Expert Commentary

Clinicians can use a pair of large surgical bolt cutters to safely and quickly cut a titanium ring from a patient’s swollen finger, and then can pull apart the edges with two paper clips, according to a letter published online in Emergency Medicine Journal.

“Our method used simple equipment that is readily available in most hospitals at all times, took less than 30 seconds to perform, and could be performed by a sole operator without damage to the underlying finger,” wrote Dr. Andrej Salibi and Dr. Andrew Morritt at Sheffield (England) Teaching Hospital NHS Foundation (2015 Aug 13; doi: 10.1136/emermed-2015-204962).

Ring constriction is a fairly common problem that can cause necrosis and loss of the digit if the ring is not removed. Basic ring cutters can sever gold and silver, but not titanium, which has become popular for rings because it is hypoallergenic, durable, lightweight, and strong – so strong that diamond-tipped saws or drills can take up to 15 minutes to cut these rings, the surgeons noted. Many facilities also lack access to such equipment, and it generates enough heat that an assistant must irrigate the surrounding skin to prevent burns, they said.

Their case report described a patient who bathed in warm water at a spa and developed a painful, swollen finger that was constricted by a titanium wedding band. Elevation and lubrication at the emergency department failed to remove the ring, as did finger binding and use of a manual ring cutter.

“The fire service was called and attempted removal using specialized cutting equipment, which also failed,” the surgeons wrote. “The patient was then admitted under the plastic surgery service for hand elevation, and further attempts 8 hours later blunted two manual ring cutters.” At this point, they borrowed a large pair of bolt cutters from the operating room, which quickly severed the ring without harming the finger. Then they applied lateral traction with a pair of paper clips and removed it, they said.

The authors declared no funding sources or conflicts of interest.

Clinicians can use a pair of large surgical bolt cutters to safely and quickly cut a titanium ring from a patient’s swollen finger, and then can pull apart the edges with two paper clips, according to a letter published online in Emergency Medicine Journal.

“Our method used simple equipment that is readily available in most hospitals at all times, took less than 30 seconds to perform, and could be performed by a sole operator without damage to the underlying finger,” wrote Dr. Andrej Salibi and Dr. Andrew Morritt at Sheffield (England) Teaching Hospital NHS Foundation (2015 Aug 13; doi: 10.1136/emermed-2015-204962).

Ring constriction is a fairly common problem that can cause necrosis and loss of the digit if the ring is not removed. Basic ring cutters can sever gold and silver, but not titanium, which has become popular for rings because it is hypoallergenic, durable, lightweight, and strong – so strong that diamond-tipped saws or drills can take up to 15 minutes to cut these rings, the surgeons noted. Many facilities also lack access to such equipment, and it generates enough heat that an assistant must irrigate the surrounding skin to prevent burns, they said.

Their case report described a patient who bathed in warm water at a spa and developed a painful, swollen finger that was constricted by a titanium wedding band. Elevation and lubrication at the emergency department failed to remove the ring, as did finger binding and use of a manual ring cutter.

“The fire service was called and attempted removal using specialized cutting equipment, which also failed,” the surgeons wrote. “The patient was then admitted under the plastic surgery service for hand elevation, and further attempts 8 hours later blunted two manual ring cutters.” At this point, they borrowed a large pair of bolt cutters from the operating room, which quickly severed the ring without harming the finger. Then they applied lateral traction with a pair of paper clips and removed it, they said.

The authors declared no funding sources or conflicts of interest.

Clinicians can use a pair of large surgical bolt cutters to safely and quickly cut a titanium ring from a patient’s swollen finger, and then can pull apart the edges with two paper clips, according to a letter published online in Emergency Medicine Journal.

“Our method used simple equipment that is readily available in most hospitals at all times, took less than 30 seconds to perform, and could be performed by a sole operator without damage to the underlying finger,” wrote Dr. Andrej Salibi and Dr. Andrew Morritt at Sheffield (England) Teaching Hospital NHS Foundation (2015 Aug 13; doi: 10.1136/emermed-2015-204962).

Ring constriction is a fairly common problem that can cause necrosis and loss of the digit if the ring is not removed. Basic ring cutters can sever gold and silver, but not titanium, which has become popular for rings because it is hypoallergenic, durable, lightweight, and strong – so strong that diamond-tipped saws or drills can take up to 15 minutes to cut these rings, the surgeons noted. Many facilities also lack access to such equipment, and it generates enough heat that an assistant must irrigate the surrounding skin to prevent burns, they said.

Their case report described a patient who bathed in warm water at a spa and developed a painful, swollen finger that was constricted by a titanium wedding band. Elevation and lubrication at the emergency department failed to remove the ring, as did finger binding and use of a manual ring cutter.

“The fire service was called and attempted removal using specialized cutting equipment, which also failed,” the surgeons wrote. “The patient was then admitted under the plastic surgery service for hand elevation, and further attempts 8 hours later blunted two manual ring cutters.” At this point, they borrowed a large pair of bolt cutters from the operating room, which quickly severed the ring without harming the finger. Then they applied lateral traction with a pair of paper clips and removed it, they said.

The authors declared no funding sources or conflicts of interest.

VANCOUVER – Two serious emerging skin and soft tissue infections whose progress physicians will want to chart are melioidosis and Acinetobacter baumannii infection, Dr. Dirk M. Elston advised at the World Congress of Dermatology.

Both Burkholderia pseudomallei – the cause of melioidosis – and Acinetobacter baumannii are gram-negative organisms that laboratory staff sometimes mistakenly dismiss as culture contaminants. But melioidosis has a case fatality rate of up to 40%, and A. baumannii is an increasingly multidrug-resistant cause of community-acquired cellulitis, according to Dr. Elston, chair of the department of dermatology and dermatologic surgery at the Medical University of South Carolina, Charleston.

Dr. Elston, also managing director of the Ackerman Academy of Dermatopathology in New York, offered his views on these two emerging infections.

Melioidosis

“We know melioidosis from the rice paddies of Vietnam as a plaguelike ulceroglandular syndrome. It has reemerged in the Caribbean,” Dr. Elston reported.

Indeed, investigators at the Centers for Disease Control and Prevention reported earlier this year that melioidosis is now endemic in Puerto Rico based upon its findings of high seropositivity rates among patient contacts plus isolation of the causative organism from soil samples (Clin Infect Dis. 2015 Jan 15;60(2):243-250). The infection, which is believed to be underdiagnosed, also has been reported at numerous other sites in the Caribbean basin and in Latin America and Africa, as well as in Southeast Asia.

Although skin and soft tissue abscesses are common manifestations of this acute febrile illness, the most common clinical presentation of melioidosis is acute pneumonia with or without septicemia, which can be fulminant.

According to the CDC investigators, up to 80% of patients with melioidosis have diabetes, chronic lung disease, and/or excessive alcohol use as risk factors for the infection. In the Puerto Rican study, a history of injection drug use was for the first time identified as another risk factor. When in endemic areas such as Puerto Rico, individuals with diabetes or other risk factors should protect themselves from direct exposure to soil and water to reduce their risk of what is believed to be a transcutaneously acquired infection. The investigators advised that individuals with skin wounds or sores do the same.

The recommended treatment for melioidosis is intravenous ceftazidime, imipenem, or meropenem (N Engl J Med. 2012 Sep 13;367(11):1035-1044).

A. baumannii infection

In a recent report, Dr. Adam J. Friedman and his colleagues at the Albert Einstein College of Medicine in New York said that A. baumannii’s pattern of evolution to date is strikingly similar to that of methicillin-resistant Staphylococcus aureus. A. baumannii has displayed increasing pathogenicity and antibiotic resistance. The investigators warned that there is a real danger that, like MRSA, extensively drug-resistant A. baumannii will become a common community-acquired infection arising in previously healthy patients (JAMA Dermatol. 2014 Aug;150(8):905-906).

“There are some strains of gonococcus and some strains of Acinetobacter baumannii that appear to be resistant to all known antibiotics,” Dr. Elston said.

He reported having no relevant financial conflicts of interest.

[email protected]

VANCOUVER – Two serious emerging skin and soft tissue infections whose progress physicians will want to chart are melioidosis and Acinetobacter baumannii infection, Dr. Dirk M. Elston advised at the World Congress of Dermatology.

Both Burkholderia pseudomallei – the cause of melioidosis – and Acinetobacter baumannii are gram-negative organisms that laboratory staff sometimes mistakenly dismiss as culture contaminants. But melioidosis has a case fatality rate of up to 40%, and A. baumannii is an increasingly multidrug-resistant cause of community-acquired cellulitis, according to Dr. Elston, chair of the department of dermatology and dermatologic surgery at the Medical University of South Carolina, Charleston.

Dr. Elston, also managing director of the Ackerman Academy of Dermatopathology in New York, offered his views on these two emerging infections.

Melioidosis

“We know melioidosis from the rice paddies of Vietnam as a plaguelike ulceroglandular syndrome. It has reemerged in the Caribbean,” Dr. Elston reported.

Indeed, investigators at the Centers for Disease Control and Prevention reported earlier this year that melioidosis is now endemic in Puerto Rico based upon its findings of high seropositivity rates among patient contacts plus isolation of the causative organism from soil samples (Clin Infect Dis. 2015 Jan 15;60(2):243-250). The infection, which is believed to be underdiagnosed, also has been reported at numerous other sites in the Caribbean basin and in Latin America and Africa, as well as in Southeast Asia.

Although skin and soft tissue abscesses are common manifestations of this acute febrile illness, the most common clinical presentation of melioidosis is acute pneumonia with or without septicemia, which can be fulminant.

According to the CDC investigators, up to 80% of patients with melioidosis have diabetes, chronic lung disease, and/or excessive alcohol use as risk factors for the infection. In the Puerto Rican study, a history of injection drug use was for the first time identified as another risk factor. When in endemic areas such as Puerto Rico, individuals with diabetes or other risk factors should protect themselves from direct exposure to soil and water to reduce their risk of what is believed to be a transcutaneously acquired infection. The investigators advised that individuals with skin wounds or sores do the same.

The recommended treatment for melioidosis is intravenous ceftazidime, imipenem, or meropenem (N Engl J Med. 2012 Sep 13;367(11):1035-1044).

A. baumannii infection

In a recent report, Dr. Adam J. Friedman and his colleagues at the Albert Einstein College of Medicine in New York said that A. baumannii’s pattern of evolution to date is strikingly similar to that of methicillin-resistant Staphylococcus aureus. A. baumannii has displayed increasing pathogenicity and antibiotic resistance. The investigators warned that there is a real danger that, like MRSA, extensively drug-resistant A. baumannii will become a common community-acquired infection arising in previously healthy patients (JAMA Dermatol. 2014 Aug;150(8):905-906).

“There are some strains of gonococcus and some strains of Acinetobacter baumannii that appear to be resistant to all known antibiotics,” Dr. Elston said.

He reported having no relevant financial conflicts of interest.

[email protected]

VANCOUVER – Two serious emerging skin and soft tissue infections whose progress physicians will want to chart are melioidosis and Acinetobacter baumannii infection, Dr. Dirk M. Elston advised at the World Congress of Dermatology.

Both Burkholderia pseudomallei – the cause of melioidosis – and Acinetobacter baumannii are gram-negative organisms that laboratory staff sometimes mistakenly dismiss as culture contaminants. But melioidosis has a case fatality rate of up to 40%, and A. baumannii is an increasingly multidrug-resistant cause of community-acquired cellulitis, according to Dr. Elston, chair of the department of dermatology and dermatologic surgery at the Medical University of South Carolina, Charleston.

Dr. Elston, also managing director of the Ackerman Academy of Dermatopathology in New York, offered his views on these two emerging infections.

Melioidosis

“We know melioidosis from the rice paddies of Vietnam as a plaguelike ulceroglandular syndrome. It has reemerged in the Caribbean,” Dr. Elston reported.

Indeed, investigators at the Centers for Disease Control and Prevention reported earlier this year that melioidosis is now endemic in Puerto Rico based upon its findings of high seropositivity rates among patient contacts plus isolation of the causative organism from soil samples (Clin Infect Dis. 2015 Jan 15;60(2):243-250). The infection, which is believed to be underdiagnosed, also has been reported at numerous other sites in the Caribbean basin and in Latin America and Africa, as well as in Southeast Asia.

Although skin and soft tissue abscesses are common manifestations of this acute febrile illness, the most common clinical presentation of melioidosis is acute pneumonia with or without septicemia, which can be fulminant.

According to the CDC investigators, up to 80% of patients with melioidosis have diabetes, chronic lung disease, and/or excessive alcohol use as risk factors for the infection. In the Puerto Rican study, a history of injection drug use was for the first time identified as another risk factor. When in endemic areas such as Puerto Rico, individuals with diabetes or other risk factors should protect themselves from direct exposure to soil and water to reduce their risk of what is believed to be a transcutaneously acquired infection. The investigators advised that individuals with skin wounds or sores do the same.

The recommended treatment for melioidosis is intravenous ceftazidime, imipenem, or meropenem (N Engl J Med. 2012 Sep 13;367(11):1035-1044).

A. baumannii infection

In a recent report, Dr. Adam J. Friedman and his colleagues at the Albert Einstein College of Medicine in New York said that A. baumannii’s pattern of evolution to date is strikingly similar to that of methicillin-resistant Staphylococcus aureus. A. baumannii has displayed increasing pathogenicity and antibiotic resistance. The investigators warned that there is a real danger that, like MRSA, extensively drug-resistant A. baumannii will become a common community-acquired infection arising in previously healthy patients (JAMA Dermatol. 2014 Aug;150(8):905-906).

“There are some strains of gonococcus and some strains of Acinetobacter baumannii that appear to be resistant to all known antibiotics,” Dr. Elston said.

He reported having no relevant financial conflicts of interest.

[email protected]

In their review, Rachaneni and Latthe included randomized controlled trials (RCTs) comparing surgical outcomes in women investigated by urodynamics and women who had office evaluation only. Three RCTs met their a priori criteria of women with pure stress incontinence or stress-predominant mixed urinary incontinence, with outcomes describing cure or improvement of stress urinary incontinence (SUI). There were no statistical differences in the risk ratios of subjective cure, objective cure, voiding dysfunction, or urinary urgency between the 2 groups. Rachaneni and Latthe appropriately concluded that: “In women undergoing primary surgery for SUI or stress-predominant mixed urinary incontinence without voiding difficulties, urodynamics does not improve outcomes—as long as the women undergo careful office evaluation.”

Thorough evaluation is critical
It cannot be emphasized strongly enough that the mere presence of symptoms of SUI is insufficient justification for surgery. Providers should demonstrate SUI during office evaluation before operating on someone without urodynamics. The addition of a full-bladder standing stress test usually is sufficient to demonstrate incontinence in women with bothersome SUI.

National professional societies agree on what is involved in office evaluation. In June 2014, the American College of Obstetricians and Gynecologists and the American Urogynecologic Society published a joint committee opinion on evaluation of uncomplicated SUI in women before surgical treatment.¹ The committee opinion states¹:

Although the most recent Cochrane review found no evidence about urodynamic use in men, children, and people with neurologic disease and noted that large definitive trials are needed in which people are randomly allocated to urodynamics or not,² most experts believe, and this review confirms, that the issue has been settled for preoperative urodynamics in women with uncomplicated SUI before surgery.

What this evidence means for practic
It is safe to proceed to surgery for SUI without urodynamic testing in women who meet all the following criteria: no previous surgery, no prolapse beyond the introitus, presence of predominant SUI complaints, demonstration of stress incontinence on cough stress testing, normal postvoid residual, mobile urethra, and normal urinalysis.
— Charles W. Nager, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In their review, Rachaneni and Latthe included randomized controlled trials (RCTs) comparing surgical outcomes in women investigated by urodynamics and women who had office evaluation only. Three RCTs met their a priori criteria of women with pure stress incontinence or stress-predominant mixed urinary incontinence, with outcomes describing cure or improvement of stress urinary incontinence (SUI). There were no statistical differences in the risk ratios of subjective cure, objective cure, voiding dysfunction, or urinary urgency between the 2 groups. Rachaneni and Latthe appropriately concluded that: “In women undergoing primary surgery for SUI or stress-predominant mixed urinary incontinence without voiding difficulties, urodynamics does not improve outcomes—as long as the women undergo careful office evaluation.”

Thorough evaluation is critical
It cannot be emphasized strongly enough that the mere presence of symptoms of SUI is insufficient justification for surgery. Providers should demonstrate SUI during office evaluation before operating on someone without urodynamics. The addition of a full-bladder standing stress test usually is sufficient to demonstrate incontinence in women with bothersome SUI.

National professional societies agree on what is involved in office evaluation. In June 2014, the American College of Obstetricians and Gynecologists and the American Urogynecologic Society published a joint committee opinion on evaluation of uncomplicated SUI in women before surgical treatment.¹ The committee opinion states¹:

Although the most recent Cochrane review found no evidence about urodynamic use in men, children, and people with neurologic disease and noted that large definitive trials are needed in which people are randomly allocated to urodynamics or not,² most experts believe, and this review confirms, that the issue has been settled for preoperative urodynamics in women with uncomplicated SUI before surgery.

What this evidence means for practic
It is safe to proceed to surgery for SUI without urodynamic testing in women who meet all the following criteria: no previous surgery, no prolapse beyond the introitus, presence of predominant SUI complaints, demonstration of stress incontinence on cough stress testing, normal postvoid residual, mobile urethra, and normal urinalysis.
— Charles W. Nager, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In their review, Rachaneni and Latthe included randomized controlled trials (RCTs) comparing surgical outcomes in women investigated by urodynamics and women who had office evaluation only. Three RCTs met their a priori criteria of women with pure stress incontinence or stress-predominant mixed urinary incontinence, with outcomes describing cure or improvement of stress urinary incontinence (SUI). There were no statistical differences in the risk ratios of subjective cure, objective cure, voiding dysfunction, or urinary urgency between the 2 groups. Rachaneni and Latthe appropriately concluded that: “In women undergoing primary surgery for SUI or stress-predominant mixed urinary incontinence without voiding difficulties, urodynamics does not improve outcomes—as long as the women undergo careful office evaluation.”

Thorough evaluation is critical
It cannot be emphasized strongly enough that the mere presence of symptoms of SUI is insufficient justification for surgery. Providers should demonstrate SUI during office evaluation before operating on someone without urodynamics. The addition of a full-bladder standing stress test usually is sufficient to demonstrate incontinence in women with bothersome SUI.

National professional societies agree on what is involved in office evaluation. In June 2014, the American College of Obstetricians and Gynecologists and the American Urogynecologic Society published a joint committee opinion on evaluation of uncomplicated SUI in women before surgical treatment.¹ The committee opinion states¹:

Although the most recent Cochrane review found no evidence about urodynamic use in men, children, and people with neurologic disease and noted that large definitive trials are needed in which people are randomly allocated to urodynamics or not,² most experts believe, and this review confirms, that the issue has been settled for preoperative urodynamics in women with uncomplicated SUI before surgery.

What this evidence means for practic
It is safe to proceed to surgery for SUI without urodynamic testing in women who meet all the following criteria: no previous surgery, no prolapse beyond the introitus, presence of predominant SUI complaints, demonstration of stress incontinence on cough stress testing, normal postvoid residual, mobile urethra, and normal urinalysis.
— Charles W. Nager, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Past research into outcomes for induction of labor for women attempting trial of labor after cesarean (TOLAC) has compared labor induction with spontaneous labor. This comparison may be biased against induction, say Lappen and colleagues, who conducted this recent study with the goal of characterizing the likelihood of failed TOLAC with induction and assessing maternal and neonatal outcomes of induction, compared with expectant management, by week of gestation (between 37 and 40 completed weeks).

Details of the study
The researchers analyzed data from the Consortium on Safe Labor,¹ excluding women who had:

Their final, primary cohort included 6,033 women undergoing TOLAC (1,626 underwent induction of labor; 4,407 did not). For this group, induction of labor was defined to include all medically indicated and elective inductions.

They also analyzed a secondary cohort, for which they redefined the induction group to only include those inductions that were nonmedically indicated. This was a “low risk” cohort (n = 500) that excluded women with chronic conditions (hypertension, gestational diabetes, etc) that could result in medically indicated induction.

Induction of labor still associated with failed TOLAC
Comparing induction of labor with expectant management, the frequency of failed TOLAC was higher at each week of gestation, but not at 40 weeks. The adjusted odds ratios were:

Induction was associated with an increased risk of composite maternal morbidity at 39 weeks’ gestation. The authors attributed this to a statistically significant increase in the risk of transfusion. Induction was not associated with increased neonatal morbidity.

The authors point out that, since their data set collection, ACOG recommended against nonmedically indicated inductions before 39 weeks’ gestation, but argue that their results remain generalizable and clinically pertinent because medically indicated early-term inductions remain common.

What this evidence means for practice
The authors identified a significant increase in risk of failed TOLAC with induction of labor. These findings are consistent with prior work describing the favorable relationship between TOLAC success and spontaneous labor and thus should not alter current obstetric practice. The study authors used a large, reliable database for the analysis and controlled for maternal age, body mass index, and history of any prior vaginal birth. However, as the authors point out, the study was limited by a lack of data on obstetric factors that have been identified in prior studies to be pertinent to the likelihood of success of TOLAC, such as Bishop score, indication for prior cesarean delivery, and history of any successful vaginal birth after cesarean. Clinicians should consider each patient’s predictors for successful TOLAC individually and provide appropriate counseling. An induction of labor remains appropriate in well-selected patients attempting TOLAC.
— Janine S. Rhoades, MD, and Alison G. Cahill, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Past research into outcomes for induction of labor for women attempting trial of labor after cesarean (TOLAC) has compared labor induction with spontaneous labor. This comparison may be biased against induction, say Lappen and colleagues, who conducted this recent study with the goal of characterizing the likelihood of failed TOLAC with induction and assessing maternal and neonatal outcomes of induction, compared with expectant management, by week of gestation (between 37 and 40 completed weeks).

Details of the study
The researchers analyzed data from the Consortium on Safe Labor,¹ excluding women who had:

Their final, primary cohort included 6,033 women undergoing TOLAC (1,626 underwent induction of labor; 4,407 did not). For this group, induction of labor was defined to include all medically indicated and elective inductions.

They also analyzed a secondary cohort, for which they redefined the induction group to only include those inductions that were nonmedically indicated. This was a “low risk” cohort (n = 500) that excluded women with chronic conditions (hypertension, gestational diabetes, etc) that could result in medically indicated induction.

Induction of labor still associated with failed TOLAC
Comparing induction of labor with expectant management, the frequency of failed TOLAC was higher at each week of gestation, but not at 40 weeks. The adjusted odds ratios were:

Induction was associated with an increased risk of composite maternal morbidity at 39 weeks’ gestation. The authors attributed this to a statistically significant increase in the risk of transfusion. Induction was not associated with increased neonatal morbidity.

The authors point out that, since their data set collection, ACOG recommended against nonmedically indicated inductions before 39 weeks’ gestation, but argue that their results remain generalizable and clinically pertinent because medically indicated early-term inductions remain common.

What this evidence means for practice
The authors identified a significant increase in risk of failed TOLAC with induction of labor. These findings are consistent with prior work describing the favorable relationship between TOLAC success and spontaneous labor and thus should not alter current obstetric practice. The study authors used a large, reliable database for the analysis and controlled for maternal age, body mass index, and history of any prior vaginal birth. However, as the authors point out, the study was limited by a lack of data on obstetric factors that have been identified in prior studies to be pertinent to the likelihood of success of TOLAC, such as Bishop score, indication for prior cesarean delivery, and history of any successful vaginal birth after cesarean. Clinicians should consider each patient’s predictors for successful TOLAC individually and provide appropriate counseling. An induction of labor remains appropriate in well-selected patients attempting TOLAC.
— Janine S. Rhoades, MD, and Alison G. Cahill, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Past research into outcomes for induction of labor for women attempting trial of labor after cesarean (TOLAC) has compared labor induction with spontaneous labor. This comparison may be biased against induction, say Lappen and colleagues, who conducted this recent study with the goal of characterizing the likelihood of failed TOLAC with induction and assessing maternal and neonatal outcomes of induction, compared with expectant management, by week of gestation (between 37 and 40 completed weeks).

Details of the study
The researchers analyzed data from the Consortium on Safe Labor,¹ excluding women who had:

Their final, primary cohort included 6,033 women undergoing TOLAC (1,626 underwent induction of labor; 4,407 did not). For this group, induction of labor was defined to include all medically indicated and elective inductions.

They also analyzed a secondary cohort, for which they redefined the induction group to only include those inductions that were nonmedically indicated. This was a “low risk” cohort (n = 500) that excluded women with chronic conditions (hypertension, gestational diabetes, etc) that could result in medically indicated induction.

Induction of labor still associated with failed TOLAC
Comparing induction of labor with expectant management, the frequency of failed TOLAC was higher at each week of gestation, but not at 40 weeks. The adjusted odds ratios were:

Induction was associated with an increased risk of composite maternal morbidity at 39 weeks’ gestation. The authors attributed this to a statistically significant increase in the risk of transfusion. Induction was not associated with increased neonatal morbidity.

The authors point out that, since their data set collection, ACOG recommended against nonmedically indicated inductions before 39 weeks’ gestation, but argue that their results remain generalizable and clinically pertinent because medically indicated early-term inductions remain common.

What this evidence means for practice
The authors identified a significant increase in risk of failed TOLAC with induction of labor. These findings are consistent with prior work describing the favorable relationship between TOLAC success and spontaneous labor and thus should not alter current obstetric practice. The study authors used a large, reliable database for the analysis and controlled for maternal age, body mass index, and history of any prior vaginal birth. However, as the authors point out, the study was limited by a lack of data on obstetric factors that have been identified in prior studies to be pertinent to the likelihood of success of TOLAC, such as Bishop score, indication for prior cesarean delivery, and history of any successful vaginal birth after cesarean. Clinicians should consider each patient’s predictors for successful TOLAC individually and provide appropriate counseling. An induction of labor remains appropriate in well-selected patients attempting TOLAC.
— Janine S. Rhoades, MD, and Alison G. Cahill, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The objective of this investigation was to compare a standard-dose trivalent influenza vaccine with a high-dose vaccine in adults older than 65 years. The standard dose of the vaccine contained 15 µg of hemagglutinin per strain, and the high dose contained 60 µg hemagglutinin per strain. The study was conducted during the 2011–2012 and 2012–2013 flu seasons. Key outcome measures were efficacy, as assessed by the occurrence of laboratory-confirmed influenza at least 14 days after vaccination; immunogenicity of the vaccines; and frequency of adverse events.

Details of the study
The study involved 15,991 patients in the high-dose group and 15,998 patients in the standard-dose group. Two hundred twenty-eight participants (1.4%) in the high-dose group developed influenza, compared with 301 participants (1.9%) in the standard-dose group.

The overall efficacy of the high-dose vaccine was 24.2% (95% confidence interval [CI], 9.7–36.5), meaning that approximately 24% of influenza cases could have been prevented if the high-dose vaccine had been administered to all patients.

In the high-dose group, 8.3% of patients had at least 1 adverse event, compared with 9% in the standard-dose group (relative risk, 0.92; 95% CI, 0.85–0.99).

After vaccination, the hemagglutination inhibition titers were significantly higher in the high-dose group.

Fewer adverse events with the higher dose, but some events were graver
Influenza is a serious viral illness, and it can be associated with mortality in certain populations, such as very young children, pregnant women, and people older than 65 years. 

As a general rule, older patients do not respond as well to the vaccine as younger patients do. The standard dose of vaccine provides about 50% protection against influenza in older patients, compared with approximately 60% to 65% in younger individuals. With the added protection of the high-dose vaccine (overall efficacy, 24.2%), approximately 62% of adults older than age 65 would be protected—a figure similar to that reported for younger patients.

The increase in effectiveness was achieved with no increase in the overall frequency of adverse effects. In fact, the frequency of adverse effects was actually slightly lower in the recipients of the higher dose. However, in 3 recipients of the high-dose vaccine the adverse effects were notable. One had a transient sixth cranial nerve palsy that started 1 day after vaccination. One had hypovolemic shock due to diarrhea that started 1 day after vaccination. One had acute disseminated encephalomyelitis that started 117 days after vaccination. All 3 patients recovered fully. No such serious events occurred in the standard-dose group.

Several barriers prevent widespread vaccination
The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices strongly recommends influenza vaccination for everyone over the age of 6 months. Barriers to widespread vaccination include reluctance on the part of the patient, failure on the part of the physician to advocate for vaccination, and cost of the vaccine for patients who have suboptimal insurance or no insurance.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
We should strongly advise older women in our practice to receive the high-dose influenza vaccine. We should caution them that the overall risk of adverse effects is actually lower than with the standard-dose vaccine but that serious effects can occur in rare instances. 
—Patrick Duff, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The objective of this investigation was to compare a standard-dose trivalent influenza vaccine with a high-dose vaccine in adults older than 65 years. The standard dose of the vaccine contained 15 µg of hemagglutinin per strain, and the high dose contained 60 µg hemagglutinin per strain. The study was conducted during the 2011–2012 and 2012–2013 flu seasons. Key outcome measures were efficacy, as assessed by the occurrence of laboratory-confirmed influenza at least 14 days after vaccination; immunogenicity of the vaccines; and frequency of adverse events.

Details of the study
The study involved 15,991 patients in the high-dose group and 15,998 patients in the standard-dose group. Two hundred twenty-eight participants (1.4%) in the high-dose group developed influenza, compared with 301 participants (1.9%) in the standard-dose group.

The overall efficacy of the high-dose vaccine was 24.2% (95% confidence interval [CI], 9.7–36.5), meaning that approximately 24% of influenza cases could have been prevented if the high-dose vaccine had been administered to all patients.

In the high-dose group, 8.3% of patients had at least 1 adverse event, compared with 9% in the standard-dose group (relative risk, 0.92; 95% CI, 0.85–0.99).

After vaccination, the hemagglutination inhibition titers were significantly higher in the high-dose group.

Fewer adverse events with the higher dose, but some events were graver
Influenza is a serious viral illness, and it can be associated with mortality in certain populations, such as very young children, pregnant women, and people older than 65 years. 

As a general rule, older patients do not respond as well to the vaccine as younger patients do. The standard dose of vaccine provides about 50% protection against influenza in older patients, compared with approximately 60% to 65% in younger individuals. With the added protection of the high-dose vaccine (overall efficacy, 24.2%), approximately 62% of adults older than age 65 would be protected—a figure similar to that reported for younger patients.

The increase in effectiveness was achieved with no increase in the overall frequency of adverse effects. In fact, the frequency of adverse effects was actually slightly lower in the recipients of the higher dose. However, in 3 recipients of the high-dose vaccine the adverse effects were notable. One had a transient sixth cranial nerve palsy that started 1 day after vaccination. One had hypovolemic shock due to diarrhea that started 1 day after vaccination. One had acute disseminated encephalomyelitis that started 117 days after vaccination. All 3 patients recovered fully. No such serious events occurred in the standard-dose group.

Several barriers prevent widespread vaccination
The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices strongly recommends influenza vaccination for everyone over the age of 6 months. Barriers to widespread vaccination include reluctance on the part of the patient, failure on the part of the physician to advocate for vaccination, and cost of the vaccine for patients who have suboptimal insurance or no insurance.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
We should strongly advise older women in our practice to receive the high-dose influenza vaccine. We should caution them that the overall risk of adverse effects is actually lower than with the standard-dose vaccine but that serious effects can occur in rare instances. 
—Patrick Duff, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The objective of this investigation was to compare a standard-dose trivalent influenza vaccine with a high-dose vaccine in adults older than 65 years. The standard dose of the vaccine contained 15 µg of hemagglutinin per strain, and the high dose contained 60 µg hemagglutinin per strain. The study was conducted during the 2011–2012 and 2012–2013 flu seasons. Key outcome measures were efficacy, as assessed by the occurrence of laboratory-confirmed influenza at least 14 days after vaccination; immunogenicity of the vaccines; and frequency of adverse events.

Details of the study
The study involved 15,991 patients in the high-dose group and 15,998 patients in the standard-dose group. Two hundred twenty-eight participants (1.4%) in the high-dose group developed influenza, compared with 301 participants (1.9%) in the standard-dose group.

The overall efficacy of the high-dose vaccine was 24.2% (95% confidence interval [CI], 9.7–36.5), meaning that approximately 24% of influenza cases could have been prevented if the high-dose vaccine had been administered to all patients.

In the high-dose group, 8.3% of patients had at least 1 adverse event, compared with 9% in the standard-dose group (relative risk, 0.92; 95% CI, 0.85–0.99).

After vaccination, the hemagglutination inhibition titers were significantly higher in the high-dose group.

Fewer adverse events with the higher dose, but some events were graver
Influenza is a serious viral illness, and it can be associated with mortality in certain populations, such as very young children, pregnant women, and people older than 65 years. 

As a general rule, older patients do not respond as well to the vaccine as younger patients do. The standard dose of vaccine provides about 50% protection against influenza in older patients, compared with approximately 60% to 65% in younger individuals. With the added protection of the high-dose vaccine (overall efficacy, 24.2%), approximately 62% of adults older than age 65 would be protected—a figure similar to that reported for younger patients.

The increase in effectiveness was achieved with no increase in the overall frequency of adverse effects. In fact, the frequency of adverse effects was actually slightly lower in the recipients of the higher dose. However, in 3 recipients of the high-dose vaccine the adverse effects were notable. One had a transient sixth cranial nerve palsy that started 1 day after vaccination. One had hypovolemic shock due to diarrhea that started 1 day after vaccination. One had acute disseminated encephalomyelitis that started 117 days after vaccination. All 3 patients recovered fully. No such serious events occurred in the standard-dose group.

Several barriers prevent widespread vaccination
The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices strongly recommends influenza vaccination for everyone over the age of 6 months. Barriers to widespread vaccination include reluctance on the part of the patient, failure on the part of the physician to advocate for vaccination, and cost of the vaccine for patients who have suboptimal insurance or no insurance.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
We should strongly advise older women in our practice to receive the high-dose influenza vaccine. We should caution them that the overall risk of adverse effects is actually lower than with the standard-dose vaccine but that serious effects can occur in rare instances. 
—Patrick Duff, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Women’s sexual health took a step forward last month when an advisory panel to the US Food and Drug Administration (FDA) recommended approval of the drug flibanserin for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The approval came with some reservations regarding safety (use with certain medications and alcohol). And it’s worthwhile to note that the FDA had on hand its own Drug Safety and Risk Management Committee during deliberations. However, assuming the agency follows the recommendations of the Bone, Reproductive, and Urologic Drugs Advisory Committee, women will soon have available the first agent for sexual dysfunction—aside from a medication for intercourse-associated pain—developed specifically for them.

Had the panel voted down the approval, it would have set a dangerous precedent that likely would have led to a standstill in new drug development in all therapeutic classes of women’s sexual health for the next decade.

Why do I say that—and state it so emphatically? 

To answer that question, let’s review the approval process for flibanserin, as well as for the 2 testosterone products that preceded its appearance before the FDA.

Hypoactive sexual desire disorder (HSDD) is the most common sexual dysfunction in women. Few interventions have proven to be effective for the treatment of HSDD. Education, counseling, and psychotherapy may be helpful in some women. Exogenous testosterone has been reported to be effective in the treatment of low sexual desire in postmenopausal women taking estrogen, but this treatment is not approved by the US Food and Drug Administration (FDA), and the long-term safety of exogenous testosterone in women is not established. Clinicians who treat women with sexual desire disorders are frustrated by their inability to prescribe an effective treatment for this common problem. An FDA advisory panel recently voted to support the approval of flibanserin for the treatment of HSDD in premenopausal women. In this month’s editorial, Dr. James Simon provides a history of the FDA review process for medications designed to treat HSDD, including the decision to not approve testosterone and the vote of the FDA advisory panel to support the approval of flibanserin. Readers of OBG Management should be aware that Dr. Simon, as is apparent in this piece and fully disclosed, has served as Medical Director and an advisor to Sprout Pharmaceuticals, the company with the rights to flibanserin. As editors we have concluded that Dr. Simon’s unique perspective, knowledge, and insights about the history of the FDA review of treatments of HSDD, including testosterone, would be of great interest to our readers.
—Robert L. Barbieri, MD, Editor in Chief
—Lila O’Connor, Editor

A tale of 2 products: The testosterone story
In 2004, Procter & Gamble filed a new drug application (NDA) for a testosterone patch (Intrinsa) developed for the treatment of female sexual dysfunction. Specifically, the patch was created for the treatment of HSDD in surgically menopausal women (those who had undergone bilateral oophorectomy) who were receiving concomitant estrogen therapy.

Both the FDA and the advisory committee considering the NDA agreed that the patch was effective. The question was whether its efficacy outweighed its risks. Recall that this discussion was taking place only 2 years after the initial publication of findings from the Women’s Health Initiative (WHI) estrogen-progestin arm. That arm had been halted prematurely because the risk of breast cancer exceeded the prespecified stopping boundary. In addition, the global index summarizing the balance of risks and benefits showed that risks outweighed benefits in ­regard to breast cancer, coronary heart disease, stroke, and pulmonary embolism.¹ As a result, the safety of all forms of hormone therapy was being closely scrutinized.

The FDA was also on “high alert” for safety as rofecoxib (Vioxx) had just been removed from the market due to unforeseen risks, with much media fanfare and large numbers of lawsuits.

After consideration of the NDA for the testosterone patch, the FDA advised Procter & Gamble to ­undertake an adequately designed and powered safety study to confirm that it would not increase the risks of coronary heart disease or breast cancer among users, since testosterone can be converted to estradiol in women.

Procter & Gamble ultimately withdrew its NDA. Such a safety study would have taken an additional 5 years to complete and cost upwards of $300 million. And because testosterone is not a patentable compound, a study that long and costly didn’t seem like a smart business proposition. Shortly after the NDA was withdrawn, the European Medicines Agency—the European counterpart of the FDA—approved the Intrinsa testosterone patch for the same indication as proposed in the United States.

Next up, BioSante Pharmaceuticals filed its NDA for LibiGel, a testosterone gel formulated specifically for postmenopausal women with HSDD. In its efficacy study, LibiGel failed to demonstrate superiority above and beyond placebo. The manufacturer, which was concurrently conducting a large, long-term safety study to satisfy the FDA’s concerns, ran out of money shortly thereafter, and that was the end of that.

Flibanserin’s focus: premenopausal women
In contrast to the 2 testosterone products, flibanserin was developed for premenopausal women. Although preliminary data on flibanserin use among postmenopausal women are available,² the drug was studied primarily in premenopausal women with HSDD, the indication sought at this time.

In the premenopausal population, problems such as pain with intercourse or hypoestrogenism aren’t typically present, simplifying the identification of HSDD. (See the sidebar below, “What is HSDD and how is it diagnosed?”) In clinical trials of the drug, HSDD was secondary, generalized, and acquired—that is, it followed a period of normal sexual function. And it didn’t come and go but was present regardless of location and circumstance. Study participants had had a normal sex drive before their desire “turned off,” an occurrence they found distressing.^3–6
 

In the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), hypoactive sexual desire disorder (HSDD) is described as having the following characteristics:

In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), published in 2013, HSDD was folded with female sexual arousal disorder into a new diagnosis, female sexual interest and arousal disorder. This is somewhat confusing in that the physiologies of these 2 disorders are quite separate and distinct.

In clinical practice, HSDD is easily identified using the Decreased Sexual Desire Screener (DSDS), a simple screening test that asks 4 yes/no questions:

A “yes” response to each of these questions is required. In addition, a fifth question asks whether a number of conditions, drugs, or circumstances might be responsible for the decreased desire or interest:

Boehringer Ingelheim, a German concern, developed flibanserin and filed the initial NDA in 2009. In clinical trials, that company ran into problems because the electronic diary it was using to measure desire failed to demonstrate efficacy for flibanserin. It turns out that, if you ask women who are distressed about having low desire to report their level of desire every single day, they quickly get turned off by the question and eventually stop answering altogether. Such changes in behavior play havoc with the validity of the instrument to assess desire.

After flibanserin failed the electronic diary desire domain—one of the study’s endpoints—the ­company substituted a different measure, the Female Sexual Function Index (FSFI) desire domain. Although the FSFI showed statistically significantly greater efficacy for flibanserin than placebo, the FDA argued that it was unreasonable for the company to change the rules to fit the outcome. For that and other reasons, it turned down the NDA.

In response, Boehringer Ingelheim went back to the drawing board and undertook a new study intended to achieve several goals:

About the time this study was drawing to a conclusion, the company got cold feet and decided to shelve its plans for the drug.

Sprout steps in
I was among the delegation of medical and pharmaceutical professionals who visited Boehringer Ingelheim in 2011 to explore the possibility of Sprout Pharmaceuticals acquiring flibanserin. Boehringer Ingelheim agreed to the deal, and Sprout took over drug development, resubmitting the NDA to the FDA in 2013 with the additional study and other data. The FDA again denied the application. In response, Sprout filed a request for a dispute resolution, a formal procedure convened when the sponsor of an NDA cannot reach agreement with the FDA. In the course of this procedure, the FDA asked for additional analyses, as well as some pharmacogenomics and a driving study.

Around this time, the FDA had determined that the sleep aid zolpidem (Ambien) is metabolized differently in women than in men and that, in some of these women, there is a significant cognitive deficit carried over to the next day when the drug is taken as prescribed at bedtime. Because flibanserin came on the heels of this determination and was known to cause drowsiness, the FDA requested the driving study. It also requested a drug-drug interaction study to determine whether flibanserin is metabolized differently in some women with genetically different medication metabolism.

Sprout conducted those studies, both of which came back “clean.” Armed with this new data, the FDA scheduled a meeting of its advisory committee on June 4, 2015. And the rest, as they say, is history.

Flibanserin vs placebo
During the advisory committee’s deliberations on June 4, discussion focused, in part, on how flibanserin performed in comparison with placebo. It was ­noted that flibanserin increased the number of satisfying sexual events (SSEs) by only 1 per month, compared with placebo. But that conclusion doesn’t accurately convey the findings of the efficacy studies.

First, even without flibanserin, women in the trials reported that they continued to have sex with their partners 2 to 3 times per month. That established a baseline number of SSEs of approximately 2.5. The consent form for the flibanserin trial contained a clause stating that the woman would agree to try and have sex at least 1 additional time per month. This requirement, independent of any treatment, was bound to increase the placebo effect because, regardless of the drug given (flibanserin or placebo), the participant was going to try to have sex at least 1 more time per month.

In the flibanserin trials, the placebo effect was 1.5 additional SSEs per month. Add that to the baseline number of SSEs and you have a total of 4 SSEs per month. Among flibanserin users, the number of SSEs per month was about 5. And even though that’s only 1 more time per month than the placebo group, those 5 events were more desired events. That means that the baseline of 2.5 SSEs, among flibanserin users, had a different character by the end of the study period.

There is also a ceiling effect in play. Consider that the participants in the flibanserin trials were women who had been married an average of 10 years, with an average age of approximately 36 years. How much more sex is likely even possible in this population?

This isn’t to say that women are incapable of having more sex. It is merely a reflection of the data, which show that, among married women aged 30 to 39 years, only roughly 25% have sex more often than weekly, and only 5.1% have sex 4 or more times per week.⁷ If women were shown to be having sex more than 5 times per month, a likely criticism would have been that the drug was making them hypersexual or even abnormal.

Also keep in mind that the drug doesn’t work in every woman, just as antidepressants are not effective in every person. So when the responders and nonresponders were lumped together, the magnitude of the drug’s response in the combined group was smaller. In reality, approximately 25% of women in the flibanserin trials experienced an increase of 4 or more SSEs per month, compared with 15% among placebo users.
 

Flibanserin is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women. It is taken daily in a 100-mg tablet. Bedtime dosing is preferred to mitigate potential side effects such as drowsiness, hypotension, and syncope. These effects can occur with flibanserin alone, in combination with certain drugs, or in combination with alcohol.

Significant drug-drug interactions have been documented for flibanserin in combination with moderate and strong CYP3A4 inhibitors such as fluconazole and ketoconazole. Package labeling for flibanserin will detail this risk.

Why now?
As I stated earlier, a failure to approve flibanserin would set a dangerous precedent. Why? Because the company did everything the FDA asked it to do, and the results came out statistically significantly better than placebo—which was the desired endpoint. If the FDA were to deny approval of the drug, it would be saying, in effect, that it can change its mind in the middle of the argument—something it faulted Boehringer Ingelheim for in earlier deliberations (switching the insensitive electronic diary for the statistically significant FSFI).

In reality, the FDA is likely to say yes to approval, but with restrictions, as that is what its advisory committee recommended. What those restrictions will be remains to be determined, but they are likely to resemble those of other drugs in the class, such as selective serotonin reuptake inhibitors (SSRIs), including a warning to be careful using flibanserin with alcohol until the drug’s effects are clear.

Opposition to flibanserin misses the mark
During the public hearing portion of the advisory committee meeting, most of the testimony came from women seeking approval of the drug. However, there were some naysayers. Their arguments against approval boiled down to 4 perspectives:

There is also the sociological view that HSDD is a normal variant of healthy sexual function. Its adherents argue that women with HSDD feel distress because their male partners are forcing them to feel inadequate. But I have yet to hear a single critical voice from a physician who actually treats women and who can prescribe drugs. The opposition to flibanserin, such as it is, flows from people who don’t see patients and can’t prescribe medications.

These naysayers are negative in a theoretical vacuum. It’s very easy to fall into that trap when you don’t have to look across the consultation desk to a patient who is asking you for a remedy—a woman who’s been suffering for 25 years, say—and have to tell her you have nothing to offer. You might mention testosterone, explaining that it was approved for men but you’ll try to prescribe an appropriate dose. But be sure to include discussion of its many side effects.

A long and winding road
Flibanserin’s journey from inception to probable approval has been long and eventful, and you can be sure that the pharmaceutical industry has been paying attention. Hundreds of millions of dollars in funding for drug development hang in the balance. That women deserve remedies developed specifically for their needs and metabolism is a given. The approval of flibanserin will send a hopeful signal to them as well as to industry—that the FDA takes them seriously and seeks to identify effective remedies. In this case, it seems likely, the agency will end up on the right side of history.
 

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Women’s sexual health took a step forward last month when an advisory panel to the US Food and Drug Administration (FDA) recommended approval of the drug flibanserin for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The approval came with some reservations regarding safety (use with certain medications and alcohol). And it’s worthwhile to note that the FDA had on hand its own Drug Safety and Risk Management Committee during deliberations. However, assuming the agency follows the recommendations of the Bone, Reproductive, and Urologic Drugs Advisory Committee, women will soon have available the first agent for sexual dysfunction—aside from a medication for intercourse-associated pain—developed specifically for them.

Had the panel voted down the approval, it would have set a dangerous precedent that likely would have led to a standstill in new drug development in all therapeutic classes of women’s sexual health for the next decade.

Why do I say that—and state it so emphatically? 

To answer that question, let’s review the approval process for flibanserin, as well as for the 2 testosterone products that preceded its appearance before the FDA.

Hypoactive sexual desire disorder (HSDD) is the most common sexual dysfunction in women. Few interventions have proven to be effective for the treatment of HSDD. Education, counseling, and psychotherapy may be helpful in some women. Exogenous testosterone has been reported to be effective in the treatment of low sexual desire in postmenopausal women taking estrogen, but this treatment is not approved by the US Food and Drug Administration (FDA), and the long-term safety of exogenous testosterone in women is not established. Clinicians who treat women with sexual desire disorders are frustrated by their inability to prescribe an effective treatment for this common problem. An FDA advisory panel recently voted to support the approval of flibanserin for the treatment of HSDD in premenopausal women. In this month’s editorial, Dr. James Simon provides a history of the FDA review process for medications designed to treat HSDD, including the decision to not approve testosterone and the vote of the FDA advisory panel to support the approval of flibanserin. Readers of OBG Management should be aware that Dr. Simon, as is apparent in this piece and fully disclosed, has served as Medical Director and an advisor to Sprout Pharmaceuticals, the company with the rights to flibanserin. As editors we have concluded that Dr. Simon’s unique perspective, knowledge, and insights about the history of the FDA review of treatments of HSDD, including testosterone, would be of great interest to our readers.
—Robert L. Barbieri, MD, Editor in Chief
—Lila O’Connor, Editor

A tale of 2 products: The testosterone story
In 2004, Procter & Gamble filed a new drug application (NDA) for a testosterone patch (Intrinsa) developed for the treatment of female sexual dysfunction. Specifically, the patch was created for the treatment of HSDD in surgically menopausal women (those who had undergone bilateral oophorectomy) who were receiving concomitant estrogen therapy.

Both the FDA and the advisory committee considering the NDA agreed that the patch was effective. The question was whether its efficacy outweighed its risks. Recall that this discussion was taking place only 2 years after the initial publication of findings from the Women’s Health Initiative (WHI) estrogen-progestin arm. That arm had been halted prematurely because the risk of breast cancer exceeded the prespecified stopping boundary. In addition, the global index summarizing the balance of risks and benefits showed that risks outweighed benefits in ­regard to breast cancer, coronary heart disease, stroke, and pulmonary embolism.¹ As a result, the safety of all forms of hormone therapy was being closely scrutinized.

The FDA was also on “high alert” for safety as rofecoxib (Vioxx) had just been removed from the market due to unforeseen risks, with much media fanfare and large numbers of lawsuits.

After consideration of the NDA for the testosterone patch, the FDA advised Procter & Gamble to ­undertake an adequately designed and powered safety study to confirm that it would not increase the risks of coronary heart disease or breast cancer among users, since testosterone can be converted to estradiol in women.

Procter & Gamble ultimately withdrew its NDA. Such a safety study would have taken an additional 5 years to complete and cost upwards of $300 million. And because testosterone is not a patentable compound, a study that long and costly didn’t seem like a smart business proposition. Shortly after the NDA was withdrawn, the European Medicines Agency—the European counterpart of the FDA—approved the Intrinsa testosterone patch for the same indication as proposed in the United States.

Next up, BioSante Pharmaceuticals filed its NDA for LibiGel, a testosterone gel formulated specifically for postmenopausal women with HSDD. In its efficacy study, LibiGel failed to demonstrate superiority above and beyond placebo. The manufacturer, which was concurrently conducting a large, long-term safety study to satisfy the FDA’s concerns, ran out of money shortly thereafter, and that was the end of that.

Flibanserin’s focus: premenopausal women
In contrast to the 2 testosterone products, flibanserin was developed for premenopausal women. Although preliminary data on flibanserin use among postmenopausal women are available,² the drug was studied primarily in premenopausal women with HSDD, the indication sought at this time.

In the premenopausal population, problems such as pain with intercourse or hypoestrogenism aren’t typically present, simplifying the identification of HSDD. (See the sidebar below, “What is HSDD and how is it diagnosed?”) In clinical trials of the drug, HSDD was secondary, generalized, and acquired—that is, it followed a period of normal sexual function. And it didn’t come and go but was present regardless of location and circumstance. Study participants had had a normal sex drive before their desire “turned off,” an occurrence they found distressing.^3–6
 

In the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), hypoactive sexual desire disorder (HSDD) is described as having the following characteristics:

In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), published in 2013, HSDD was folded with female sexual arousal disorder into a new diagnosis, female sexual interest and arousal disorder. This is somewhat confusing in that the physiologies of these 2 disorders are quite separate and distinct.

In clinical practice, HSDD is easily identified using the Decreased Sexual Desire Screener (DSDS), a simple screening test that asks 4 yes/no questions:

A “yes” response to each of these questions is required. In addition, a fifth question asks whether a number of conditions, drugs, or circumstances might be responsible for the decreased desire or interest:

Boehringer Ingelheim, a German concern, developed flibanserin and filed the initial NDA in 2009. In clinical trials, that company ran into problems because the electronic diary it was using to measure desire failed to demonstrate efficacy for flibanserin. It turns out that, if you ask women who are distressed about having low desire to report their level of desire every single day, they quickly get turned off by the question and eventually stop answering altogether. Such changes in behavior play havoc with the validity of the instrument to assess desire.

After flibanserin failed the electronic diary desire domain—one of the study’s endpoints—the ­company substituted a different measure, the Female Sexual Function Index (FSFI) desire domain. Although the FSFI showed statistically significantly greater efficacy for flibanserin than placebo, the FDA argued that it was unreasonable for the company to change the rules to fit the outcome. For that and other reasons, it turned down the NDA.

In response, Boehringer Ingelheim went back to the drawing board and undertook a new study intended to achieve several goals:

About the time this study was drawing to a conclusion, the company got cold feet and decided to shelve its plans for the drug.

Sprout steps in
I was among the delegation of medical and pharmaceutical professionals who visited Boehringer Ingelheim in 2011 to explore the possibility of Sprout Pharmaceuticals acquiring flibanserin. Boehringer Ingelheim agreed to the deal, and Sprout took over drug development, resubmitting the NDA to the FDA in 2013 with the additional study and other data. The FDA again denied the application. In response, Sprout filed a request for a dispute resolution, a formal procedure convened when the sponsor of an NDA cannot reach agreement with the FDA. In the course of this procedure, the FDA asked for additional analyses, as well as some pharmacogenomics and a driving study.

Around this time, the FDA had determined that the sleep aid zolpidem (Ambien) is metabolized differently in women than in men and that, in some of these women, there is a significant cognitive deficit carried over to the next day when the drug is taken as prescribed at bedtime. Because flibanserin came on the heels of this determination and was known to cause drowsiness, the FDA requested the driving study. It also requested a drug-drug interaction study to determine whether flibanserin is metabolized differently in some women with genetically different medication metabolism.

Sprout conducted those studies, both of which came back “clean.” Armed with this new data, the FDA scheduled a meeting of its advisory committee on June 4, 2015. And the rest, as they say, is history.

Flibanserin vs placebo
During the advisory committee’s deliberations on June 4, discussion focused, in part, on how flibanserin performed in comparison with placebo. It was ­noted that flibanserin increased the number of satisfying sexual events (SSEs) by only 1 per month, compared with placebo. But that conclusion doesn’t accurately convey the findings of the efficacy studies.

First, even without flibanserin, women in the trials reported that they continued to have sex with their partners 2 to 3 times per month. That established a baseline number of SSEs of approximately 2.5. The consent form for the flibanserin trial contained a clause stating that the woman would agree to try and have sex at least 1 additional time per month. This requirement, independent of any treatment, was bound to increase the placebo effect because, regardless of the drug given (flibanserin or placebo), the participant was going to try to have sex at least 1 more time per month.

In the flibanserin trials, the placebo effect was 1.5 additional SSEs per month. Add that to the baseline number of SSEs and you have a total of 4 SSEs per month. Among flibanserin users, the number of SSEs per month was about 5. And even though that’s only 1 more time per month than the placebo group, those 5 events were more desired events. That means that the baseline of 2.5 SSEs, among flibanserin users, had a different character by the end of the study period.

There is also a ceiling effect in play. Consider that the participants in the flibanserin trials were women who had been married an average of 10 years, with an average age of approximately 36 years. How much more sex is likely even possible in this population?

This isn’t to say that women are incapable of having more sex. It is merely a reflection of the data, which show that, among married women aged 30 to 39 years, only roughly 25% have sex more often than weekly, and only 5.1% have sex 4 or more times per week.⁷ If women were shown to be having sex more than 5 times per month, a likely criticism would have been that the drug was making them hypersexual or even abnormal.

Also keep in mind that the drug doesn’t work in every woman, just as antidepressants are not effective in every person. So when the responders and nonresponders were lumped together, the magnitude of the drug’s response in the combined group was smaller. In reality, approximately 25% of women in the flibanserin trials experienced an increase of 4 or more SSEs per month, compared with 15% among placebo users.
 

Flibanserin is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women. It is taken daily in a 100-mg tablet. Bedtime dosing is preferred to mitigate potential side effects such as drowsiness, hypotension, and syncope. These effects can occur with flibanserin alone, in combination with certain drugs, or in combination with alcohol.

Significant drug-drug interactions have been documented for flibanserin in combination with moderate and strong CYP3A4 inhibitors such as fluconazole and ketoconazole. Package labeling for flibanserin will detail this risk.

Why now?
As I stated earlier, a failure to approve flibanserin would set a dangerous precedent. Why? Because the company did everything the FDA asked it to do, and the results came out statistically significantly better than placebo—which was the desired endpoint. If the FDA were to deny approval of the drug, it would be saying, in effect, that it can change its mind in the middle of the argument—something it faulted Boehringer Ingelheim for in earlier deliberations (switching the insensitive electronic diary for the statistically significant FSFI).

In reality, the FDA is likely to say yes to approval, but with restrictions, as that is what its advisory committee recommended. What those restrictions will be remains to be determined, but they are likely to resemble those of other drugs in the class, such as selective serotonin reuptake inhibitors (SSRIs), including a warning to be careful using flibanserin with alcohol until the drug’s effects are clear.

Opposition to flibanserin misses the mark
During the public hearing portion of the advisory committee meeting, most of the testimony came from women seeking approval of the drug. However, there were some naysayers. Their arguments against approval boiled down to 4 perspectives:

There is also the sociological view that HSDD is a normal variant of healthy sexual function. Its adherents argue that women with HSDD feel distress because their male partners are forcing them to feel inadequate. But I have yet to hear a single critical voice from a physician who actually treats women and who can prescribe drugs. The opposition to flibanserin, such as it is, flows from people who don’t see patients and can’t prescribe medications.

These naysayers are negative in a theoretical vacuum. It’s very easy to fall into that trap when you don’t have to look across the consultation desk to a patient who is asking you for a remedy—a woman who’s been suffering for 25 years, say—and have to tell her you have nothing to offer. You might mention testosterone, explaining that it was approved for men but you’ll try to prescribe an appropriate dose. But be sure to include discussion of its many side effects.

A long and winding road
Flibanserin’s journey from inception to probable approval has been long and eventful, and you can be sure that the pharmaceutical industry has been paying attention. Hundreds of millions of dollars in funding for drug development hang in the balance. That women deserve remedies developed specifically for their needs and metabolism is a given. The approval of flibanserin will send a hopeful signal to them as well as to industry—that the FDA takes them seriously and seeks to identify effective remedies. In this case, it seems likely, the agency will end up on the right side of history.
 

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Women’s sexual health took a step forward last month when an advisory panel to the US Food and Drug Administration (FDA) recommended approval of the drug flibanserin for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The approval came with some reservations regarding safety (use with certain medications and alcohol). And it’s worthwhile to note that the FDA had on hand its own Drug Safety and Risk Management Committee during deliberations. However, assuming the agency follows the recommendations of the Bone, Reproductive, and Urologic Drugs Advisory Committee, women will soon have available the first agent for sexual dysfunction—aside from a medication for intercourse-associated pain—developed specifically for them.

Had the panel voted down the approval, it would have set a dangerous precedent that likely would have led to a standstill in new drug development in all therapeutic classes of women’s sexual health for the next decade.

Why do I say that—and state it so emphatically? 

To answer that question, let’s review the approval process for flibanserin, as well as for the 2 testosterone products that preceded its appearance before the FDA.

Hypoactive sexual desire disorder (HSDD) is the most common sexual dysfunction in women. Few interventions have proven to be effective for the treatment of HSDD. Education, counseling, and psychotherapy may be helpful in some women. Exogenous testosterone has been reported to be effective in the treatment of low sexual desire in postmenopausal women taking estrogen, but this treatment is not approved by the US Food and Drug Administration (FDA), and the long-term safety of exogenous testosterone in women is not established. Clinicians who treat women with sexual desire disorders are frustrated by their inability to prescribe an effective treatment for this common problem. An FDA advisory panel recently voted to support the approval of flibanserin for the treatment of HSDD in premenopausal women. In this month’s editorial, Dr. James Simon provides a history of the FDA review process for medications designed to treat HSDD, including the decision to not approve testosterone and the vote of the FDA advisory panel to support the approval of flibanserin. Readers of OBG Management should be aware that Dr. Simon, as is apparent in this piece and fully disclosed, has served as Medical Director and an advisor to Sprout Pharmaceuticals, the company with the rights to flibanserin. As editors we have concluded that Dr. Simon’s unique perspective, knowledge, and insights about the history of the FDA review of treatments of HSDD, including testosterone, would be of great interest to our readers.
—Robert L. Barbieri, MD, Editor in Chief
—Lila O’Connor, Editor

A tale of 2 products: The testosterone story
In 2004, Procter & Gamble filed a new drug application (NDA) for a testosterone patch (Intrinsa) developed for the treatment of female sexual dysfunction. Specifically, the patch was created for the treatment of HSDD in surgically menopausal women (those who had undergone bilateral oophorectomy) who were receiving concomitant estrogen therapy.

Both the FDA and the advisory committee considering the NDA agreed that the patch was effective. The question was whether its efficacy outweighed its risks. Recall that this discussion was taking place only 2 years after the initial publication of findings from the Women’s Health Initiative (WHI) estrogen-progestin arm. That arm had been halted prematurely because the risk of breast cancer exceeded the prespecified stopping boundary. In addition, the global index summarizing the balance of risks and benefits showed that risks outweighed benefits in ­regard to breast cancer, coronary heart disease, stroke, and pulmonary embolism.¹ As a result, the safety of all forms of hormone therapy was being closely scrutinized.

The FDA was also on “high alert” for safety as rofecoxib (Vioxx) had just been removed from the market due to unforeseen risks, with much media fanfare and large numbers of lawsuits.

After consideration of the NDA for the testosterone patch, the FDA advised Procter & Gamble to ­undertake an adequately designed and powered safety study to confirm that it would not increase the risks of coronary heart disease or breast cancer among users, since testosterone can be converted to estradiol in women.

Procter & Gamble ultimately withdrew its NDA. Such a safety study would have taken an additional 5 years to complete and cost upwards of $300 million. And because testosterone is not a patentable compound, a study that long and costly didn’t seem like a smart business proposition. Shortly after the NDA was withdrawn, the European Medicines Agency—the European counterpart of the FDA—approved the Intrinsa testosterone patch for the same indication as proposed in the United States.

Next up, BioSante Pharmaceuticals filed its NDA for LibiGel, a testosterone gel formulated specifically for postmenopausal women with HSDD. In its efficacy study, LibiGel failed to demonstrate superiority above and beyond placebo. The manufacturer, which was concurrently conducting a large, long-term safety study to satisfy the FDA’s concerns, ran out of money shortly thereafter, and that was the end of that.

Flibanserin’s focus: premenopausal women
In contrast to the 2 testosterone products, flibanserin was developed for premenopausal women. Although preliminary data on flibanserin use among postmenopausal women are available,² the drug was studied primarily in premenopausal women with HSDD, the indication sought at this time.

In the premenopausal population, problems such as pain with intercourse or hypoestrogenism aren’t typically present, simplifying the identification of HSDD. (See the sidebar below, “What is HSDD and how is it diagnosed?”) In clinical trials of the drug, HSDD was secondary, generalized, and acquired—that is, it followed a period of normal sexual function. And it didn’t come and go but was present regardless of location and circumstance. Study participants had had a normal sex drive before their desire “turned off,” an occurrence they found distressing.^3–6
 

In the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), hypoactive sexual desire disorder (HSDD) is described as having the following characteristics:

In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), published in 2013, HSDD was folded with female sexual arousal disorder into a new diagnosis, female sexual interest and arousal disorder. This is somewhat confusing in that the physiologies of these 2 disorders are quite separate and distinct.

In clinical practice, HSDD is easily identified using the Decreased Sexual Desire Screener (DSDS), a simple screening test that asks 4 yes/no questions:

A “yes” response to each of these questions is required. In addition, a fifth question asks whether a number of conditions, drugs, or circumstances might be responsible for the decreased desire or interest:

Boehringer Ingelheim, a German concern, developed flibanserin and filed the initial NDA in 2009. In clinical trials, that company ran into problems because the electronic diary it was using to measure desire failed to demonstrate efficacy for flibanserin. It turns out that, if you ask women who are distressed about having low desire to report their level of desire every single day, they quickly get turned off by the question and eventually stop answering altogether. Such changes in behavior play havoc with the validity of the instrument to assess desire.

After flibanserin failed the electronic diary desire domain—one of the study’s endpoints—the ­company substituted a different measure, the Female Sexual Function Index (FSFI) desire domain. Although the FSFI showed statistically significantly greater efficacy for flibanserin than placebo, the FDA argued that it was unreasonable for the company to change the rules to fit the outcome. For that and other reasons, it turned down the NDA.

In response, Boehringer Ingelheim went back to the drawing board and undertook a new study intended to achieve several goals:

About the time this study was drawing to a conclusion, the company got cold feet and decided to shelve its plans for the drug.

Sprout steps in
I was among the delegation of medical and pharmaceutical professionals who visited Boehringer Ingelheim in 2011 to explore the possibility of Sprout Pharmaceuticals acquiring flibanserin. Boehringer Ingelheim agreed to the deal, and Sprout took over drug development, resubmitting the NDA to the FDA in 2013 with the additional study and other data. The FDA again denied the application. In response, Sprout filed a request for a dispute resolution, a formal procedure convened when the sponsor of an NDA cannot reach agreement with the FDA. In the course of this procedure, the FDA asked for additional analyses, as well as some pharmacogenomics and a driving study.

Around this time, the FDA had determined that the sleep aid zolpidem (Ambien) is metabolized differently in women than in men and that, in some of these women, there is a significant cognitive deficit carried over to the next day when the drug is taken as prescribed at bedtime. Because flibanserin came on the heels of this determination and was known to cause drowsiness, the FDA requested the driving study. It also requested a drug-drug interaction study to determine whether flibanserin is metabolized differently in some women with genetically different medication metabolism.

Sprout conducted those studies, both of which came back “clean.” Armed with this new data, the FDA scheduled a meeting of its advisory committee on June 4, 2015. And the rest, as they say, is history.

Flibanserin vs placebo
During the advisory committee’s deliberations on June 4, discussion focused, in part, on how flibanserin performed in comparison with placebo. It was ­noted that flibanserin increased the number of satisfying sexual events (SSEs) by only 1 per month, compared with placebo. But that conclusion doesn’t accurately convey the findings of the efficacy studies.

First, even without flibanserin, women in the trials reported that they continued to have sex with their partners 2 to 3 times per month. That established a baseline number of SSEs of approximately 2.5. The consent form for the flibanserin trial contained a clause stating that the woman would agree to try and have sex at least 1 additional time per month. This requirement, independent of any treatment, was bound to increase the placebo effect because, regardless of the drug given (flibanserin or placebo), the participant was going to try to have sex at least 1 more time per month.

In the flibanserin trials, the placebo effect was 1.5 additional SSEs per month. Add that to the baseline number of SSEs and you have a total of 4 SSEs per month. Among flibanserin users, the number of SSEs per month was about 5. And even though that’s only 1 more time per month than the placebo group, those 5 events were more desired events. That means that the baseline of 2.5 SSEs, among flibanserin users, had a different character by the end of the study period.

There is also a ceiling effect in play. Consider that the participants in the flibanserin trials were women who had been married an average of 10 years, with an average age of approximately 36 years. How much more sex is likely even possible in this population?

This isn’t to say that women are incapable of having more sex. It is merely a reflection of the data, which show that, among married women aged 30 to 39 years, only roughly 25% have sex more often than weekly, and only 5.1% have sex 4 or more times per week.⁷ If women were shown to be having sex more than 5 times per month, a likely criticism would have been that the drug was making them hypersexual or even abnormal.

Also keep in mind that the drug doesn’t work in every woman, just as antidepressants are not effective in every person. So when the responders and nonresponders were lumped together, the magnitude of the drug’s response in the combined group was smaller. In reality, approximately 25% of women in the flibanserin trials experienced an increase of 4 or more SSEs per month, compared with 15% among placebo users.
 

Flibanserin is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women. It is taken daily in a 100-mg tablet. Bedtime dosing is preferred to mitigate potential side effects such as drowsiness, hypotension, and syncope. These effects can occur with flibanserin alone, in combination with certain drugs, or in combination with alcohol.

Significant drug-drug interactions have been documented for flibanserin in combination with moderate and strong CYP3A4 inhibitors such as fluconazole and ketoconazole. Package labeling for flibanserin will detail this risk.

Why now?
As I stated earlier, a failure to approve flibanserin would set a dangerous precedent. Why? Because the company did everything the FDA asked it to do, and the results came out statistically significantly better than placebo—which was the desired endpoint. If the FDA were to deny approval of the drug, it would be saying, in effect, that it can change its mind in the middle of the argument—something it faulted Boehringer Ingelheim for in earlier deliberations (switching the insensitive electronic diary for the statistically significant FSFI).

In reality, the FDA is likely to say yes to approval, but with restrictions, as that is what its advisory committee recommended. What those restrictions will be remains to be determined, but they are likely to resemble those of other drugs in the class, such as selective serotonin reuptake inhibitors (SSRIs), including a warning to be careful using flibanserin with alcohol until the drug’s effects are clear.

Opposition to flibanserin misses the mark
During the public hearing portion of the advisory committee meeting, most of the testimony came from women seeking approval of the drug. However, there were some naysayers. Their arguments against approval boiled down to 4 perspectives:

There is also the sociological view that HSDD is a normal variant of healthy sexual function. Its adherents argue that women with HSDD feel distress because their male partners are forcing them to feel inadequate. But I have yet to hear a single critical voice from a physician who actually treats women and who can prescribe drugs. The opposition to flibanserin, such as it is, flows from people who don’t see patients and can’t prescribe medications.

These naysayers are negative in a theoretical vacuum. It’s very easy to fall into that trap when you don’t have to look across the consultation desk to a patient who is asking you for a remedy—a woman who’s been suffering for 25 years, say—and have to tell her you have nothing to offer. You might mention testosterone, explaining that it was approved for men but you’ll try to prescribe an appropriate dose. But be sure to include discussion of its many side effects.

A long and winding road
Flibanserin’s journey from inception to probable approval has been long and eventful, and you can be sure that the pharmaceutical industry has been paying attention. Hundreds of millions of dollars in funding for drug development hang in the balance. That women deserve remedies developed specifically for their needs and metabolism is a given. The approval of flibanserin will send a hopeful signal to them as well as to industry—that the FDA takes them seriously and seeks to identify effective remedies. In this case, it seems likely, the agency will end up on the right side of history.
 

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The number of states that require notification to a woman who is identified on mammography as having heterogeneous (Breast Imaging-Reporting and Data System [BI-RADS] C) or extremely dense breasts (BI-RADS D) is growing. In fact, Michigan became the 22nd state to require such notification when its law went into effect on June 1, 2015. How do we advise our patients who come to us wondering what they should do with the new-found information?

Since supplemental imaging after normal mammography findings can result in false positives and potentially unnecessary biopsies or treatment, Kerlikowski and colleagues investigated for which patients supplemental screening could be beneficial. In other words, which patients are at highest risk for interval cancer (invasive cancer diagnosed within 12 months of a normal mammogram), as these women would be most likely to benefit from supplemental imaging that could potentially detect a tumor not identified on digital screening mammography.

Details of the study
The researchers included 831,455 digital screening mammography examinations performed among 365,426 women aged 40 to 74 years who did not have a history of breast cancer or breast implants and had complete information on demographic and breast health history. To calculate breast cancer risk, they used the Breast Cancer Surveillance Consortium (BCSC) 5-year risk model, which requires 5 risk factors: first-degree relatives with history of breast cancer, history of breast biopsy, BI-RADS breast density, and race/ethnicity. They used breast density to stratify women by risk for interval cancer within the next year and to identify women at increased 5-year risk for breast cancer.

In which patient populations are cases of interval cancer highest?
The authors found the interval cancer rates to exceed 1 case per 1,000 mammography examinations among:

The authors point out that, together, these 2 latter groups represent 24% of women aged 40 to 74 years with dense breasts, or 12% of women having screening mammography.

For women aged 40 to 49 years, interval cancer rates were less than 1 case per 1,000 examinations for all density categories. For 51% of these women with heterogeneously dense breasts, the 5-year risk of breast cancer was low to average (0% to 1.66%), with interval cancer rates of 0.58 to 0.63 per 1,000 examinations. For 52.5% of 40- to 49-year-old women with extremely dense breasts, the 5-year risk of breast cancer was low to average, with interval cancer rates of 0.72 to 0.89 cases per 1,000 examinations.

The interval cancer rate for women with scattered fibroglandular densities (BI-RADS B) and 5-year risk of 2.50% or greater was 0.90 cases per 1,000 mammography examinations.

Kerlikowski and colleagues conclude that breast density should not be the sole criterion for deciding whether supplemental imaging is justified because not all women with dense breasts have high interval cancer rates. 

What this evidence means for practice
BCSC 5-year risk combined with BI-RADS breast density can identify women at high risk for interval cancer to inform patient–provider discussions about alternative screening strategies, as the study authors state. However, there remains a huge gap in our knowledge about whether supplemental imaging in any of these risk groups improved stage of diagnosis or breast cancer–specific mortality.

Nearly all national guidelines groups (US Preventive Services Task Force,¹ American College of Obstetricians and Gynecologists,² National Comprehensive Cancer Network,³ and the American Cancer Society⁴) concur that supplemental breast imaging should not be performed on women with dense breasts until there are reasonable data that demonstrate an improvement in stage of diagnosis or breast cancer mortality.
—Mark D. Pearlman, MD

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The number of states that require notification to a woman who is identified on mammography as having heterogeneous (Breast Imaging-Reporting and Data System [BI-RADS] C) or extremely dense breasts (BI-RADS D) is growing. In fact, Michigan became the 22nd state to require such notification when its law went into effect on June 1, 2015. How do we advise our patients who come to us wondering what they should do with the new-found information?

Since supplemental imaging after normal mammography findings can result in false positives and potentially unnecessary biopsies or treatment, Kerlikowski and colleagues investigated for which patients supplemental screening could be beneficial. In other words, which patients are at highest risk for interval cancer (invasive cancer diagnosed within 12 months of a normal mammogram), as these women would be most likely to benefit from supplemental imaging that could potentially detect a tumor not identified on digital screening mammography.

Details of the study
The researchers included 831,455 digital screening mammography examinations performed among 365,426 women aged 40 to 74 years who did not have a history of breast cancer or breast implants and had complete information on demographic and breast health history. To calculate breast cancer risk, they used the Breast Cancer Surveillance Consortium (BCSC) 5-year risk model, which requires 5 risk factors: first-degree relatives with history of breast cancer, history of breast biopsy, BI-RADS breast density, and race/ethnicity. They used breast density to stratify women by risk for interval cancer within the next year and to identify women at increased 5-year risk for breast cancer.

In which patient populations are cases of interval cancer highest?
The authors found the interval cancer rates to exceed 1 case per 1,000 mammography examinations among:

The authors point out that, together, these 2 latter groups represent 24% of women aged 40 to 74 years with dense breasts, or 12% of women having screening mammography.

For women aged 40 to 49 years, interval cancer rates were less than 1 case per 1,000 examinations for all density categories. For 51% of these women with heterogeneously dense breasts, the 5-year risk of breast cancer was low to average (0% to 1.66%), with interval cancer rates of 0.58 to 0.63 per 1,000 examinations. For 52.5% of 40- to 49-year-old women with extremely dense breasts, the 5-year risk of breast cancer was low to average, with interval cancer rates of 0.72 to 0.89 cases per 1,000 examinations.

The interval cancer rate for women with scattered fibroglandular densities (BI-RADS B) and 5-year risk of 2.50% or greater was 0.90 cases per 1,000 mammography examinations.

Kerlikowski and colleagues conclude that breast density should not be the sole criterion for deciding whether supplemental imaging is justified because not all women with dense breasts have high interval cancer rates. 

What this evidence means for practice
BCSC 5-year risk combined with BI-RADS breast density can identify women at high risk for interval cancer to inform patient–provider discussions about alternative screening strategies, as the study authors state. However, there remains a huge gap in our knowledge about whether supplemental imaging in any of these risk groups improved stage of diagnosis or breast cancer–specific mortality.

Nearly all national guidelines groups (US Preventive Services Task Force,¹ American College of Obstetricians and Gynecologists,² National Comprehensive Cancer Network,³ and the American Cancer Society⁴) concur that supplemental breast imaging should not be performed on women with dense breasts until there are reasonable data that demonstrate an improvement in stage of diagnosis or breast cancer mortality.
—Mark D. Pearlman, MD

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The number of states that require notification to a woman who is identified on mammography as having heterogeneous (Breast Imaging-Reporting and Data System [BI-RADS] C) or extremely dense breasts (BI-RADS D) is growing. In fact, Michigan became the 22nd state to require such notification when its law went into effect on June 1, 2015. How do we advise our patients who come to us wondering what they should do with the new-found information?

Since supplemental imaging after normal mammography findings can result in false positives and potentially unnecessary biopsies or treatment, Kerlikowski and colleagues investigated for which patients supplemental screening could be beneficial. In other words, which patients are at highest risk for interval cancer (invasive cancer diagnosed within 12 months of a normal mammogram), as these women would be most likely to benefit from supplemental imaging that could potentially detect a tumor not identified on digital screening mammography.

Details of the study
The researchers included 831,455 digital screening mammography examinations performed among 365,426 women aged 40 to 74 years who did not have a history of breast cancer or breast implants and had complete information on demographic and breast health history. To calculate breast cancer risk, they used the Breast Cancer Surveillance Consortium (BCSC) 5-year risk model, which requires 5 risk factors: first-degree relatives with history of breast cancer, history of breast biopsy, BI-RADS breast density, and race/ethnicity. They used breast density to stratify women by risk for interval cancer within the next year and to identify women at increased 5-year risk for breast cancer.

In which patient populations are cases of interval cancer highest?
The authors found the interval cancer rates to exceed 1 case per 1,000 mammography examinations among:

The authors point out that, together, these 2 latter groups represent 24% of women aged 40 to 74 years with dense breasts, or 12% of women having screening mammography.

For women aged 40 to 49 years, interval cancer rates were less than 1 case per 1,000 examinations for all density categories. For 51% of these women with heterogeneously dense breasts, the 5-year risk of breast cancer was low to average (0% to 1.66%), with interval cancer rates of 0.58 to 0.63 per 1,000 examinations. For 52.5% of 40- to 49-year-old women with extremely dense breasts, the 5-year risk of breast cancer was low to average, with interval cancer rates of 0.72 to 0.89 cases per 1,000 examinations.

The interval cancer rate for women with scattered fibroglandular densities (BI-RADS B) and 5-year risk of 2.50% or greater was 0.90 cases per 1,000 mammography examinations.

Kerlikowski and colleagues conclude that breast density should not be the sole criterion for deciding whether supplemental imaging is justified because not all women with dense breasts have high interval cancer rates. 

What this evidence means for practice
BCSC 5-year risk combined with BI-RADS breast density can identify women at high risk for interval cancer to inform patient–provider discussions about alternative screening strategies, as the study authors state. However, there remains a huge gap in our knowledge about whether supplemental imaging in any of these risk groups improved stage of diagnosis or breast cancer–specific mortality.

Nearly all national guidelines groups (US Preventive Services Task Force,¹ American College of Obstetricians and Gynecologists,² National Comprehensive Cancer Network,³ and the American Cancer Society⁴) concur that supplemental breast imaging should not be performed on women with dense breasts until there are reasonable data that demonstrate an improvement in stage of diagnosis or breast cancer mortality.
—Mark D. Pearlman, MD

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.