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NAMS hormone therapy guidelines stress individualized treatment
An update from the society’s 2012 recommendations, the new statement will also give targeted recommendations for special populations of women to help guide clinicians in individualized treatment.
Highlights from the new position statement were released at the NAMS 2016 annual meeting, and the full document is expected to be published later this year. Among the highlights is the assertion that the clearest benefit for hormone therapy (HT) for treating hot flashes and preventing bone loss is in the early postmenopausal group.
The position statement also represents something of a shift away from the old mantra of “the lowest dose for the shortest period of time,” said Dr. Pinkerton, professor of obstetrics and gynecology at the University of Virginia Health System, Charlottesville.
As a practical matter, clinicians should budget time for these individualized discussions, Cynthia Stuenkel, MD, another member of the guidelines committee, said in an interview.
Currently, HT is approved by the Food and Drug administration as first-line therapy for menopausal vasomotor symptoms (VMS) for women without contraindications. For prevention of bone loss and fractures in postmenopausal women at higher risk, HT may be considered, especially for women younger than 60 years old and less than 10 years post menopause, according to the position statement.
When the predominant symptom pattern involves genitourinary syndrome of menopause (GSM, also known as vulvovaginal atrophy), the position statement recommends starting with low-dose vaginal estrogen as first-line treatment. These are all level I recommendations.
The use of HT in early menopause both provides the most effective treatment for symptoms and the greatest skeletal benefits, according to Michael R. McClung, MD, founding director of the Oregon Osteoporosis Center in Portland. “The benefit far outweighs the risk,” he said, especially in women at risk for bone density loss without contraindication for HT.
Special populations
Several special populations are addressed in the updated position statement. These include those who have reached early menopause because of primary ovarian insufficiency or because of oophorectomy. For these women, NAMS recommends hormone therapy until at least the median age of menopause. Making a level II recommendation, the NAMS committee wrote, “Observational studies suggest that benefits appear to outweigh the risks for effects on bone, heart, cognition, GSM, sexual function, and mood.”
Other special populations for whom HT may be considered include women with a family history of breast cancer and women who are positive for the BRCA gene. Again turning to observational evidence, the NAMS committee makes a level II recommendation that “use of HT does not alter the risk for breast cancer in women with family history of breast cancer, although family history is one risk, among many, that should be assessed.”
BRCA-positive women who do not have breast cancer are at higher risk for primarily estrogen receptor–negative breast cancer. BRCA-positive women may have opted for elective oophorectomy, though, and the committee recommends considering the potential negative effects of estrogen depletion at a premenopausal age when weighing risks and benefits in surgically menopausal BRCA-positive patients. It’s appropriate to offer systemic HT until the median age of menopause in this population, if there are no contraindications, and after appropriate counseling, according to the position statement.
Individualized discussions about continuing HT beyond the median age of menopause are recommended, said Dr. Pinkerton. “We reviewed the literature and found no increased risk in observational studies of women with BRCA genes after oophorectomy who receive hormone therapy,” she said. “These decisions are best taken on an individual basis.” The recommendations for the BRCA population are also a level II recommendation.
Duration of use
Regarding extended use of HT, the NAMS statement breaks with the Beers criteria, saying that routine discontinuation of HT after the age of 65 years “is not supported by data.” These decisions, according to the new recommendations, should be individualized. This is a level III recommendation. Still, said Dr. Kaunitz, “many women grow out of their vasomotor symptoms,” and so an individualized approach might include indefinite use of low-dose vaginal estrogen therapy for GSM, he said.
The overall benefit-risk ratio for HT is also addressed in the position statement, which emphasizes an individualized approach that includes periodic reassessment of risk and benefit for particular patients. However, for patients younger than 60 years of age, or who are within 10 years of menopause, NAMS endorses an overall favorable risk-benefit profile for HT in two particular areas, barring contraindications. For this younger postmenopausal population, hormone therapy is beneficial for bothersome vasomotor symptoms, according to the position statement, and women with an increased risk of osteoporosis or fracture may also benefit from HT.
The benefit-risk profile may tip against HT for women who are starting hormone therapy more than 10 years after menopause, or when they are 60 years old or older, according to the statement. The authors cite elevated risks of coronary heart disease, stroke, venous thromboembolism, and dementia.
The recommendations embodied in the new position statement take into account the “substantial benefit” of estrogen for many women, and provide an updated view of the safety of HT, Dr. McClung said. It’s important for physicians to talk to their patients, because “that information has not made it back to the Internet,” he said.
Dr. Pinkerton, Dr. McClung, and Dr. Kaunitz all reported financial relationships with several pharmaceutical companies. Dr. Kaunitz reported receiving royalties from UpToDate. Dr. Stuenkel reported no relevant financial disclosures.
[email protected]
On Twitter @karioakes
An update from the society’s 2012 recommendations, the new statement will also give targeted recommendations for special populations of women to help guide clinicians in individualized treatment.
Highlights from the new position statement were released at the NAMS 2016 annual meeting, and the full document is expected to be published later this year. Among the highlights is the assertion that the clearest benefit for hormone therapy (HT) for treating hot flashes and preventing bone loss is in the early postmenopausal group.
The position statement also represents something of a shift away from the old mantra of “the lowest dose for the shortest period of time,” said Dr. Pinkerton, professor of obstetrics and gynecology at the University of Virginia Health System, Charlottesville.
As a practical matter, clinicians should budget time for these individualized discussions, Cynthia Stuenkel, MD, another member of the guidelines committee, said in an interview.
Currently, HT is approved by the Food and Drug administration as first-line therapy for menopausal vasomotor symptoms (VMS) for women without contraindications. For prevention of bone loss and fractures in postmenopausal women at higher risk, HT may be considered, especially for women younger than 60 years old and less than 10 years post menopause, according to the position statement.
When the predominant symptom pattern involves genitourinary syndrome of menopause (GSM, also known as vulvovaginal atrophy), the position statement recommends starting with low-dose vaginal estrogen as first-line treatment. These are all level I recommendations.
The use of HT in early menopause both provides the most effective treatment for symptoms and the greatest skeletal benefits, according to Michael R. McClung, MD, founding director of the Oregon Osteoporosis Center in Portland. “The benefit far outweighs the risk,” he said, especially in women at risk for bone density loss without contraindication for HT.
Special populations
Several special populations are addressed in the updated position statement. These include those who have reached early menopause because of primary ovarian insufficiency or because of oophorectomy. For these women, NAMS recommends hormone therapy until at least the median age of menopause. Making a level II recommendation, the NAMS committee wrote, “Observational studies suggest that benefits appear to outweigh the risks for effects on bone, heart, cognition, GSM, sexual function, and mood.”
Other special populations for whom HT may be considered include women with a family history of breast cancer and women who are positive for the BRCA gene. Again turning to observational evidence, the NAMS committee makes a level II recommendation that “use of HT does not alter the risk for breast cancer in women with family history of breast cancer, although family history is one risk, among many, that should be assessed.”
BRCA-positive women who do not have breast cancer are at higher risk for primarily estrogen receptor–negative breast cancer. BRCA-positive women may have opted for elective oophorectomy, though, and the committee recommends considering the potential negative effects of estrogen depletion at a premenopausal age when weighing risks and benefits in surgically menopausal BRCA-positive patients. It’s appropriate to offer systemic HT until the median age of menopause in this population, if there are no contraindications, and after appropriate counseling, according to the position statement.
Individualized discussions about continuing HT beyond the median age of menopause are recommended, said Dr. Pinkerton. “We reviewed the literature and found no increased risk in observational studies of women with BRCA genes after oophorectomy who receive hormone therapy,” she said. “These decisions are best taken on an individual basis.” The recommendations for the BRCA population are also a level II recommendation.
Duration of use
Regarding extended use of HT, the NAMS statement breaks with the Beers criteria, saying that routine discontinuation of HT after the age of 65 years “is not supported by data.” These decisions, according to the new recommendations, should be individualized. This is a level III recommendation. Still, said Dr. Kaunitz, “many women grow out of their vasomotor symptoms,” and so an individualized approach might include indefinite use of low-dose vaginal estrogen therapy for GSM, he said.
The overall benefit-risk ratio for HT is also addressed in the position statement, which emphasizes an individualized approach that includes periodic reassessment of risk and benefit for particular patients. However, for patients younger than 60 years of age, or who are within 10 years of menopause, NAMS endorses an overall favorable risk-benefit profile for HT in two particular areas, barring contraindications. For this younger postmenopausal population, hormone therapy is beneficial for bothersome vasomotor symptoms, according to the position statement, and women with an increased risk of osteoporosis or fracture may also benefit from HT.
The benefit-risk profile may tip against HT for women who are starting hormone therapy more than 10 years after menopause, or when they are 60 years old or older, according to the statement. The authors cite elevated risks of coronary heart disease, stroke, venous thromboembolism, and dementia.
The recommendations embodied in the new position statement take into account the “substantial benefit” of estrogen for many women, and provide an updated view of the safety of HT, Dr. McClung said. It’s important for physicians to talk to their patients, because “that information has not made it back to the Internet,” he said.
Dr. Pinkerton, Dr. McClung, and Dr. Kaunitz all reported financial relationships with several pharmaceutical companies. Dr. Kaunitz reported receiving royalties from UpToDate. Dr. Stuenkel reported no relevant financial disclosures.
[email protected]
On Twitter @karioakes
An update from the society’s 2012 recommendations, the new statement will also give targeted recommendations for special populations of women to help guide clinicians in individualized treatment.
Highlights from the new position statement were released at the NAMS 2016 annual meeting, and the full document is expected to be published later this year. Among the highlights is the assertion that the clearest benefit for hormone therapy (HT) for treating hot flashes and preventing bone loss is in the early postmenopausal group.
The position statement also represents something of a shift away from the old mantra of “the lowest dose for the shortest period of time,” said Dr. Pinkerton, professor of obstetrics and gynecology at the University of Virginia Health System, Charlottesville.
As a practical matter, clinicians should budget time for these individualized discussions, Cynthia Stuenkel, MD, another member of the guidelines committee, said in an interview.
Currently, HT is approved by the Food and Drug administration as first-line therapy for menopausal vasomotor symptoms (VMS) for women without contraindications. For prevention of bone loss and fractures in postmenopausal women at higher risk, HT may be considered, especially for women younger than 60 years old and less than 10 years post menopause, according to the position statement.
When the predominant symptom pattern involves genitourinary syndrome of menopause (GSM, also known as vulvovaginal atrophy), the position statement recommends starting with low-dose vaginal estrogen as first-line treatment. These are all level I recommendations.
The use of HT in early menopause both provides the most effective treatment for symptoms and the greatest skeletal benefits, according to Michael R. McClung, MD, founding director of the Oregon Osteoporosis Center in Portland. “The benefit far outweighs the risk,” he said, especially in women at risk for bone density loss without contraindication for HT.
Special populations
Several special populations are addressed in the updated position statement. These include those who have reached early menopause because of primary ovarian insufficiency or because of oophorectomy. For these women, NAMS recommends hormone therapy until at least the median age of menopause. Making a level II recommendation, the NAMS committee wrote, “Observational studies suggest that benefits appear to outweigh the risks for effects on bone, heart, cognition, GSM, sexual function, and mood.”
Other special populations for whom HT may be considered include women with a family history of breast cancer and women who are positive for the BRCA gene. Again turning to observational evidence, the NAMS committee makes a level II recommendation that “use of HT does not alter the risk for breast cancer in women with family history of breast cancer, although family history is one risk, among many, that should be assessed.”
BRCA-positive women who do not have breast cancer are at higher risk for primarily estrogen receptor–negative breast cancer. BRCA-positive women may have opted for elective oophorectomy, though, and the committee recommends considering the potential negative effects of estrogen depletion at a premenopausal age when weighing risks and benefits in surgically menopausal BRCA-positive patients. It’s appropriate to offer systemic HT until the median age of menopause in this population, if there are no contraindications, and after appropriate counseling, according to the position statement.
Individualized discussions about continuing HT beyond the median age of menopause are recommended, said Dr. Pinkerton. “We reviewed the literature and found no increased risk in observational studies of women with BRCA genes after oophorectomy who receive hormone therapy,” she said. “These decisions are best taken on an individual basis.” The recommendations for the BRCA population are also a level II recommendation.
Duration of use
Regarding extended use of HT, the NAMS statement breaks with the Beers criteria, saying that routine discontinuation of HT after the age of 65 years “is not supported by data.” These decisions, according to the new recommendations, should be individualized. This is a level III recommendation. Still, said Dr. Kaunitz, “many women grow out of their vasomotor symptoms,” and so an individualized approach might include indefinite use of low-dose vaginal estrogen therapy for GSM, he said.
The overall benefit-risk ratio for HT is also addressed in the position statement, which emphasizes an individualized approach that includes periodic reassessment of risk and benefit for particular patients. However, for patients younger than 60 years of age, or who are within 10 years of menopause, NAMS endorses an overall favorable risk-benefit profile for HT in two particular areas, barring contraindications. For this younger postmenopausal population, hormone therapy is beneficial for bothersome vasomotor symptoms, according to the position statement, and women with an increased risk of osteoporosis or fracture may also benefit from HT.
The benefit-risk profile may tip against HT for women who are starting hormone therapy more than 10 years after menopause, or when they are 60 years old or older, according to the statement. The authors cite elevated risks of coronary heart disease, stroke, venous thromboembolism, and dementia.
The recommendations embodied in the new position statement take into account the “substantial benefit” of estrogen for many women, and provide an updated view of the safety of HT, Dr. McClung said. It’s important for physicians to talk to their patients, because “that information has not made it back to the Internet,” he said.
Dr. Pinkerton, Dr. McClung, and Dr. Kaunitz all reported financial relationships with several pharmaceutical companies. Dr. Kaunitz reported receiving royalties from UpToDate. Dr. Stuenkel reported no relevant financial disclosures.
[email protected]
On Twitter @karioakes
Odanacatib reduced fractures but upped stroke risk
The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.
Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.
Compared with placebo, odanacatib resulted in relative risk reductions of 52% for vertebral fracture, 48% for hip fracture, 26% for nonvertebral fracture, and 67% for clinical vertebral fracture (all values, P less than .001). Lumbar spine bone density increased by a mean of 10.9%, as did total hip bone density by a mean of 10.3%, in the odanacatib group (for both, P less than .001), according to results presented at the meeting.
The Long-Term Odanacatib Fracture Trial (LOFT) was a randomized, double-blind placebo-controlled study that investigated the efficacy and safety of odanacatib, a cathepsin K inhibitor, as a treatment for osteoporosis and for fracture prevention in postmenopausal women. Odanacatib was taken as an oral, once-weekly 50-mg pill.
During the base period of the study, 16,071 postmenopausal women aged 65 and older were enrolled, and 12,290 completed the study. Women had to have total hip or femoral neck bone mineral density T scores less than or equal to –2.5, or a radiographically confirmed vertebral fracture and total hip or femoral neck T scores less than or equal to –1.5. Participants were demographically well matched between study arms; 6,092 odanacatib patients and 6,198 on placebo completed the base period of the study.
The original phase III study was stopped early because of robust efficacy data (Osteoporos Int. 2015 Feb;26[2]:699-712). Participants were eligible to continue in a preplanned 5-year double-blind, placebo-controlled extension period of the LOFT study; 3,432 odanacatib and 2,615 placebo participants completed the full 5 years.
An early, but statistically nonsignificant, signal for increased stroke and atrial fibrillation and flutter was seen at the end of the study’s base period. The trend continued and appeared to be amplified during the 5-year, double-blind, placebo-controlled extension period of the LOFT study.
In an interview, Dr. O’Donoghue said that the TIMI study group was brought in by Merck for a “second perspective,” to add rigor to an examination of events that had not been anticipated in the base period of the LOFT study. This was an important step, said Dr. O’Donoghue, because LOFT was not a dedicated cardiovascular safety trial.
The prespecified primary endpoints for TIMI’s safety analysis included new-onset atrial flutter or atrial fibrillation, as well as a composite endpoint of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or cardiovascular death.
Examination of the composite MACE endpoint showed a numeric, but not statistically significant, difference between the odanacatib and placebo arms of the extension study. However, in a preplanned subanalysis, when the 324 stroke events were isolated, a hazard ratio (HR) for stroke of 1.37 for odanacatib emerged (95% confidence interval [CI], 1.10-1.71; P = .005).
Atrial fibrillation and atrial flutter were more common in the odanacatib group, but the difference was not significant (HR, 1.22; 95% CI, 0.99-1.50; P = .06). Dr. O’Donoghue said that the individuals with supraventricular arrhythmias were not the same individuals who had strokes, although the strokes were almost entirely ischemic, rather than hemorrhagic, events.
Dr. O’Donoghue, a cardiovascular medicine specialist at Brigham and Women’s Hospital, noted in her presentation that “preclinical data suggested that inhibition of cathepsin K may reduce atherosclerosis progression and promote plaque stability.”
Odanacatib is a cathepsin K inhibitor, one of a member of a class of proteases. Cathepsin K targets kinins that are involved in bone resorption, but it is expressed in other tissues as well, and it may target other classes of kinins. However, exactly how odanacatib may have contributed to strokes in the study population remains a mystery.
“The mechanistic underpinnings to explain these findings is unknown and warrants investigation,” Dr. O’Donoghue said. “It’s a little bit more unsatisfying when you’re not able to provide a cause. … I share the disappointment of the endocrinologists in the community who were very hopeful for the cathepsin K class to be the next breakthrough in the management of osteoporosis.”
Dr. McClung reported financial relationships with Merck and several other pharmaceutical companies. Dr. O’Donoghue reported receiving grant support from several pharmaceutical companies. The LOFT trial and the TIMI study group analysis were sponsored by Merck.
[email protected]
On Twitter @karioakes
The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.
Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.
Compared with placebo, odanacatib resulted in relative risk reductions of 52% for vertebral fracture, 48% for hip fracture, 26% for nonvertebral fracture, and 67% for clinical vertebral fracture (all values, P less than .001). Lumbar spine bone density increased by a mean of 10.9%, as did total hip bone density by a mean of 10.3%, in the odanacatib group (for both, P less than .001), according to results presented at the meeting.
The Long-Term Odanacatib Fracture Trial (LOFT) was a randomized, double-blind placebo-controlled study that investigated the efficacy and safety of odanacatib, a cathepsin K inhibitor, as a treatment for osteoporosis and for fracture prevention in postmenopausal women. Odanacatib was taken as an oral, once-weekly 50-mg pill.
During the base period of the study, 16,071 postmenopausal women aged 65 and older were enrolled, and 12,290 completed the study. Women had to have total hip or femoral neck bone mineral density T scores less than or equal to –2.5, or a radiographically confirmed vertebral fracture and total hip or femoral neck T scores less than or equal to –1.5. Participants were demographically well matched between study arms; 6,092 odanacatib patients and 6,198 on placebo completed the base period of the study.
The original phase III study was stopped early because of robust efficacy data (Osteoporos Int. 2015 Feb;26[2]:699-712). Participants were eligible to continue in a preplanned 5-year double-blind, placebo-controlled extension period of the LOFT study; 3,432 odanacatib and 2,615 placebo participants completed the full 5 years.
An early, but statistically nonsignificant, signal for increased stroke and atrial fibrillation and flutter was seen at the end of the study’s base period. The trend continued and appeared to be amplified during the 5-year, double-blind, placebo-controlled extension period of the LOFT study.
In an interview, Dr. O’Donoghue said that the TIMI study group was brought in by Merck for a “second perspective,” to add rigor to an examination of events that had not been anticipated in the base period of the LOFT study. This was an important step, said Dr. O’Donoghue, because LOFT was not a dedicated cardiovascular safety trial.
The prespecified primary endpoints for TIMI’s safety analysis included new-onset atrial flutter or atrial fibrillation, as well as a composite endpoint of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or cardiovascular death.
Examination of the composite MACE endpoint showed a numeric, but not statistically significant, difference between the odanacatib and placebo arms of the extension study. However, in a preplanned subanalysis, when the 324 stroke events were isolated, a hazard ratio (HR) for stroke of 1.37 for odanacatib emerged (95% confidence interval [CI], 1.10-1.71; P = .005).
Atrial fibrillation and atrial flutter were more common in the odanacatib group, but the difference was not significant (HR, 1.22; 95% CI, 0.99-1.50; P = .06). Dr. O’Donoghue said that the individuals with supraventricular arrhythmias were not the same individuals who had strokes, although the strokes were almost entirely ischemic, rather than hemorrhagic, events.
Dr. O’Donoghue, a cardiovascular medicine specialist at Brigham and Women’s Hospital, noted in her presentation that “preclinical data suggested that inhibition of cathepsin K may reduce atherosclerosis progression and promote plaque stability.”
Odanacatib is a cathepsin K inhibitor, one of a member of a class of proteases. Cathepsin K targets kinins that are involved in bone resorption, but it is expressed in other tissues as well, and it may target other classes of kinins. However, exactly how odanacatib may have contributed to strokes in the study population remains a mystery.
“The mechanistic underpinnings to explain these findings is unknown and warrants investigation,” Dr. O’Donoghue said. “It’s a little bit more unsatisfying when you’re not able to provide a cause. … I share the disappointment of the endocrinologists in the community who were very hopeful for the cathepsin K class to be the next breakthrough in the management of osteoporosis.”
Dr. McClung reported financial relationships with Merck and several other pharmaceutical companies. Dr. O’Donoghue reported receiving grant support from several pharmaceutical companies. The LOFT trial and the TIMI study group analysis were sponsored by Merck.
[email protected]
On Twitter @karioakes
The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.
Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.
Compared with placebo, odanacatib resulted in relative risk reductions of 52% for vertebral fracture, 48% for hip fracture, 26% for nonvertebral fracture, and 67% for clinical vertebral fracture (all values, P less than .001). Lumbar spine bone density increased by a mean of 10.9%, as did total hip bone density by a mean of 10.3%, in the odanacatib group (for both, P less than .001), according to results presented at the meeting.
The Long-Term Odanacatib Fracture Trial (LOFT) was a randomized, double-blind placebo-controlled study that investigated the efficacy and safety of odanacatib, a cathepsin K inhibitor, as a treatment for osteoporosis and for fracture prevention in postmenopausal women. Odanacatib was taken as an oral, once-weekly 50-mg pill.
During the base period of the study, 16,071 postmenopausal women aged 65 and older were enrolled, and 12,290 completed the study. Women had to have total hip or femoral neck bone mineral density T scores less than or equal to –2.5, or a radiographically confirmed vertebral fracture and total hip or femoral neck T scores less than or equal to –1.5. Participants were demographically well matched between study arms; 6,092 odanacatib patients and 6,198 on placebo completed the base period of the study.
The original phase III study was stopped early because of robust efficacy data (Osteoporos Int. 2015 Feb;26[2]:699-712). Participants were eligible to continue in a preplanned 5-year double-blind, placebo-controlled extension period of the LOFT study; 3,432 odanacatib and 2,615 placebo participants completed the full 5 years.
An early, but statistically nonsignificant, signal for increased stroke and atrial fibrillation and flutter was seen at the end of the study’s base period. The trend continued and appeared to be amplified during the 5-year, double-blind, placebo-controlled extension period of the LOFT study.
In an interview, Dr. O’Donoghue said that the TIMI study group was brought in by Merck for a “second perspective,” to add rigor to an examination of events that had not been anticipated in the base period of the LOFT study. This was an important step, said Dr. O’Donoghue, because LOFT was not a dedicated cardiovascular safety trial.
The prespecified primary endpoints for TIMI’s safety analysis included new-onset atrial flutter or atrial fibrillation, as well as a composite endpoint of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or cardiovascular death.
Examination of the composite MACE endpoint showed a numeric, but not statistically significant, difference between the odanacatib and placebo arms of the extension study. However, in a preplanned subanalysis, when the 324 stroke events were isolated, a hazard ratio (HR) for stroke of 1.37 for odanacatib emerged (95% confidence interval [CI], 1.10-1.71; P = .005).
Atrial fibrillation and atrial flutter were more common in the odanacatib group, but the difference was not significant (HR, 1.22; 95% CI, 0.99-1.50; P = .06). Dr. O’Donoghue said that the individuals with supraventricular arrhythmias were not the same individuals who had strokes, although the strokes were almost entirely ischemic, rather than hemorrhagic, events.
Dr. O’Donoghue, a cardiovascular medicine specialist at Brigham and Women’s Hospital, noted in her presentation that “preclinical data suggested that inhibition of cathepsin K may reduce atherosclerosis progression and promote plaque stability.”
Odanacatib is a cathepsin K inhibitor, one of a member of a class of proteases. Cathepsin K targets kinins that are involved in bone resorption, but it is expressed in other tissues as well, and it may target other classes of kinins. However, exactly how odanacatib may have contributed to strokes in the study population remains a mystery.
“The mechanistic underpinnings to explain these findings is unknown and warrants investigation,” Dr. O’Donoghue said. “It’s a little bit more unsatisfying when you’re not able to provide a cause. … I share the disappointment of the endocrinologists in the community who were very hopeful for the cathepsin K class to be the next breakthrough in the management of osteoporosis.”
Dr. McClung reported financial relationships with Merck and several other pharmaceutical companies. Dr. O’Donoghue reported receiving grant support from several pharmaceutical companies. The LOFT trial and the TIMI study group analysis were sponsored by Merck.
[email protected]
On Twitter @karioakes
FROM THE NAMS 2016 ANNUAL MEETING
Early menopause a risk factor for type 2 diabetes
“What we see in our data is that indeed, early onset of menopause is associated with increased risk of type 2 diabetes, and this association is independent of potential intermediate risk factors: obesity, insulin, glucose, inflammation, but also of estradiol and other endogenous sex hormone levels,” said Taulant Muka, MD, PhD, in an interview.
Dr. Muka, a postdoctoral fellow at Erasmus Medical College, Rotterdam, the Netherlands, presented the analysis from a large, prospective cohort of menopausal women at the annual meeting of the North American Menopause Society.
In an interview, Dr. Muka noted that the study investigated whether the association between early age at natural menopause (ANM) and type 2 diabetes is independent of intermediate risk factors for type 2 diabetes, such as obesity. Finally, the study also assessed whether endogenous sex hormone levels play a role in the link between early ANM and type 2 diabetes.
Enrollment in the Rotterdam study has been continuing in waves since the 1990s, with enrollment for participants in this particular study cohort occurring in 1997 and with additional cohorts enrolled in 2000-2001 and 2006-2008.
“I think this is the first prospective study with such long follow-up data and with a broad adjustment for confounding factors. Previous studies have been mainly cross-sectional, providing conflicting results,” said Dr. Muka.
Using self-reported age at menopause, the investigators excluded from the study women whose menopausal status was not known, who were actually not menopausal, or whose menopause had not occurred naturally. The study population also excluded women with prevalent type 2 diabetes or for whom no information about diabetes follow-up could be found.
The remaining 3,210 women who were included in the study had a median age of 67 years and had reached menopause at a median of 49.9 years. Most women (82.6%) had an ANM of 45-55 years; ANM for 8.8% was 40-44 years, while just 2.3% had an ANM of under 40 years. Mean body mass index was 27.1 kg/m2.
Participants were considered to have incident diabetes based on several sources: a general practitioner’s records, hospital discharge paperwork, or glucose measurements from visits during the Rotterdam study. Participants also were classified as having diabetes if they used a hypoglycemic medication or had a fasting blood glucose level of at least 7 mmol/L (126 mg/dL) or, in the absence of a fasting blood glucose measurement, a nonfasting blood glucose of at least 11.1 mmol/L (200 mg/dL).
Dr. Muka said he and his coinvestigators identified and adjusted for a large number of variables, using a series of three Cox proportion hazard models.
The first model adjusted for age, which wave of enrollment (cohort) participants were in, hormone therapy status, age at menarche, and the number of pregnancies that reached at least 6 months’ gestation.
The second model used all of the factors in model 1, and added BMI and glucose and insulin levels. The third model used all of the factors in model 2, and also added total cholesterol level, systolic blood pressure, the use of lipid-lowering or antihypertensive medications, alcohol and tobacco use, educational level, prevalent cardiovascular disease, and C-reactive protein levels.
The association of early ANM with the risk of type 2 diabetes was statistically significant in all three models (P less than .001), with very similar hazard ratios (HRs) in all models. For the third, the most comprehensive model, the HR was 1.42 (95% confidence interval, 0.83-2.45).
Extensive sensitivity analyses were carried out, and the association held independent of physical activity level, smoking status, use of hormone therapy, and age. The investigators also used multivariable analyses to ensure that the effect was not mediated by serum levels of thyroid-stimulating hormone, dihydroepiandosterone (DHEA) and DHEA sulfate, estradiol, testosterone, sex hormone–binding globulin (SHBG), or androstenedione.
This study was the first in this population to obtain and adjust for serum sex hormone and SHBG levels, said Dr. Muka.
The prospective design of the study and the long follow-up period were study strengths, said Dr. Muka. Additionally, blood glucose readings taken at study visits, together with electronically linked pharmacy dispensing records, were used for incident diabetes diagnoses.
Study limitations, Dr. Muka said, included the possibility of survival bias, since enrollees “may represent survivors of early menopause who did not develop [type 2 diabetes] or die prior to enrollment.” However, he said, this would mean that “we have underestimated the association, so the risk would be even higher.” Also, all study participants were white, so the results cannot be extrapolated to nonwhite populations.
Dr. Muka said that the largely American audience for his presentation was interested in the fact that the association existed independent of BMI, an obesity marker, based on questions and comments following the talk. “Indeed, we stratified the analysis, and we didn’t find any difference between participants who were obese and nonobese.” Also, he said that there were queries about whether the analyses had corrected for DEXA measurements, in order to assess lean versus fat body composition more accurately. This analysis has not been done, but Dr. Muka plans to complete it on his return to Rotterdam, he said.
Up to 10% of women will reach menopause before the age of 45, said Dr. Muka, so this analysis has the potential to impact primary care for millions of women. “Women who undergo early menopause may be a target for type 2 diabetes prevention measures and might need to be screened for other cardiovascular risk factors like high blood pressure and dyslipidemia, since they are also at risk for cardiovascular disease.”
Dr. Muka reported no outside funding sources and had no relevant financial disclosures.
[email protected]
On Twitter @karioakes
“What we see in our data is that indeed, early onset of menopause is associated with increased risk of type 2 diabetes, and this association is independent of potential intermediate risk factors: obesity, insulin, glucose, inflammation, but also of estradiol and other endogenous sex hormone levels,” said Taulant Muka, MD, PhD, in an interview.
Dr. Muka, a postdoctoral fellow at Erasmus Medical College, Rotterdam, the Netherlands, presented the analysis from a large, prospective cohort of menopausal women at the annual meeting of the North American Menopause Society.
In an interview, Dr. Muka noted that the study investigated whether the association between early age at natural menopause (ANM) and type 2 diabetes is independent of intermediate risk factors for type 2 diabetes, such as obesity. Finally, the study also assessed whether endogenous sex hormone levels play a role in the link between early ANM and type 2 diabetes.
Enrollment in the Rotterdam study has been continuing in waves since the 1990s, with enrollment for participants in this particular study cohort occurring in 1997 and with additional cohorts enrolled in 2000-2001 and 2006-2008.
“I think this is the first prospective study with such long follow-up data and with a broad adjustment for confounding factors. Previous studies have been mainly cross-sectional, providing conflicting results,” said Dr. Muka.
Using self-reported age at menopause, the investigators excluded from the study women whose menopausal status was not known, who were actually not menopausal, or whose menopause had not occurred naturally. The study population also excluded women with prevalent type 2 diabetes or for whom no information about diabetes follow-up could be found.
The remaining 3,210 women who were included in the study had a median age of 67 years and had reached menopause at a median of 49.9 years. Most women (82.6%) had an ANM of 45-55 years; ANM for 8.8% was 40-44 years, while just 2.3% had an ANM of under 40 years. Mean body mass index was 27.1 kg/m2.
Participants were considered to have incident diabetes based on several sources: a general practitioner’s records, hospital discharge paperwork, or glucose measurements from visits during the Rotterdam study. Participants also were classified as having diabetes if they used a hypoglycemic medication or had a fasting blood glucose level of at least 7 mmol/L (126 mg/dL) or, in the absence of a fasting blood glucose measurement, a nonfasting blood glucose of at least 11.1 mmol/L (200 mg/dL).
Dr. Muka said he and his coinvestigators identified and adjusted for a large number of variables, using a series of three Cox proportion hazard models.
The first model adjusted for age, which wave of enrollment (cohort) participants were in, hormone therapy status, age at menarche, and the number of pregnancies that reached at least 6 months’ gestation.
The second model used all of the factors in model 1, and added BMI and glucose and insulin levels. The third model used all of the factors in model 2, and also added total cholesterol level, systolic blood pressure, the use of lipid-lowering or antihypertensive medications, alcohol and tobacco use, educational level, prevalent cardiovascular disease, and C-reactive protein levels.
The association of early ANM with the risk of type 2 diabetes was statistically significant in all three models (P less than .001), with very similar hazard ratios (HRs) in all models. For the third, the most comprehensive model, the HR was 1.42 (95% confidence interval, 0.83-2.45).
Extensive sensitivity analyses were carried out, and the association held independent of physical activity level, smoking status, use of hormone therapy, and age. The investigators also used multivariable analyses to ensure that the effect was not mediated by serum levels of thyroid-stimulating hormone, dihydroepiandosterone (DHEA) and DHEA sulfate, estradiol, testosterone, sex hormone–binding globulin (SHBG), or androstenedione.
This study was the first in this population to obtain and adjust for serum sex hormone and SHBG levels, said Dr. Muka.
The prospective design of the study and the long follow-up period were study strengths, said Dr. Muka. Additionally, blood glucose readings taken at study visits, together with electronically linked pharmacy dispensing records, were used for incident diabetes diagnoses.
Study limitations, Dr. Muka said, included the possibility of survival bias, since enrollees “may represent survivors of early menopause who did not develop [type 2 diabetes] or die prior to enrollment.” However, he said, this would mean that “we have underestimated the association, so the risk would be even higher.” Also, all study participants were white, so the results cannot be extrapolated to nonwhite populations.
Dr. Muka said that the largely American audience for his presentation was interested in the fact that the association existed independent of BMI, an obesity marker, based on questions and comments following the talk. “Indeed, we stratified the analysis, and we didn’t find any difference between participants who were obese and nonobese.” Also, he said that there were queries about whether the analyses had corrected for DEXA measurements, in order to assess lean versus fat body composition more accurately. This analysis has not been done, but Dr. Muka plans to complete it on his return to Rotterdam, he said.
Up to 10% of women will reach menopause before the age of 45, said Dr. Muka, so this analysis has the potential to impact primary care for millions of women. “Women who undergo early menopause may be a target for type 2 diabetes prevention measures and might need to be screened for other cardiovascular risk factors like high blood pressure and dyslipidemia, since they are also at risk for cardiovascular disease.”
Dr. Muka reported no outside funding sources and had no relevant financial disclosures.
[email protected]
On Twitter @karioakes
“What we see in our data is that indeed, early onset of menopause is associated with increased risk of type 2 diabetes, and this association is independent of potential intermediate risk factors: obesity, insulin, glucose, inflammation, but also of estradiol and other endogenous sex hormone levels,” said Taulant Muka, MD, PhD, in an interview.
Dr. Muka, a postdoctoral fellow at Erasmus Medical College, Rotterdam, the Netherlands, presented the analysis from a large, prospective cohort of menopausal women at the annual meeting of the North American Menopause Society.
In an interview, Dr. Muka noted that the study investigated whether the association between early age at natural menopause (ANM) and type 2 diabetes is independent of intermediate risk factors for type 2 diabetes, such as obesity. Finally, the study also assessed whether endogenous sex hormone levels play a role in the link between early ANM and type 2 diabetes.
Enrollment in the Rotterdam study has been continuing in waves since the 1990s, with enrollment for participants in this particular study cohort occurring in 1997 and with additional cohorts enrolled in 2000-2001 and 2006-2008.
“I think this is the first prospective study with such long follow-up data and with a broad adjustment for confounding factors. Previous studies have been mainly cross-sectional, providing conflicting results,” said Dr. Muka.
Using self-reported age at menopause, the investigators excluded from the study women whose menopausal status was not known, who were actually not menopausal, or whose menopause had not occurred naturally. The study population also excluded women with prevalent type 2 diabetes or for whom no information about diabetes follow-up could be found.
The remaining 3,210 women who were included in the study had a median age of 67 years and had reached menopause at a median of 49.9 years. Most women (82.6%) had an ANM of 45-55 years; ANM for 8.8% was 40-44 years, while just 2.3% had an ANM of under 40 years. Mean body mass index was 27.1 kg/m2.
Participants were considered to have incident diabetes based on several sources: a general practitioner’s records, hospital discharge paperwork, or glucose measurements from visits during the Rotterdam study. Participants also were classified as having diabetes if they used a hypoglycemic medication or had a fasting blood glucose level of at least 7 mmol/L (126 mg/dL) or, in the absence of a fasting blood glucose measurement, a nonfasting blood glucose of at least 11.1 mmol/L (200 mg/dL).
Dr. Muka said he and his coinvestigators identified and adjusted for a large number of variables, using a series of three Cox proportion hazard models.
The first model adjusted for age, which wave of enrollment (cohort) participants were in, hormone therapy status, age at menarche, and the number of pregnancies that reached at least 6 months’ gestation.
The second model used all of the factors in model 1, and added BMI and glucose and insulin levels. The third model used all of the factors in model 2, and also added total cholesterol level, systolic blood pressure, the use of lipid-lowering or antihypertensive medications, alcohol and tobacco use, educational level, prevalent cardiovascular disease, and C-reactive protein levels.
The association of early ANM with the risk of type 2 diabetes was statistically significant in all three models (P less than .001), with very similar hazard ratios (HRs) in all models. For the third, the most comprehensive model, the HR was 1.42 (95% confidence interval, 0.83-2.45).
Extensive sensitivity analyses were carried out, and the association held independent of physical activity level, smoking status, use of hormone therapy, and age. The investigators also used multivariable analyses to ensure that the effect was not mediated by serum levels of thyroid-stimulating hormone, dihydroepiandosterone (DHEA) and DHEA sulfate, estradiol, testosterone, sex hormone–binding globulin (SHBG), or androstenedione.
This study was the first in this population to obtain and adjust for serum sex hormone and SHBG levels, said Dr. Muka.
The prospective design of the study and the long follow-up period were study strengths, said Dr. Muka. Additionally, blood glucose readings taken at study visits, together with electronically linked pharmacy dispensing records, were used for incident diabetes diagnoses.
Study limitations, Dr. Muka said, included the possibility of survival bias, since enrollees “may represent survivors of early menopause who did not develop [type 2 diabetes] or die prior to enrollment.” However, he said, this would mean that “we have underestimated the association, so the risk would be even higher.” Also, all study participants were white, so the results cannot be extrapolated to nonwhite populations.
Dr. Muka said that the largely American audience for his presentation was interested in the fact that the association existed independent of BMI, an obesity marker, based on questions and comments following the talk. “Indeed, we stratified the analysis, and we didn’t find any difference between participants who were obese and nonobese.” Also, he said that there were queries about whether the analyses had corrected for DEXA measurements, in order to assess lean versus fat body composition more accurately. This analysis has not been done, but Dr. Muka plans to complete it on his return to Rotterdam, he said.
Up to 10% of women will reach menopause before the age of 45, said Dr. Muka, so this analysis has the potential to impact primary care for millions of women. “Women who undergo early menopause may be a target for type 2 diabetes prevention measures and might need to be screened for other cardiovascular risk factors like high blood pressure and dyslipidemia, since they are also at risk for cardiovascular disease.”
Dr. Muka reported no outside funding sources and had no relevant financial disclosures.
[email protected]
On Twitter @karioakes
Key clinical point: Early menopause is associated with an increased risk for type 2 diabetes.
Major finding: Age at menopause between 40 and 45 was associated with a relative risk of 1.49 for type 2 diabetes.
Data source: A prospective cohort study of an initial cohort of 3,210 menopausal women.
Disclosures: No outside funding source was reported. Dr. Muka reported having no relevant financial conflicts.
Novel fractional laser eased genitourinary syndrome of menopause
DENVER – Novel fractional laser therapy achieved significant 12-month reductions in vaginal dryness, burning, pain, and itching associated with menopause, Eric Sokol, MD, reported at Pelvic Floor Disorders Week, sponsored by the American Urogynecologic Society.
Most patients – 92% – said they were satisfied or very satisfied with the treatment, said Dr. Sokol of Stanford (Calif.) University. “Treatments take 45 seconds and are painless,” he added. “We are part of a group that is planning a larger multicenter randomized trial of this laser, as well as some histologic studies.”
The two-center pilot study included 30 women with vulvovaginal atrophy treated with a novel fractional carbon dioxide laser system called SmartXide2 V2LR (MonaLisa Touch). The system has a maximum power of 60 W and emits laser energy at a 10,600-nm wavelength, Dr. Sokol noted. Patients underwent three treatments spaced by 6 weeks, and used 10-point visual analogue scales to score baseline and subsequent levels of vaginal pain, burning, itching, dryness, dyspareunia, and dysuria.
Average scores on the Female Sexual Function Index rose from 11.3 at baseline to 21.25 at 12 months, a statistically significant improvement.
Laser therapy caused no major adverse events, but about 10% of patients developed slight vaginal discharge or minor spotting after treatment, Dr. Sokol reported. Patients were not allowed to use lubricants or estrogens during the study.
The study was supported by DEKA M.E.L.A. Srl, using an investigator-initiated protocol. Patients did not pay for treatment. Dr. Sokol reported that he has no financial disclosures related to this study. His coinvestigator is a paid consultant for Cynosure.
DENVER – Novel fractional laser therapy achieved significant 12-month reductions in vaginal dryness, burning, pain, and itching associated with menopause, Eric Sokol, MD, reported at Pelvic Floor Disorders Week, sponsored by the American Urogynecologic Society.
Most patients – 92% – said they were satisfied or very satisfied with the treatment, said Dr. Sokol of Stanford (Calif.) University. “Treatments take 45 seconds and are painless,” he added. “We are part of a group that is planning a larger multicenter randomized trial of this laser, as well as some histologic studies.”
The two-center pilot study included 30 women with vulvovaginal atrophy treated with a novel fractional carbon dioxide laser system called SmartXide2 V2LR (MonaLisa Touch). The system has a maximum power of 60 W and emits laser energy at a 10,600-nm wavelength, Dr. Sokol noted. Patients underwent three treatments spaced by 6 weeks, and used 10-point visual analogue scales to score baseline and subsequent levels of vaginal pain, burning, itching, dryness, dyspareunia, and dysuria.
Average scores on the Female Sexual Function Index rose from 11.3 at baseline to 21.25 at 12 months, a statistically significant improvement.
Laser therapy caused no major adverse events, but about 10% of patients developed slight vaginal discharge or minor spotting after treatment, Dr. Sokol reported. Patients were not allowed to use lubricants or estrogens during the study.
The study was supported by DEKA M.E.L.A. Srl, using an investigator-initiated protocol. Patients did not pay for treatment. Dr. Sokol reported that he has no financial disclosures related to this study. His coinvestigator is a paid consultant for Cynosure.
DENVER – Novel fractional laser therapy achieved significant 12-month reductions in vaginal dryness, burning, pain, and itching associated with menopause, Eric Sokol, MD, reported at Pelvic Floor Disorders Week, sponsored by the American Urogynecologic Society.
Most patients – 92% – said they were satisfied or very satisfied with the treatment, said Dr. Sokol of Stanford (Calif.) University. “Treatments take 45 seconds and are painless,” he added. “We are part of a group that is planning a larger multicenter randomized trial of this laser, as well as some histologic studies.”
The two-center pilot study included 30 women with vulvovaginal atrophy treated with a novel fractional carbon dioxide laser system called SmartXide2 V2LR (MonaLisa Touch). The system has a maximum power of 60 W and emits laser energy at a 10,600-nm wavelength, Dr. Sokol noted. Patients underwent three treatments spaced by 6 weeks, and used 10-point visual analogue scales to score baseline and subsequent levels of vaginal pain, burning, itching, dryness, dyspareunia, and dysuria.
Average scores on the Female Sexual Function Index rose from 11.3 at baseline to 21.25 at 12 months, a statistically significant improvement.
Laser therapy caused no major adverse events, but about 10% of patients developed slight vaginal discharge or minor spotting after treatment, Dr. Sokol reported. Patients were not allowed to use lubricants or estrogens during the study.
The study was supported by DEKA M.E.L.A. Srl, using an investigator-initiated protocol. Patients did not pay for treatment. Dr. Sokol reported that he has no financial disclosures related to this study. His coinvestigator is a paid consultant for Cynosure.
Key clinical point:
Major finding: Reductions in dryness and dyspareunia were especially marked, dropping by an average of about 75% and 66%, respectively.
Data source: A two-center pilot study of 30 women with genitourinary syndrome of atrophy (previously known as vaginal atrophy).
Disclosures: The study was supported by DEKA M.E.L.A. Srl, using an investigator-initiated protocol. Patients did not pay for treatment. Dr. Sokol reported that he has no financial disclosures related to this study. His coinvestigator is a paid consultant for Cynosure.
When is it time to stop hormone therapy?
Extended use of systemic hormone therapy represents one area that clinicians commonly encounter. However, because randomized trial data are not available, helping women make decisions regarding long-term use of hormone therapy is controversial. When it is finalized, the 2016 hormone therapy position statement from the North American Menopause Society will address this topic.
Here I’m referring to the patient who likely started systemic hormone therapy when she was a younger, or more recently menopausal, woman (perhaps in her early 50s), but now she’s in her 60s. In my practice, a patient in this age range would likely be on a lower-than-standard dose of hormone therapy than what she began with originally.
And now the question is, Should she continue, or should she stop, hormone therapy? The median duration of bothersome symptoms is about 10 or 11 years, from the best available data – far longer than what many physicians assume.
And risk stratification also becomes relevant. Let’s say the patient is a slender white or Asian woman with a low body mass index , or she has a parent who had a hip fracture. Continuing low-dose systemic hormone therapy in this case, particularly for osteoporosis prevention when vasomotor symptoms are no longer present, might make sense. However, if the patient is obese, and, therefore has a lower risk for osteoporosis, it may be that ongoing use of systemic hormone therapy would not be indicated, and that patient should be encouraged to discontinue at that point.
Also, if a uterus is not present – and we’re talking only about estrogen therapy, given its greater safety profile with long-term use with respect to breast cancer – clinicians and women can be more comfortable with continued use of low-dose systemic hormone therapy for osteoporosis prevention. If a uterus is present, then women making decisions about long-term use of hormone therapy need to be aware of the small, but I believe real, elevated risk of breast cancer. With each office visit and when decisions about refilling prescriptions or continuing hormone therapy are made, this is an important issue to discuss, particularly if there’s an intact uterus. These discussions also need to be documented in the record.
What about the route of estrogen? Age, BMI, and oral estrogen therapy each represent independent risk factors for venous thromboembolism. For older, as well as obese menopausal women, who are candidates for systemic hormone therapy, I prefer transdermal over oral estrogen therapy.
Finally, I counsel women that although vasomotor symptoms/hot flashes improve as women age, the same is not true for genitourinary syndrome of menopause (GSM, also known as genital atrophy). If vaginal dryness, pain with sex, or other manifestations of GSM occur in women tapering their dose of systemic hormone therapy or in women who have discontinued systemic hormone therapy, initiation and long-term use of low-dose vaginal estrogen should be considered.
References
1. Menopause. 2014 Jun;21(6):679-81.
Dr. Kaunitz is a professor and associate chair of the department of obstetrics and gynecology, University of Florida in Jacksonville. He is on the board of trustees of the North American Menopause Society. He reports being a consultant or on the advisory board or review panel of several pharmaceutical companies, and receiving grant support from several pharmaceutical companies. He receives royalties from UpToDate.
Extended use of systemic hormone therapy represents one area that clinicians commonly encounter. However, because randomized trial data are not available, helping women make decisions regarding long-term use of hormone therapy is controversial. When it is finalized, the 2016 hormone therapy position statement from the North American Menopause Society will address this topic.
Here I’m referring to the patient who likely started systemic hormone therapy when she was a younger, or more recently menopausal, woman (perhaps in her early 50s), but now she’s in her 60s. In my practice, a patient in this age range would likely be on a lower-than-standard dose of hormone therapy than what she began with originally.
And now the question is, Should she continue, or should she stop, hormone therapy? The median duration of bothersome symptoms is about 10 or 11 years, from the best available data – far longer than what many physicians assume.
And risk stratification also becomes relevant. Let’s say the patient is a slender white or Asian woman with a low body mass index , or she has a parent who had a hip fracture. Continuing low-dose systemic hormone therapy in this case, particularly for osteoporosis prevention when vasomotor symptoms are no longer present, might make sense. However, if the patient is obese, and, therefore has a lower risk for osteoporosis, it may be that ongoing use of systemic hormone therapy would not be indicated, and that patient should be encouraged to discontinue at that point.
Also, if a uterus is not present – and we’re talking only about estrogen therapy, given its greater safety profile with long-term use with respect to breast cancer – clinicians and women can be more comfortable with continued use of low-dose systemic hormone therapy for osteoporosis prevention. If a uterus is present, then women making decisions about long-term use of hormone therapy need to be aware of the small, but I believe real, elevated risk of breast cancer. With each office visit and when decisions about refilling prescriptions or continuing hormone therapy are made, this is an important issue to discuss, particularly if there’s an intact uterus. These discussions also need to be documented in the record.
What about the route of estrogen? Age, BMI, and oral estrogen therapy each represent independent risk factors for venous thromboembolism. For older, as well as obese menopausal women, who are candidates for systemic hormone therapy, I prefer transdermal over oral estrogen therapy.
Finally, I counsel women that although vasomotor symptoms/hot flashes improve as women age, the same is not true for genitourinary syndrome of menopause (GSM, also known as genital atrophy). If vaginal dryness, pain with sex, or other manifestations of GSM occur in women tapering their dose of systemic hormone therapy or in women who have discontinued systemic hormone therapy, initiation and long-term use of low-dose vaginal estrogen should be considered.
References
1. Menopause. 2014 Jun;21(6):679-81.
Dr. Kaunitz is a professor and associate chair of the department of obstetrics and gynecology, University of Florida in Jacksonville. He is on the board of trustees of the North American Menopause Society. He reports being a consultant or on the advisory board or review panel of several pharmaceutical companies, and receiving grant support from several pharmaceutical companies. He receives royalties from UpToDate.
Extended use of systemic hormone therapy represents one area that clinicians commonly encounter. However, because randomized trial data are not available, helping women make decisions regarding long-term use of hormone therapy is controversial. When it is finalized, the 2016 hormone therapy position statement from the North American Menopause Society will address this topic.
Here I’m referring to the patient who likely started systemic hormone therapy when she was a younger, or more recently menopausal, woman (perhaps in her early 50s), but now she’s in her 60s. In my practice, a patient in this age range would likely be on a lower-than-standard dose of hormone therapy than what she began with originally.
And now the question is, Should she continue, or should she stop, hormone therapy? The median duration of bothersome symptoms is about 10 or 11 years, from the best available data – far longer than what many physicians assume.
And risk stratification also becomes relevant. Let’s say the patient is a slender white or Asian woman with a low body mass index , or she has a parent who had a hip fracture. Continuing low-dose systemic hormone therapy in this case, particularly for osteoporosis prevention when vasomotor symptoms are no longer present, might make sense. However, if the patient is obese, and, therefore has a lower risk for osteoporosis, it may be that ongoing use of systemic hormone therapy would not be indicated, and that patient should be encouraged to discontinue at that point.
Also, if a uterus is not present – and we’re talking only about estrogen therapy, given its greater safety profile with long-term use with respect to breast cancer – clinicians and women can be more comfortable with continued use of low-dose systemic hormone therapy for osteoporosis prevention. If a uterus is present, then women making decisions about long-term use of hormone therapy need to be aware of the small, but I believe real, elevated risk of breast cancer. With each office visit and when decisions about refilling prescriptions or continuing hormone therapy are made, this is an important issue to discuss, particularly if there’s an intact uterus. These discussions also need to be documented in the record.
What about the route of estrogen? Age, BMI, and oral estrogen therapy each represent independent risk factors for venous thromboembolism. For older, as well as obese menopausal women, who are candidates for systemic hormone therapy, I prefer transdermal over oral estrogen therapy.
Finally, I counsel women that although vasomotor symptoms/hot flashes improve as women age, the same is not true for genitourinary syndrome of menopause (GSM, also known as genital atrophy). If vaginal dryness, pain with sex, or other manifestations of GSM occur in women tapering their dose of systemic hormone therapy or in women who have discontinued systemic hormone therapy, initiation and long-term use of low-dose vaginal estrogen should be considered.
References
1. Menopause. 2014 Jun;21(6):679-81.
Dr. Kaunitz is a professor and associate chair of the department of obstetrics and gynecology, University of Florida in Jacksonville. He is on the board of trustees of the North American Menopause Society. He reports being a consultant or on the advisory board or review panel of several pharmaceutical companies, and receiving grant support from several pharmaceutical companies. He receives royalties from UpToDate.
NAMS 2016 hormone therapy position statement
JoAnn Pinkerton, MD, Professor of Obstetrics and Gynecology at the University of Virginia, Executive Director of the North American Menopause Society (NAMS), and OBG Management Board of Editors Member, revealed the 2016 NAMS position statement on hormone therapy (HT) in Orlando, Florida, on Thursday, October 6, at the NAMS 2016 Annual Scientific Meeting.
The process of consensus among the more than 20 menopause experts who authored the 2016 statement was at times a challenge, indicated Pinkerton, given the variance in views on the significance of published clinical trial findings since the Society’s 20121 HT position statement. Over a 9-month period, the experts developed guidelines for clinicians, using levels of evidence to identify strength of the recommendations.
The clearest benefit for HT to treat hot flashes and prevent bone loss was found for women aged younger than 60 years and within 10 years of menopause onset.
According to the 2016 statement presented at NAMS:
Level I US Food and Drug Administration (FDA)-approved indications for HT include:
- as first-line therapy for women with vasomotor symptoms (VMS) of menopause without contraindications
- possible first-line therapy for prevention of bone loss and fracture in postmenopausal women at elevated risk for fracture (primarily for women aged younger than 60 years and within 10 years of menopause onset)
- low-dose vaginal estrogen as first-line treatment for women with isolated genitourinary symptoms caused by menopause (genitourinary syndrome of menopause [GSM]/vulvovaginal atrophy).
Level II FDA-approved indications for HT include:
- at least until age 52 (the median age of menopause onset) for women with early onset menopause (women with hypogonadism, primary ovarian insufficiency, or premature surgical menopause) and no HT contraindications.
Other level II indications, with observational data indicating benefit over risk, for HT include:
- at least until the median age of menopause for women with early onset menopause
- consideration among women with a family history of breast cancer, although family history is one risk among many for breast cancer that should be assessed
- benefit/risk consideration for women with a BRCA gene mutation who have undergone risk-reducing oophorectomy
- consideration of systemic use until the median age of menopause—after appropriate counseling and in the absence of HT contraindications, with longer duration of HT use individualized.
Level III indications for HT include:
- individualized decisions on use after the age of 60. (The position statement authors did not find that the current Beers criteria recommendation to routinely discontinue HT at age 65 was supported by data.)
The 2016 bottom line on HT
Overall, HT has clear benefits for the treatment of VMS and bone loss prevention, according to the presented position statement. These benefits are most favorable among women aged younger than 60 years who are within 10 years of menopause onset and have no contraindications to HT use. Women older than age 60 who initiate HT beyond 10 years of menopause onset appear to have a less favorable benefit-risk ratio because of elevated risks of coronary heart disease, stroke, venous thromboembolism, and dementia.
The risks of HT vary among women depending on the HT type, duration of use, administration route, timing of treatment initiation, and whether a progestogen is needed. (With longer HT use, estrogen therapy is more favorable than estrogen-progestin therapy.) Therefore, HT should be individualized and reevaluated periodically to maximize the benefits as well as minimize the risks of use, according to the position statement.
Nonhormonal therapies for menopausal symptoms
The Society released its position on nonhormonal management of menopause-associated VMS in 2015.2 Based on examination of 340 original research articles and 105 systematic reviews, clinical and research experts categorized therapies as recommended, recommended with caution, and not recommended at this time.
Recommended non-HT to reduce VMS include:
- cognitive-behavioral therapy
- clinical hypnosis
- low-dose salt of paroxetine (FDA approved for menopausal VMS management)
- other SSRIs/SNRIs
- gabapentinoids
- clonidine.
Recommended-with-caution non-HT for VMS include:
- weight loss
- stress reduction (mindfulness based)
- S-equol derivatives of soy isoflavones
- stellate ganglion block.
Not recommended non-HT for VMS due to negative, insufficient, or inconclusive data include:
- cooling techniques
- avoidance of triggers
- exercise
- yoga
- paced respiration
- relaxation
- over-the-counter supplements and herbs
- acupuncture
- calibration of neural oscillations
- chiropractic interventions.
Note that the NAMS 2016 Hormone Therapy Position Statement was presented at the 2016 Annual Scientific Meeting of the North American Menopause Society, but the statement is not yet published.
- North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause. 2012;19(3):257−271.
- Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society. Menopause. 2015;(11):1155−1172.
JoAnn Pinkerton, MD, Professor of Obstetrics and Gynecology at the University of Virginia, Executive Director of the North American Menopause Society (NAMS), and OBG Management Board of Editors Member, revealed the 2016 NAMS position statement on hormone therapy (HT) in Orlando, Florida, on Thursday, October 6, at the NAMS 2016 Annual Scientific Meeting.
The process of consensus among the more than 20 menopause experts who authored the 2016 statement was at times a challenge, indicated Pinkerton, given the variance in views on the significance of published clinical trial findings since the Society’s 20121 HT position statement. Over a 9-month period, the experts developed guidelines for clinicians, using levels of evidence to identify strength of the recommendations.
The clearest benefit for HT to treat hot flashes and prevent bone loss was found for women aged younger than 60 years and within 10 years of menopause onset.
According to the 2016 statement presented at NAMS:
Level I US Food and Drug Administration (FDA)-approved indications for HT include:
- as first-line therapy for women with vasomotor symptoms (VMS) of menopause without contraindications
- possible first-line therapy for prevention of bone loss and fracture in postmenopausal women at elevated risk for fracture (primarily for women aged younger than 60 years and within 10 years of menopause onset)
- low-dose vaginal estrogen as first-line treatment for women with isolated genitourinary symptoms caused by menopause (genitourinary syndrome of menopause [GSM]/vulvovaginal atrophy).
Level II FDA-approved indications for HT include:
- at least until age 52 (the median age of menopause onset) for women with early onset menopause (women with hypogonadism, primary ovarian insufficiency, or premature surgical menopause) and no HT contraindications.
Other level II indications, with observational data indicating benefit over risk, for HT include:
- at least until the median age of menopause for women with early onset menopause
- consideration among women with a family history of breast cancer, although family history is one risk among many for breast cancer that should be assessed
- benefit/risk consideration for women with a BRCA gene mutation who have undergone risk-reducing oophorectomy
- consideration of systemic use until the median age of menopause—after appropriate counseling and in the absence of HT contraindications, with longer duration of HT use individualized.
Level III indications for HT include:
- individualized decisions on use after the age of 60. (The position statement authors did not find that the current Beers criteria recommendation to routinely discontinue HT at age 65 was supported by data.)
The 2016 bottom line on HT
Overall, HT has clear benefits for the treatment of VMS and bone loss prevention, according to the presented position statement. These benefits are most favorable among women aged younger than 60 years who are within 10 years of menopause onset and have no contraindications to HT use. Women older than age 60 who initiate HT beyond 10 years of menopause onset appear to have a less favorable benefit-risk ratio because of elevated risks of coronary heart disease, stroke, venous thromboembolism, and dementia.
The risks of HT vary among women depending on the HT type, duration of use, administration route, timing of treatment initiation, and whether a progestogen is needed. (With longer HT use, estrogen therapy is more favorable than estrogen-progestin therapy.) Therefore, HT should be individualized and reevaluated periodically to maximize the benefits as well as minimize the risks of use, according to the position statement.
Nonhormonal therapies for menopausal symptoms
The Society released its position on nonhormonal management of menopause-associated VMS in 2015.2 Based on examination of 340 original research articles and 105 systematic reviews, clinical and research experts categorized therapies as recommended, recommended with caution, and not recommended at this time.
Recommended non-HT to reduce VMS include:
- cognitive-behavioral therapy
- clinical hypnosis
- low-dose salt of paroxetine (FDA approved for menopausal VMS management)
- other SSRIs/SNRIs
- gabapentinoids
- clonidine.
Recommended-with-caution non-HT for VMS include:
- weight loss
- stress reduction (mindfulness based)
- S-equol derivatives of soy isoflavones
- stellate ganglion block.
Not recommended non-HT for VMS due to negative, insufficient, or inconclusive data include:
- cooling techniques
- avoidance of triggers
- exercise
- yoga
- paced respiration
- relaxation
- over-the-counter supplements and herbs
- acupuncture
- calibration of neural oscillations
- chiropractic interventions.
Note that the NAMS 2016 Hormone Therapy Position Statement was presented at the 2016 Annual Scientific Meeting of the North American Menopause Society, but the statement is not yet published.
JoAnn Pinkerton, MD, Professor of Obstetrics and Gynecology at the University of Virginia, Executive Director of the North American Menopause Society (NAMS), and OBG Management Board of Editors Member, revealed the 2016 NAMS position statement on hormone therapy (HT) in Orlando, Florida, on Thursday, October 6, at the NAMS 2016 Annual Scientific Meeting.
The process of consensus among the more than 20 menopause experts who authored the 2016 statement was at times a challenge, indicated Pinkerton, given the variance in views on the significance of published clinical trial findings since the Society’s 20121 HT position statement. Over a 9-month period, the experts developed guidelines for clinicians, using levels of evidence to identify strength of the recommendations.
The clearest benefit for HT to treat hot flashes and prevent bone loss was found for women aged younger than 60 years and within 10 years of menopause onset.
According to the 2016 statement presented at NAMS:
Level I US Food and Drug Administration (FDA)-approved indications for HT include:
- as first-line therapy for women with vasomotor symptoms (VMS) of menopause without contraindications
- possible first-line therapy for prevention of bone loss and fracture in postmenopausal women at elevated risk for fracture (primarily for women aged younger than 60 years and within 10 years of menopause onset)
- low-dose vaginal estrogen as first-line treatment for women with isolated genitourinary symptoms caused by menopause (genitourinary syndrome of menopause [GSM]/vulvovaginal atrophy).
Level II FDA-approved indications for HT include:
- at least until age 52 (the median age of menopause onset) for women with early onset menopause (women with hypogonadism, primary ovarian insufficiency, or premature surgical menopause) and no HT contraindications.
Other level II indications, with observational data indicating benefit over risk, for HT include:
- at least until the median age of menopause for women with early onset menopause
- consideration among women with a family history of breast cancer, although family history is one risk among many for breast cancer that should be assessed
- benefit/risk consideration for women with a BRCA gene mutation who have undergone risk-reducing oophorectomy
- consideration of systemic use until the median age of menopause—after appropriate counseling and in the absence of HT contraindications, with longer duration of HT use individualized.
Level III indications for HT include:
- individualized decisions on use after the age of 60. (The position statement authors did not find that the current Beers criteria recommendation to routinely discontinue HT at age 65 was supported by data.)
The 2016 bottom line on HT
Overall, HT has clear benefits for the treatment of VMS and bone loss prevention, according to the presented position statement. These benefits are most favorable among women aged younger than 60 years who are within 10 years of menopause onset and have no contraindications to HT use. Women older than age 60 who initiate HT beyond 10 years of menopause onset appear to have a less favorable benefit-risk ratio because of elevated risks of coronary heart disease, stroke, venous thromboembolism, and dementia.
The risks of HT vary among women depending on the HT type, duration of use, administration route, timing of treatment initiation, and whether a progestogen is needed. (With longer HT use, estrogen therapy is more favorable than estrogen-progestin therapy.) Therefore, HT should be individualized and reevaluated periodically to maximize the benefits as well as minimize the risks of use, according to the position statement.
Nonhormonal therapies for menopausal symptoms
The Society released its position on nonhormonal management of menopause-associated VMS in 2015.2 Based on examination of 340 original research articles and 105 systematic reviews, clinical and research experts categorized therapies as recommended, recommended with caution, and not recommended at this time.
Recommended non-HT to reduce VMS include:
- cognitive-behavioral therapy
- clinical hypnosis
- low-dose salt of paroxetine (FDA approved for menopausal VMS management)
- other SSRIs/SNRIs
- gabapentinoids
- clonidine.
Recommended-with-caution non-HT for VMS include:
- weight loss
- stress reduction (mindfulness based)
- S-equol derivatives of soy isoflavones
- stellate ganglion block.
Not recommended non-HT for VMS due to negative, insufficient, or inconclusive data include:
- cooling techniques
- avoidance of triggers
- exercise
- yoga
- paced respiration
- relaxation
- over-the-counter supplements and herbs
- acupuncture
- calibration of neural oscillations
- chiropractic interventions.
Note that the NAMS 2016 Hormone Therapy Position Statement was presented at the 2016 Annual Scientific Meeting of the North American Menopause Society, but the statement is not yet published.
- North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause. 2012;19(3):257−271.
- Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society. Menopause. 2015;(11):1155−1172.
- North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause. 2012;19(3):257−271.
- Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society. Menopause. 2015;(11):1155−1172.
Breast arterial calcifications predict atherosclerotic cardiovascular events
Longitudinal results of a prospective study of women with and without breast arterial calcifications showed that women with the calcifications were significantly more likely to have atherosclerotic cardiovascular events than were women without them.
In a 10-year follow-up of a cohort of women receiving screening mammograms, women who did not have cardiovascular disease at baseline and were positive for breast arterial calcifications (BACs) were three times more likely to develop atherosclerotic cardiovascular disease (ASCVD) as those who were BAC negative at baseline (9.8% vs. 3.3%; P = .001).
These results paralleled those found 5 years previously among the cohort. At that point, 6.3% of the BAC-positive group developed ASCVD, compared with 2.3% of the BAC-negative group (P = .003). At 10 years, “multiple logistic regression analysis found BAC to be strongly associated with ASCVD events, with an odds ratio of 2.29,” senior investigator Peter Schnatz, DO, said in an interview.
Based on these results, Dr. Schnatz and his coinvestigators are suggesting that BACs be routinely reported on mammograms and viewed as a marker for the development of cardiovascular disease.
Presenting the unpublished 10-year findings at the annual meeting of the North American Menopause Society, Dr. Schnatz, the society’s 2015-2016 president, said that the BAC-positive group was also more likely to develop risk factors for ASCVD (86.8% vs. 76.3; P = .01).
These risk factors were age, hypertension, hypercholesterolemia, diabetes, and menopause. The other results were significant after the investigators controlled for age, so the increased risk was not merely caused by the passage of time and the normal aging process.
The prospective study compared age-matched controls with and without BACs to determine whether BACs seen on routine mammography can predict the development of ASCVD, by tracking the presence of BACs and gathering information about ASCVD risk factors and events via patient self-report in an annual questionnaire. The events that were considered ASCVD markers were angina, myocardial infarction, an abnormal angiogram, coronary artery bypass grafting, and stroke.
The initial baseline study upon which the longitudinal prospective studies are based gathered data from 1,919 women with a median age of 56, plus or minus 12.7 years (range, 25-96), to determine whether women with BAC had an increased frequency of cardiovascular disease risk factors, and of ASCVD. Baseline findings showed an independent association of BAC with multiple risk factors and with ASCVD events, even after age was controlled for.
Dr. Schnatz, who is a professor of ob.gyn. and internal medicine at Thomas Jefferson University, Philadelphia, said in his presentation that BACs “appear to be a risk indicator of the presence of ASCVD. More importantly, in this first prospective analysis of BAC as a risk predictor, BAC appears to be a risk predictor for the future development of ASCVD.”
Patients were considered BAC positive if their mammograms showed BAC on at least one of two standard views of either or both breasts. The screening mammograms were read in a uniform fashion by 1 of 21 radiologists, who used identical and well-accepted criteria for BACs. Overall, 268 women (14%) were BAC positive, in line with the 9%-17.5% prevalence reported in the literature, Dr. Schnatz said.
BACs are diffuse calcifications of the arterial tunica media, which are common but often unreported by radiologists who find them on screening mammograms, though they are seen in up to 17.5% of mammograms.
Medial arterial calcifications, such as BACs, are fine-grained deposits seen in small- to medium-sized muscular arteries. Though they have been observed for some time, their significance has been unknown, and they are often seen as part of the normal aging process, Dr. Schnatz said. With the advent of newer mammography technology in the 2000s, much smaller calcifications could be seen, and research into the significance of BACs detected on screening mammogram was revived and refined, he said.
“If BAC has value as a marker for coronary artery disease, then mammograms could be a practical tool for detecting CAD risk in women,” Dr. Schnatz said. “This might contribute to earlier detection of vascular damage, especially important in women at high risk of CAD or with unrecognized heart disease.”
Dr. Schnatz said he plans to incorporate BAC status into validated cardiovascular risk predictors, and see how a prediction model that includes BAC fares.
Dr. Schnatz reported having no relevant financial disclosures.
[email protected]
On Twitter @karioakes
Longitudinal results of a prospective study of women with and without breast arterial calcifications showed that women with the calcifications were significantly more likely to have atherosclerotic cardiovascular events than were women without them.
In a 10-year follow-up of a cohort of women receiving screening mammograms, women who did not have cardiovascular disease at baseline and were positive for breast arterial calcifications (BACs) were three times more likely to develop atherosclerotic cardiovascular disease (ASCVD) as those who were BAC negative at baseline (9.8% vs. 3.3%; P = .001).
These results paralleled those found 5 years previously among the cohort. At that point, 6.3% of the BAC-positive group developed ASCVD, compared with 2.3% of the BAC-negative group (P = .003). At 10 years, “multiple logistic regression analysis found BAC to be strongly associated with ASCVD events, with an odds ratio of 2.29,” senior investigator Peter Schnatz, DO, said in an interview.
Based on these results, Dr. Schnatz and his coinvestigators are suggesting that BACs be routinely reported on mammograms and viewed as a marker for the development of cardiovascular disease.
Presenting the unpublished 10-year findings at the annual meeting of the North American Menopause Society, Dr. Schnatz, the society’s 2015-2016 president, said that the BAC-positive group was also more likely to develop risk factors for ASCVD (86.8% vs. 76.3; P = .01).
These risk factors were age, hypertension, hypercholesterolemia, diabetes, and menopause. The other results were significant after the investigators controlled for age, so the increased risk was not merely caused by the passage of time and the normal aging process.
The prospective study compared age-matched controls with and without BACs to determine whether BACs seen on routine mammography can predict the development of ASCVD, by tracking the presence of BACs and gathering information about ASCVD risk factors and events via patient self-report in an annual questionnaire. The events that were considered ASCVD markers were angina, myocardial infarction, an abnormal angiogram, coronary artery bypass grafting, and stroke.
The initial baseline study upon which the longitudinal prospective studies are based gathered data from 1,919 women with a median age of 56, plus or minus 12.7 years (range, 25-96), to determine whether women with BAC had an increased frequency of cardiovascular disease risk factors, and of ASCVD. Baseline findings showed an independent association of BAC with multiple risk factors and with ASCVD events, even after age was controlled for.
Dr. Schnatz, who is a professor of ob.gyn. and internal medicine at Thomas Jefferson University, Philadelphia, said in his presentation that BACs “appear to be a risk indicator of the presence of ASCVD. More importantly, in this first prospective analysis of BAC as a risk predictor, BAC appears to be a risk predictor for the future development of ASCVD.”
Patients were considered BAC positive if their mammograms showed BAC on at least one of two standard views of either or both breasts. The screening mammograms were read in a uniform fashion by 1 of 21 radiologists, who used identical and well-accepted criteria for BACs. Overall, 268 women (14%) were BAC positive, in line with the 9%-17.5% prevalence reported in the literature, Dr. Schnatz said.
BACs are diffuse calcifications of the arterial tunica media, which are common but often unreported by radiologists who find them on screening mammograms, though they are seen in up to 17.5% of mammograms.
Medial arterial calcifications, such as BACs, are fine-grained deposits seen in small- to medium-sized muscular arteries. Though they have been observed for some time, their significance has been unknown, and they are often seen as part of the normal aging process, Dr. Schnatz said. With the advent of newer mammography technology in the 2000s, much smaller calcifications could be seen, and research into the significance of BACs detected on screening mammogram was revived and refined, he said.
“If BAC has value as a marker for coronary artery disease, then mammograms could be a practical tool for detecting CAD risk in women,” Dr. Schnatz said. “This might contribute to earlier detection of vascular damage, especially important in women at high risk of CAD or with unrecognized heart disease.”
Dr. Schnatz said he plans to incorporate BAC status into validated cardiovascular risk predictors, and see how a prediction model that includes BAC fares.
Dr. Schnatz reported having no relevant financial disclosures.
[email protected]
On Twitter @karioakes
Longitudinal results of a prospective study of women with and without breast arterial calcifications showed that women with the calcifications were significantly more likely to have atherosclerotic cardiovascular events than were women without them.
In a 10-year follow-up of a cohort of women receiving screening mammograms, women who did not have cardiovascular disease at baseline and were positive for breast arterial calcifications (BACs) were three times more likely to develop atherosclerotic cardiovascular disease (ASCVD) as those who were BAC negative at baseline (9.8% vs. 3.3%; P = .001).
These results paralleled those found 5 years previously among the cohort. At that point, 6.3% of the BAC-positive group developed ASCVD, compared with 2.3% of the BAC-negative group (P = .003). At 10 years, “multiple logistic regression analysis found BAC to be strongly associated with ASCVD events, with an odds ratio of 2.29,” senior investigator Peter Schnatz, DO, said in an interview.
Based on these results, Dr. Schnatz and his coinvestigators are suggesting that BACs be routinely reported on mammograms and viewed as a marker for the development of cardiovascular disease.
Presenting the unpublished 10-year findings at the annual meeting of the North American Menopause Society, Dr. Schnatz, the society’s 2015-2016 president, said that the BAC-positive group was also more likely to develop risk factors for ASCVD (86.8% vs. 76.3; P = .01).
These risk factors were age, hypertension, hypercholesterolemia, diabetes, and menopause. The other results were significant after the investigators controlled for age, so the increased risk was not merely caused by the passage of time and the normal aging process.
The prospective study compared age-matched controls with and without BACs to determine whether BACs seen on routine mammography can predict the development of ASCVD, by tracking the presence of BACs and gathering information about ASCVD risk factors and events via patient self-report in an annual questionnaire. The events that were considered ASCVD markers were angina, myocardial infarction, an abnormal angiogram, coronary artery bypass grafting, and stroke.
The initial baseline study upon which the longitudinal prospective studies are based gathered data from 1,919 women with a median age of 56, plus or minus 12.7 years (range, 25-96), to determine whether women with BAC had an increased frequency of cardiovascular disease risk factors, and of ASCVD. Baseline findings showed an independent association of BAC with multiple risk factors and with ASCVD events, even after age was controlled for.
Dr. Schnatz, who is a professor of ob.gyn. and internal medicine at Thomas Jefferson University, Philadelphia, said in his presentation that BACs “appear to be a risk indicator of the presence of ASCVD. More importantly, in this first prospective analysis of BAC as a risk predictor, BAC appears to be a risk predictor for the future development of ASCVD.”
Patients were considered BAC positive if their mammograms showed BAC on at least one of two standard views of either or both breasts. The screening mammograms were read in a uniform fashion by 1 of 21 radiologists, who used identical and well-accepted criteria for BACs. Overall, 268 women (14%) were BAC positive, in line with the 9%-17.5% prevalence reported in the literature, Dr. Schnatz said.
BACs are diffuse calcifications of the arterial tunica media, which are common but often unreported by radiologists who find them on screening mammograms, though they are seen in up to 17.5% of mammograms.
Medial arterial calcifications, such as BACs, are fine-grained deposits seen in small- to medium-sized muscular arteries. Though they have been observed for some time, their significance has been unknown, and they are often seen as part of the normal aging process, Dr. Schnatz said. With the advent of newer mammography technology in the 2000s, much smaller calcifications could be seen, and research into the significance of BACs detected on screening mammogram was revived and refined, he said.
“If BAC has value as a marker for coronary artery disease, then mammograms could be a practical tool for detecting CAD risk in women,” Dr. Schnatz said. “This might contribute to earlier detection of vascular damage, especially important in women at high risk of CAD or with unrecognized heart disease.”
Dr. Schnatz said he plans to incorporate BAC status into validated cardiovascular risk predictors, and see how a prediction model that includes BAC fares.
Dr. Schnatz reported having no relevant financial disclosures.
[email protected]
On Twitter @karioakes
FROM THE NAMS 2016 ANNUAL MEETING
Key clinical point:
Major finding: BAC-positive women were three times more likely to develop ASCVD than were BAC-negative women (9.8% vs. 3.3%; P = .001)
Data source: A prospective longitudinal study of an initial cohort of 1,919 women receiving screening mammograms.
Disclosures: No outside funding source was reported. Dr. Schnatz reported having no relevant financial disclosures.
Hot flashes and sleep disruption contribute independently to depression in menopause
Hot flashes and sleep disruption contribute independently to the development of depression in menopause, judging from the findings of a recent study.
In that study, 29 premenopausal women, aged 18-45 years, received a single dose of the GnRH agonist leuprolide in order to induce hypoestrogenism and ovarian suppression for the study period. The women in the study had no history of primary sleep disturbances, low estrogen levels, or depression, according to Hadine Joffe, MD, director of the Women’s Hormone and Aging Research Program at Harvard Medical School, in Boston, and her associates.
All the study participants underwent baseline mood evaluation using both the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI). Existing sleep disturbances were ruled out at baseline with sleep diaries, questionnaires, and two ambulatory screening polysomnography (PSG) studies.
After 4 weeks of administration of leuprolide, depressive symptoms had developed among most of the women in the study. The mean MADRS score was 4.1, and overall, it was 3.1 points higher than it had been at baseline. One woman had a 15-point increase in her score, suggesting significant depression. The MADRS score increased by at least 5 points in 24% of the women and remained unchanged in 38%, reflecting variability among the women on the impact of leuprolide on depressive symptoms, the investigators reported (J Clin Endocrinol Metab. 2016 Sep 20. doi: 10.1210/jc.2016-2348).
Leuprolide universally suppressed estradiol to postmenopausal levels in the women within 2 weeks. Hot flashes developed in 20 (69%) women, with a median of 3.6 hot flashes during the day and 3.8 at night. The median number of objectively measured nighttime hot flashes per night was 3.
Changes to sleep patterns varied widely for each woman; for example, wake time after sleep onset ranged from an additional 140 minutes to 23 fewer minutes for one woman. There was a correlation between the number of subjectively reported nighttime hot flashes with increased sleep fragmentation as measured by PSG. The number of reported nighttime hot flashes was associated with an increase in depressive symptoms that was disproportionate to the number of nighttime hot flashes reported, according to the findings of a univariate analysis. The number of daytime hot flashes had no such effect.
In light of these findings, Dr. Joffe and her associates urged clinicians to screen women who report nighttime hot flashes and sleep interruption for mood disturbance. “Treatment of those with menopause-related depressive symptoms should encompass therapies that improve sleep interruption as well as nocturnal [hot flashes],” they wrote.
The study was sponsored by the National Institute of Mental Health. Dr. Joffe has received grant support from Merck and has served as a consultant/adviser for Merck, Mitsubishi Tanabe, NeRRe Therapeutics, and Noven.
Hot flashes and sleep disruption contribute independently to the development of depression in menopause, judging from the findings of a recent study.
In that study, 29 premenopausal women, aged 18-45 years, received a single dose of the GnRH agonist leuprolide in order to induce hypoestrogenism and ovarian suppression for the study period. The women in the study had no history of primary sleep disturbances, low estrogen levels, or depression, according to Hadine Joffe, MD, director of the Women’s Hormone and Aging Research Program at Harvard Medical School, in Boston, and her associates.
All the study participants underwent baseline mood evaluation using both the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI). Existing sleep disturbances were ruled out at baseline with sleep diaries, questionnaires, and two ambulatory screening polysomnography (PSG) studies.
After 4 weeks of administration of leuprolide, depressive symptoms had developed among most of the women in the study. The mean MADRS score was 4.1, and overall, it was 3.1 points higher than it had been at baseline. One woman had a 15-point increase in her score, suggesting significant depression. The MADRS score increased by at least 5 points in 24% of the women and remained unchanged in 38%, reflecting variability among the women on the impact of leuprolide on depressive symptoms, the investigators reported (J Clin Endocrinol Metab. 2016 Sep 20. doi: 10.1210/jc.2016-2348).
Leuprolide universally suppressed estradiol to postmenopausal levels in the women within 2 weeks. Hot flashes developed in 20 (69%) women, with a median of 3.6 hot flashes during the day and 3.8 at night. The median number of objectively measured nighttime hot flashes per night was 3.
Changes to sleep patterns varied widely for each woman; for example, wake time after sleep onset ranged from an additional 140 minutes to 23 fewer minutes for one woman. There was a correlation between the number of subjectively reported nighttime hot flashes with increased sleep fragmentation as measured by PSG. The number of reported nighttime hot flashes was associated with an increase in depressive symptoms that was disproportionate to the number of nighttime hot flashes reported, according to the findings of a univariate analysis. The number of daytime hot flashes had no such effect.
In light of these findings, Dr. Joffe and her associates urged clinicians to screen women who report nighttime hot flashes and sleep interruption for mood disturbance. “Treatment of those with menopause-related depressive symptoms should encompass therapies that improve sleep interruption as well as nocturnal [hot flashes],” they wrote.
The study was sponsored by the National Institute of Mental Health. Dr. Joffe has received grant support from Merck and has served as a consultant/adviser for Merck, Mitsubishi Tanabe, NeRRe Therapeutics, and Noven.
Hot flashes and sleep disruption contribute independently to the development of depression in menopause, judging from the findings of a recent study.
In that study, 29 premenopausal women, aged 18-45 years, received a single dose of the GnRH agonist leuprolide in order to induce hypoestrogenism and ovarian suppression for the study period. The women in the study had no history of primary sleep disturbances, low estrogen levels, or depression, according to Hadine Joffe, MD, director of the Women’s Hormone and Aging Research Program at Harvard Medical School, in Boston, and her associates.
All the study participants underwent baseline mood evaluation using both the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI). Existing sleep disturbances were ruled out at baseline with sleep diaries, questionnaires, and two ambulatory screening polysomnography (PSG) studies.
After 4 weeks of administration of leuprolide, depressive symptoms had developed among most of the women in the study. The mean MADRS score was 4.1, and overall, it was 3.1 points higher than it had been at baseline. One woman had a 15-point increase in her score, suggesting significant depression. The MADRS score increased by at least 5 points in 24% of the women and remained unchanged in 38%, reflecting variability among the women on the impact of leuprolide on depressive symptoms, the investigators reported (J Clin Endocrinol Metab. 2016 Sep 20. doi: 10.1210/jc.2016-2348).
Leuprolide universally suppressed estradiol to postmenopausal levels in the women within 2 weeks. Hot flashes developed in 20 (69%) women, with a median of 3.6 hot flashes during the day and 3.8 at night. The median number of objectively measured nighttime hot flashes per night was 3.
Changes to sleep patterns varied widely for each woman; for example, wake time after sleep onset ranged from an additional 140 minutes to 23 fewer minutes for one woman. There was a correlation between the number of subjectively reported nighttime hot flashes with increased sleep fragmentation as measured by PSG. The number of reported nighttime hot flashes was associated with an increase in depressive symptoms that was disproportionate to the number of nighttime hot flashes reported, according to the findings of a univariate analysis. The number of daytime hot flashes had no such effect.
In light of these findings, Dr. Joffe and her associates urged clinicians to screen women who report nighttime hot flashes and sleep interruption for mood disturbance. “Treatment of those with menopause-related depressive symptoms should encompass therapies that improve sleep interruption as well as nocturnal [hot flashes],” they wrote.
The study was sponsored by the National Institute of Mental Health. Dr. Joffe has received grant support from Merck and has served as a consultant/adviser for Merck, Mitsubishi Tanabe, NeRRe Therapeutics, and Noven.
FROM THE JOURNAL OF ENDOCRINOLOGY & METABOLISM
Key clinical point: Hot flashes and sleep disruption contribute independently to the development of depression in menopause.
Major finding: Depression scores increased by 3 points on the MADRS after 4 weeks on GnRH agonist leuprolide. Sleep disruption was also common among the women in the study. Depression developed among many, but not all the women, with univariate analysis showing that hot flashes and sleep disruption contributed independently to their mood changes.
Data source: A prospective study in which 29 young women without depression were subjected to rapid, premature, and reversible menopause with one open-label dose of leuprolide in an experimental model.
Disclosures: The study was sponsored by the National Institute of Mental Health. Dr. Hadine Joffe has received grant support from Merck and has served as a consultant/adviser for Merck, Mitsubishi Tanabe, NeRRe Therapeutics, and Noven.
Letter to the Editor: Menopause and HT
“2016 UPDATE ON MENOPAUSE”
ANDREW M. KAUNITZ, MD (JULY 2016)
Menopause and hormone therapy
As a long-term believer (proven!) of the value of the old comment, “estrogen forever,” I was pleased to see all the positive comments about estrogen in Dr. Kaunitz’s article. I was disappointed, however, in the comments in the box (page 39), “What this evidence means for practice.”
While my prejudice, statistically supported, is old fashioned, omission of the newer and marvelous way to counteract the only bad effects of estrogen (endometrial stimulation leading to endometrial adenocarcinoma) seems to be a major oversight. The new and least (if any) side-effect method means a levonorgestrel-releasing intrauterine device (LNG-IUD) yielding local progesterone counteraction to this major side effect of estrogen therapy.
Arthur A. Fleisher II, MD
Northridge, California
Dr. Kaunitz responds
I thank Dr. Fleisher for his interest in my 2016 Update on Menopause. I agree that off-label use of the LNG-IUD represents an appropriate alternative to systemic progestin when using estrogen to treat menopausal symptoms in women with an intact uterus.
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.
“2016 UPDATE ON MENOPAUSE”
ANDREW M. KAUNITZ, MD (JULY 2016)
Menopause and hormone therapy
As a long-term believer (proven!) of the value of the old comment, “estrogen forever,” I was pleased to see all the positive comments about estrogen in Dr. Kaunitz’s article. I was disappointed, however, in the comments in the box (page 39), “What this evidence means for practice.”
While my prejudice, statistically supported, is old fashioned, omission of the newer and marvelous way to counteract the only bad effects of estrogen (endometrial stimulation leading to endometrial adenocarcinoma) seems to be a major oversight. The new and least (if any) side-effect method means a levonorgestrel-releasing intrauterine device (LNG-IUD) yielding local progesterone counteraction to this major side effect of estrogen therapy.
Arthur A. Fleisher II, MD
Northridge, California
Dr. Kaunitz responds
I thank Dr. Fleisher for his interest in my 2016 Update on Menopause. I agree that off-label use of the LNG-IUD represents an appropriate alternative to systemic progestin when using estrogen to treat menopausal symptoms in women with an intact uterus.
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.
“2016 UPDATE ON MENOPAUSE”
ANDREW M. KAUNITZ, MD (JULY 2016)
Menopause and hormone therapy
As a long-term believer (proven!) of the value of the old comment, “estrogen forever,” I was pleased to see all the positive comments about estrogen in Dr. Kaunitz’s article. I was disappointed, however, in the comments in the box (page 39), “What this evidence means for practice.”
While my prejudice, statistically supported, is old fashioned, omission of the newer and marvelous way to counteract the only bad effects of estrogen (endometrial stimulation leading to endometrial adenocarcinoma) seems to be a major oversight. The new and least (if any) side-effect method means a levonorgestrel-releasing intrauterine device (LNG-IUD) yielding local progesterone counteraction to this major side effect of estrogen therapy.
Arthur A. Fleisher II, MD
Northridge, California
Dr. Kaunitz responds
I thank Dr. Fleisher for his interest in my 2016 Update on Menopause. I agree that off-label use of the LNG-IUD represents an appropriate alternative to systemic progestin when using estrogen to treat menopausal symptoms in women with an intact uterus.
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Decision rule identifies unprovoked VTE patients who can halt anticoagulation
ROME – Half of all women who experience a first unprovoked venous thromboembolism (VTE) can safely be spared lifelong anticoagulation through application of the newly validated HERDOO2 decision rule, Marc A. Rodger, MD, reported at the annual congress of the European Society of Cardiology.
“We’ve validated that a simple, memorable decision rule on anticoagulation applied at the clinically relevant time point works. And it is the only clinical decision rule that has now been prospectively validated,” said Dr. Rodger, professor of medicine, chief and chair of the division of hematology, and head of the thrombosis program at the University of Ottawa.
He presented the results of the validation study, known as the REVERSE II study, which included 2,779 patients with a first unprovoked VTE at 44 centers in seven countries. The full name of the decision rule is “Men Continue and HERDOO2,” a name that says it all: the rule posits that all men as well as those women with a HERDOO2 (Hyperpigmentation, Edema, Redness, d-dimer, Obesity, Older age, 2 or more points) score of at least 2 out of a possible 4 points need to stay on anticoagulation indefinitely because their risk of a recurrent VTE off-therapy clearly exceeds that of a bleeding event on-therapy. In contrast, women with a HERDOO2 score of 0 or 1 can safely stop anticoagulation after the standard 3-6 months of acute short-term therapy.
“Sorry, gentlemen, but we could find no low-risk group of men. They were all high risk,” he said. “But 50% of women with unprovoked vein blood clots can be spared the burdens, costs, and risks of lifelong blood thinners.”
Dr. Rodger and coinvestigators began work on developing a multivariate clinical decision rule in 2001. They examined 69 risk predictors, eventually winnowing down to a manageable four potent risk predictors identified by the acronym HERDOO2.
The derivation study was published 8 years ago (CMAJ. 2008;Aug 26;179[5]:417-26). It showed that women with a HERDOO2 score of 2 or more as well as all men had roughly a 14% rate of recurrent VTE in the first year after stopping anticoagulation, while women with a score of 0 or 1 had about a 1.6% risk. The International Society on Thrombosis and Haemostasis suggests that it’s safe to discontinue anticoagulants if the risk of recurrent thrombosis at 1 year off-therapy is less than 5%, given the significant risk of serious bleeding on-therapy and the fact that a serious bleed event is two to three times more likely than a VTE to be fatal.
Dr. Rodger and coinvestigators recognized that a clinical decision rule needs to be externally validated before it’s ready for prime-time use in clinical practice. Thus, they conducted the REVERSE II study, in which the decision rule was applied after the 2,799 participants had been on anticoagulation for 5-12 months. All had a first proximal deep vein thrombosis and/or a segmental or greater pulmonary embolism. Patients were still on anticoagulation at the time the rule was applied, which is why the cut point for a positive d-dimer test in HERDOO2 is 250 mcg/L, half of the threshold value for a positive test in patients not on anticoagulation.
They identified 631 women as low risk, with a HERDOO2 score of 0 or 1. They and their physicians were instructed to stop anticoagulation at that time. The 2,148 high-risk subjects – that is, all of the men and the high-risk women – were advised to remain on anticoagulation. The primary study endpoint was the rate of recurrent VTE in the 12 months following testing and patient guidance. The lost-to-follow-up rate was 2.2%.
The recurrent VTE rate was 3% in the 591 low-risk women who discontinued anticoagulants and zero in 31 others who elected to stay on medication. In the high-risk group identified by the HERDOO2 rule, the recurrent VTE rate at 12 months was 8.1% in the 323 who opted to discontinue anticoagulants and just 1.6% in 1,802 who continued on therapy as advised, a finding that underscores the effectiveness of selectively applied long-term anticoagulation therapy, he continued.
The recurrent VTE rate among the 291 women with a HERDOO2 score of 0 or 1 who were on exogenous estrogen was 1.4%, while in high-risk women taking estrogen the rate was more than doubled at 3.1%. But in women aged 50-64 identified by the HERDOO2 rule as being low risk, the actual recurrent VTE rate was 5.7%, a finding that raised a red flag for the investigators.
“There may be an evolution of the HERDOO2 decision rule to a lower age cut point. But that’s something that requires further study in postmenopausal women,” according to Dr. Rodger.
The investigators defined a first unprovoked VTE as one occurring in the absence during the previous 90 days of major surgery, a fracture or cast, more than 3 days of immobilization, or malignancy within the last 5 years.
Venous thromboembolism is the second most common cardiovascular disorder and the third most common cause of cardiovascular death. Unprovoked VTEs account for half of all VTEs. Their management has been a controversial subject. Both the American College of Chest Physicians and the European Society of Cardiology recommend continuing anticoagulation indefinitely in patients who aren’t at high bleeding risk.
“But this is a relatively weak 2B recommendation because of the tightly balanced competing risks of recurrent thrombosis off anticoagulation and major bleeding on anticoagulation,” Dr. Rodger said. He added that he considers REVERSE II to be practice changing, and predicted that once the results are published the guidelines will be revised.
Discussant Giancarlo Agnelli, MD, was a tough critic who gave fair warning.
“I am friends with many of the authors of this paper, and in this country we are usually gentle with enemies and nasty with friends,” declared Dr. Agnelli, professor of internal medicine and director of internal and cardiovascular medicine and the stroke unit at the University of Perugia, Italy.
He didn’t find the REVERSE II study or the HERDOO2 rule persuasive. On the plus side, he said, the HERDOO2 rule has now been validated, unlike the proposed DASH and Vienna rules. And it was tested in a diverse multinational patient population. But the fact that the HERDOO2 rule is only applicable in women is a major limitation. And REVERSE II was not a randomized trial, Dr. Agnelli noted.
Moreover, 1 year of follow-up seems insufficient, he continued. He cited a French multicenter trial in which patients with a first unprovoked VTE received 6 months of anticoagulants and were then randomized to another 18 months of anticoagulation or placebo. During that 18 months, the group on anticoagulants had a significantly lower rate of the composite endpoint comprised of recurrent VTE or major bleeding, but once that period was over they experienced catchup. By the time the study ended at 42 months, the two study arms didn’t differ significantly in the composite endpoint (JAMA. 2015 Jul 7;314[1]:31-40).
More broadly, Dr. Agnelli also questioned the need for an anticoagulation discontinuation rule in the contemporary era of new oral anticoagulants (NOACs). He was lead investigator in the AMPLIFY study, a major randomized trial of fixed-dose apixaban (Eliquis) versus conventional therapy with subcutaneous enoxaparin (Lovenox) bridging to warfarin in 5,395 patients with acute VTE. The NOAC was associated with a 69% reduction in the relative risk of bleeding and was noninferior to standard therapy in the risk of recurrent VTE (N Engl J Med. 2013 Aug 29;369[9]:799-808).
“Why should we think about withholding anticoagulation in some patients when we now have such a safe approach?” he asked.
Dr. Rodger reported receiving research grants from the French government as well as from Biomerieux, which funded the REVERSE II study. Dr. Agnelli reported having no financial conflicts.
ROME – Half of all women who experience a first unprovoked venous thromboembolism (VTE) can safely be spared lifelong anticoagulation through application of the newly validated HERDOO2 decision rule, Marc A. Rodger, MD, reported at the annual congress of the European Society of Cardiology.
“We’ve validated that a simple, memorable decision rule on anticoagulation applied at the clinically relevant time point works. And it is the only clinical decision rule that has now been prospectively validated,” said Dr. Rodger, professor of medicine, chief and chair of the division of hematology, and head of the thrombosis program at the University of Ottawa.
He presented the results of the validation study, known as the REVERSE II study, which included 2,779 patients with a first unprovoked VTE at 44 centers in seven countries. The full name of the decision rule is “Men Continue and HERDOO2,” a name that says it all: the rule posits that all men as well as those women with a HERDOO2 (Hyperpigmentation, Edema, Redness, d-dimer, Obesity, Older age, 2 or more points) score of at least 2 out of a possible 4 points need to stay on anticoagulation indefinitely because their risk of a recurrent VTE off-therapy clearly exceeds that of a bleeding event on-therapy. In contrast, women with a HERDOO2 score of 0 or 1 can safely stop anticoagulation after the standard 3-6 months of acute short-term therapy.
“Sorry, gentlemen, but we could find no low-risk group of men. They were all high risk,” he said. “But 50% of women with unprovoked vein blood clots can be spared the burdens, costs, and risks of lifelong blood thinners.”
Dr. Rodger and coinvestigators began work on developing a multivariate clinical decision rule in 2001. They examined 69 risk predictors, eventually winnowing down to a manageable four potent risk predictors identified by the acronym HERDOO2.
The derivation study was published 8 years ago (CMAJ. 2008;Aug 26;179[5]:417-26). It showed that women with a HERDOO2 score of 2 or more as well as all men had roughly a 14% rate of recurrent VTE in the first year after stopping anticoagulation, while women with a score of 0 or 1 had about a 1.6% risk. The International Society on Thrombosis and Haemostasis suggests that it’s safe to discontinue anticoagulants if the risk of recurrent thrombosis at 1 year off-therapy is less than 5%, given the significant risk of serious bleeding on-therapy and the fact that a serious bleed event is two to three times more likely than a VTE to be fatal.
Dr. Rodger and coinvestigators recognized that a clinical decision rule needs to be externally validated before it’s ready for prime-time use in clinical practice. Thus, they conducted the REVERSE II study, in which the decision rule was applied after the 2,799 participants had been on anticoagulation for 5-12 months. All had a first proximal deep vein thrombosis and/or a segmental or greater pulmonary embolism. Patients were still on anticoagulation at the time the rule was applied, which is why the cut point for a positive d-dimer test in HERDOO2 is 250 mcg/L, half of the threshold value for a positive test in patients not on anticoagulation.
They identified 631 women as low risk, with a HERDOO2 score of 0 or 1. They and their physicians were instructed to stop anticoagulation at that time. The 2,148 high-risk subjects – that is, all of the men and the high-risk women – were advised to remain on anticoagulation. The primary study endpoint was the rate of recurrent VTE in the 12 months following testing and patient guidance. The lost-to-follow-up rate was 2.2%.
The recurrent VTE rate was 3% in the 591 low-risk women who discontinued anticoagulants and zero in 31 others who elected to stay on medication. In the high-risk group identified by the HERDOO2 rule, the recurrent VTE rate at 12 months was 8.1% in the 323 who opted to discontinue anticoagulants and just 1.6% in 1,802 who continued on therapy as advised, a finding that underscores the effectiveness of selectively applied long-term anticoagulation therapy, he continued.
The recurrent VTE rate among the 291 women with a HERDOO2 score of 0 or 1 who were on exogenous estrogen was 1.4%, while in high-risk women taking estrogen the rate was more than doubled at 3.1%. But in women aged 50-64 identified by the HERDOO2 rule as being low risk, the actual recurrent VTE rate was 5.7%, a finding that raised a red flag for the investigators.
“There may be an evolution of the HERDOO2 decision rule to a lower age cut point. But that’s something that requires further study in postmenopausal women,” according to Dr. Rodger.
The investigators defined a first unprovoked VTE as one occurring in the absence during the previous 90 days of major surgery, a fracture or cast, more than 3 days of immobilization, or malignancy within the last 5 years.
Venous thromboembolism is the second most common cardiovascular disorder and the third most common cause of cardiovascular death. Unprovoked VTEs account for half of all VTEs. Their management has been a controversial subject. Both the American College of Chest Physicians and the European Society of Cardiology recommend continuing anticoagulation indefinitely in patients who aren’t at high bleeding risk.
“But this is a relatively weak 2B recommendation because of the tightly balanced competing risks of recurrent thrombosis off anticoagulation and major bleeding on anticoagulation,” Dr. Rodger said. He added that he considers REVERSE II to be practice changing, and predicted that once the results are published the guidelines will be revised.
Discussant Giancarlo Agnelli, MD, was a tough critic who gave fair warning.
“I am friends with many of the authors of this paper, and in this country we are usually gentle with enemies and nasty with friends,” declared Dr. Agnelli, professor of internal medicine and director of internal and cardiovascular medicine and the stroke unit at the University of Perugia, Italy.
He didn’t find the REVERSE II study or the HERDOO2 rule persuasive. On the plus side, he said, the HERDOO2 rule has now been validated, unlike the proposed DASH and Vienna rules. And it was tested in a diverse multinational patient population. But the fact that the HERDOO2 rule is only applicable in women is a major limitation. And REVERSE II was not a randomized trial, Dr. Agnelli noted.
Moreover, 1 year of follow-up seems insufficient, he continued. He cited a French multicenter trial in which patients with a first unprovoked VTE received 6 months of anticoagulants and were then randomized to another 18 months of anticoagulation or placebo. During that 18 months, the group on anticoagulants had a significantly lower rate of the composite endpoint comprised of recurrent VTE or major bleeding, but once that period was over they experienced catchup. By the time the study ended at 42 months, the two study arms didn’t differ significantly in the composite endpoint (JAMA. 2015 Jul 7;314[1]:31-40).
More broadly, Dr. Agnelli also questioned the need for an anticoagulation discontinuation rule in the contemporary era of new oral anticoagulants (NOACs). He was lead investigator in the AMPLIFY study, a major randomized trial of fixed-dose apixaban (Eliquis) versus conventional therapy with subcutaneous enoxaparin (Lovenox) bridging to warfarin in 5,395 patients with acute VTE. The NOAC was associated with a 69% reduction in the relative risk of bleeding and was noninferior to standard therapy in the risk of recurrent VTE (N Engl J Med. 2013 Aug 29;369[9]:799-808).
“Why should we think about withholding anticoagulation in some patients when we now have such a safe approach?” he asked.
Dr. Rodger reported receiving research grants from the French government as well as from Biomerieux, which funded the REVERSE II study. Dr. Agnelli reported having no financial conflicts.
ROME – Half of all women who experience a first unprovoked venous thromboembolism (VTE) can safely be spared lifelong anticoagulation through application of the newly validated HERDOO2 decision rule, Marc A. Rodger, MD, reported at the annual congress of the European Society of Cardiology.
“We’ve validated that a simple, memorable decision rule on anticoagulation applied at the clinically relevant time point works. And it is the only clinical decision rule that has now been prospectively validated,” said Dr. Rodger, professor of medicine, chief and chair of the division of hematology, and head of the thrombosis program at the University of Ottawa.
He presented the results of the validation study, known as the REVERSE II study, which included 2,779 patients with a first unprovoked VTE at 44 centers in seven countries. The full name of the decision rule is “Men Continue and HERDOO2,” a name that says it all: the rule posits that all men as well as those women with a HERDOO2 (Hyperpigmentation, Edema, Redness, d-dimer, Obesity, Older age, 2 or more points) score of at least 2 out of a possible 4 points need to stay on anticoagulation indefinitely because their risk of a recurrent VTE off-therapy clearly exceeds that of a bleeding event on-therapy. In contrast, women with a HERDOO2 score of 0 or 1 can safely stop anticoagulation after the standard 3-6 months of acute short-term therapy.
“Sorry, gentlemen, but we could find no low-risk group of men. They were all high risk,” he said. “But 50% of women with unprovoked vein blood clots can be spared the burdens, costs, and risks of lifelong blood thinners.”
Dr. Rodger and coinvestigators began work on developing a multivariate clinical decision rule in 2001. They examined 69 risk predictors, eventually winnowing down to a manageable four potent risk predictors identified by the acronym HERDOO2.
The derivation study was published 8 years ago (CMAJ. 2008;Aug 26;179[5]:417-26). It showed that women with a HERDOO2 score of 2 or more as well as all men had roughly a 14% rate of recurrent VTE in the first year after stopping anticoagulation, while women with a score of 0 or 1 had about a 1.6% risk. The International Society on Thrombosis and Haemostasis suggests that it’s safe to discontinue anticoagulants if the risk of recurrent thrombosis at 1 year off-therapy is less than 5%, given the significant risk of serious bleeding on-therapy and the fact that a serious bleed event is two to three times more likely than a VTE to be fatal.
Dr. Rodger and coinvestigators recognized that a clinical decision rule needs to be externally validated before it’s ready for prime-time use in clinical practice. Thus, they conducted the REVERSE II study, in which the decision rule was applied after the 2,799 participants had been on anticoagulation for 5-12 months. All had a first proximal deep vein thrombosis and/or a segmental or greater pulmonary embolism. Patients were still on anticoagulation at the time the rule was applied, which is why the cut point for a positive d-dimer test in HERDOO2 is 250 mcg/L, half of the threshold value for a positive test in patients not on anticoagulation.
They identified 631 women as low risk, with a HERDOO2 score of 0 or 1. They and their physicians were instructed to stop anticoagulation at that time. The 2,148 high-risk subjects – that is, all of the men and the high-risk women – were advised to remain on anticoagulation. The primary study endpoint was the rate of recurrent VTE in the 12 months following testing and patient guidance. The lost-to-follow-up rate was 2.2%.
The recurrent VTE rate was 3% in the 591 low-risk women who discontinued anticoagulants and zero in 31 others who elected to stay on medication. In the high-risk group identified by the HERDOO2 rule, the recurrent VTE rate at 12 months was 8.1% in the 323 who opted to discontinue anticoagulants and just 1.6% in 1,802 who continued on therapy as advised, a finding that underscores the effectiveness of selectively applied long-term anticoagulation therapy, he continued.
The recurrent VTE rate among the 291 women with a HERDOO2 score of 0 or 1 who were on exogenous estrogen was 1.4%, while in high-risk women taking estrogen the rate was more than doubled at 3.1%. But in women aged 50-64 identified by the HERDOO2 rule as being low risk, the actual recurrent VTE rate was 5.7%, a finding that raised a red flag for the investigators.
“There may be an evolution of the HERDOO2 decision rule to a lower age cut point. But that’s something that requires further study in postmenopausal women,” according to Dr. Rodger.
The investigators defined a first unprovoked VTE as one occurring in the absence during the previous 90 days of major surgery, a fracture or cast, more than 3 days of immobilization, or malignancy within the last 5 years.
Venous thromboembolism is the second most common cardiovascular disorder and the third most common cause of cardiovascular death. Unprovoked VTEs account for half of all VTEs. Their management has been a controversial subject. Both the American College of Chest Physicians and the European Society of Cardiology recommend continuing anticoagulation indefinitely in patients who aren’t at high bleeding risk.
“But this is a relatively weak 2B recommendation because of the tightly balanced competing risks of recurrent thrombosis off anticoagulation and major bleeding on anticoagulation,” Dr. Rodger said. He added that he considers REVERSE II to be practice changing, and predicted that once the results are published the guidelines will be revised.
Discussant Giancarlo Agnelli, MD, was a tough critic who gave fair warning.
“I am friends with many of the authors of this paper, and in this country we are usually gentle with enemies and nasty with friends,” declared Dr. Agnelli, professor of internal medicine and director of internal and cardiovascular medicine and the stroke unit at the University of Perugia, Italy.
He didn’t find the REVERSE II study or the HERDOO2 rule persuasive. On the plus side, he said, the HERDOO2 rule has now been validated, unlike the proposed DASH and Vienna rules. And it was tested in a diverse multinational patient population. But the fact that the HERDOO2 rule is only applicable in women is a major limitation. And REVERSE II was not a randomized trial, Dr. Agnelli noted.
Moreover, 1 year of follow-up seems insufficient, he continued. He cited a French multicenter trial in which patients with a first unprovoked VTE received 6 months of anticoagulants and were then randomized to another 18 months of anticoagulation or placebo. During that 18 months, the group on anticoagulants had a significantly lower rate of the composite endpoint comprised of recurrent VTE or major bleeding, but once that period was over they experienced catchup. By the time the study ended at 42 months, the two study arms didn’t differ significantly in the composite endpoint (JAMA. 2015 Jul 7;314[1]:31-40).
More broadly, Dr. Agnelli also questioned the need for an anticoagulation discontinuation rule in the contemporary era of new oral anticoagulants (NOACs). He was lead investigator in the AMPLIFY study, a major randomized trial of fixed-dose apixaban (Eliquis) versus conventional therapy with subcutaneous enoxaparin (Lovenox) bridging to warfarin in 5,395 patients with acute VTE. The NOAC was associated with a 69% reduction in the relative risk of bleeding and was noninferior to standard therapy in the risk of recurrent VTE (N Engl J Med. 2013 Aug 29;369[9]:799-808).
“Why should we think about withholding anticoagulation in some patients when we now have such a safe approach?” he asked.
Dr. Rodger reported receiving research grants from the French government as well as from Biomerieux, which funded the REVERSE II study. Dr. Agnelli reported having no financial conflicts.
AT THE ESC CONGRESS 2016
Key clinical point: Half of women who have a first unprovoked venous thromboembolism can safely be spared lifelong anticoagulation through application of the newly validated HERDOO2 decision rule.
Major finding: Women with a first unprovoked venous thromboembolism identified as being at low risk of recurrence on the basis of the HERDOO2 decision rule had a 3% recurrence rate in the year after stopping anticoagulation therapy, while those identified as high risk had an 8.1% recurrence rate if they discontinued anticoagulants.
Data source: This was a prospective, multinational, observational study involving 2,779 patients with a first unprovoked venous thromboembolism.
Disclosures: The presenter reported receiving research grants from the French government as well as from Biomerieux, which funded the REVERSE II study.
