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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.
New single-dose treatment for bacterial vaginosis
What Are the Consequences of Changing Antiepileptic Drug Regimens as Part of Pregnancy Planning?
WASHINGTON, DC—Women with epilepsy of reproductive age have a high likelihood of successfully changing their antiepi
Mitigating Risk to Offspring
Studies have found that certain AEDs increase the risk of structural and neurodevelopmental teratogenicity. “Women with epilepsy of childbearing age require careful reconsideration of their AED type and dose, given that the maternal benefits of treatment during potential future pregnancies should be weighed against adverse effects on the developing fetus,” said P. Emanuela Voinescu, MD, PhD, and colleagues. “Too often, not switching AEDs leads to exposing future offspring to undue risk.” Neurologists may be hesitant to change an AED regimen due to concerns about worsening seizures, however, and data to predict the risk of seizure worsening with an AED regimen change are lacking, the researchers said. Dr. Voinescu is an Instructor in Neurology at Harvard University and a neurologist at Brigham and Woman’s Hospital in Boston.
Dr. Voinescu and colleagues conducted a retrospective study to quantify the risk of failure when altering an AED regimen for reproductive safety, and to identify the causes of failure. The study included 40 women with epilepsy between ages 16 and 45 who had been on a stable AED regimen for more than six months and whose AED regimen was changed to improve the outcome of a future pregnancy. Changes included AED switch, AED dose reduction, AED number reduction, and complete discontinuation of AEDs.
The researchers excluded patients with psychogenic nonepileptic seizures, history of substance abuse, history of nonadherence to medications or scheduled visits, progressive cerebral disease or lesion, or other major medical illness. The patients’ AED regimen changes occurred between 2005 and 2017.
The investigators conducted a retrospective chart review for seizure frequency during the six months prior to the AED regimen change, during the transition interval, and in the six months after achieving the final regimen. They also collected demographic and epilepsy history details and reviewed patients’ most recent neurology clinic notes to assess long-term prognosis.
An AED regimen change was considered successful if the new regimen was continued without additional alterations. Otherwise, the change was considered a failure, and researchers documented the reason for continued alterations and the final outcome.
Most Changes Were Successful
The initial AED regimen change was successful for 75% of patients (n = 30). After taking into account patients whose regimens underwent a second change, 90% of patients (n = 36) had a successful change.
“A failed first change is not a predictor of failure for a subsequent alteration,” the researchers said. Half of the failed first changes occurred because of medication side effects. In those cases, a trial of another medication or complete AED discontinuation were successful strategies. Seven out of nine patients (78%) who initially were on valproic acid discontinued it successfully.
Persistent seizure worsening occurred in two patients with medically refractory epilepsy. Patients rarely and only transiently lost seizure-free status. Potential covariates (eg, epilepsy and seizure types, seizure freedom status, AED type, and type of alteration) did not seem to significantly affect outcomes.
To further study AED regimen changes for reproductive safety, the researchers are conducting a prospective, observational, parallel-group, switch-control study.
—Jake Remaly
WASHINGTON, DC—Women with epilepsy of reproductive age have a high likelihood of successfully changing their antiepi
Mitigating Risk to Offspring
Studies have found that certain AEDs increase the risk of structural and neurodevelopmental teratogenicity. “Women with epilepsy of childbearing age require careful reconsideration of their AED type and dose, given that the maternal benefits of treatment during potential future pregnancies should be weighed against adverse effects on the developing fetus,” said P. Emanuela Voinescu, MD, PhD, and colleagues. “Too often, not switching AEDs leads to exposing future offspring to undue risk.” Neurologists may be hesitant to change an AED regimen due to concerns about worsening seizures, however, and data to predict the risk of seizure worsening with an AED regimen change are lacking, the researchers said. Dr. Voinescu is an Instructor in Neurology at Harvard University and a neurologist at Brigham and Woman’s Hospital in Boston.
Dr. Voinescu and colleagues conducted a retrospective study to quantify the risk of failure when altering an AED regimen for reproductive safety, and to identify the causes of failure. The study included 40 women with epilepsy between ages 16 and 45 who had been on a stable AED regimen for more than six months and whose AED regimen was changed to improve the outcome of a future pregnancy. Changes included AED switch, AED dose reduction, AED number reduction, and complete discontinuation of AEDs.
The researchers excluded patients with psychogenic nonepileptic seizures, history of substance abuse, history of nonadherence to medications or scheduled visits, progressive cerebral disease or lesion, or other major medical illness. The patients’ AED regimen changes occurred between 2005 and 2017.
The investigators conducted a retrospective chart review for seizure frequency during the six months prior to the AED regimen change, during the transition interval, and in the six months after achieving the final regimen. They also collected demographic and epilepsy history details and reviewed patients’ most recent neurology clinic notes to assess long-term prognosis.
An AED regimen change was considered successful if the new regimen was continued without additional alterations. Otherwise, the change was considered a failure, and researchers documented the reason for continued alterations and the final outcome.
Most Changes Were Successful
The initial AED regimen change was successful for 75% of patients (n = 30). After taking into account patients whose regimens underwent a second change, 90% of patients (n = 36) had a successful change.
“A failed first change is not a predictor of failure for a subsequent alteration,” the researchers said. Half of the failed first changes occurred because of medication side effects. In those cases, a trial of another medication or complete AED discontinuation were successful strategies. Seven out of nine patients (78%) who initially were on valproic acid discontinued it successfully.
Persistent seizure worsening occurred in two patients with medically refractory epilepsy. Patients rarely and only transiently lost seizure-free status. Potential covariates (eg, epilepsy and seizure types, seizure freedom status, AED type, and type of alteration) did not seem to significantly affect outcomes.
To further study AED regimen changes for reproductive safety, the researchers are conducting a prospective, observational, parallel-group, switch-control study.
—Jake Remaly
WASHINGTON, DC—Women with epilepsy of reproductive age have a high likelihood of successfully changing their antiepi
Mitigating Risk to Offspring
Studies have found that certain AEDs increase the risk of structural and neurodevelopmental teratogenicity. “Women with epilepsy of childbearing age require careful reconsideration of their AED type and dose, given that the maternal benefits of treatment during potential future pregnancies should be weighed against adverse effects on the developing fetus,” said P. Emanuela Voinescu, MD, PhD, and colleagues. “Too often, not switching AEDs leads to exposing future offspring to undue risk.” Neurologists may be hesitant to change an AED regimen due to concerns about worsening seizures, however, and data to predict the risk of seizure worsening with an AED regimen change are lacking, the researchers said. Dr. Voinescu is an Instructor in Neurology at Harvard University and a neurologist at Brigham and Woman’s Hospital in Boston.
Dr. Voinescu and colleagues conducted a retrospective study to quantify the risk of failure when altering an AED regimen for reproductive safety, and to identify the causes of failure. The study included 40 women with epilepsy between ages 16 and 45 who had been on a stable AED regimen for more than six months and whose AED regimen was changed to improve the outcome of a future pregnancy. Changes included AED switch, AED dose reduction, AED number reduction, and complete discontinuation of AEDs.
The researchers excluded patients with psychogenic nonepileptic seizures, history of substance abuse, history of nonadherence to medications or scheduled visits, progressive cerebral disease or lesion, or other major medical illness. The patients’ AED regimen changes occurred between 2005 and 2017.
The investigators conducted a retrospective chart review for seizure frequency during the six months prior to the AED regimen change, during the transition interval, and in the six months after achieving the final regimen. They also collected demographic and epilepsy history details and reviewed patients’ most recent neurology clinic notes to assess long-term prognosis.
An AED regimen change was considered successful if the new regimen was continued without additional alterations. Otherwise, the change was considered a failure, and researchers documented the reason for continued alterations and the final outcome.
Most Changes Were Successful
The initial AED regimen change was successful for 75% of patients (n = 30). After taking into account patients whose regimens underwent a second change, 90% of patients (n = 36) had a successful change.
“A failed first change is not a predictor of failure for a subsequent alteration,” the researchers said. Half of the failed first changes occurred because of medication side effects. In those cases, a trial of another medication or complete AED discontinuation were successful strategies. Seven out of nine patients (78%) who initially were on valproic acid discontinued it successfully.
Persistent seizure worsening occurred in two patients with medically refractory epilepsy. Patients rarely and only transiently lost seizure-free status. Potential covariates (eg, epilepsy and seizure types, seizure freedom status, AED type, and type of alteration) did not seem to significantly affect outcomes.
To further study AED regimen changes for reproductive safety, the researchers are conducting a prospective, observational, parallel-group, switch-control study.
—Jake Remaly
Aim for remission, not low disease activity, in rheumatoid arthritis
LIVERPOOL, ENGLAND – , according to the conclusion of a study presented at the British Society for Rheumatology annual conference.
The study showed clear differences in functional and quality of life outcomes over time when comparing patients who achieved remission with those who achieved low disease activity.
Indeed, from baseline assessments to 12 months follow-up, HAQ scores fell from an average of about 0.8 for those in remission and 0.9 for those with a low disease activity index to approximately 0.4 and 0.6, respectively.
The physical component score of the SF-36 also improved from around 35 and 30 at baseline in the remission and low disease activity groups to just above 40 and just under 35, respectively, at 12 months.
Baseline SF-36 mental component scores were around 51 and 49 in each group, respectively, at baseline but improved to around 55 with remission and remained steady in the low disease activity group at 12 months.
“This is something you often don’t see,” observed Sam Norton, PhD, who presented the findings on behalf of the lead author Elena Nikiphorou, MD. Dr. Norton is a senior lecturer in the department of health psychology at King’s College London whose research interests lie in studying the psychological well-being and illness outcomes in rheumatoid arthritis and other chronic physical illnesses.
“Of course, there could be a bit of reverse causality with people with good mental health being more likely to hit remission, which is why you can see there is a gap at baseline as well,” Dr. Norton suggested.
The researchers used data on 2,701 patients who were enrolled in the Early Rheumatoid Arthritis Network (ERAN) and Early Rheumatoid Arthritis Study (ERAS) cohorts. The research question was whether achieving low disease activity was an acceptable target in rheumatoid arthritis, and if disease outcomes made a difference to those who achieved remission.
The mean age of participants was 55 years in ERAS and 57 years in ERAN, with a similar percentage of female participants (67%), and slightly better baseline HAQ and Disease Activity Scale scores in the ERAN cohort, which is to be expected, Dr. Norton said, as this was a later-recruited population of patients (2002-2013 vs. 1986-2000 for ERAS).
Disease activity was categorized in three ways: firstly, remission or low disease activity over 1-5 years were defined as mean DAS28 score of less than 2.6 and a score of 2.6-3.2, respectively. Secondly, sustained low disease activity or remission was considered over 1-2 years, and thirdly, Boolean remission over 1-2 years, which are strict criteria of remission to meet.
Overall, 23.4% of patients achieved remission and 13.7% achieved low disease activity, and a respective 10.3% and 13.7% met criteria for sustained remission or sustained low disease activity. Just 3.4% met Boolean criteria for remission.
“The key messages are: There is a really important difference between remission and low disease activity score categories and that treating people to a remission target means they will do better in terms of quality of life outcomes over time compared to just stopping at a low disease activity,” Dr. Norton noted.
There was an important caveat to stating that remission should be the primary treat-to-target goal, in that there will likely be a relatively small proportion of patients that will achieve the strictest definition of remission, he added. Perhaps different targets need to be set for those with comorbidities or who are older.
“So, while remission should be a primary target there should be other targets considered alongside that,” he proposed.
Dr. Norton and his coauthors had nothing to disclose.
SOURCE: Nikiphorou E et al. Rheumatology. 2018;57[Suppl. 3]:key075.189.
LIVERPOOL, ENGLAND – , according to the conclusion of a study presented at the British Society for Rheumatology annual conference.
The study showed clear differences in functional and quality of life outcomes over time when comparing patients who achieved remission with those who achieved low disease activity.
Indeed, from baseline assessments to 12 months follow-up, HAQ scores fell from an average of about 0.8 for those in remission and 0.9 for those with a low disease activity index to approximately 0.4 and 0.6, respectively.
The physical component score of the SF-36 also improved from around 35 and 30 at baseline in the remission and low disease activity groups to just above 40 and just under 35, respectively, at 12 months.
Baseline SF-36 mental component scores were around 51 and 49 in each group, respectively, at baseline but improved to around 55 with remission and remained steady in the low disease activity group at 12 months.
“This is something you often don’t see,” observed Sam Norton, PhD, who presented the findings on behalf of the lead author Elena Nikiphorou, MD. Dr. Norton is a senior lecturer in the department of health psychology at King’s College London whose research interests lie in studying the psychological well-being and illness outcomes in rheumatoid arthritis and other chronic physical illnesses.
“Of course, there could be a bit of reverse causality with people with good mental health being more likely to hit remission, which is why you can see there is a gap at baseline as well,” Dr. Norton suggested.
The researchers used data on 2,701 patients who were enrolled in the Early Rheumatoid Arthritis Network (ERAN) and Early Rheumatoid Arthritis Study (ERAS) cohorts. The research question was whether achieving low disease activity was an acceptable target in rheumatoid arthritis, and if disease outcomes made a difference to those who achieved remission.
The mean age of participants was 55 years in ERAS and 57 years in ERAN, with a similar percentage of female participants (67%), and slightly better baseline HAQ and Disease Activity Scale scores in the ERAN cohort, which is to be expected, Dr. Norton said, as this was a later-recruited population of patients (2002-2013 vs. 1986-2000 for ERAS).
Disease activity was categorized in three ways: firstly, remission or low disease activity over 1-5 years were defined as mean DAS28 score of less than 2.6 and a score of 2.6-3.2, respectively. Secondly, sustained low disease activity or remission was considered over 1-2 years, and thirdly, Boolean remission over 1-2 years, which are strict criteria of remission to meet.
Overall, 23.4% of patients achieved remission and 13.7% achieved low disease activity, and a respective 10.3% and 13.7% met criteria for sustained remission or sustained low disease activity. Just 3.4% met Boolean criteria for remission.
“The key messages are: There is a really important difference between remission and low disease activity score categories and that treating people to a remission target means they will do better in terms of quality of life outcomes over time compared to just stopping at a low disease activity,” Dr. Norton noted.
There was an important caveat to stating that remission should be the primary treat-to-target goal, in that there will likely be a relatively small proportion of patients that will achieve the strictest definition of remission, he added. Perhaps different targets need to be set for those with comorbidities or who are older.
“So, while remission should be a primary target there should be other targets considered alongside that,” he proposed.
Dr. Norton and his coauthors had nothing to disclose.
SOURCE: Nikiphorou E et al. Rheumatology. 2018;57[Suppl. 3]:key075.189.
LIVERPOOL, ENGLAND – , according to the conclusion of a study presented at the British Society for Rheumatology annual conference.
The study showed clear differences in functional and quality of life outcomes over time when comparing patients who achieved remission with those who achieved low disease activity.
Indeed, from baseline assessments to 12 months follow-up, HAQ scores fell from an average of about 0.8 for those in remission and 0.9 for those with a low disease activity index to approximately 0.4 and 0.6, respectively.
The physical component score of the SF-36 also improved from around 35 and 30 at baseline in the remission and low disease activity groups to just above 40 and just under 35, respectively, at 12 months.
Baseline SF-36 mental component scores were around 51 and 49 in each group, respectively, at baseline but improved to around 55 with remission and remained steady in the low disease activity group at 12 months.
“This is something you often don’t see,” observed Sam Norton, PhD, who presented the findings on behalf of the lead author Elena Nikiphorou, MD. Dr. Norton is a senior lecturer in the department of health psychology at King’s College London whose research interests lie in studying the psychological well-being and illness outcomes in rheumatoid arthritis and other chronic physical illnesses.
“Of course, there could be a bit of reverse causality with people with good mental health being more likely to hit remission, which is why you can see there is a gap at baseline as well,” Dr. Norton suggested.
The researchers used data on 2,701 patients who were enrolled in the Early Rheumatoid Arthritis Network (ERAN) and Early Rheumatoid Arthritis Study (ERAS) cohorts. The research question was whether achieving low disease activity was an acceptable target in rheumatoid arthritis, and if disease outcomes made a difference to those who achieved remission.
The mean age of participants was 55 years in ERAS and 57 years in ERAN, with a similar percentage of female participants (67%), and slightly better baseline HAQ and Disease Activity Scale scores in the ERAN cohort, which is to be expected, Dr. Norton said, as this was a later-recruited population of patients (2002-2013 vs. 1986-2000 for ERAS).
Disease activity was categorized in three ways: firstly, remission or low disease activity over 1-5 years were defined as mean DAS28 score of less than 2.6 and a score of 2.6-3.2, respectively. Secondly, sustained low disease activity or remission was considered over 1-2 years, and thirdly, Boolean remission over 1-2 years, which are strict criteria of remission to meet.
Overall, 23.4% of patients achieved remission and 13.7% achieved low disease activity, and a respective 10.3% and 13.7% met criteria for sustained remission or sustained low disease activity. Just 3.4% met Boolean criteria for remission.
“The key messages are: There is a really important difference between remission and low disease activity score categories and that treating people to a remission target means they will do better in terms of quality of life outcomes over time compared to just stopping at a low disease activity,” Dr. Norton noted.
There was an important caveat to stating that remission should be the primary treat-to-target goal, in that there will likely be a relatively small proportion of patients that will achieve the strictest definition of remission, he added. Perhaps different targets need to be set for those with comorbidities or who are older.
“So, while remission should be a primary target there should be other targets considered alongside that,” he proposed.
Dr. Norton and his coauthors had nothing to disclose.
SOURCE: Nikiphorou E et al. Rheumatology. 2018;57[Suppl. 3]:key075.189.
REPORTING FROM RHEUMATOLOGY 2018
Key clinical point: Better outcomes were achieved if patients with rheumatoid arthritis met criteria for remission rather than low disease activity.
Major finding: The study showed clear differences in functional and quality of life outcomes over time when comparing patients who achieved remission with those who achieved low disease activity.
Study details: A prospective study of 2,701 patients enrolled in two early rheumatoid arthritis cohorts.
Disclosures: Dr. Norton and his coauthors had nothing to disclose.
Source: Nikiphorou E et al. Rheumatology. 2018;57[Suppl. 3]:key075.189.
Cost-effectiveness battle: FFR vs. iFR in DEFINE-FLAIR trial
ORLANDO – The use of an instantaneous wave-free ratio (iFR)–guided strategy to identify physiologically significant coronary stenoses that warrant revascularization proved substantially more cost effective than did a fractional flow reserve (FFR)–based strategy in a prespecified secondary analysis of the randomized DEFINE-FLAIR trial, Manesh R. Patel, MD, reported at the annual meeting of the American College of Cardiology.
The difference in total health care costs over the course of a year of follow-up was $896 per patient in favor of the instantaneous wave-free ratio (iFR) approach, said Dr. Patel, a professor of medicine, the chief of the division of cardiology, and the chief of the division of clinical pharmacology at Duke University in Durham, N.C.
DEFINE-FLAIR was a multicenter study in which 2,492 patients with coronary artery disease were randomized to undergo either iFR- or FFR-guided coronary revascularization. It had previously been established that decision making regarding coronary revascularization or deferral that was guided by FFR leads to better patient outcomes than decision making guided by angiography alone.
DEFINE-FLAIR showed that iFR provides clinical benefits similar to those of FFR. The 1-year primary endpoint, a composite of all-cause mortality, nonfatal MI, or unplanned revascularization, occurred in 6.8% of the iFR group and 7.0% of the FFR group, while the revascularization rate was significantly lower in the iFR group, by a margin of 47.5% to 53.4% (N Engl J Med. 2017 May 11;376(19):1824-34).
Dr. Patel presented a formal study of total health care costs and quality of life in the two study arms through 1 year of follow-up. The cost of coronary physiologic assessment by iFR was lower because, unlike FFR, iFR doesn’t use adenosine for vasodilation. Plus, median procedural time was 4.5 minutes shorter in the iFR group, resulting in lower costs for staff time. After investigators added up the costs of balloons, stents, laboratory testing, and a year’s worth of primary care visits, specialty consults, and unplanned revascularization procedures, the total cost per patient was $7,442.23 in 2017 U.S. dollars in the iFR group and $8,243.39 in the FFR group.
Session cochair Christopher Granger, MD, was favorably impressed.
“With equal clinical outcomes, the iFR – in not using adenosine and by identifying fewer patients needing referral for coronary artery bypass surgery or percutaneous coronary intervention – had a better cost effectiveness by about $900. That’s pretty good,” commented Dr. Granger, a professor of medicine at Duke University.
“At the moment, there is a longer track record for FFR data than iFR data for outcomes, but this is a fairly strong finding in a large population in a well-conducted study, and it shows very positive favorable economic results,” the cardiologist added. “There is no doubt that this [iFR] does have streamlined work flow, lower cost, and the same outcomes. So I think this is actually quite a positive effect.”
Dr. Patel, in acknowledging that there is a spirited ongoing debate among some interventional cardiologists as to which coronary physiology assessment tool should be used, declared, “We should stop arguing about which one to use and just use more of it, first and foremost.”
“I couldn’t agree more,” Dr. Granger said. “Coronary physiology for best decision making, whichever index you decide to choose, will lead to better outcomes and lower cost.”
Dr. Patel estimated that, worldwide, coronary physiology assessment is used in cardiac catheterization laboratories in fewer than 20% of patients. Achieving a substantial increase in that number is a matter of physician education perhaps coupled with payer requirements that interventional cardiologists must demonstrate evidence of ischemia before performing percutaneous coronary intervention on a given coronary lesion. Also, the American College of Cardiology/American Heart Association guidelines, which at present give a Class IIa recommendation for the use of FFR in patients with an intermediate stenosis, probably need to be revisited in light of DEFINE-FLAIR.
“One might argue that the recommendation could be a little stronger. And we have other proven technologies now besides FFR,” he observed.
Dr. Patel reported receiving research grants from Philips Volcano, sponsor of the DEFINE-FLAIR trial, as well as from AstraZeneca, Bayer, Janssen, ProCyrion, and the National Heart, Lung, and Blood Institute. He serves as a consultant to AstraZeneca, Bayer, Janssen, and Medscape.
SOURCE: Patel MR et al. ACC 18, Abstract 402-09.
ORLANDO – The use of an instantaneous wave-free ratio (iFR)–guided strategy to identify physiologically significant coronary stenoses that warrant revascularization proved substantially more cost effective than did a fractional flow reserve (FFR)–based strategy in a prespecified secondary analysis of the randomized DEFINE-FLAIR trial, Manesh R. Patel, MD, reported at the annual meeting of the American College of Cardiology.
The difference in total health care costs over the course of a year of follow-up was $896 per patient in favor of the instantaneous wave-free ratio (iFR) approach, said Dr. Patel, a professor of medicine, the chief of the division of cardiology, and the chief of the division of clinical pharmacology at Duke University in Durham, N.C.
DEFINE-FLAIR was a multicenter study in which 2,492 patients with coronary artery disease were randomized to undergo either iFR- or FFR-guided coronary revascularization. It had previously been established that decision making regarding coronary revascularization or deferral that was guided by FFR leads to better patient outcomes than decision making guided by angiography alone.
DEFINE-FLAIR showed that iFR provides clinical benefits similar to those of FFR. The 1-year primary endpoint, a composite of all-cause mortality, nonfatal MI, or unplanned revascularization, occurred in 6.8% of the iFR group and 7.0% of the FFR group, while the revascularization rate was significantly lower in the iFR group, by a margin of 47.5% to 53.4% (N Engl J Med. 2017 May 11;376(19):1824-34).
Dr. Patel presented a formal study of total health care costs and quality of life in the two study arms through 1 year of follow-up. The cost of coronary physiologic assessment by iFR was lower because, unlike FFR, iFR doesn’t use adenosine for vasodilation. Plus, median procedural time was 4.5 minutes shorter in the iFR group, resulting in lower costs for staff time. After investigators added up the costs of balloons, stents, laboratory testing, and a year’s worth of primary care visits, specialty consults, and unplanned revascularization procedures, the total cost per patient was $7,442.23 in 2017 U.S. dollars in the iFR group and $8,243.39 in the FFR group.
Session cochair Christopher Granger, MD, was favorably impressed.
“With equal clinical outcomes, the iFR – in not using adenosine and by identifying fewer patients needing referral for coronary artery bypass surgery or percutaneous coronary intervention – had a better cost effectiveness by about $900. That’s pretty good,” commented Dr. Granger, a professor of medicine at Duke University.
“At the moment, there is a longer track record for FFR data than iFR data for outcomes, but this is a fairly strong finding in a large population in a well-conducted study, and it shows very positive favorable economic results,” the cardiologist added. “There is no doubt that this [iFR] does have streamlined work flow, lower cost, and the same outcomes. So I think this is actually quite a positive effect.”
Dr. Patel, in acknowledging that there is a spirited ongoing debate among some interventional cardiologists as to which coronary physiology assessment tool should be used, declared, “We should stop arguing about which one to use and just use more of it, first and foremost.”
“I couldn’t agree more,” Dr. Granger said. “Coronary physiology for best decision making, whichever index you decide to choose, will lead to better outcomes and lower cost.”
Dr. Patel estimated that, worldwide, coronary physiology assessment is used in cardiac catheterization laboratories in fewer than 20% of patients. Achieving a substantial increase in that number is a matter of physician education perhaps coupled with payer requirements that interventional cardiologists must demonstrate evidence of ischemia before performing percutaneous coronary intervention on a given coronary lesion. Also, the American College of Cardiology/American Heart Association guidelines, which at present give a Class IIa recommendation for the use of FFR in patients with an intermediate stenosis, probably need to be revisited in light of DEFINE-FLAIR.
“One might argue that the recommendation could be a little stronger. And we have other proven technologies now besides FFR,” he observed.
Dr. Patel reported receiving research grants from Philips Volcano, sponsor of the DEFINE-FLAIR trial, as well as from AstraZeneca, Bayer, Janssen, ProCyrion, and the National Heart, Lung, and Blood Institute. He serves as a consultant to AstraZeneca, Bayer, Janssen, and Medscape.
SOURCE: Patel MR et al. ACC 18, Abstract 402-09.
ORLANDO – The use of an instantaneous wave-free ratio (iFR)–guided strategy to identify physiologically significant coronary stenoses that warrant revascularization proved substantially more cost effective than did a fractional flow reserve (FFR)–based strategy in a prespecified secondary analysis of the randomized DEFINE-FLAIR trial, Manesh R. Patel, MD, reported at the annual meeting of the American College of Cardiology.
The difference in total health care costs over the course of a year of follow-up was $896 per patient in favor of the instantaneous wave-free ratio (iFR) approach, said Dr. Patel, a professor of medicine, the chief of the division of cardiology, and the chief of the division of clinical pharmacology at Duke University in Durham, N.C.
DEFINE-FLAIR was a multicenter study in which 2,492 patients with coronary artery disease were randomized to undergo either iFR- or FFR-guided coronary revascularization. It had previously been established that decision making regarding coronary revascularization or deferral that was guided by FFR leads to better patient outcomes than decision making guided by angiography alone.
DEFINE-FLAIR showed that iFR provides clinical benefits similar to those of FFR. The 1-year primary endpoint, a composite of all-cause mortality, nonfatal MI, or unplanned revascularization, occurred in 6.8% of the iFR group and 7.0% of the FFR group, while the revascularization rate was significantly lower in the iFR group, by a margin of 47.5% to 53.4% (N Engl J Med. 2017 May 11;376(19):1824-34).
Dr. Patel presented a formal study of total health care costs and quality of life in the two study arms through 1 year of follow-up. The cost of coronary physiologic assessment by iFR was lower because, unlike FFR, iFR doesn’t use adenosine for vasodilation. Plus, median procedural time was 4.5 minutes shorter in the iFR group, resulting in lower costs for staff time. After investigators added up the costs of balloons, stents, laboratory testing, and a year’s worth of primary care visits, specialty consults, and unplanned revascularization procedures, the total cost per patient was $7,442.23 in 2017 U.S. dollars in the iFR group and $8,243.39 in the FFR group.
Session cochair Christopher Granger, MD, was favorably impressed.
“With equal clinical outcomes, the iFR – in not using adenosine and by identifying fewer patients needing referral for coronary artery bypass surgery or percutaneous coronary intervention – had a better cost effectiveness by about $900. That’s pretty good,” commented Dr. Granger, a professor of medicine at Duke University.
“At the moment, there is a longer track record for FFR data than iFR data for outcomes, but this is a fairly strong finding in a large population in a well-conducted study, and it shows very positive favorable economic results,” the cardiologist added. “There is no doubt that this [iFR] does have streamlined work flow, lower cost, and the same outcomes. So I think this is actually quite a positive effect.”
Dr. Patel, in acknowledging that there is a spirited ongoing debate among some interventional cardiologists as to which coronary physiology assessment tool should be used, declared, “We should stop arguing about which one to use and just use more of it, first and foremost.”
“I couldn’t agree more,” Dr. Granger said. “Coronary physiology for best decision making, whichever index you decide to choose, will lead to better outcomes and lower cost.”
Dr. Patel estimated that, worldwide, coronary physiology assessment is used in cardiac catheterization laboratories in fewer than 20% of patients. Achieving a substantial increase in that number is a matter of physician education perhaps coupled with payer requirements that interventional cardiologists must demonstrate evidence of ischemia before performing percutaneous coronary intervention on a given coronary lesion. Also, the American College of Cardiology/American Heart Association guidelines, which at present give a Class IIa recommendation for the use of FFR in patients with an intermediate stenosis, probably need to be revisited in light of DEFINE-FLAIR.
“One might argue that the recommendation could be a little stronger. And we have other proven technologies now besides FFR,” he observed.
Dr. Patel reported receiving research grants from Philips Volcano, sponsor of the DEFINE-FLAIR trial, as well as from AstraZeneca, Bayer, Janssen, ProCyrion, and the National Heart, Lung, and Blood Institute. He serves as a consultant to AstraZeneca, Bayer, Janssen, and Medscape.
SOURCE: Patel MR et al. ACC 18, Abstract 402-09.
REPORTING FROM ACC 2018
Key clinical point:
Major finding: A coronary revascularization strategy guided by physiologic information provided by instantaneous wave-free ratio resulted in $896 less in health care costs per patient over 1 year of follow-up than a fractional flow reserve–guided strategy had.
Study details: This was a prespecified analysis of all health care costs during 1 year of follow-up in the 2,492-patient randomized DEFINE-FLAIR study.
Disclosures: The study presenter reported receiving a research grant from Philips Volcano, sponsor of the DEFINE-FLAIR trial.
Source: Patel MR et al. ACC 18, Abstract 402-09.
Challenging dogma: Postop fever
The dogma
During our medical school and residency years, many of us learned the “Rule of W” as a helpful mnemonic for causes of postoperative fever: Wind (pulmonary causes, including atelectasis), Water (urinary tract infection), Wound (infection), Walking (deep venous thrombosis), and Wonder Drugs (drug fever). Classic teaching has been that noninfectious causes predominate during the first 48 hours post op, with infectious diseases taking over after that. Atelectasis is also very common in the immediate postoperative period, seen in up to 90% of patients by postoperative day 3, and is often taught as the primary cause of fever in the immediate postoperative period.1,2 But is this backed up by the evidence?
The evidence
A 2011 systematic review looked at the association between atelectasis and fever. Eight studies involving 998 postoperative patients were included, with the majority of cases being postcardiac or abdominal surgeries. Seven of the eight studies failed to show a significant association between early postoperative fever (EPF) and atelectasis; in the one “positive” study, atelectasis was assessed only once on postop day 4. The authors of the review concluded that “there is no clinical evidence suggesting that atelectasis is a major cause of early EPF”.3 A subsequent study of postoperative fever in pediatric patients showed similar negative results.4 This begs the question – does atelectasis cause fever at all? Likely not. In an animal study from 1963, experimentally induced atelectasis resulted in fever, but the fever appeared secondary to infectious causes (i.e. pneumonia in the affected lung) and resolved with antibiotic administration.5 It seems more likely that EPF is due to other factors, such as the increase in pyrogenic cytokines seen in the postoperative period.3
Takeaway
Atelectasis and early postoperative fever are both commonly seen after surgery, but the relationship appears to be simply an association, not causal. The “Rule of W” can be an effective mnemonic for the causes of postop fever – just make sure you use the updated version.
Dr. Sehgal is clinical associate professor of medicine, division of hospital medicine, South Texas Veterans Health Care System and University of Texas Health Sciences Center at San Antonio. He is a member of the editorial advisory board for The Hospitalist.
References
1. Carter AR, et al. Thoracic Alterations After Cardiac Surgery. AJR. 1983;140(3):475-81.
2. Chu DI, Agarwal S. Postoperative Complications. In: Doherty GM. eds. CURRENT Diagnosis & Treatment: Surgery, 14e New York, NY: McGraw-Hill; 2014.
3. Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a Cause of Postoperative Fever. Chest. 2011;140(2):418-24. doi: 10.1378/chest.11-0127.
4. Kane JM, Friedman M, Mitchell JB, Wang D, Huang Z, Backer CL. Association Between Postoperative Fever and Atelectasis in Pediatric Patients. World J Pediatr Congenit Heart Surg. 2011;2(3):359-63. doi: 10.1177/2150135111403778.
5. Lansing AM, Jamieson WG. Mechanisms of fever in pulmonary atelectasis. Arch Surg. 1963;87:168-74.
6. Hyder JA, Wakeam E, Arora V, Hevelone ND, Lipsitz SR, Nguyen LL. Investigating the “Rule of W,” a Mnemonic for Teaching on Postoperative Complications. J Surg Educ. 2015;72(3):430-7. doi: 10.1016/j.jsurg.2014.11.004.
The dogma
During our medical school and residency years, many of us learned the “Rule of W” as a helpful mnemonic for causes of postoperative fever: Wind (pulmonary causes, including atelectasis), Water (urinary tract infection), Wound (infection), Walking (deep venous thrombosis), and Wonder Drugs (drug fever). Classic teaching has been that noninfectious causes predominate during the first 48 hours post op, with infectious diseases taking over after that. Atelectasis is also very common in the immediate postoperative period, seen in up to 90% of patients by postoperative day 3, and is often taught as the primary cause of fever in the immediate postoperative period.1,2 But is this backed up by the evidence?
The evidence
A 2011 systematic review looked at the association between atelectasis and fever. Eight studies involving 998 postoperative patients were included, with the majority of cases being postcardiac or abdominal surgeries. Seven of the eight studies failed to show a significant association between early postoperative fever (EPF) and atelectasis; in the one “positive” study, atelectasis was assessed only once on postop day 4. The authors of the review concluded that “there is no clinical evidence suggesting that atelectasis is a major cause of early EPF”.3 A subsequent study of postoperative fever in pediatric patients showed similar negative results.4 This begs the question – does atelectasis cause fever at all? Likely not. In an animal study from 1963, experimentally induced atelectasis resulted in fever, but the fever appeared secondary to infectious causes (i.e. pneumonia in the affected lung) and resolved with antibiotic administration.5 It seems more likely that EPF is due to other factors, such as the increase in pyrogenic cytokines seen in the postoperative period.3
Takeaway
Atelectasis and early postoperative fever are both commonly seen after surgery, but the relationship appears to be simply an association, not causal. The “Rule of W” can be an effective mnemonic for the causes of postop fever – just make sure you use the updated version.
Dr. Sehgal is clinical associate professor of medicine, division of hospital medicine, South Texas Veterans Health Care System and University of Texas Health Sciences Center at San Antonio. He is a member of the editorial advisory board for The Hospitalist.
References
1. Carter AR, et al. Thoracic Alterations After Cardiac Surgery. AJR. 1983;140(3):475-81.
2. Chu DI, Agarwal S. Postoperative Complications. In: Doherty GM. eds. CURRENT Diagnosis & Treatment: Surgery, 14e New York, NY: McGraw-Hill; 2014.
3. Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a Cause of Postoperative Fever. Chest. 2011;140(2):418-24. doi: 10.1378/chest.11-0127.
4. Kane JM, Friedman M, Mitchell JB, Wang D, Huang Z, Backer CL. Association Between Postoperative Fever and Atelectasis in Pediatric Patients. World J Pediatr Congenit Heart Surg. 2011;2(3):359-63. doi: 10.1177/2150135111403778.
5. Lansing AM, Jamieson WG. Mechanisms of fever in pulmonary atelectasis. Arch Surg. 1963;87:168-74.
6. Hyder JA, Wakeam E, Arora V, Hevelone ND, Lipsitz SR, Nguyen LL. Investigating the “Rule of W,” a Mnemonic for Teaching on Postoperative Complications. J Surg Educ. 2015;72(3):430-7. doi: 10.1016/j.jsurg.2014.11.004.
The dogma
During our medical school and residency years, many of us learned the “Rule of W” as a helpful mnemonic for causes of postoperative fever: Wind (pulmonary causes, including atelectasis), Water (urinary tract infection), Wound (infection), Walking (deep venous thrombosis), and Wonder Drugs (drug fever). Classic teaching has been that noninfectious causes predominate during the first 48 hours post op, with infectious diseases taking over after that. Atelectasis is also very common in the immediate postoperative period, seen in up to 90% of patients by postoperative day 3, and is often taught as the primary cause of fever in the immediate postoperative period.1,2 But is this backed up by the evidence?
The evidence
A 2011 systematic review looked at the association between atelectasis and fever. Eight studies involving 998 postoperative patients were included, with the majority of cases being postcardiac or abdominal surgeries. Seven of the eight studies failed to show a significant association between early postoperative fever (EPF) and atelectasis; in the one “positive” study, atelectasis was assessed only once on postop day 4. The authors of the review concluded that “there is no clinical evidence suggesting that atelectasis is a major cause of early EPF”.3 A subsequent study of postoperative fever in pediatric patients showed similar negative results.4 This begs the question – does atelectasis cause fever at all? Likely not. In an animal study from 1963, experimentally induced atelectasis resulted in fever, but the fever appeared secondary to infectious causes (i.e. pneumonia in the affected lung) and resolved with antibiotic administration.5 It seems more likely that EPF is due to other factors, such as the increase in pyrogenic cytokines seen in the postoperative period.3
Takeaway
Atelectasis and early postoperative fever are both commonly seen after surgery, but the relationship appears to be simply an association, not causal. The “Rule of W” can be an effective mnemonic for the causes of postop fever – just make sure you use the updated version.
Dr. Sehgal is clinical associate professor of medicine, division of hospital medicine, South Texas Veterans Health Care System and University of Texas Health Sciences Center at San Antonio. He is a member of the editorial advisory board for The Hospitalist.
References
1. Carter AR, et al. Thoracic Alterations After Cardiac Surgery. AJR. 1983;140(3):475-81.
2. Chu DI, Agarwal S. Postoperative Complications. In: Doherty GM. eds. CURRENT Diagnosis & Treatment: Surgery, 14e New York, NY: McGraw-Hill; 2014.
3. Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a Cause of Postoperative Fever. Chest. 2011;140(2):418-24. doi: 10.1378/chest.11-0127.
4. Kane JM, Friedman M, Mitchell JB, Wang D, Huang Z, Backer CL. Association Between Postoperative Fever and Atelectasis in Pediatric Patients. World J Pediatr Congenit Heart Surg. 2011;2(3):359-63. doi: 10.1177/2150135111403778.
5. Lansing AM, Jamieson WG. Mechanisms of fever in pulmonary atelectasis. Arch Surg. 1963;87:168-74.
6. Hyder JA, Wakeam E, Arora V, Hevelone ND, Lipsitz SR, Nguyen LL. Investigating the “Rule of W,” a Mnemonic for Teaching on Postoperative Complications. J Surg Educ. 2015;72(3):430-7. doi: 10.1016/j.jsurg.2014.11.004.