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Single injection could treat hemophilia B long-term
Cell therapy could produce lasting effects in hemophilia B, according to a group of researchers.
They genetically modified induced pluripotent cells (iPSCs) derived from patients with hemophilia B and converted those iPSCs into hepatocyte-like cells (HLCs).
When transplanted into mouse models of hemophilia B, the HLCs remained functional for months, increasing levels of factor IX (FIX) and clotting efficiency.
However, the HLCs were substantially less effective than cryopreserved human hepatocytes (hHeps), which were able to correct clotting defects in mice long-term.
“The appeal of a cell-based approach is that you minimize the number of treatments that a patient needs,” explained Suvasini Ramaswamy, PhD, of The Boston Consulting Group in Massachusetts.
“Rather than constant injections, you can do this in one shot.”
Dr Ramaswamy and her colleagues described their results with this approach in Cell Reports. Study authors include employees of Shire Therapeutics, Vertex Pharmaceuticals, and Thermo Fisher Scientific.
The researchers first developed a quadruple knockout mouse model of hemophilia B that allows for the engraftment and expansion of hHeps. The team crossed transgenic FIX-/--deficient mice with Rag2-/- IL2rg -/- Fah-/- mice to create this model.
The researchers transplanted cryopreserved hHeps into the mice and observed a sustained increase in circulating levels of human albumin, human FIX, and clusters of FIX- or Fah-positive cells in the liver.
The team said the hHeps were able to restore clotting function to wild-type levels in the mice—at least 10-fold higher than levels needed for a significant improvement in hemophilia B.
The hHeps remained functional for up to a year, and the researchers believe the cells could persist even longer. The team noted that there was no difference in the efficacy of hHeps from different donors or vendors.
The researchers then tested the cell therapy they developed using iPSCs. They collected blood samples from 2 patients with severe hemophilia B, reprogrammed peripheral blood-derived mononuclear cells into iPSCs, and used CRISPR/Cas9 to repair the mutations in each patient’s FIX gene.
The team coaxed those repaired cells into HLCs and tested the HLCs in the mouse model of hemophilia B. The HLCs were transplanted through the spleen so the cells were distributed uniformly in the liver.
The researchers said the HLCs were present and functional in the liver for up to a year, but they were less effective than hHeps. Mice that received HLCs experienced “modest” increases in clotting efficiency, from less than 10% to about 25% of wild-type activity.
The researchers believe this work demonstrates the value of combining stem cell reprogramming and gene-modifying approaches to treat genetic diseases. However, more work is needed to optimize this approach for hemophilia B.
Cell therapy could produce lasting effects in hemophilia B, according to a group of researchers.
They genetically modified induced pluripotent cells (iPSCs) derived from patients with hemophilia B and converted those iPSCs into hepatocyte-like cells (HLCs).
When transplanted into mouse models of hemophilia B, the HLCs remained functional for months, increasing levels of factor IX (FIX) and clotting efficiency.
However, the HLCs were substantially less effective than cryopreserved human hepatocytes (hHeps), which were able to correct clotting defects in mice long-term.
“The appeal of a cell-based approach is that you minimize the number of treatments that a patient needs,” explained Suvasini Ramaswamy, PhD, of The Boston Consulting Group in Massachusetts.
“Rather than constant injections, you can do this in one shot.”
Dr Ramaswamy and her colleagues described their results with this approach in Cell Reports. Study authors include employees of Shire Therapeutics, Vertex Pharmaceuticals, and Thermo Fisher Scientific.
The researchers first developed a quadruple knockout mouse model of hemophilia B that allows for the engraftment and expansion of hHeps. The team crossed transgenic FIX-/--deficient mice with Rag2-/- IL2rg -/- Fah-/- mice to create this model.
The researchers transplanted cryopreserved hHeps into the mice and observed a sustained increase in circulating levels of human albumin, human FIX, and clusters of FIX- or Fah-positive cells in the liver.
The team said the hHeps were able to restore clotting function to wild-type levels in the mice—at least 10-fold higher than levels needed for a significant improvement in hemophilia B.
The hHeps remained functional for up to a year, and the researchers believe the cells could persist even longer. The team noted that there was no difference in the efficacy of hHeps from different donors or vendors.
The researchers then tested the cell therapy they developed using iPSCs. They collected blood samples from 2 patients with severe hemophilia B, reprogrammed peripheral blood-derived mononuclear cells into iPSCs, and used CRISPR/Cas9 to repair the mutations in each patient’s FIX gene.
The team coaxed those repaired cells into HLCs and tested the HLCs in the mouse model of hemophilia B. The HLCs were transplanted through the spleen so the cells were distributed uniformly in the liver.
The researchers said the HLCs were present and functional in the liver for up to a year, but they were less effective than hHeps. Mice that received HLCs experienced “modest” increases in clotting efficiency, from less than 10% to about 25% of wild-type activity.
The researchers believe this work demonstrates the value of combining stem cell reprogramming and gene-modifying approaches to treat genetic diseases. However, more work is needed to optimize this approach for hemophilia B.
Cell therapy could produce lasting effects in hemophilia B, according to a group of researchers.
They genetically modified induced pluripotent cells (iPSCs) derived from patients with hemophilia B and converted those iPSCs into hepatocyte-like cells (HLCs).
When transplanted into mouse models of hemophilia B, the HLCs remained functional for months, increasing levels of factor IX (FIX) and clotting efficiency.
However, the HLCs were substantially less effective than cryopreserved human hepatocytes (hHeps), which were able to correct clotting defects in mice long-term.
“The appeal of a cell-based approach is that you minimize the number of treatments that a patient needs,” explained Suvasini Ramaswamy, PhD, of The Boston Consulting Group in Massachusetts.
“Rather than constant injections, you can do this in one shot.”
Dr Ramaswamy and her colleagues described their results with this approach in Cell Reports. Study authors include employees of Shire Therapeutics, Vertex Pharmaceuticals, and Thermo Fisher Scientific.
The researchers first developed a quadruple knockout mouse model of hemophilia B that allows for the engraftment and expansion of hHeps. The team crossed transgenic FIX-/--deficient mice with Rag2-/- IL2rg -/- Fah-/- mice to create this model.
The researchers transplanted cryopreserved hHeps into the mice and observed a sustained increase in circulating levels of human albumin, human FIX, and clusters of FIX- or Fah-positive cells in the liver.
The team said the hHeps were able to restore clotting function to wild-type levels in the mice—at least 10-fold higher than levels needed for a significant improvement in hemophilia B.
The hHeps remained functional for up to a year, and the researchers believe the cells could persist even longer. The team noted that there was no difference in the efficacy of hHeps from different donors or vendors.
The researchers then tested the cell therapy they developed using iPSCs. They collected blood samples from 2 patients with severe hemophilia B, reprogrammed peripheral blood-derived mononuclear cells into iPSCs, and used CRISPR/Cas9 to repair the mutations in each patient’s FIX gene.
The team coaxed those repaired cells into HLCs and tested the HLCs in the mouse model of hemophilia B. The HLCs were transplanted through the spleen so the cells were distributed uniformly in the liver.
The researchers said the HLCs were present and functional in the liver for up to a year, but they were less effective than hHeps. Mice that received HLCs experienced “modest” increases in clotting efficiency, from less than 10% to about 25% of wild-type activity.
The researchers believe this work demonstrates the value of combining stem cell reprogramming and gene-modifying approaches to treat genetic diseases. However, more work is needed to optimize this approach for hemophilia B.
FDA issues CRL for proposed biosimilar rituximab
The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) saying the agency cannot approve Sandoz’s proposed biosimilar rituximab.
Sandoz submitted the biologics licensing application for the product, known as GP2013, in September 2017.
The company was seeking approval for GP2013 to treat follicular lymphoma (FL), diffuse large B-cell lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.
The drug already has approval for these indications in Europe. The European Commission approved GP2013 (Rixathon) in June 2017.
As for US approval, Sandoz said it is evaluating the content of the FDA’s CRL and “remains committed to further discussions with FDA in order to bring this important medicine to US patients as soon as possible.”
The company said it “stands behind the robust body of evidence included in the regulatory submission” for GP2013.
Part of this evidence is the ASSIST-FL trial, in which researchers compared GP2013 to the reference product, Roche’s MabThera. Results from this trial were published in The Lancet Haematology and presented at ESMO 2017 Congress.
This phase 3 trial included adults with previously untreated, advanced stage FL. Patients received 8 cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.
At a median follow-up of 11.6 months, the overall response rate was 87% (271/311) in the GP2013 arm and 88% in the rituximab arm (274/313). Complete response rates were 15% (n=46) and 13% (n=42), respectively.
Rates of adverse events (AEs) were 93% in the GP2013 arm and 91% in the rituximab arm. Rates of serious AEs were 23% and 20%, respectively. The rate of discontinuation due to AEs was 7% in both arms.
The most common AE was neutropenia, which occurred in 26% of patients in the GP2013 arm and 30% of those in the rituximab arm in the combination phase. Rates of neutropenia in the maintenance phase were 10% and 6%, respectively.
The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) saying the agency cannot approve Sandoz’s proposed biosimilar rituximab.
Sandoz submitted the biologics licensing application for the product, known as GP2013, in September 2017.
The company was seeking approval for GP2013 to treat follicular lymphoma (FL), diffuse large B-cell lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.
The drug already has approval for these indications in Europe. The European Commission approved GP2013 (Rixathon) in June 2017.
As for US approval, Sandoz said it is evaluating the content of the FDA’s CRL and “remains committed to further discussions with FDA in order to bring this important medicine to US patients as soon as possible.”
The company said it “stands behind the robust body of evidence included in the regulatory submission” for GP2013.
Part of this evidence is the ASSIST-FL trial, in which researchers compared GP2013 to the reference product, Roche’s MabThera. Results from this trial were published in The Lancet Haematology and presented at ESMO 2017 Congress.
This phase 3 trial included adults with previously untreated, advanced stage FL. Patients received 8 cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.
At a median follow-up of 11.6 months, the overall response rate was 87% (271/311) in the GP2013 arm and 88% in the rituximab arm (274/313). Complete response rates were 15% (n=46) and 13% (n=42), respectively.
Rates of adverse events (AEs) were 93% in the GP2013 arm and 91% in the rituximab arm. Rates of serious AEs were 23% and 20%, respectively. The rate of discontinuation due to AEs was 7% in both arms.
The most common AE was neutropenia, which occurred in 26% of patients in the GP2013 arm and 30% of those in the rituximab arm in the combination phase. Rates of neutropenia in the maintenance phase were 10% and 6%, respectively.
The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) saying the agency cannot approve Sandoz’s proposed biosimilar rituximab.
Sandoz submitted the biologics licensing application for the product, known as GP2013, in September 2017.
The company was seeking approval for GP2013 to treat follicular lymphoma (FL), diffuse large B-cell lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.
The drug already has approval for these indications in Europe. The European Commission approved GP2013 (Rixathon) in June 2017.
As for US approval, Sandoz said it is evaluating the content of the FDA’s CRL and “remains committed to further discussions with FDA in order to bring this important medicine to US patients as soon as possible.”
The company said it “stands behind the robust body of evidence included in the regulatory submission” for GP2013.
Part of this evidence is the ASSIST-FL trial, in which researchers compared GP2013 to the reference product, Roche’s MabThera. Results from this trial were published in The Lancet Haematology and presented at ESMO 2017 Congress.
This phase 3 trial included adults with previously untreated, advanced stage FL. Patients received 8 cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.
At a median follow-up of 11.6 months, the overall response rate was 87% (271/311) in the GP2013 arm and 88% in the rituximab arm (274/313). Complete response rates were 15% (n=46) and 13% (n=42), respectively.
Rates of adverse events (AEs) were 93% in the GP2013 arm and 91% in the rituximab arm. Rates of serious AEs were 23% and 20%, respectively. The rate of discontinuation due to AEs was 7% in both arms.
The most common AE was neutropenia, which occurred in 26% of patients in the GP2013 arm and 30% of those in the rituximab arm in the combination phase. Rates of neutropenia in the maintenance phase were 10% and 6%, respectively.
JAK inhibitor reduces GVHD in mice
An investigational JAK1/2 inhibitor can fight graft-versus-host disease (GVHD), according to preclinical research published in Leukemia.
The inhibitor, baricitinib, reduced GVHD in mice while preserving T-cell expansion and the graft-versus-leukemia (GVL) effect.
Baricitinib proved more effective than ruxolitinib for the treatment and prevention of GVHD and enabled 100% survival in a mouse model of severe GVHD.
“We were surprised to achieve 100% survival of mice with the most severe model of graft-versus-host disease,” said study author Jaebok Choi, PhD, of the Washington University School of Medicine in St. Louis, Missouri.
“We are now studying the multi-pronged ways this drug behaves in an effort to develop an even better version for eventual use in clinical trials.”
For the current study, Dr Choi and his colleagues tested baricitinib and ruxolitinib in murine recipients of allogeneic hematopoietic stem cell transplants (allo-HSCTs). Mice received either drug for 31 days post-HSCT.
Mice treated with baricitinib had a significant reduction in intestinal GVHD compared to both ruxolitinib recipients and vehicle-treated controls (P=0.037).
In addition, 100% of baricitinib recipients were still alive at 60 days after HSCT, compared to about 60% of ruxolitinib recipients (P=0.0025) and almost none of the vehicle-treated controls.
The researchers found that baricitinib recipients had significantly better blood cell count recovery than control mice. Baricitinib recipients also had full donor chimerism and significantly higher percentages of donor bone marrow-derived B and T cells.
Furthermore, baricitinib recipients had higher levels of donor-derived regulatory T cells (Tregs) compared to vehicle- or ruxolitinib-treated mice.
However, the researchers noted that baricitinib recipients had a survival rate of about 70% even in the absence of donor Tregs. The team said this suggests baricitinib fights GVHD independently of the enhanced expansion of Tregs.
Further investigation revealed that baricitinib decreases helper T-cell 1 and 2 differentiation and reduces the expression of MHC II, CD80/86, and PD-L1 on allogeneic antigen-presenting cells.
The researchers also found that baricitinib could reverse ongoing GVHD. The team withheld baricitinib until mice developed GVHD, then tested the drug at doses of 200 μg and 400 μg per day.
Both doses reduced clinical GVHD scores and enabled 100% overall survival rates.
Finally, the researchers found that baricitinib “preserves and enhances” GVL effects. The team infused A20 cells and T-cell-depleted bone marrow cells into lethally irradiated mice, waited for the B-cell lymphoma to become established, and infused donor T cells.
The researchers found that baricitinib alone did not inhibit tumor growth, but it enhanced the GVL effects of donor T cells, significantly lowering the tumor burden.
“We don’t know yet exactly how this happens, but we’re working to understand it,” Dr Choi said. “We think at least part of the explanation is the drug strips the leukemia cells of their immune defenses, making them more vulnerable to attack by the donor T cells.”
“At the same time, the drug also stops the donor T cells from being able to make their way to important healthy tissues, such as the skin, liver, and gastrointestinal tract, where they often do the most damage.”
An investigational JAK1/2 inhibitor can fight graft-versus-host disease (GVHD), according to preclinical research published in Leukemia.
The inhibitor, baricitinib, reduced GVHD in mice while preserving T-cell expansion and the graft-versus-leukemia (GVL) effect.
Baricitinib proved more effective than ruxolitinib for the treatment and prevention of GVHD and enabled 100% survival in a mouse model of severe GVHD.
“We were surprised to achieve 100% survival of mice with the most severe model of graft-versus-host disease,” said study author Jaebok Choi, PhD, of the Washington University School of Medicine in St. Louis, Missouri.
“We are now studying the multi-pronged ways this drug behaves in an effort to develop an even better version for eventual use in clinical trials.”
For the current study, Dr Choi and his colleagues tested baricitinib and ruxolitinib in murine recipients of allogeneic hematopoietic stem cell transplants (allo-HSCTs). Mice received either drug for 31 days post-HSCT.
Mice treated with baricitinib had a significant reduction in intestinal GVHD compared to both ruxolitinib recipients and vehicle-treated controls (P=0.037).
In addition, 100% of baricitinib recipients were still alive at 60 days after HSCT, compared to about 60% of ruxolitinib recipients (P=0.0025) and almost none of the vehicle-treated controls.
The researchers found that baricitinib recipients had significantly better blood cell count recovery than control mice. Baricitinib recipients also had full donor chimerism and significantly higher percentages of donor bone marrow-derived B and T cells.
Furthermore, baricitinib recipients had higher levels of donor-derived regulatory T cells (Tregs) compared to vehicle- or ruxolitinib-treated mice.
However, the researchers noted that baricitinib recipients had a survival rate of about 70% even in the absence of donor Tregs. The team said this suggests baricitinib fights GVHD independently of the enhanced expansion of Tregs.
Further investigation revealed that baricitinib decreases helper T-cell 1 and 2 differentiation and reduces the expression of MHC II, CD80/86, and PD-L1 on allogeneic antigen-presenting cells.
The researchers also found that baricitinib could reverse ongoing GVHD. The team withheld baricitinib until mice developed GVHD, then tested the drug at doses of 200 μg and 400 μg per day.
Both doses reduced clinical GVHD scores and enabled 100% overall survival rates.
Finally, the researchers found that baricitinib “preserves and enhances” GVL effects. The team infused A20 cells and T-cell-depleted bone marrow cells into lethally irradiated mice, waited for the B-cell lymphoma to become established, and infused donor T cells.
The researchers found that baricitinib alone did not inhibit tumor growth, but it enhanced the GVL effects of donor T cells, significantly lowering the tumor burden.
“We don’t know yet exactly how this happens, but we’re working to understand it,” Dr Choi said. “We think at least part of the explanation is the drug strips the leukemia cells of their immune defenses, making them more vulnerable to attack by the donor T cells.”
“At the same time, the drug also stops the donor T cells from being able to make their way to important healthy tissues, such as the skin, liver, and gastrointestinal tract, where they often do the most damage.”
An investigational JAK1/2 inhibitor can fight graft-versus-host disease (GVHD), according to preclinical research published in Leukemia.
The inhibitor, baricitinib, reduced GVHD in mice while preserving T-cell expansion and the graft-versus-leukemia (GVL) effect.
Baricitinib proved more effective than ruxolitinib for the treatment and prevention of GVHD and enabled 100% survival in a mouse model of severe GVHD.
“We were surprised to achieve 100% survival of mice with the most severe model of graft-versus-host disease,” said study author Jaebok Choi, PhD, of the Washington University School of Medicine in St. Louis, Missouri.
“We are now studying the multi-pronged ways this drug behaves in an effort to develop an even better version for eventual use in clinical trials.”
For the current study, Dr Choi and his colleagues tested baricitinib and ruxolitinib in murine recipients of allogeneic hematopoietic stem cell transplants (allo-HSCTs). Mice received either drug for 31 days post-HSCT.
Mice treated with baricitinib had a significant reduction in intestinal GVHD compared to both ruxolitinib recipients and vehicle-treated controls (P=0.037).
In addition, 100% of baricitinib recipients were still alive at 60 days after HSCT, compared to about 60% of ruxolitinib recipients (P=0.0025) and almost none of the vehicle-treated controls.
The researchers found that baricitinib recipients had significantly better blood cell count recovery than control mice. Baricitinib recipients also had full donor chimerism and significantly higher percentages of donor bone marrow-derived B and T cells.
Furthermore, baricitinib recipients had higher levels of donor-derived regulatory T cells (Tregs) compared to vehicle- or ruxolitinib-treated mice.
However, the researchers noted that baricitinib recipients had a survival rate of about 70% even in the absence of donor Tregs. The team said this suggests baricitinib fights GVHD independently of the enhanced expansion of Tregs.
Further investigation revealed that baricitinib decreases helper T-cell 1 and 2 differentiation and reduces the expression of MHC II, CD80/86, and PD-L1 on allogeneic antigen-presenting cells.
The researchers also found that baricitinib could reverse ongoing GVHD. The team withheld baricitinib until mice developed GVHD, then tested the drug at doses of 200 μg and 400 μg per day.
Both doses reduced clinical GVHD scores and enabled 100% overall survival rates.
Finally, the researchers found that baricitinib “preserves and enhances” GVL effects. The team infused A20 cells and T-cell-depleted bone marrow cells into lethally irradiated mice, waited for the B-cell lymphoma to become established, and infused donor T cells.
The researchers found that baricitinib alone did not inhibit tumor growth, but it enhanced the GVL effects of donor T cells, significantly lowering the tumor burden.
“We don’t know yet exactly how this happens, but we’re working to understand it,” Dr Choi said. “We think at least part of the explanation is the drug strips the leukemia cells of their immune defenses, making them more vulnerable to attack by the donor T cells.”
“At the same time, the drug also stops the donor T cells from being able to make their way to important healthy tissues, such as the skin, liver, and gastrointestinal tract, where they often do the most damage.”
Brown spot on right foot
The FP recognized this as a benign congenital nevus.
While most congenital nevi are visible at birth, there are some that appear in the first year of life and are known as tardive congenital nevi. The FP used a dermatoscope to look at this nevus and found that its features were benign.
The parents wondered whether this needed to be removed to prevent it from becoming skin cancer in the future. The FP reassured them that the risk of melanoma from this one nevus was too small to warrant a prophylactic surgical excision. The parents agreed to the standard 6-month immunizations.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith, M. Congenital nevi. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:953-957.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.
The FP recognized this as a benign congenital nevus.
While most congenital nevi are visible at birth, there are some that appear in the first year of life and are known as tardive congenital nevi. The FP used a dermatoscope to look at this nevus and found that its features were benign.
The parents wondered whether this needed to be removed to prevent it from becoming skin cancer in the future. The FP reassured them that the risk of melanoma from this one nevus was too small to warrant a prophylactic surgical excision. The parents agreed to the standard 6-month immunizations.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith, M. Congenital nevi. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:953-957.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.
The FP recognized this as a benign congenital nevus.
While most congenital nevi are visible at birth, there are some that appear in the first year of life and are known as tardive congenital nevi. The FP used a dermatoscope to look at this nevus and found that its features were benign.
The parents wondered whether this needed to be removed to prevent it from becoming skin cancer in the future. The FP reassured them that the risk of melanoma from this one nevus was too small to warrant a prophylactic surgical excision. The parents agreed to the standard 6-month immunizations.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith, M. Congenital nevi. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:953-957.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.
No benefits from bath emollients for childhood eczema
In a trial of 482 children with atopic dermatitis who were randomized to either use of prescribed emollient bath additives regularly for 12 months or no additives, in addition to usual care, there was no significant difference between the two groups in the patient-oriented eczema measure (POEM) – a score of symptoms in the previous week – for the first 16 weeks of treatment, reported Miriam Santer, MD, of the University of Southampton, England, and her coauthors. The mean POEM score was 7.5 in the bath additives group and 8.4 in the no bath additives group.
There also was no significant effect of emollient bath additives on the secondary outcomes, which included POEM over 52 weeks, dermatitis family impact, generic quality of life, number of eczema exacerbations, or topical corticosteroid or topical calcineurin inhibitor use.
The authors noted that there was the suggestion of benefit in children who bathed five or more times a week, and in children aged under 5 years, but in both cases, the numbers were small.
“Although there is evidence for the need for leave-on emollients and widespread clinical consensus around soap substitutes, there is less agreement about the potential additional benefits of bath additives and a dearth of evidence on their effectiveness,” wrote Dr. Santer and her associates. “Bath additives are, however, widely prescribed at a cost of more than 23 million pounds ($33 million US; 26 million euros) annually to the National Health Service in England.”
The bath emollients used in the study included Aveeno bath oil, and Oilatum bath additive and Balneum bath oil – products available largely in the United Kingdom – along with others. Adherence was reasonable, with 93% of participants in the emollient group using bath additives more than half or all the time, and 92% of those in the no bath additives group using them less than half the time or never.
The authors stressed that there was strong evidence that supported regular use of leave-on emollients, and clinical consensus around the use of emollients as soap substitutes. “These findings are timely for clinicians and prescribing advisers, as prescribing guidelines vary widely in their advice on the use of bath additives, and pressure on budgets has led to formularies becoming increasingly restrictive.”
The study was supported by the National Institute for Health Research. No conflicts of interest were declared.
SOURCE: Santer M et al. BMJ 2018 May 2. doi: 10.1136/bmj.k1332
The National Institute for Health and Care Excellence in the United Kingdom currently recommends regular use of “emollient wash products” for children with eczema, despite the fact that little good evidence of their benefit exists. It is therefore heartening that this study has largely addressed that evidence gap: There was no statistically significant difference between those children prescribed one of three bath additives in addition to standard care and those who received standard care alone.
However, there is still the question of whether younger children – particularly those who are bathed daily – might still benefit from bath emollients. Likewise, children who experience recurrent skin infections may derive some additional benefit from emollient bath additives with antiseptic properties.
Carsten Flohr, MD, is with the St. John’s Institute of Dermatology at Kings College London, and Amina Ahmed is a patient panel member at the Centre of Evidence-Based Dermatology in Nottingham, England. These comments are taken from an editorial accompanying the article by Santer et al. (BMJ. 2018 May 2. doi: 10.1136/bmj.k1791.) No conflicts of interest were declared.
The National Institute for Health and Care Excellence in the United Kingdom currently recommends regular use of “emollient wash products” for children with eczema, despite the fact that little good evidence of their benefit exists. It is therefore heartening that this study has largely addressed that evidence gap: There was no statistically significant difference between those children prescribed one of three bath additives in addition to standard care and those who received standard care alone.
However, there is still the question of whether younger children – particularly those who are bathed daily – might still benefit from bath emollients. Likewise, children who experience recurrent skin infections may derive some additional benefit from emollient bath additives with antiseptic properties.
Carsten Flohr, MD, is with the St. John’s Institute of Dermatology at Kings College London, and Amina Ahmed is a patient panel member at the Centre of Evidence-Based Dermatology in Nottingham, England. These comments are taken from an editorial accompanying the article by Santer et al. (BMJ. 2018 May 2. doi: 10.1136/bmj.k1791.) No conflicts of interest were declared.
The National Institute for Health and Care Excellence in the United Kingdom currently recommends regular use of “emollient wash products” for children with eczema, despite the fact that little good evidence of their benefit exists. It is therefore heartening that this study has largely addressed that evidence gap: There was no statistically significant difference between those children prescribed one of three bath additives in addition to standard care and those who received standard care alone.
However, there is still the question of whether younger children – particularly those who are bathed daily – might still benefit from bath emollients. Likewise, children who experience recurrent skin infections may derive some additional benefit from emollient bath additives with antiseptic properties.
Carsten Flohr, MD, is with the St. John’s Institute of Dermatology at Kings College London, and Amina Ahmed is a patient panel member at the Centre of Evidence-Based Dermatology in Nottingham, England. These comments are taken from an editorial accompanying the article by Santer et al. (BMJ. 2018 May 2. doi: 10.1136/bmj.k1791.) No conflicts of interest were declared.
In a trial of 482 children with atopic dermatitis who were randomized to either use of prescribed emollient bath additives regularly for 12 months or no additives, in addition to usual care, there was no significant difference between the two groups in the patient-oriented eczema measure (POEM) – a score of symptoms in the previous week – for the first 16 weeks of treatment, reported Miriam Santer, MD, of the University of Southampton, England, and her coauthors. The mean POEM score was 7.5 in the bath additives group and 8.4 in the no bath additives group.
There also was no significant effect of emollient bath additives on the secondary outcomes, which included POEM over 52 weeks, dermatitis family impact, generic quality of life, number of eczema exacerbations, or topical corticosteroid or topical calcineurin inhibitor use.
The authors noted that there was the suggestion of benefit in children who bathed five or more times a week, and in children aged under 5 years, but in both cases, the numbers were small.
“Although there is evidence for the need for leave-on emollients and widespread clinical consensus around soap substitutes, there is less agreement about the potential additional benefits of bath additives and a dearth of evidence on their effectiveness,” wrote Dr. Santer and her associates. “Bath additives are, however, widely prescribed at a cost of more than 23 million pounds ($33 million US; 26 million euros) annually to the National Health Service in England.”
The bath emollients used in the study included Aveeno bath oil, and Oilatum bath additive and Balneum bath oil – products available largely in the United Kingdom – along with others. Adherence was reasonable, with 93% of participants in the emollient group using bath additives more than half or all the time, and 92% of those in the no bath additives group using them less than half the time or never.
The authors stressed that there was strong evidence that supported regular use of leave-on emollients, and clinical consensus around the use of emollients as soap substitutes. “These findings are timely for clinicians and prescribing advisers, as prescribing guidelines vary widely in their advice on the use of bath additives, and pressure on budgets has led to formularies becoming increasingly restrictive.”
The study was supported by the National Institute for Health Research. No conflicts of interest were declared.
SOURCE: Santer M et al. BMJ 2018 May 2. doi: 10.1136/bmj.k1332
In a trial of 482 children with atopic dermatitis who were randomized to either use of prescribed emollient bath additives regularly for 12 months or no additives, in addition to usual care, there was no significant difference between the two groups in the patient-oriented eczema measure (POEM) – a score of symptoms in the previous week – for the first 16 weeks of treatment, reported Miriam Santer, MD, of the University of Southampton, England, and her coauthors. The mean POEM score was 7.5 in the bath additives group and 8.4 in the no bath additives group.
There also was no significant effect of emollient bath additives on the secondary outcomes, which included POEM over 52 weeks, dermatitis family impact, generic quality of life, number of eczema exacerbations, or topical corticosteroid or topical calcineurin inhibitor use.
The authors noted that there was the suggestion of benefit in children who bathed five or more times a week, and in children aged under 5 years, but in both cases, the numbers were small.
“Although there is evidence for the need for leave-on emollients and widespread clinical consensus around soap substitutes, there is less agreement about the potential additional benefits of bath additives and a dearth of evidence on their effectiveness,” wrote Dr. Santer and her associates. “Bath additives are, however, widely prescribed at a cost of more than 23 million pounds ($33 million US; 26 million euros) annually to the National Health Service in England.”
The bath emollients used in the study included Aveeno bath oil, and Oilatum bath additive and Balneum bath oil – products available largely in the United Kingdom – along with others. Adherence was reasonable, with 93% of participants in the emollient group using bath additives more than half or all the time, and 92% of those in the no bath additives group using them less than half the time or never.
The authors stressed that there was strong evidence that supported regular use of leave-on emollients, and clinical consensus around the use of emollients as soap substitutes. “These findings are timely for clinicians and prescribing advisers, as prescribing guidelines vary widely in their advice on the use of bath additives, and pressure on budgets has led to formularies becoming increasingly restrictive.”
The study was supported by the National Institute for Health Research. No conflicts of interest were declared.
SOURCE: Santer M et al. BMJ 2018 May 2. doi: 10.1136/bmj.k1332
FROM THE BMJ
Key clinical point: Emollient bath additives do not improve eczema scores in children.
Major finding: There was no significant difference in eczema scores between bath emollients or no bath emollients: the mean POEM score was 7.5 in the bath additives group and 8.4 in the no bath additives group.
Study details: An open-label randomized trial in 482 children with atopic dermatitis.
Disclosures: The study was supported by the National Institute for Health Research. No conflicts of interest were declared.
Source: Santer M et al. BMJ 2018 May 2. doi: 10.1136/bmj.k1332
Maternal morbidity and BMI: A dose-response relationship
AUSTIN, TEX. – Women with the highest levels of obesity were at higher odds of experiencing a composite serious maternal morbidity outcome, while women at all levels of obesity experienced elevated risks of some serious complications of pregnancy, compared with women with a body mass index (BMI) in the normal range, according to a recent study.
Looking at individual indicators of severe maternal morbidity, Marissa Platner, MD, and her study coauthors saw that women who fell into the higher levels of obesity had significantly elevated odds of some complications.
“Those risks are really impressive, with odds ratios of two and three times that of a normal-weight patient,” said Dr. Platner in a video interview.
The adjusted odds ratio of acute renal failure for women with superobesity (BMI of 50 kg/m2 or more) was 3.62 (95% confidence interval, 1.75-7.52); odds ratios for renal failure were not significantly elevated for less-obese women.
Women with all levels of obesity had elevated risks of experiencing heart failure during a procedure or surgery, with adjusted odds ratios ranging from 1.68 (95% CI, 1.48-1.93) for women with class I obesity (BMI, 30-34.9 kg/m2) to 2.23 for women with superobesity (95% CI, 1.15-4.33).
Results from the retrospective cohort study were presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.
Dr. Platner and her colleagues examined 4 years of New York City delivery data that were linked to birth certificates, identifying those singleton live births for whom maternal prepregnancy BMI data were available.
From this group, they included women aged 15-50 years who delivered at 20-45 weeks’ gestational age. Women with prepregnancy BMIs less than 18.5 kg/m2 – those who were underweight – were excluded.
Dr. Platner and her coinvestigators used multivariable analysis to see what association the full range of obesity classes had with severe maternal morbidity, adjusting for many socioeconomic and demographic factors.
Of the 539,870 women included in the study, 3.3% experienced severe maternal morbidity, and 17.4% of patients met criteria for obesity. “Across all classes of obesity, there was a significantly greater risk of severe maternal morbidity, compared to nonobese women,” wrote Dr. Platner and her colleagues in the poster accompanying the presentation.
These risks climbed for women with the highest BMIs, however. “Women with higher levels of obesity, not surprisingly, are at increased risk” of severe maternal morbidity, said Dr. Platner. She and her colleagues noted in the poster that, “There is a significant dose-response relationship between increasing obesity class and risk of [severe maternal morbidity] at delivery hospitalization.”
It had been known that women with obesity are at increased risk of some serious complications of pregnancy, including severe maternal morbidity and mortality, and that those considered morbidly obese – with BMIs of 40 and above – are most likely to experience these complications, Dr. Platner said. However, she added, there’s a paucity of data to inform maternal risk stratification by level of obesity.
“We included the group of superobese women, which is significant in the surgical literature, and that’s a BMI of 50 and above ... we thought that would be an important subgroup to analyze in this population,” she said.
Dr. Platner said that she and her colleagues already had the clinical impressions that women with the highest BMIs were most likely to have serious complications. “I don’t think that these findings are particularly surprising,” she said. “This is what our hypothesis was in terms of why we did this study.”
The greater surprise, she said, was the magnitude of increased risk seen for serious morbidity with higher levels of obesity.
“Really, the risk is truly increased for those women with class III or superobesity, and when we start to stratify ... those are the women we need to be concerned about in terms of our prenatal counseling,” said Dr. Platner, a maternal-fetal medicine fellow at Yale University, New Haven, Conn.
“What can we do to intervene before we get there?” asked Dr. Platner. Although data are lacking about what specific interventions might be able to reduce the risk of these serious complications, she said she could envision such steps as acquiring predelivery baseline ECGs and cardiac ultrasounds in women with higher levels of obesity and being sure to follow renal function closely as well.
The findings also may help physicians provide more evidence-based preconception advice to women who are among the 35% of American adults who have obesity.
Dr. Platner reported no relevant financial disclosures.
SOURCE: Platner M et al. ACOG 2018, Abstract 39I.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AUSTIN, TEX. – Women with the highest levels of obesity were at higher odds of experiencing a composite serious maternal morbidity outcome, while women at all levels of obesity experienced elevated risks of some serious complications of pregnancy, compared with women with a body mass index (BMI) in the normal range, according to a recent study.
Looking at individual indicators of severe maternal morbidity, Marissa Platner, MD, and her study coauthors saw that women who fell into the higher levels of obesity had significantly elevated odds of some complications.
“Those risks are really impressive, with odds ratios of two and three times that of a normal-weight patient,” said Dr. Platner in a video interview.
The adjusted odds ratio of acute renal failure for women with superobesity (BMI of 50 kg/m2 or more) was 3.62 (95% confidence interval, 1.75-7.52); odds ratios for renal failure were not significantly elevated for less-obese women.
Women with all levels of obesity had elevated risks of experiencing heart failure during a procedure or surgery, with adjusted odds ratios ranging from 1.68 (95% CI, 1.48-1.93) for women with class I obesity (BMI, 30-34.9 kg/m2) to 2.23 for women with superobesity (95% CI, 1.15-4.33).
Results from the retrospective cohort study were presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.
Dr. Platner and her colleagues examined 4 years of New York City delivery data that were linked to birth certificates, identifying those singleton live births for whom maternal prepregnancy BMI data were available.
From this group, they included women aged 15-50 years who delivered at 20-45 weeks’ gestational age. Women with prepregnancy BMIs less than 18.5 kg/m2 – those who were underweight – were excluded.
Dr. Platner and her coinvestigators used multivariable analysis to see what association the full range of obesity classes had with severe maternal morbidity, adjusting for many socioeconomic and demographic factors.
Of the 539,870 women included in the study, 3.3% experienced severe maternal morbidity, and 17.4% of patients met criteria for obesity. “Across all classes of obesity, there was a significantly greater risk of severe maternal morbidity, compared to nonobese women,” wrote Dr. Platner and her colleagues in the poster accompanying the presentation.
These risks climbed for women with the highest BMIs, however. “Women with higher levels of obesity, not surprisingly, are at increased risk” of severe maternal morbidity, said Dr. Platner. She and her colleagues noted in the poster that, “There is a significant dose-response relationship between increasing obesity class and risk of [severe maternal morbidity] at delivery hospitalization.”
It had been known that women with obesity are at increased risk of some serious complications of pregnancy, including severe maternal morbidity and mortality, and that those considered morbidly obese – with BMIs of 40 and above – are most likely to experience these complications, Dr. Platner said. However, she added, there’s a paucity of data to inform maternal risk stratification by level of obesity.
“We included the group of superobese women, which is significant in the surgical literature, and that’s a BMI of 50 and above ... we thought that would be an important subgroup to analyze in this population,” she said.
Dr. Platner said that she and her colleagues already had the clinical impressions that women with the highest BMIs were most likely to have serious complications. “I don’t think that these findings are particularly surprising,” she said. “This is what our hypothesis was in terms of why we did this study.”
The greater surprise, she said, was the magnitude of increased risk seen for serious morbidity with higher levels of obesity.
“Really, the risk is truly increased for those women with class III or superobesity, and when we start to stratify ... those are the women we need to be concerned about in terms of our prenatal counseling,” said Dr. Platner, a maternal-fetal medicine fellow at Yale University, New Haven, Conn.
“What can we do to intervene before we get there?” asked Dr. Platner. Although data are lacking about what specific interventions might be able to reduce the risk of these serious complications, she said she could envision such steps as acquiring predelivery baseline ECGs and cardiac ultrasounds in women with higher levels of obesity and being sure to follow renal function closely as well.
The findings also may help physicians provide more evidence-based preconception advice to women who are among the 35% of American adults who have obesity.
Dr. Platner reported no relevant financial disclosures.
SOURCE: Platner M et al. ACOG 2018, Abstract 39I.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AUSTIN, TEX. – Women with the highest levels of obesity were at higher odds of experiencing a composite serious maternal morbidity outcome, while women at all levels of obesity experienced elevated risks of some serious complications of pregnancy, compared with women with a body mass index (BMI) in the normal range, according to a recent study.
Looking at individual indicators of severe maternal morbidity, Marissa Platner, MD, and her study coauthors saw that women who fell into the higher levels of obesity had significantly elevated odds of some complications.
“Those risks are really impressive, with odds ratios of two and three times that of a normal-weight patient,” said Dr. Platner in a video interview.
The adjusted odds ratio of acute renal failure for women with superobesity (BMI of 50 kg/m2 or more) was 3.62 (95% confidence interval, 1.75-7.52); odds ratios for renal failure were not significantly elevated for less-obese women.
Women with all levels of obesity had elevated risks of experiencing heart failure during a procedure or surgery, with adjusted odds ratios ranging from 1.68 (95% CI, 1.48-1.93) for women with class I obesity (BMI, 30-34.9 kg/m2) to 2.23 for women with superobesity (95% CI, 1.15-4.33).
Results from the retrospective cohort study were presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.
Dr. Platner and her colleagues examined 4 years of New York City delivery data that were linked to birth certificates, identifying those singleton live births for whom maternal prepregnancy BMI data were available.
From this group, they included women aged 15-50 years who delivered at 20-45 weeks’ gestational age. Women with prepregnancy BMIs less than 18.5 kg/m2 – those who were underweight – were excluded.
Dr. Platner and her coinvestigators used multivariable analysis to see what association the full range of obesity classes had with severe maternal morbidity, adjusting for many socioeconomic and demographic factors.
Of the 539,870 women included in the study, 3.3% experienced severe maternal morbidity, and 17.4% of patients met criteria for obesity. “Across all classes of obesity, there was a significantly greater risk of severe maternal morbidity, compared to nonobese women,” wrote Dr. Platner and her colleagues in the poster accompanying the presentation.
These risks climbed for women with the highest BMIs, however. “Women with higher levels of obesity, not surprisingly, are at increased risk” of severe maternal morbidity, said Dr. Platner. She and her colleagues noted in the poster that, “There is a significant dose-response relationship between increasing obesity class and risk of [severe maternal morbidity] at delivery hospitalization.”
It had been known that women with obesity are at increased risk of some serious complications of pregnancy, including severe maternal morbidity and mortality, and that those considered morbidly obese – with BMIs of 40 and above – are most likely to experience these complications, Dr. Platner said. However, she added, there’s a paucity of data to inform maternal risk stratification by level of obesity.
“We included the group of superobese women, which is significant in the surgical literature, and that’s a BMI of 50 and above ... we thought that would be an important subgroup to analyze in this population,” she said.
Dr. Platner said that she and her colleagues already had the clinical impressions that women with the highest BMIs were most likely to have serious complications. “I don’t think that these findings are particularly surprising,” she said. “This is what our hypothesis was in terms of why we did this study.”
The greater surprise, she said, was the magnitude of increased risk seen for serious morbidity with higher levels of obesity.
“Really, the risk is truly increased for those women with class III or superobesity, and when we start to stratify ... those are the women we need to be concerned about in terms of our prenatal counseling,” said Dr. Platner, a maternal-fetal medicine fellow at Yale University, New Haven, Conn.
“What can we do to intervene before we get there?” asked Dr. Platner. Although data are lacking about what specific interventions might be able to reduce the risk of these serious complications, she said she could envision such steps as acquiring predelivery baseline ECGs and cardiac ultrasounds in women with higher levels of obesity and being sure to follow renal function closely as well.
The findings also may help physicians provide more evidence-based preconception advice to women who are among the 35% of American adults who have obesity.
Dr. Platner reported no relevant financial disclosures.
SOURCE: Platner M et al. ACOG 2018, Abstract 39I.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
REPORTING FROM ACOG 2018
FDA advisory committee votes to recommend first once-daily aminoglycoside antibiotic
The Antimicrobial Drugs Advisory Committee of the Food and Drug Administration has voted to recommend plazomicin, a new aminoglycoside, for systemic use in the treatment of complicated urinary tract infections (cUTI) but rejected it for treatment of blood stream infections (BSIs) that are caused by multidrug resistant (MDR) Enterobacteriaceae.
Advisers voted unanimously to recommend plazomicin for cUTI, but rejected the drug for BSIs in an 11-4 no vote, based on the results of two phase 3 clinical trials: EPIC and CARE.
“Today’s meeting brought the committee face to face with the crisis of multidrug resistant bacteria,” he said. “Results of the 009 [EPIC] study, in my mind, clearly showed plazomicin met the noninferiority endpoints.”
EPIC study
EPIC was a phase 3 clinical trial to assess the noninferiority of plazomicin to meropenem in patients with cUTI and/or acute pyelonephritis (AP). Many patients with drug resistant infections have limited treatment options, so plazomicin was reviewed under the Limited Population Antibacterial Drug pathway.
Patients in the study were stratified by geographical region and infection type – cUTI or acute pyelonephritis (AP). In total, 609 patients were randomized in the intent-to-treat (ITT) group with 306 and 303 receiving plazomicin or meropenem, respectively. Using the coprimary efficacy endpoints of microbiological eradication and clinical cure, a measure known as composite cure was developed to assess efficacy at Day 5 and the test of cure (TOC) visit in the microbiological modified intent-to-treat (mMITT) population. The mMITT group consisted of all patients who had received any dose of study drug and had at least one qualified baseline pathogen with 105 or more colony-forming units/mL that was susceptible to both meropenem and plazomicin.Plazomicin was noninferior to meropenem with a margin of 15%. At day 5, the composite cure rate was 88% in the plazomicin group, compared with 91.4% in the meropenem group. Similar results were seen at the test of cure visit, with composite cure rates of 81.7% and 70.1% in the plazomicin and meropenem groups, respectively.
In a secondary analysis of microbiologically evaluable populations, or patients who had an appropriately collected urine specimen yielding interpretable culture results, plazomicin again showed noninferiority. Composite cure rates at Day 5 were 89.4% in the plazomicin group, compared with 94.2% in the meropenem group. TOC composite scores also were similar, at 89.4% and 75.1%, respectively.An analysis of composite cure scores at the end of the intravenous therapy visit revealed that Day 5 scores were comparable between the plazomicin and meropenem groups at 93.7% and 94.9%, respectively, demonstrating that high cure rates were achieved with IV treatment, irrespective of the drug used.
In a pooled safety analysis of a phase 2 trial and the EPIC trial, 22.5% experienced a treatment-emergent adverse event (TEAE); of these, 2.9% had a severe TEAE and 2.7% experienced a TEAE that led to discontinuation of the intravenous study drug. All adverse events were related to renal function, diarrhea, headache, nausea, and vomiting.
CARE study
CARE was an open-label trial to assess the safety and efficacy of plazomicin as compared with colistin in patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia (HABP/VABP) or bloodstream infections caused by CRE. The primary endpoint in the study was all-cause mortality at Day 28 or significant disease-related complications in the mMITT population, which included all patients with a confirmed CRE pathogen who had at least one dose of the study drug.
Overall, CARE enrolled 69 patients and split them into two cohorts. In Cohort 1, there were 39 randomized patients; 30 with blood stream infections and 9 with HABP or VABP. Cohort 2 was uncontrolled and consisted of 30 total patients; 27 patients who were in the mMITT population included 14 patients with BSI, 9 with HABP/VABP, and 4 with cUTI, all of whom received plazomicin.
Overall in Cohort 1, all-cause mortality at Day 28 or significant disease-related complications were lower with plazomicin than with colistin (23.5% vs. 50.0%). Because of the small patient HABP/VABP population in Cohort 1, the trial focused on patients with blood stream infections.
The rates of all-cause mortality and significant disease-related complications at Day 28 were much lower with plazomicin therapy than with colistin for patients with blood infections (14.3% vs. 53.3%, respectively). All-cause mortality alone at Day 28 was 7.1% in the plazomicin patients and 40.0% in colistin patients.
In the BSI subgroup, plazomicin reduced the rate of death by 86% and 63% on days 28 and 60, respectively, compared with colistin.
The uncontrolled data from Cohort 2 were supportive of the all-cause mortality rate in Cohort 1, with a rate of 14.3% at Day 28.
Because this was a severely ill patient population, there was a higher rate of adverse events. In fact, nearly all the patients in this study (16/18) experienced one treatment-emergent adverse event; 61.1% experienced severe TEAEs, with 11.1% severe enough to discontinue the study drug use.
Despite the study results, many of the panel members were not comfortable recommending it for approval.
Dr. Green, who supported plazomicin for use in cUTI but rejected it for use in BSIs, shared some of his concerns: “Because of the clear need, I was really tempted to vote yes and I actually came here today, thinking that I was going to vote yes. But this study clearly had a number of limitations that impacted the interpretation of results to support the approval for bloodstream infection,” he said. “The limitation that I could just not overcome was the small numbers [of participants].”
Plazomicin has a Prescription Drug User Fee Act date of June 25 of this year by which time the FDA will decide on its approval. While the FDA does not always follow the recommendations of these committees, they usually accept them and proceed accordingly.
The Antimicrobial Drugs Advisory Committee of the Food and Drug Administration has voted to recommend plazomicin, a new aminoglycoside, for systemic use in the treatment of complicated urinary tract infections (cUTI) but rejected it for treatment of blood stream infections (BSIs) that are caused by multidrug resistant (MDR) Enterobacteriaceae.
Advisers voted unanimously to recommend plazomicin for cUTI, but rejected the drug for BSIs in an 11-4 no vote, based on the results of two phase 3 clinical trials: EPIC and CARE.
“Today’s meeting brought the committee face to face with the crisis of multidrug resistant bacteria,” he said. “Results of the 009 [EPIC] study, in my mind, clearly showed plazomicin met the noninferiority endpoints.”
EPIC study
EPIC was a phase 3 clinical trial to assess the noninferiority of plazomicin to meropenem in patients with cUTI and/or acute pyelonephritis (AP). Many patients with drug resistant infections have limited treatment options, so plazomicin was reviewed under the Limited Population Antibacterial Drug pathway.
Patients in the study were stratified by geographical region and infection type – cUTI or acute pyelonephritis (AP). In total, 609 patients were randomized in the intent-to-treat (ITT) group with 306 and 303 receiving plazomicin or meropenem, respectively. Using the coprimary efficacy endpoints of microbiological eradication and clinical cure, a measure known as composite cure was developed to assess efficacy at Day 5 and the test of cure (TOC) visit in the microbiological modified intent-to-treat (mMITT) population. The mMITT group consisted of all patients who had received any dose of study drug and had at least one qualified baseline pathogen with 105 or more colony-forming units/mL that was susceptible to both meropenem and plazomicin.Plazomicin was noninferior to meropenem with a margin of 15%. At day 5, the composite cure rate was 88% in the plazomicin group, compared with 91.4% in the meropenem group. Similar results were seen at the test of cure visit, with composite cure rates of 81.7% and 70.1% in the plazomicin and meropenem groups, respectively.
In a secondary analysis of microbiologically evaluable populations, or patients who had an appropriately collected urine specimen yielding interpretable culture results, plazomicin again showed noninferiority. Composite cure rates at Day 5 were 89.4% in the plazomicin group, compared with 94.2% in the meropenem group. TOC composite scores also were similar, at 89.4% and 75.1%, respectively.An analysis of composite cure scores at the end of the intravenous therapy visit revealed that Day 5 scores were comparable between the plazomicin and meropenem groups at 93.7% and 94.9%, respectively, demonstrating that high cure rates were achieved with IV treatment, irrespective of the drug used.
In a pooled safety analysis of a phase 2 trial and the EPIC trial, 22.5% experienced a treatment-emergent adverse event (TEAE); of these, 2.9% had a severe TEAE and 2.7% experienced a TEAE that led to discontinuation of the intravenous study drug. All adverse events were related to renal function, diarrhea, headache, nausea, and vomiting.
CARE study
CARE was an open-label trial to assess the safety and efficacy of plazomicin as compared with colistin in patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia (HABP/VABP) or bloodstream infections caused by CRE. The primary endpoint in the study was all-cause mortality at Day 28 or significant disease-related complications in the mMITT population, which included all patients with a confirmed CRE pathogen who had at least one dose of the study drug.
Overall, CARE enrolled 69 patients and split them into two cohorts. In Cohort 1, there were 39 randomized patients; 30 with blood stream infections and 9 with HABP or VABP. Cohort 2 was uncontrolled and consisted of 30 total patients; 27 patients who were in the mMITT population included 14 patients with BSI, 9 with HABP/VABP, and 4 with cUTI, all of whom received plazomicin.
Overall in Cohort 1, all-cause mortality at Day 28 or significant disease-related complications were lower with plazomicin than with colistin (23.5% vs. 50.0%). Because of the small patient HABP/VABP population in Cohort 1, the trial focused on patients with blood stream infections.
The rates of all-cause mortality and significant disease-related complications at Day 28 were much lower with plazomicin therapy than with colistin for patients with blood infections (14.3% vs. 53.3%, respectively). All-cause mortality alone at Day 28 was 7.1% in the plazomicin patients and 40.0% in colistin patients.
In the BSI subgroup, plazomicin reduced the rate of death by 86% and 63% on days 28 and 60, respectively, compared with colistin.
The uncontrolled data from Cohort 2 were supportive of the all-cause mortality rate in Cohort 1, with a rate of 14.3% at Day 28.
Because this was a severely ill patient population, there was a higher rate of adverse events. In fact, nearly all the patients in this study (16/18) experienced one treatment-emergent adverse event; 61.1% experienced severe TEAEs, with 11.1% severe enough to discontinue the study drug use.
Despite the study results, many of the panel members were not comfortable recommending it for approval.
Dr. Green, who supported plazomicin for use in cUTI but rejected it for use in BSIs, shared some of his concerns: “Because of the clear need, I was really tempted to vote yes and I actually came here today, thinking that I was going to vote yes. But this study clearly had a number of limitations that impacted the interpretation of results to support the approval for bloodstream infection,” he said. “The limitation that I could just not overcome was the small numbers [of participants].”
Plazomicin has a Prescription Drug User Fee Act date of June 25 of this year by which time the FDA will decide on its approval. While the FDA does not always follow the recommendations of these committees, they usually accept them and proceed accordingly.
The Antimicrobial Drugs Advisory Committee of the Food and Drug Administration has voted to recommend plazomicin, a new aminoglycoside, for systemic use in the treatment of complicated urinary tract infections (cUTI) but rejected it for treatment of blood stream infections (BSIs) that are caused by multidrug resistant (MDR) Enterobacteriaceae.
Advisers voted unanimously to recommend plazomicin for cUTI, but rejected the drug for BSIs in an 11-4 no vote, based on the results of two phase 3 clinical trials: EPIC and CARE.
“Today’s meeting brought the committee face to face with the crisis of multidrug resistant bacteria,” he said. “Results of the 009 [EPIC] study, in my mind, clearly showed plazomicin met the noninferiority endpoints.”
EPIC study
EPIC was a phase 3 clinical trial to assess the noninferiority of plazomicin to meropenem in patients with cUTI and/or acute pyelonephritis (AP). Many patients with drug resistant infections have limited treatment options, so plazomicin was reviewed under the Limited Population Antibacterial Drug pathway.
Patients in the study were stratified by geographical region and infection type – cUTI or acute pyelonephritis (AP). In total, 609 patients were randomized in the intent-to-treat (ITT) group with 306 and 303 receiving plazomicin or meropenem, respectively. Using the coprimary efficacy endpoints of microbiological eradication and clinical cure, a measure known as composite cure was developed to assess efficacy at Day 5 and the test of cure (TOC) visit in the microbiological modified intent-to-treat (mMITT) population. The mMITT group consisted of all patients who had received any dose of study drug and had at least one qualified baseline pathogen with 105 or more colony-forming units/mL that was susceptible to both meropenem and plazomicin.Plazomicin was noninferior to meropenem with a margin of 15%. At day 5, the composite cure rate was 88% in the plazomicin group, compared with 91.4% in the meropenem group. Similar results were seen at the test of cure visit, with composite cure rates of 81.7% and 70.1% in the plazomicin and meropenem groups, respectively.
In a secondary analysis of microbiologically evaluable populations, or patients who had an appropriately collected urine specimen yielding interpretable culture results, plazomicin again showed noninferiority. Composite cure rates at Day 5 were 89.4% in the plazomicin group, compared with 94.2% in the meropenem group. TOC composite scores also were similar, at 89.4% and 75.1%, respectively.An analysis of composite cure scores at the end of the intravenous therapy visit revealed that Day 5 scores were comparable between the plazomicin and meropenem groups at 93.7% and 94.9%, respectively, demonstrating that high cure rates were achieved with IV treatment, irrespective of the drug used.
In a pooled safety analysis of a phase 2 trial and the EPIC trial, 22.5% experienced a treatment-emergent adverse event (TEAE); of these, 2.9% had a severe TEAE and 2.7% experienced a TEAE that led to discontinuation of the intravenous study drug. All adverse events were related to renal function, diarrhea, headache, nausea, and vomiting.
CARE study
CARE was an open-label trial to assess the safety and efficacy of plazomicin as compared with colistin in patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia (HABP/VABP) or bloodstream infections caused by CRE. The primary endpoint in the study was all-cause mortality at Day 28 or significant disease-related complications in the mMITT population, which included all patients with a confirmed CRE pathogen who had at least one dose of the study drug.
Overall, CARE enrolled 69 patients and split them into two cohorts. In Cohort 1, there were 39 randomized patients; 30 with blood stream infections and 9 with HABP or VABP. Cohort 2 was uncontrolled and consisted of 30 total patients; 27 patients who were in the mMITT population included 14 patients with BSI, 9 with HABP/VABP, and 4 with cUTI, all of whom received plazomicin.
Overall in Cohort 1, all-cause mortality at Day 28 or significant disease-related complications were lower with plazomicin than with colistin (23.5% vs. 50.0%). Because of the small patient HABP/VABP population in Cohort 1, the trial focused on patients with blood stream infections.
The rates of all-cause mortality and significant disease-related complications at Day 28 were much lower with plazomicin therapy than with colistin for patients with blood infections (14.3% vs. 53.3%, respectively). All-cause mortality alone at Day 28 was 7.1% in the plazomicin patients and 40.0% in colistin patients.
In the BSI subgroup, plazomicin reduced the rate of death by 86% and 63% on days 28 and 60, respectively, compared with colistin.
The uncontrolled data from Cohort 2 were supportive of the all-cause mortality rate in Cohort 1, with a rate of 14.3% at Day 28.
Because this was a severely ill patient population, there was a higher rate of adverse events. In fact, nearly all the patients in this study (16/18) experienced one treatment-emergent adverse event; 61.1% experienced severe TEAEs, with 11.1% severe enough to discontinue the study drug use.
Despite the study results, many of the panel members were not comfortable recommending it for approval.
Dr. Green, who supported plazomicin for use in cUTI but rejected it for use in BSIs, shared some of his concerns: “Because of the clear need, I was really tempted to vote yes and I actually came here today, thinking that I was going to vote yes. But this study clearly had a number of limitations that impacted the interpretation of results to support the approval for bloodstream infection,” he said. “The limitation that I could just not overcome was the small numbers [of participants].”
Plazomicin has a Prescription Drug User Fee Act date of June 25 of this year by which time the FDA will decide on its approval. While the FDA does not always follow the recommendations of these committees, they usually accept them and proceed accordingly.
Early endovenous ablation speeds venous ulcer healing
Intervening early with endovenous ablation in patients with venous leg ulcers could significantly improve ulcer healing times and delay their recurrence, new research has found.
A randomized study presented at the International Charing Cross Symposium and published simultaneously in the April 24 issue of the New England Journal of Medicine compared the effects of early endovenous ablation with those of deferred ablation in 450 patients with venous leg ulcers, all of whom also received compression therapy.
The study showed that patients who received endovenous ablation within 2 weeks of randomization had significantly shorter healing times, compared with patients whose ablation was deferred for 6 months or until after the ulcer healed.
In the early-treatment group, the median time to ulcer healing was 56 days, while in the deferred-treatment group, it was 82 days. By 12 months, 93.8% of the early-intervention group had healed ulcers, compared with 85.8% in the deferred-intervention group.
Even after adjustment for factors such as patient age, ulcer size, ulcer duration, and recruitment center, patients who received early endovenous ablation were 38% more likely to have healed by 12 months, compared with the deferred-intervention group.
Researchers also saw significantly higher healing rates at 12 weeks in the early-intervention group, compared with the deferred-intervention group (63.5% vs. 51.6%, respectively).
“Observational studies have suggested that endovenous treatment of varicose veins – a treatment that may be particularly appropriate for the elderly population with venous leg ulcers – may improve ulcer healing,” wrote Manjit S. Gohel, MD, from the Cambridge (United Kingdom) University Hospitals NHS Foundation Trust and from Imperial College London and his coauthors. “In the current trial, we found that faster ulcer healing can be attained if an endovenous intervention is performed promptly.”
Early endovenous ablation also was associated with a delay in the recurrence of ulcers. The rate of recurrence was 11.4% among patients in the early-intervention group whose ulcers had healed and 16.5% among those in the delayed-intervention group whose ulcers had healed.
Patients who received the early endovenous ablation had a median ulcer-free time of 306 days, compared with 278 days in the delayed-intervention group, a significant difference.
The authors noted that all patients in the study also received high-quality compression therapy, which may account for the good healing rates seen in both groups that might not otherwise be observed in a real-world clinical setting.
“Accordingly, the improvement in ulcer healing with early endovenous intervention is likely to be greater in clinical practice than was observed in this trial,” the authors wrote. “Because endovenous intervention is usually performed as a single procedure, the clinical benefits are likely to be less dependent on ongoing patient adherence than they would be with compression therapy.”
The most common method for endovenous ablation used in this multicenter study was ultrasound-guided foam sclerotherapy, a minimally-invasive procedure the authors said had versatility and acceptability.
However, they commented that some previous, large randomized trials have suggested that the rates of complete venous occlusion are lower with foam sclerotherapy than with thermal ablation.
The main complications seen with endovenous ablation were pain and deep vein thrombosis.
The authors pointed out that two limitations of their trial were that patients with a leg ulcer that had been present for more than 6 months were excluded from patient selection and that the 450 patients enrolled had been selected from a larger group of around 6,500.
The study was supported by a grant from the National Institute for Health Research Health Technology Assessment Program. One author declared grants from a pharmaceutical company outside the submitted work, and seven declared funding from the NIHR as part of the conduct of the study. No other conflicts of interest were declared.
SOURCE: Gohel MS et al. NEJM. 2018 April 24. doi: 10.1056/NEJMoa1801214
Finally! A randomized controlled trial (RCT) which proves what we all kind of expected but which until now was unsupported by available literature. That is that endovenous ablation (EVA) in the presence of a concomitant venous ulcer not only decreases ulcer recurrence rates and increases ulcer-free time, it also significantly hastens ulcer healing times. I don’t know about you, but it always made sense to me that treatment of an incompetent saphenous vein, a known cause of ulceration, could be a factor in the time to ulcer healing.
But that’s what a whole host of retrospective and or nonrandomized studies seemed to suggest: Garbage in, garbage out. Enter the RCT – Issue resolved? Yes, with some caveats, and maybe no.
First, as the authors readily admit, the compression therapy which was applied to patients in both arms of the study was of “high quality” and would not likely be reproduced in real world practice. The authors also suggest that, in a real-world, clinical practice, the benefits of early EVA may prove to be even more pronounced because of poor patient compliance with compression. Not sure about that. In fact, if – in a real-world setting – the rate of compliance with compression in both groups turned out to be less than optimal, particularly in the patients who had EVA, the benefits of early ablation with respect to ulcer healing times might disappear.
In other words, we do not know from this study whether there would be the same advantages to early saphenous vein intervention without the addition of compression as compared with compression alone. This might explain why shorter ulcer healing times of EVA have been difficult to prove in non-RCT, more real-world studies. Perhaps a randomized trial comparing ulcer healing times with early EVA without compression versus compression therapy only? Hmmm.
Also, would the outcomes of the current study be similar on this side of the pond? Only 31.7% of limbs were treated with endothermal ablation only, by far the most common form of ablation performed in the United States. Almost 65% of limbs in the study were ablated with either foamed sclerotherapy alone or in conjunction with endothermal or mechanical modalities – not a common form of treatment here in the colonies. Inexplicably, the authors do not indicate whether outcomes were in any way influenced by the type of ablation performed. I am going to assume for now that it did not.
In summary, this study does not answer all the questions related to the use of EVA for the treatment of venous ulcers, but it comes pretty close. My take away is that there is no downside (or none that I can think of) to the use of EVA early on in the treatment of venous ulcers but a whole lot of potential upside for the patient. Now I, and probably you, have proof that what we were already doing really does have some increased benefit. Finally!
Alan M Dietzek, MD, is the Linda and Stephen R. Cohen Chair in Vascular Surgery at Danbury (Conn.) Hospital and a clinical professor of surgery at the University of Vermont, Burlington. He is also an associate medical editor for Vascular Specialist.
Finally! A randomized controlled trial (RCT) which proves what we all kind of expected but which until now was unsupported by available literature. That is that endovenous ablation (EVA) in the presence of a concomitant venous ulcer not only decreases ulcer recurrence rates and increases ulcer-free time, it also significantly hastens ulcer healing times. I don’t know about you, but it always made sense to me that treatment of an incompetent saphenous vein, a known cause of ulceration, could be a factor in the time to ulcer healing.
But that’s what a whole host of retrospective and or nonrandomized studies seemed to suggest: Garbage in, garbage out. Enter the RCT – Issue resolved? Yes, with some caveats, and maybe no.
First, as the authors readily admit, the compression therapy which was applied to patients in both arms of the study was of “high quality” and would not likely be reproduced in real world practice. The authors also suggest that, in a real-world, clinical practice, the benefits of early EVA may prove to be even more pronounced because of poor patient compliance with compression. Not sure about that. In fact, if – in a real-world setting – the rate of compliance with compression in both groups turned out to be less than optimal, particularly in the patients who had EVA, the benefits of early ablation with respect to ulcer healing times might disappear.
In other words, we do not know from this study whether there would be the same advantages to early saphenous vein intervention without the addition of compression as compared with compression alone. This might explain why shorter ulcer healing times of EVA have been difficult to prove in non-RCT, more real-world studies. Perhaps a randomized trial comparing ulcer healing times with early EVA without compression versus compression therapy only? Hmmm.
Also, would the outcomes of the current study be similar on this side of the pond? Only 31.7% of limbs were treated with endothermal ablation only, by far the most common form of ablation performed in the United States. Almost 65% of limbs in the study were ablated with either foamed sclerotherapy alone or in conjunction with endothermal or mechanical modalities – not a common form of treatment here in the colonies. Inexplicably, the authors do not indicate whether outcomes were in any way influenced by the type of ablation performed. I am going to assume for now that it did not.
In summary, this study does not answer all the questions related to the use of EVA for the treatment of venous ulcers, but it comes pretty close. My take away is that there is no downside (or none that I can think of) to the use of EVA early on in the treatment of venous ulcers but a whole lot of potential upside for the patient. Now I, and probably you, have proof that what we were already doing really does have some increased benefit. Finally!
Alan M Dietzek, MD, is the Linda and Stephen R. Cohen Chair in Vascular Surgery at Danbury (Conn.) Hospital and a clinical professor of surgery at the University of Vermont, Burlington. He is also an associate medical editor for Vascular Specialist.
Finally! A randomized controlled trial (RCT) which proves what we all kind of expected but which until now was unsupported by available literature. That is that endovenous ablation (EVA) in the presence of a concomitant venous ulcer not only decreases ulcer recurrence rates and increases ulcer-free time, it also significantly hastens ulcer healing times. I don’t know about you, but it always made sense to me that treatment of an incompetent saphenous vein, a known cause of ulceration, could be a factor in the time to ulcer healing.
But that’s what a whole host of retrospective and or nonrandomized studies seemed to suggest: Garbage in, garbage out. Enter the RCT – Issue resolved? Yes, with some caveats, and maybe no.
First, as the authors readily admit, the compression therapy which was applied to patients in both arms of the study was of “high quality” and would not likely be reproduced in real world practice. The authors also suggest that, in a real-world, clinical practice, the benefits of early EVA may prove to be even more pronounced because of poor patient compliance with compression. Not sure about that. In fact, if – in a real-world setting – the rate of compliance with compression in both groups turned out to be less than optimal, particularly in the patients who had EVA, the benefits of early ablation with respect to ulcer healing times might disappear.
In other words, we do not know from this study whether there would be the same advantages to early saphenous vein intervention without the addition of compression as compared with compression alone. This might explain why shorter ulcer healing times of EVA have been difficult to prove in non-RCT, more real-world studies. Perhaps a randomized trial comparing ulcer healing times with early EVA without compression versus compression therapy only? Hmmm.
Also, would the outcomes of the current study be similar on this side of the pond? Only 31.7% of limbs were treated with endothermal ablation only, by far the most common form of ablation performed in the United States. Almost 65% of limbs in the study were ablated with either foamed sclerotherapy alone or in conjunction with endothermal or mechanical modalities – not a common form of treatment here in the colonies. Inexplicably, the authors do not indicate whether outcomes were in any way influenced by the type of ablation performed. I am going to assume for now that it did not.
In summary, this study does not answer all the questions related to the use of EVA for the treatment of venous ulcers, but it comes pretty close. My take away is that there is no downside (or none that I can think of) to the use of EVA early on in the treatment of venous ulcers but a whole lot of potential upside for the patient. Now I, and probably you, have proof that what we were already doing really does have some increased benefit. Finally!
Alan M Dietzek, MD, is the Linda and Stephen R. Cohen Chair in Vascular Surgery at Danbury (Conn.) Hospital and a clinical professor of surgery at the University of Vermont, Burlington. He is also an associate medical editor for Vascular Specialist.
Intervening early with endovenous ablation in patients with venous leg ulcers could significantly improve ulcer healing times and delay their recurrence, new research has found.
A randomized study presented at the International Charing Cross Symposium and published simultaneously in the April 24 issue of the New England Journal of Medicine compared the effects of early endovenous ablation with those of deferred ablation in 450 patients with venous leg ulcers, all of whom also received compression therapy.
The study showed that patients who received endovenous ablation within 2 weeks of randomization had significantly shorter healing times, compared with patients whose ablation was deferred for 6 months or until after the ulcer healed.
In the early-treatment group, the median time to ulcer healing was 56 days, while in the deferred-treatment group, it was 82 days. By 12 months, 93.8% of the early-intervention group had healed ulcers, compared with 85.8% in the deferred-intervention group.
Even after adjustment for factors such as patient age, ulcer size, ulcer duration, and recruitment center, patients who received early endovenous ablation were 38% more likely to have healed by 12 months, compared with the deferred-intervention group.
Researchers also saw significantly higher healing rates at 12 weeks in the early-intervention group, compared with the deferred-intervention group (63.5% vs. 51.6%, respectively).
“Observational studies have suggested that endovenous treatment of varicose veins – a treatment that may be particularly appropriate for the elderly population with venous leg ulcers – may improve ulcer healing,” wrote Manjit S. Gohel, MD, from the Cambridge (United Kingdom) University Hospitals NHS Foundation Trust and from Imperial College London and his coauthors. “In the current trial, we found that faster ulcer healing can be attained if an endovenous intervention is performed promptly.”
Early endovenous ablation also was associated with a delay in the recurrence of ulcers. The rate of recurrence was 11.4% among patients in the early-intervention group whose ulcers had healed and 16.5% among those in the delayed-intervention group whose ulcers had healed.
Patients who received the early endovenous ablation had a median ulcer-free time of 306 days, compared with 278 days in the delayed-intervention group, a significant difference.
The authors noted that all patients in the study also received high-quality compression therapy, which may account for the good healing rates seen in both groups that might not otherwise be observed in a real-world clinical setting.
“Accordingly, the improvement in ulcer healing with early endovenous intervention is likely to be greater in clinical practice than was observed in this trial,” the authors wrote. “Because endovenous intervention is usually performed as a single procedure, the clinical benefits are likely to be less dependent on ongoing patient adherence than they would be with compression therapy.”
The most common method for endovenous ablation used in this multicenter study was ultrasound-guided foam sclerotherapy, a minimally-invasive procedure the authors said had versatility and acceptability.
However, they commented that some previous, large randomized trials have suggested that the rates of complete venous occlusion are lower with foam sclerotherapy than with thermal ablation.
The main complications seen with endovenous ablation were pain and deep vein thrombosis.
The authors pointed out that two limitations of their trial were that patients with a leg ulcer that had been present for more than 6 months were excluded from patient selection and that the 450 patients enrolled had been selected from a larger group of around 6,500.
The study was supported by a grant from the National Institute for Health Research Health Technology Assessment Program. One author declared grants from a pharmaceutical company outside the submitted work, and seven declared funding from the NIHR as part of the conduct of the study. No other conflicts of interest were declared.
SOURCE: Gohel MS et al. NEJM. 2018 April 24. doi: 10.1056/NEJMoa1801214
Intervening early with endovenous ablation in patients with venous leg ulcers could significantly improve ulcer healing times and delay their recurrence, new research has found.
A randomized study presented at the International Charing Cross Symposium and published simultaneously in the April 24 issue of the New England Journal of Medicine compared the effects of early endovenous ablation with those of deferred ablation in 450 patients with venous leg ulcers, all of whom also received compression therapy.
The study showed that patients who received endovenous ablation within 2 weeks of randomization had significantly shorter healing times, compared with patients whose ablation was deferred for 6 months or until after the ulcer healed.
In the early-treatment group, the median time to ulcer healing was 56 days, while in the deferred-treatment group, it was 82 days. By 12 months, 93.8% of the early-intervention group had healed ulcers, compared with 85.8% in the deferred-intervention group.
Even after adjustment for factors such as patient age, ulcer size, ulcer duration, and recruitment center, patients who received early endovenous ablation were 38% more likely to have healed by 12 months, compared with the deferred-intervention group.
Researchers also saw significantly higher healing rates at 12 weeks in the early-intervention group, compared with the deferred-intervention group (63.5% vs. 51.6%, respectively).
“Observational studies have suggested that endovenous treatment of varicose veins – a treatment that may be particularly appropriate for the elderly population with venous leg ulcers – may improve ulcer healing,” wrote Manjit S. Gohel, MD, from the Cambridge (United Kingdom) University Hospitals NHS Foundation Trust and from Imperial College London and his coauthors. “In the current trial, we found that faster ulcer healing can be attained if an endovenous intervention is performed promptly.”
Early endovenous ablation also was associated with a delay in the recurrence of ulcers. The rate of recurrence was 11.4% among patients in the early-intervention group whose ulcers had healed and 16.5% among those in the delayed-intervention group whose ulcers had healed.
Patients who received the early endovenous ablation had a median ulcer-free time of 306 days, compared with 278 days in the delayed-intervention group, a significant difference.
The authors noted that all patients in the study also received high-quality compression therapy, which may account for the good healing rates seen in both groups that might not otherwise be observed in a real-world clinical setting.
“Accordingly, the improvement in ulcer healing with early endovenous intervention is likely to be greater in clinical practice than was observed in this trial,” the authors wrote. “Because endovenous intervention is usually performed as a single procedure, the clinical benefits are likely to be less dependent on ongoing patient adherence than they would be with compression therapy.”
The most common method for endovenous ablation used in this multicenter study was ultrasound-guided foam sclerotherapy, a minimally-invasive procedure the authors said had versatility and acceptability.
However, they commented that some previous, large randomized trials have suggested that the rates of complete venous occlusion are lower with foam sclerotherapy than with thermal ablation.
The main complications seen with endovenous ablation were pain and deep vein thrombosis.
The authors pointed out that two limitations of their trial were that patients with a leg ulcer that had been present for more than 6 months were excluded from patient selection and that the 450 patients enrolled had been selected from a larger group of around 6,500.
The study was supported by a grant from the National Institute for Health Research Health Technology Assessment Program. One author declared grants from a pharmaceutical company outside the submitted work, and seven declared funding from the NIHR as part of the conduct of the study. No other conflicts of interest were declared.
SOURCE: Gohel MS et al. NEJM. 2018 April 24. doi: 10.1056/NEJMoa1801214
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Early endovenous ablation can speed healing of venous ulcers.
Major finding: Median ulcer healing time was 56 days with early venous ablation, compared with 82 days with deferred ablation.
Study details: Randomized controlled trial in 450 patients with venous leg ulcers.
Disclosures: The study was supported by a grant from the National Institute for Health Research Health Technology Assessment Program. One author declared grants from a pharmaceutical company outside the submitted work, and seven declared funding from the NIHR as part of the conduct of the study. No other conflicts of interest were declared.
Source: Gohel M et al. NEJM. 2018 April 24. doi: 10.1056/NEJMoa1801214
Pregnancy and safety rates evaluated for Liletta at 5 years of use
Liletta, a levonorgestrel 52 mg contraceptive intrauterine system (IUS) (Allergan), is currently approved by the US Food and Drug Administration for up to 4 years of use. A multicenter trial is continuing to measure Liletta’s efficacy and safety for a total of 8 years of use.1
Meanwhile, investigators led by Stephanie B. Teal, MD, from the University of Colorado, Aurora, have evaluated the 5-year data for Liletta. Resea
Study details
A total of 1,714 women aged 16−45 years were enrolled in the multicenter study for 5 years after successful IUS placement. This included 146 women aged 36−45 years who received the IUS for safety evaluation only, and 1,568 women aged 16−35 years who were evaluated for both safety and efficacy.1
Results of the study
The 16−35-year-old participants included 1,011 (57.7%) nulliparous and 438 (25.1%) obese women. Among these participants, 9 pregnancies occurred, including 4 in nulliparous women and 1 in an obese woman. In this age group, 1 pregnancy occurred after perforation and 1 following expulsion. Six (67%) of the pregnancies were ectopic.1
The Pearl Index in the first year was .15 (95% confidence interval [CI], .02−.55). Cumulative life-table pregnancy rates at the end of years 3 and 5 were .59 (95% CI, .28−1.25) and .92 (95% CI, .46–1.82), respectively.1
Of the total participants, perforation occurred in 2 (0.1%) women, both within the first year. Expulsion occurred in 63 participants (3.7%), most (50 [80.6%]) during the first year. Eleven patients (0.6%) were found to have a pelvic infection. Thirty-nine women (2.3%) discontinued use of Liletta due to bleeding complaints, primarily (n = 29 [74.3%]) in the first year.1
Conclusion
The researchers concluded that Liletta is highly effective and has an excellent safety profile over 5 years of use. Most adverse effects, including expulsion and discontinuation for bleeding, occurred during the first year.1
- Teal SB, Turok DK, Jensen JT, Chen BA, Kimble TD, Creinin MD. Five-year efficacy and safety of the Liletta® Levonorgestrel Intrauterine System. Obstet Gynecol. 2018;131(5 suppl):66S−67S.
Liletta, a levonorgestrel 52 mg contraceptive intrauterine system (IUS) (Allergan), is currently approved by the US Food and Drug Administration for up to 4 years of use. A multicenter trial is continuing to measure Liletta’s efficacy and safety for a total of 8 years of use.1
Meanwhile, investigators led by Stephanie B. Teal, MD, from the University of Colorado, Aurora, have evaluated the 5-year data for Liletta. Resea
Study details
A total of 1,714 women aged 16−45 years were enrolled in the multicenter study for 5 years after successful IUS placement. This included 146 women aged 36−45 years who received the IUS for safety evaluation only, and 1,568 women aged 16−35 years who were evaluated for both safety and efficacy.1
Results of the study
The 16−35-year-old participants included 1,011 (57.7%) nulliparous and 438 (25.1%) obese women. Among these participants, 9 pregnancies occurred, including 4 in nulliparous women and 1 in an obese woman. In this age group, 1 pregnancy occurred after perforation and 1 following expulsion. Six (67%) of the pregnancies were ectopic.1
The Pearl Index in the first year was .15 (95% confidence interval [CI], .02−.55). Cumulative life-table pregnancy rates at the end of years 3 and 5 were .59 (95% CI, .28−1.25) and .92 (95% CI, .46–1.82), respectively.1
Of the total participants, perforation occurred in 2 (0.1%) women, both within the first year. Expulsion occurred in 63 participants (3.7%), most (50 [80.6%]) during the first year. Eleven patients (0.6%) were found to have a pelvic infection. Thirty-nine women (2.3%) discontinued use of Liletta due to bleeding complaints, primarily (n = 29 [74.3%]) in the first year.1
Conclusion
The researchers concluded that Liletta is highly effective and has an excellent safety profile over 5 years of use. Most adverse effects, including expulsion and discontinuation for bleeding, occurred during the first year.1
Liletta, a levonorgestrel 52 mg contraceptive intrauterine system (IUS) (Allergan), is currently approved by the US Food and Drug Administration for up to 4 years of use. A multicenter trial is continuing to measure Liletta’s efficacy and safety for a total of 8 years of use.1
Meanwhile, investigators led by Stephanie B. Teal, MD, from the University of Colorado, Aurora, have evaluated the 5-year data for Liletta. Resea
Study details
A total of 1,714 women aged 16−45 years were enrolled in the multicenter study for 5 years after successful IUS placement. This included 146 women aged 36−45 years who received the IUS for safety evaluation only, and 1,568 women aged 16−35 years who were evaluated for both safety and efficacy.1
Results of the study
The 16−35-year-old participants included 1,011 (57.7%) nulliparous and 438 (25.1%) obese women. Among these participants, 9 pregnancies occurred, including 4 in nulliparous women and 1 in an obese woman. In this age group, 1 pregnancy occurred after perforation and 1 following expulsion. Six (67%) of the pregnancies were ectopic.1
The Pearl Index in the first year was .15 (95% confidence interval [CI], .02−.55). Cumulative life-table pregnancy rates at the end of years 3 and 5 were .59 (95% CI, .28−1.25) and .92 (95% CI, .46–1.82), respectively.1
Of the total participants, perforation occurred in 2 (0.1%) women, both within the first year. Expulsion occurred in 63 participants (3.7%), most (50 [80.6%]) during the first year. Eleven patients (0.6%) were found to have a pelvic infection. Thirty-nine women (2.3%) discontinued use of Liletta due to bleeding complaints, primarily (n = 29 [74.3%]) in the first year.1
Conclusion
The researchers concluded that Liletta is highly effective and has an excellent safety profile over 5 years of use. Most adverse effects, including expulsion and discontinuation for bleeding, occurred during the first year.1
- Teal SB, Turok DK, Jensen JT, Chen BA, Kimble TD, Creinin MD. Five-year efficacy and safety of the Liletta® Levonorgestrel Intrauterine System. Obstet Gynecol. 2018;131(5 suppl):66S−67S.
- Teal SB, Turok DK, Jensen JT, Chen BA, Kimble TD, Creinin MD. Five-year efficacy and safety of the Liletta® Levonorgestrel Intrauterine System. Obstet Gynecol. 2018;131(5 suppl):66S−67S.