice that couldn’t make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

“This may be a pathway to limit inflammation,” said study author Clay F. Semenkovich, MD, also of the Washington University School of Medicine.

“If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis.”

Dr Semenkovich said the enzymes specifically target neutrophils without affecting other immune cells, “so ether lipids appear to be a very precise target.”

The researchers also learned that inactivating the enzymes didn’t harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient’s neutrophil count would gradually rise, allowing the immune system to return to normal.

The European Commission has granted KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, orphan designation to treat patients with diffuse large B-cell lymphoma (DLBCL) in the European Union (EU).

To create KTE-C19, a patient’s T cells are genetically modified using a gammaretroviral vector to express a CAR designed to target CD19, a protein expressed on B cells.

The product received orphan designation to treat DLBCL in the US last March.

“We are pleased with the approval of orphan drug designation for KTE-C19 in the EU, another important milestone for Kite Pharma and for the progress of our lead program,” said Arie Belldegrun, MD, President and CEO of Kite Pharma, Inc., the company developing KTE-C19.

Orphan designation by the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 persons in the EU, and where no satisfactory treatment is available.

In addition to a 10-year period of marketing exclusivity in the EU after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase, and direct access to the centralized authorization procedure.

KTE-C19 in DLBCL

In a study published in the Journal of Clinical Oncology last year, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a complete response to treatment, 2 achieved a partial response, and 1 had stable disease. Three of the complete responses were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.

In the entire patient population, KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.

Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.

For more information on KTE-C19, visit Kite Pharma’s website.

The European Commission has granted KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, orphan designation to treat patients with diffuse large B-cell lymphoma (DLBCL) in the European Union (EU).

To create KTE-C19, a patient’s T cells are genetically modified using a gammaretroviral vector to express a CAR designed to target CD19, a protein expressed on B cells.

The product received orphan designation to treat DLBCL in the US last March.

“We are pleased with the approval of orphan drug designation for KTE-C19 in the EU, another important milestone for Kite Pharma and for the progress of our lead program,” said Arie Belldegrun, MD, President and CEO of Kite Pharma, Inc., the company developing KTE-C19.

Orphan designation by the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 persons in the EU, and where no satisfactory treatment is available.

In addition to a 10-year period of marketing exclusivity in the EU after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase, and direct access to the centralized authorization procedure.

KTE-C19 in DLBCL

In a study published in the Journal of Clinical Oncology last year, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a complete response to treatment, 2 achieved a partial response, and 1 had stable disease. Three of the complete responses were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.

In the entire patient population, KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.

Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.

For more information on KTE-C19, visit Kite Pharma’s website.

The European Commission has granted KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, orphan designation to treat patients with diffuse large B-cell lymphoma (DLBCL) in the European Union (EU).

To create KTE-C19, a patient’s T cells are genetically modified using a gammaretroviral vector to express a CAR designed to target CD19, a protein expressed on B cells.

The product received orphan designation to treat DLBCL in the US last March.

“We are pleased with the approval of orphan drug designation for KTE-C19 in the EU, another important milestone for Kite Pharma and for the progress of our lead program,” said Arie Belldegrun, MD, President and CEO of Kite Pharma, Inc., the company developing KTE-C19.

Orphan designation by the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 persons in the EU, and where no satisfactory treatment is available.

In addition to a 10-year period of marketing exclusivity in the EU after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase, and direct access to the centralized authorization procedure.

KTE-C19 in DLBCL

In a study published in the Journal of Clinical Oncology last year, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a complete response to treatment, 2 achieved a partial response, and 1 had stable disease. Three of the complete responses were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.

In the entire patient population, KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.

Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.

For more information on KTE-C19, visit Kite Pharma’s website.

Clinical question

Is intermittent proton pump inhibitor (PPI) therapy comparable with continuous-infusion PPI for the treatment of patients with high-risk bleeding ulcers who have undergone endoscopic therapy?

Bottom line

For patients with high-risk bleeding ulcers who have been treated endoscopically, treatment with intermittent proton pump inhibitor (PPI) therapy is as effective as continuous infusion of PPIs for the prevention of rebleeding. This systematic review, however, was not able to determine the most optimal intermittent PPI regimen for this purpose because the included studies included used various dosing schedules and administration routes. (LOE = 1a)

Reference

Sachar H, Vaidya K, Laine L. Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: A systematic review and meta-analysis. JAMA Intern Med 2014;174(11):1755-1762.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Government

Allocation: Uncertain

Setting: Inpatient (ward only)

Synopsis

Current guidelines recommend that patients with bleeding ulcers and endoscopic evidence of active bleeding, nonbleeding visible vessels, and adherent clots should receive an intravenous bolus dose of PPI followed by a continuous PPI infusion for 72 hours to prevent rebleeding. In this study, investigators searched multiple databases including MEDLINE, EMBASE, and the Cochrane Register to find randomized clinical trials that evaluated this continuous PPI regimen versus the use of intermittent PPIs for the treatment of these high-risk bleeding ulcers. The intermittent PPI regimens differed in both dosage and administration, from pantoprazole 40 mg given orally every 12 hours to pantoprazole 80 mg given intravenously once, followed by 40 mg intravenously every 6 hours.

Two authors independently performed the search, selected studies for inclusion, extracted data, and assessed the risk of bias for included studies. Ten of the 13 selected studies reported on the primary outcome of recurrent bleeding within 7 days and found that intermittent PPI use was noninferior to continuous-infusion PPI therapy, with the noninferiority margin predefined as an absolute risk difference of 3%. Noninferiority criteria were also met for the secondary outcomes, including rebleeding at 3 days or 30 days, mortality, need for surgical intervention, need for transfusion, and hospital length of stay. No publication or reporting biases were detected.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Is intermittent proton pump inhibitor (PPI) therapy comparable with continuous-infusion PPI for the treatment of patients with high-risk bleeding ulcers who have undergone endoscopic therapy?

Bottom line

For patients with high-risk bleeding ulcers who have been treated endoscopically, treatment with intermittent proton pump inhibitor (PPI) therapy is as effective as continuous infusion of PPIs for the prevention of rebleeding. This systematic review, however, was not able to determine the most optimal intermittent PPI regimen for this purpose because the included studies included used various dosing schedules and administration routes. (LOE = 1a)

Reference

Sachar H, Vaidya K, Laine L. Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: A systematic review and meta-analysis. JAMA Intern Med 2014;174(11):1755-1762.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Government

Allocation: Uncertain

Setting: Inpatient (ward only)

Synopsis

Current guidelines recommend that patients with bleeding ulcers and endoscopic evidence of active bleeding, nonbleeding visible vessels, and adherent clots should receive an intravenous bolus dose of PPI followed by a continuous PPI infusion for 72 hours to prevent rebleeding. In this study, investigators searched multiple databases including MEDLINE, EMBASE, and the Cochrane Register to find randomized clinical trials that evaluated this continuous PPI regimen versus the use of intermittent PPIs for the treatment of these high-risk bleeding ulcers. The intermittent PPI regimens differed in both dosage and administration, from pantoprazole 40 mg given orally every 12 hours to pantoprazole 80 mg given intravenously once, followed by 40 mg intravenously every 6 hours.

Two authors independently performed the search, selected studies for inclusion, extracted data, and assessed the risk of bias for included studies. Ten of the 13 selected studies reported on the primary outcome of recurrent bleeding within 7 days and found that intermittent PPI use was noninferior to continuous-infusion PPI therapy, with the noninferiority margin predefined as an absolute risk difference of 3%. Noninferiority criteria were also met for the secondary outcomes, including rebleeding at 3 days or 30 days, mortality, need for surgical intervention, need for transfusion, and hospital length of stay. No publication or reporting biases were detected.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Is intermittent proton pump inhibitor (PPI) therapy comparable with continuous-infusion PPI for the treatment of patients with high-risk bleeding ulcers who have undergone endoscopic therapy?

Bottom line

For patients with high-risk bleeding ulcers who have been treated endoscopically, treatment with intermittent proton pump inhibitor (PPI) therapy is as effective as continuous infusion of PPIs for the prevention of rebleeding. This systematic review, however, was not able to determine the most optimal intermittent PPI regimen for this purpose because the included studies included used various dosing schedules and administration routes. (LOE = 1a)

Reference

Sachar H, Vaidya K, Laine L. Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: A systematic review and meta-analysis. JAMA Intern Med 2014;174(11):1755-1762.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Government

Allocation: Uncertain

Setting: Inpatient (ward only)

Synopsis

Current guidelines recommend that patients with bleeding ulcers and endoscopic evidence of active bleeding, nonbleeding visible vessels, and adherent clots should receive an intravenous bolus dose of PPI followed by a continuous PPI infusion for 72 hours to prevent rebleeding. In this study, investigators searched multiple databases including MEDLINE, EMBASE, and the Cochrane Register to find randomized clinical trials that evaluated this continuous PPI regimen versus the use of intermittent PPIs for the treatment of these high-risk bleeding ulcers. The intermittent PPI regimens differed in both dosage and administration, from pantoprazole 40 mg given orally every 12 hours to pantoprazole 80 mg given intravenously once, followed by 40 mg intravenously every 6 hours.

Two authors independently performed the search, selected studies for inclusion, extracted data, and assessed the risk of bias for included studies. Ten of the 13 selected studies reported on the primary outcome of recurrent bleeding within 7 days and found that intermittent PPI use was noninferior to continuous-infusion PPI therapy, with the noninferiority margin predefined as an absolute risk difference of 3%. Noninferiority criteria were also met for the secondary outcomes, including rebleeding at 3 days or 30 days, mortality, need for surgical intervention, need for transfusion, and hospital length of stay. No publication or reporting biases were detected.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Is polyethylene glycol 3350-electrolyte solution an effective treatment for hospitalized patients with acute hepatic encephalopathy?

Bottom line

Polyethylene glycol 3350-electrolyte solution (PEG) is a safe and effective therapy for the initial treatment of acute hepatic encephalopathy (HE) in hospitalized patients. As compared with lactulose alone, the use of PEG alone during the first 24 hours of presentation worked better at improving symptoms of HE. The benefit beyond this time is less clear as both groups in this study received lactulose after 24 hours. (LOE = 1b)

Reference

Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs. polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy: The HELP randomized clinical trial. JAMA Intern Med 2014;174(11):1727-1733.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ward only)

Synopsis

Lactulose has long been used as the standard therapy for the treatment of acute HE. This study evaluated the efficacy of PEG as compared with lactulose for the initial treatment of HE. Using concealed allocation, investigators randomized 50 adult patients with cirrhosis and evidence of acute HE to receive either PEG or lactulose.

Patients in the PEG group received 4 L of PEG orally or via nasogastric tube as a single dose over 4 hours. Patients in the lactulose group received 20 g to 30 g lactulose orally or via nasogastric tube for 3 or more doses over 24 hours, or a single dose of 200 g lactulose via rectal tube. Grade of HE was determined prior to treatment and again at 24 hours using the hepatic encephalopathy scoring algorithm (HESA).

After 24 hours, all patients received lactulose per the standard of care. Baseline characteristics of the 2 groups were similar, with an average age of 56 years and similar Model of End-stage Liver Disease (MELD) scores. Analysis was by intention to treat. Patients in both groups had a mean baseline HE grade of 2.3. For the primary outcome of improvement in HE grade by 1 or more at 24 hours, PEG was more effective than lactulose (91% vs 52% patients with improved scores, P < .01). Furthermore, the median time to HE resolution was shorter in the PEG group (1 day vs 2 days, P =.01) with a trend toward decreased hospital length of stay (4 days vs 8 days, P =.07). There were no adverse events that were definitively attributed to the study medications in either group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Is polyethylene glycol 3350-electrolyte solution an effective treatment for hospitalized patients with acute hepatic encephalopathy?

Bottom line

Polyethylene glycol 3350-electrolyte solution (PEG) is a safe and effective therapy for the initial treatment of acute hepatic encephalopathy (HE) in hospitalized patients. As compared with lactulose alone, the use of PEG alone during the first 24 hours of presentation worked better at improving symptoms of HE. The benefit beyond this time is less clear as both groups in this study received lactulose after 24 hours. (LOE = 1b)

Reference

Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs. polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy: The HELP randomized clinical trial. JAMA Intern Med 2014;174(11):1727-1733.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ward only)

Synopsis

Lactulose has long been used as the standard therapy for the treatment of acute HE. This study evaluated the efficacy of PEG as compared with lactulose for the initial treatment of HE. Using concealed allocation, investigators randomized 50 adult patients with cirrhosis and evidence of acute HE to receive either PEG or lactulose.

Patients in the PEG group received 4 L of PEG orally or via nasogastric tube as a single dose over 4 hours. Patients in the lactulose group received 20 g to 30 g lactulose orally or via nasogastric tube for 3 or more doses over 24 hours, or a single dose of 200 g lactulose via rectal tube. Grade of HE was determined prior to treatment and again at 24 hours using the hepatic encephalopathy scoring algorithm (HESA).

After 24 hours, all patients received lactulose per the standard of care. Baseline characteristics of the 2 groups were similar, with an average age of 56 years and similar Model of End-stage Liver Disease (MELD) scores. Analysis was by intention to treat. Patients in both groups had a mean baseline HE grade of 2.3. For the primary outcome of improvement in HE grade by 1 or more at 24 hours, PEG was more effective than lactulose (91% vs 52% patients with improved scores, P < .01). Furthermore, the median time to HE resolution was shorter in the PEG group (1 day vs 2 days, P =.01) with a trend toward decreased hospital length of stay (4 days vs 8 days, P =.07). There were no adverse events that were definitively attributed to the study medications in either group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Is polyethylene glycol 3350-electrolyte solution an effective treatment for hospitalized patients with acute hepatic encephalopathy?

Bottom line

Polyethylene glycol 3350-electrolyte solution (PEG) is a safe and effective therapy for the initial treatment of acute hepatic encephalopathy (HE) in hospitalized patients. As compared with lactulose alone, the use of PEG alone during the first 24 hours of presentation worked better at improving symptoms of HE. The benefit beyond this time is less clear as both groups in this study received lactulose after 24 hours. (LOE = 1b)

Reference

Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs. polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy: The HELP randomized clinical trial. JAMA Intern Med 2014;174(11):1727-1733.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ward only)

Synopsis

Lactulose has long been used as the standard therapy for the treatment of acute HE. This study evaluated the efficacy of PEG as compared with lactulose for the initial treatment of HE. Using concealed allocation, investigators randomized 50 adult patients with cirrhosis and evidence of acute HE to receive either PEG or lactulose.

Patients in the PEG group received 4 L of PEG orally or via nasogastric tube as a single dose over 4 hours. Patients in the lactulose group received 20 g to 30 g lactulose orally or via nasogastric tube for 3 or more doses over 24 hours, or a single dose of 200 g lactulose via rectal tube. Grade of HE was determined prior to treatment and again at 24 hours using the hepatic encephalopathy scoring algorithm (HESA).

After 24 hours, all patients received lactulose per the standard of care. Baseline characteristics of the 2 groups were similar, with an average age of 56 years and similar Model of End-stage Liver Disease (MELD) scores. Analysis was by intention to treat. Patients in both groups had a mean baseline HE grade of 2.3. For the primary outcome of improvement in HE grade by 1 or more at 24 hours, PEG was more effective than lactulose (91% vs 52% patients with improved scores, P < .01). Furthermore, the median time to HE resolution was shorter in the PEG group (1 day vs 2 days, P =.01) with a trend toward decreased hospital length of stay (4 days vs 8 days, P =.07). There were no adverse events that were definitively attributed to the study medications in either group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Listen to Chris Spoja, MD, a hospitalist with Sound Physicians, explain his decision to pursue a Master’s of Medical Management (MMM) degree.

Listen to Chris Spoja, MD, a hospitalist with Sound Physicians, explain his decision to pursue a Master’s of Medical Management (MMM) degree.

Listen to Chris Spoja, MD, a hospitalist with Sound Physicians, explain his decision to pursue a Master’s of Medical Management (MMM) degree.

This month, The Hospitalist features new appointments, promotions, awards, and achievements of hospital medicine physicians and healthcare industry professionals.

Douglas Carlson, MD, FAAP, SFHM, has been appointed professor and chair of the department of pediatrics at Southern Illinois University in Springfield, Ill. Dr. Carlson is a pediatric hospitalist who served as director of the pediatric hospitalist medicine division at Washington University School of Medicine in St. Louis, Mo. Dr. Carlson currently serves as co-chair of the SHM Pediatric Committee, as well as Workforce Taskforce Leader for the Pediatric Hospital Medicine Leadership Committee and chair of the Pediatric Hospital Medicine National Conference Planning Committee.

Howard Epstein, MD, FHM, has been appointed executive vice president and chief medical officer at PreferredOne, a health services and insurance provider based in Golden Valley, Minn. Dr. Epstein comes to PreferredOne from the Institute for Clinical Systems Improvement (ICSI) in Bloomington, where he served as chief health systems officer. An SHM board member, Dr. Epstein previously helped found the hospital medicine and palliative care programs at Regions Hospital and HealthPartners Medical Group in St. Paul, Minn.

Les Hall, MD, has been appointed executive dean of the University of South Carolina School of Medicine, as well as CEO of Palmetto Health-USC Medical Group in Columbia, S.C. Prior to his role at the University of South Carolina, Dr. Hall served as associate dean for clinical affairs at the University of Missouri School of Medicine and chief medical officer of the University of Missouri Health System in Columbia, Mo. Dr. Hall is a practicing hospitalist and an active member of SHM, and he has continued to care for patients throughout his career as a healthcare leader.

• Liesbet Jansen, MD, was awarded the 2014 Dr. Alexander MacIntyre Award of Excellence by the Alliston (Ontario, Canada) and Area Physician Recruitment Committee for demonstrating excellence in medical practice and commitment to the local community. Dr. Jansen serves as a hospitalist and chief of family medicine at Stevenson Memorial Hospital in Alliston, Ontario, Canada.

Hans Jeppesen, MD, is the new chief of hospital medicine at North Shore Medical Center (NSMC) in Salem, Mass. In addition to overseeing the hospitalist team at NSMC, Dr. Jeppesen will also be responsible for caring for inpatients at NSMC Salem and Union (Lynn, Mass.) Hospitals. Before joining NSMC, Dr. Jeppesen served as chief of hospitalist services at Cambridge Health Alliance in Cambridge, Mass.

Todd Kislak is the new chief development officer for Hospitalists Now, Inc. (HNI), a national physician management company based in Austin, Texas. In his new role, Kislak is responsible for sales and business development as well as marketing for HNI. Kislak formerly served as vice president of marketing and development for IPC The Hospitalist Company, based in North Hollywood, Calif.

Kelly London, PA-C, has been awarded Non-Physician Hospitalist of the Year by the Maryland chapter of the Society of Hospital Medicine. London is the first nonphysician provider to receive the award, and was nominated along with other qualified nurse practitioners and physician assistants throughout Maryland. London serves on the hospitalist team at Anne Arundel Medical Center, managed by MDICS (Physicians Inpatient Care Specialists), in Annapolis, Md.

Jennifer Miraglia is the new executive director for the Chicago region of IPC The Hospitalist Company, a national hospital medicine management company based in North Hollywood, Calif. Before coming to IPC, Miraglia worked as regional vice president of operations for RehabCare, a division of Kindred Healthcare based in Louisville, Ky. IPC manages hospitalist services in over 400 hospitals across the United States.

 

Steven Pantilat, MD, MHM, FAAHPM, recently was awarded the Ritz E. Heerman Memorial Award by the California Hospital Association Board of Trustees for his work on improving the quality of palliative care services in California. Dr. Pantilat is the founding director of the University of California, San Francisco (UCSF) Palliative Care Program, and director of the UCSF Palliative Care Leadership Center. Dr. Pantilat is a past president of SHM and currently works as a professor of clinical medicine at UCSF.

Business Moves

Sound Physicians, based in Tacoma, Wash., has acquired Cogent Healthcare of Brentwood, Tenn. The merger between the two national hospitalist management companies marks the creation of the largest private hospitalist network in the U.S., which will now serve over 180 hospitals in 35 states. In total, Sound Physicians will now employ over 1,750 physician and nonphysician providers.

• North Hollywood, Calif.-based IPC The Hospitalist Company has acquired the following practices: Hospital Practice Associates, Inc. (HPA), in Jacksonville, Fla.; John N. Campbell, MD, PC, in Grand Rapids, Mich.; Comprehensive Health Solutions, in Newtown Square, Penn.; Midland Hospitalists PLC in Midland, Mich.; and Clyo Internal Medicine in Dayton, Ohio. IPC is a national hospitalist management company serving over 400 hospitals and 1,200 post-acute care facilities across the country.

• The Greenville, S.C.-based Ob Hospitalist Group (OBHG) recently received the following honors: voted one of the Inc. 5,000 Fastest Growing Private Companies in America for the second year running for a growth rate of 239% since 2011; voted one of the Best Places to Work in South Carolina by the South Carolina Chamber of Commerce and SC Biz News, for the second consecutive year; listed on the Roaring Twenties List from SC Biz News as one of the 40 highest performing companies in South Carolina; and included on South Carolina’s 25 Fastest-Growing Companies list for the third year running. OBHG has been providing OB/GYN hospitalist services across the country since 2006.

• The OSF St. Elizabeth Medical Center in Ottawa, Ill., has just introduced a new hospitalist program at its 99-bed acute care hospital. Robert B. Maguire, MD, a veteran Ottawa doctor, has been chosen to lead the new hospitalist program as medical director. OSF St. Elizabeth will continue to recruit additional hospitalists to the new program with the help of 24ON Physicians/In Compass Health, Inc., a hospitalist staffing firm based in Alpharetta, Ga.

• Penn State Hershey Children’s Hospital is now providing pediatric care at Moses Taylor Hospital in Scranton, Penn. Moses Taylor Hospital is a 217-bed acute care facility operated by Commonwealth Health, the largest healthcare system in northern Pennsylvania, which consists of six hospitals and dozens of post-acute care practices and facilities.

• TeamHealth, a national physician management company based in Knoxville, Tenn., announced its acquisition of Premier Physician Services, Inc., based in Dayton, Ohio. Premier consists of eight hospitalist programs as well as 45 emergency medicine programs, 15 correctional care programs, and 15 occupational medicine programs, which TeamHealth will now oversee. TeamHealth provides physician management and healthcare staffing in 47 states.

This month, The Hospitalist features new appointments, promotions, awards, and achievements of hospital medicine physicians and healthcare industry professionals.

Douglas Carlson, MD, FAAP, SFHM, has been appointed professor and chair of the department of pediatrics at Southern Illinois University in Springfield, Ill. Dr. Carlson is a pediatric hospitalist who served as director of the pediatric hospitalist medicine division at Washington University School of Medicine in St. Louis, Mo. Dr. Carlson currently serves as co-chair of the SHM Pediatric Committee, as well as Workforce Taskforce Leader for the Pediatric Hospital Medicine Leadership Committee and chair of the Pediatric Hospital Medicine National Conference Planning Committee.

Howard Epstein, MD, FHM, has been appointed executive vice president and chief medical officer at PreferredOne, a health services and insurance provider based in Golden Valley, Minn. Dr. Epstein comes to PreferredOne from the Institute for Clinical Systems Improvement (ICSI) in Bloomington, where he served as chief health systems officer. An SHM board member, Dr. Epstein previously helped found the hospital medicine and palliative care programs at Regions Hospital and HealthPartners Medical Group in St. Paul, Minn.

Les Hall, MD, has been appointed executive dean of the University of South Carolina School of Medicine, as well as CEO of Palmetto Health-USC Medical Group in Columbia, S.C. Prior to his role at the University of South Carolina, Dr. Hall served as associate dean for clinical affairs at the University of Missouri School of Medicine and chief medical officer of the University of Missouri Health System in Columbia, Mo. Dr. Hall is a practicing hospitalist and an active member of SHM, and he has continued to care for patients throughout his career as a healthcare leader.

• Liesbet Jansen, MD, was awarded the 2014 Dr. Alexander MacIntyre Award of Excellence by the Alliston (Ontario, Canada) and Area Physician Recruitment Committee for demonstrating excellence in medical practice and commitment to the local community. Dr. Jansen serves as a hospitalist and chief of family medicine at Stevenson Memorial Hospital in Alliston, Ontario, Canada.

Hans Jeppesen, MD, is the new chief of hospital medicine at North Shore Medical Center (NSMC) in Salem, Mass. In addition to overseeing the hospitalist team at NSMC, Dr. Jeppesen will also be responsible for caring for inpatients at NSMC Salem and Union (Lynn, Mass.) Hospitals. Before joining NSMC, Dr. Jeppesen served as chief of hospitalist services at Cambridge Health Alliance in Cambridge, Mass.

Todd Kislak is the new chief development officer for Hospitalists Now, Inc. (HNI), a national physician management company based in Austin, Texas. In his new role, Kislak is responsible for sales and business development as well as marketing for HNI. Kislak formerly served as vice president of marketing and development for IPC The Hospitalist Company, based in North Hollywood, Calif.

Kelly London, PA-C, has been awarded Non-Physician Hospitalist of the Year by the Maryland chapter of the Society of Hospital Medicine. London is the first nonphysician provider to receive the award, and was nominated along with other qualified nurse practitioners and physician assistants throughout Maryland. London serves on the hospitalist team at Anne Arundel Medical Center, managed by MDICS (Physicians Inpatient Care Specialists), in Annapolis, Md.

Jennifer Miraglia is the new executive director for the Chicago region of IPC The Hospitalist Company, a national hospital medicine management company based in North Hollywood, Calif. Before coming to IPC, Miraglia worked as regional vice president of operations for RehabCare, a division of Kindred Healthcare based in Louisville, Ky. IPC manages hospitalist services in over 400 hospitals across the United States.

 

Steven Pantilat, MD, MHM, FAAHPM, recently was awarded the Ritz E. Heerman Memorial Award by the California Hospital Association Board of Trustees for his work on improving the quality of palliative care services in California. Dr. Pantilat is the founding director of the University of California, San Francisco (UCSF) Palliative Care Program, and director of the UCSF Palliative Care Leadership Center. Dr. Pantilat is a past president of SHM and currently works as a professor of clinical medicine at UCSF.

Business Moves

Sound Physicians, based in Tacoma, Wash., has acquired Cogent Healthcare of Brentwood, Tenn. The merger between the two national hospitalist management companies marks the creation of the largest private hospitalist network in the U.S., which will now serve over 180 hospitals in 35 states. In total, Sound Physicians will now employ over 1,750 physician and nonphysician providers.

• North Hollywood, Calif.-based IPC The Hospitalist Company has acquired the following practices: Hospital Practice Associates, Inc. (HPA), in Jacksonville, Fla.; John N. Campbell, MD, PC, in Grand Rapids, Mich.; Comprehensive Health Solutions, in Newtown Square, Penn.; Midland Hospitalists PLC in Midland, Mich.; and Clyo Internal Medicine in Dayton, Ohio. IPC is a national hospitalist management company serving over 400 hospitals and 1,200 post-acute care facilities across the country.

• The Greenville, S.C.-based Ob Hospitalist Group (OBHG) recently received the following honors: voted one of the Inc. 5,000 Fastest Growing Private Companies in America for the second year running for a growth rate of 239% since 2011; voted one of the Best Places to Work in South Carolina by the South Carolina Chamber of Commerce and SC Biz News, for the second consecutive year; listed on the Roaring Twenties List from SC Biz News as one of the 40 highest performing companies in South Carolina; and included on South Carolina’s 25 Fastest-Growing Companies list for the third year running. OBHG has been providing OB/GYN hospitalist services across the country since 2006.

• The OSF St. Elizabeth Medical Center in Ottawa, Ill., has just introduced a new hospitalist program at its 99-bed acute care hospital. Robert B. Maguire, MD, a veteran Ottawa doctor, has been chosen to lead the new hospitalist program as medical director. OSF St. Elizabeth will continue to recruit additional hospitalists to the new program with the help of 24ON Physicians/In Compass Health, Inc., a hospitalist staffing firm based in Alpharetta, Ga.

• Penn State Hershey Children’s Hospital is now providing pediatric care at Moses Taylor Hospital in Scranton, Penn. Moses Taylor Hospital is a 217-bed acute care facility operated by Commonwealth Health, the largest healthcare system in northern Pennsylvania, which consists of six hospitals and dozens of post-acute care practices and facilities.

• TeamHealth, a national physician management company based in Knoxville, Tenn., announced its acquisition of Premier Physician Services, Inc., based in Dayton, Ohio. Premier consists of eight hospitalist programs as well as 45 emergency medicine programs, 15 correctional care programs, and 15 occupational medicine programs, which TeamHealth will now oversee. TeamHealth provides physician management and healthcare staffing in 47 states.

This month, The Hospitalist features new appointments, promotions, awards, and achievements of hospital medicine physicians and healthcare industry professionals.

Douglas Carlson, MD, FAAP, SFHM, has been appointed professor and chair of the department of pediatrics at Southern Illinois University in Springfield, Ill. Dr. Carlson is a pediatric hospitalist who served as director of the pediatric hospitalist medicine division at Washington University School of Medicine in St. Louis, Mo. Dr. Carlson currently serves as co-chair of the SHM Pediatric Committee, as well as Workforce Taskforce Leader for the Pediatric Hospital Medicine Leadership Committee and chair of the Pediatric Hospital Medicine National Conference Planning Committee.

Howard Epstein, MD, FHM, has been appointed executive vice president and chief medical officer at PreferredOne, a health services and insurance provider based in Golden Valley, Minn. Dr. Epstein comes to PreferredOne from the Institute for Clinical Systems Improvement (ICSI) in Bloomington, where he served as chief health systems officer. An SHM board member, Dr. Epstein previously helped found the hospital medicine and palliative care programs at Regions Hospital and HealthPartners Medical Group in St. Paul, Minn.

Les Hall, MD, has been appointed executive dean of the University of South Carolina School of Medicine, as well as CEO of Palmetto Health-USC Medical Group in Columbia, S.C. Prior to his role at the University of South Carolina, Dr. Hall served as associate dean for clinical affairs at the University of Missouri School of Medicine and chief medical officer of the University of Missouri Health System in Columbia, Mo. Dr. Hall is a practicing hospitalist and an active member of SHM, and he has continued to care for patients throughout his career as a healthcare leader.

• Liesbet Jansen, MD, was awarded the 2014 Dr. Alexander MacIntyre Award of Excellence by the Alliston (Ontario, Canada) and Area Physician Recruitment Committee for demonstrating excellence in medical practice and commitment to the local community. Dr. Jansen serves as a hospitalist and chief of family medicine at Stevenson Memorial Hospital in Alliston, Ontario, Canada.

Hans Jeppesen, MD, is the new chief of hospital medicine at North Shore Medical Center (NSMC) in Salem, Mass. In addition to overseeing the hospitalist team at NSMC, Dr. Jeppesen will also be responsible for caring for inpatients at NSMC Salem and Union (Lynn, Mass.) Hospitals. Before joining NSMC, Dr. Jeppesen served as chief of hospitalist services at Cambridge Health Alliance in Cambridge, Mass.

Todd Kislak is the new chief development officer for Hospitalists Now, Inc. (HNI), a national physician management company based in Austin, Texas. In his new role, Kislak is responsible for sales and business development as well as marketing for HNI. Kislak formerly served as vice president of marketing and development for IPC The Hospitalist Company, based in North Hollywood, Calif.

Kelly London, PA-C, has been awarded Non-Physician Hospitalist of the Year by the Maryland chapter of the Society of Hospital Medicine. London is the first nonphysician provider to receive the award, and was nominated along with other qualified nurse practitioners and physician assistants throughout Maryland. London serves on the hospitalist team at Anne Arundel Medical Center, managed by MDICS (Physicians Inpatient Care Specialists), in Annapolis, Md.

Jennifer Miraglia is the new executive director for the Chicago region of IPC The Hospitalist Company, a national hospital medicine management company based in North Hollywood, Calif. Before coming to IPC, Miraglia worked as regional vice president of operations for RehabCare, a division of Kindred Healthcare based in Louisville, Ky. IPC manages hospitalist services in over 400 hospitals across the United States.

 

Steven Pantilat, MD, MHM, FAAHPM, recently was awarded the Ritz E. Heerman Memorial Award by the California Hospital Association Board of Trustees for his work on improving the quality of palliative care services in California. Dr. Pantilat is the founding director of the University of California, San Francisco (UCSF) Palliative Care Program, and director of the UCSF Palliative Care Leadership Center. Dr. Pantilat is a past president of SHM and currently works as a professor of clinical medicine at UCSF.

Business Moves

Sound Physicians, based in Tacoma, Wash., has acquired Cogent Healthcare of Brentwood, Tenn. The merger between the two national hospitalist management companies marks the creation of the largest private hospitalist network in the U.S., which will now serve over 180 hospitals in 35 states. In total, Sound Physicians will now employ over 1,750 physician and nonphysician providers.

• North Hollywood, Calif.-based IPC The Hospitalist Company has acquired the following practices: Hospital Practice Associates, Inc. (HPA), in Jacksonville, Fla.; John N. Campbell, MD, PC, in Grand Rapids, Mich.; Comprehensive Health Solutions, in Newtown Square, Penn.; Midland Hospitalists PLC in Midland, Mich.; and Clyo Internal Medicine in Dayton, Ohio. IPC is a national hospitalist management company serving over 400 hospitals and 1,200 post-acute care facilities across the country.

• The Greenville, S.C.-based Ob Hospitalist Group (OBHG) recently received the following honors: voted one of the Inc. 5,000 Fastest Growing Private Companies in America for the second year running for a growth rate of 239% since 2011; voted one of the Best Places to Work in South Carolina by the South Carolina Chamber of Commerce and SC Biz News, for the second consecutive year; listed on the Roaring Twenties List from SC Biz News as one of the 40 highest performing companies in South Carolina; and included on South Carolina’s 25 Fastest-Growing Companies list for the third year running. OBHG has been providing OB/GYN hospitalist services across the country since 2006.

• The OSF St. Elizabeth Medical Center in Ottawa, Ill., has just introduced a new hospitalist program at its 99-bed acute care hospital. Robert B. Maguire, MD, a veteran Ottawa doctor, has been chosen to lead the new hospitalist program as medical director. OSF St. Elizabeth will continue to recruit additional hospitalists to the new program with the help of 24ON Physicians/In Compass Health, Inc., a hospitalist staffing firm based in Alpharetta, Ga.

• Penn State Hershey Children’s Hospital is now providing pediatric care at Moses Taylor Hospital in Scranton, Penn. Moses Taylor Hospital is a 217-bed acute care facility operated by Commonwealth Health, the largest healthcare system in northern Pennsylvania, which consists of six hospitals and dozens of post-acute care practices and facilities.

• TeamHealth, a national physician management company based in Knoxville, Tenn., announced its acquisition of Premier Physician Services, Inc., based in Dayton, Ohio. Premier consists of eight hospitalist programs as well as 45 emergency medicine programs, 15 correctional care programs, and 15 occupational medicine programs, which TeamHealth will now oversee. TeamHealth provides physician management and healthcare staffing in 47 states.