User login
Thermal ablation of duodenal tissue lowers transaminases
BOSTON – An endoscopic procedure that heats and ablates a few centimeters of the surface of the duodenum reduced hepatic transaminases in patients with type 2 diabetes. According to an abstract released in advance of the annual meeting of the American Association for the Study of Liver Diseases , a reduction in transaminases was also seen in a subset of patients who had ultrasonographic evidence of hepatic steatosis.
The meeting presentation will focus on the results of two studies of patients with type 2 diabetes who received duodenal mucosal resurfacing (DMR) to about 9 circumferential cm of their duodenum. The first study, which was a single-site study of 30 patients, was the first human study of DMR. The second study was a multicenter study of 22 patients.
“A single duodenal mucosal resurfacing procedure resulted in a decrease of liver transaminases sustained for 12 months,” Annieke van Baar, an MD-PhD candidate in gastroenterology and hepatology at the Academic University Center, Amsterdam, wrote in the study abstract.
At 6 months after the one-time procedure, the composite cohort of patients in both studies saw a 25% reduction in alanine transaminase, with an absolute reduction of a mean 9.9 plus or minus 22.3 IU/mL. Mean aspartate transaminase also decreased by a mean of 21%, with absolute reduction of a mean 6.1 plus or minus 14.8 IU/mL.
For the subset of 23 patients in the composite cohort who had ultrasound-identified steatosis, AST decreased by 14.4 plus or minus 23 IU/mL at 6 months post procedure; the reduction from baseline was 7.6 plus or minus 9.8 IU/mL at 9 months.
Duodenal mucosal resurfacing, performed endoscopically as a day procedure, has been shown to improve metabolic markers for type 2 diabetes. Though the exact mechanism for improvement is not known, reduction in incretin and other hormonal signaling from the duodenum is thought to increase insulin sensitization.
Patient characteristics were similar in both studies, with a mean age of 52.8 years in the first study and 56.8 in the second. Mean body mass index was 32 kg/m2 in both studies. In the first study, mean baseline hemoglobin A1c (HbA1c) was 9.7%; HbA1c was 8.4% in the second study.
Both study groups saw significant reductions in HbA1c at 6 months post DMR, with reductions of 1.2 plus or minus 1.8% and 0.8 plus or minus 0.9% (P less than .001). Homeostatic model assessment of insulin resistance (HOMA-IR) was reduced after DMR as well, with reductions of 0.9 plus or minus 4, and 2.4 plus or minus 6.8 in the two study groups, though the decrease was not statistically significant.
The transaminase reductions and improved glycemic markers were not accompanied by significant weight loss: Patients lost a mean 1.8 plus or minus 3.6 kg in the first study, and 2.4 plus or minus 3.8 kg in the second study.
“This unique endoscopic intervention deserves further study to ascertain its potential efficacy as a treatment for fatty liver disease,” wrote Ms. van Baar and her coauthors.
The studies were funded by Fractyl Laboratories, the manufacturer of the DMR device. Ms. van Baar had no financial disclosures, but two coauthors reported relationships with Fractyl Laboratories, and another author disclosed relationships with multiple other pharmaceutical companies.
[email protected]
On Twitter @karioakes
BOSTON – An endoscopic procedure that heats and ablates a few centimeters of the surface of the duodenum reduced hepatic transaminases in patients with type 2 diabetes. According to an abstract released in advance of the annual meeting of the American Association for the Study of Liver Diseases , a reduction in transaminases was also seen in a subset of patients who had ultrasonographic evidence of hepatic steatosis.
The meeting presentation will focus on the results of two studies of patients with type 2 diabetes who received duodenal mucosal resurfacing (DMR) to about 9 circumferential cm of their duodenum. The first study, which was a single-site study of 30 patients, was the first human study of DMR. The second study was a multicenter study of 22 patients.
“A single duodenal mucosal resurfacing procedure resulted in a decrease of liver transaminases sustained for 12 months,” Annieke van Baar, an MD-PhD candidate in gastroenterology and hepatology at the Academic University Center, Amsterdam, wrote in the study abstract.
At 6 months after the one-time procedure, the composite cohort of patients in both studies saw a 25% reduction in alanine transaminase, with an absolute reduction of a mean 9.9 plus or minus 22.3 IU/mL. Mean aspartate transaminase also decreased by a mean of 21%, with absolute reduction of a mean 6.1 plus or minus 14.8 IU/mL.
For the subset of 23 patients in the composite cohort who had ultrasound-identified steatosis, AST decreased by 14.4 plus or minus 23 IU/mL at 6 months post procedure; the reduction from baseline was 7.6 plus or minus 9.8 IU/mL at 9 months.
Duodenal mucosal resurfacing, performed endoscopically as a day procedure, has been shown to improve metabolic markers for type 2 diabetes. Though the exact mechanism for improvement is not known, reduction in incretin and other hormonal signaling from the duodenum is thought to increase insulin sensitization.
Patient characteristics were similar in both studies, with a mean age of 52.8 years in the first study and 56.8 in the second. Mean body mass index was 32 kg/m2 in both studies. In the first study, mean baseline hemoglobin A1c (HbA1c) was 9.7%; HbA1c was 8.4% in the second study.
Both study groups saw significant reductions in HbA1c at 6 months post DMR, with reductions of 1.2 plus or minus 1.8% and 0.8 plus or minus 0.9% (P less than .001). Homeostatic model assessment of insulin resistance (HOMA-IR) was reduced after DMR as well, with reductions of 0.9 plus or minus 4, and 2.4 plus or minus 6.8 in the two study groups, though the decrease was not statistically significant.
The transaminase reductions and improved glycemic markers were not accompanied by significant weight loss: Patients lost a mean 1.8 plus or minus 3.6 kg in the first study, and 2.4 plus or minus 3.8 kg in the second study.
“This unique endoscopic intervention deserves further study to ascertain its potential efficacy as a treatment for fatty liver disease,” wrote Ms. van Baar and her coauthors.
The studies were funded by Fractyl Laboratories, the manufacturer of the DMR device. Ms. van Baar had no financial disclosures, but two coauthors reported relationships with Fractyl Laboratories, and another author disclosed relationships with multiple other pharmaceutical companies.
[email protected]
On Twitter @karioakes
BOSTON – An endoscopic procedure that heats and ablates a few centimeters of the surface of the duodenum reduced hepatic transaminases in patients with type 2 diabetes. According to an abstract released in advance of the annual meeting of the American Association for the Study of Liver Diseases , a reduction in transaminases was also seen in a subset of patients who had ultrasonographic evidence of hepatic steatosis.
The meeting presentation will focus on the results of two studies of patients with type 2 diabetes who received duodenal mucosal resurfacing (DMR) to about 9 circumferential cm of their duodenum. The first study, which was a single-site study of 30 patients, was the first human study of DMR. The second study was a multicenter study of 22 patients.
“A single duodenal mucosal resurfacing procedure resulted in a decrease of liver transaminases sustained for 12 months,” Annieke van Baar, an MD-PhD candidate in gastroenterology and hepatology at the Academic University Center, Amsterdam, wrote in the study abstract.
At 6 months after the one-time procedure, the composite cohort of patients in both studies saw a 25% reduction in alanine transaminase, with an absolute reduction of a mean 9.9 plus or minus 22.3 IU/mL. Mean aspartate transaminase also decreased by a mean of 21%, with absolute reduction of a mean 6.1 plus or minus 14.8 IU/mL.
For the subset of 23 patients in the composite cohort who had ultrasound-identified steatosis, AST decreased by 14.4 plus or minus 23 IU/mL at 6 months post procedure; the reduction from baseline was 7.6 plus or minus 9.8 IU/mL at 9 months.
Duodenal mucosal resurfacing, performed endoscopically as a day procedure, has been shown to improve metabolic markers for type 2 diabetes. Though the exact mechanism for improvement is not known, reduction in incretin and other hormonal signaling from the duodenum is thought to increase insulin sensitization.
Patient characteristics were similar in both studies, with a mean age of 52.8 years in the first study and 56.8 in the second. Mean body mass index was 32 kg/m2 in both studies. In the first study, mean baseline hemoglobin A1c (HbA1c) was 9.7%; HbA1c was 8.4% in the second study.
Both study groups saw significant reductions in HbA1c at 6 months post DMR, with reductions of 1.2 plus or minus 1.8% and 0.8 plus or minus 0.9% (P less than .001). Homeostatic model assessment of insulin resistance (HOMA-IR) was reduced after DMR as well, with reductions of 0.9 plus or minus 4, and 2.4 plus or minus 6.8 in the two study groups, though the decrease was not statistically significant.
The transaminase reductions and improved glycemic markers were not accompanied by significant weight loss: Patients lost a mean 1.8 plus or minus 3.6 kg in the first study, and 2.4 plus or minus 3.8 kg in the second study.
“This unique endoscopic intervention deserves further study to ascertain its potential efficacy as a treatment for fatty liver disease,” wrote Ms. van Baar and her coauthors.
The studies were funded by Fractyl Laboratories, the manufacturer of the DMR device. Ms. van Baar had no financial disclosures, but two coauthors reported relationships with Fractyl Laboratories, and another author disclosed relationships with multiple other pharmaceutical companies.
[email protected]
On Twitter @karioakes
FROM THE LIVER MEETING 2016
Liver transplant waits shorter with DAAs
The rate of wait-listing for liver transplants for patients with hepatitis C and decompensated cirrhosis has decreased by over 30% since the entry of direct-acting antiviral (DAA) therapy and now equals the wait-list rate for nonalcoholic steatohepatitis, according to an abstract of a study that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.
Using the U.S. Scientific Registry of Transplant Recipients (SRTR), Jennifer Flemming, MD, and her coauthors developed a cohort of 47,591 adults who were wait-listed for liver transplant because of HCV or hepatitis B virus infection (HBV), or for nonalcoholic steatohepatitis (NASH).
Dr. Flemming, professor of gastroenterology at Queens University, Kingston, Ont., examined trends in liver transplant wait-listing between 2003 and 2015. The time period was divided into the “interferon era,” from 2003 to 2010, the “protease inhibitor era,” from 2011 to 2013, and the “DAA era,” from 2014 to 2015.
Examining annual standardized incidence rates of wait-listing, Dr. Flemming and her collaborators found that wait-listing for HCV patients with decompensated cirrhosis dropped by 5% during the protease inhibitor era, and by 32% in the DAA era (P = .004 and P less than .001, respectively).
Wait-listing for HBV also dropped, by 17% in the protease inhibitor era and by 24% in the DAA era (P = .002 and P less than .001, respectively). For NASH patients, conversely, wait-listing increased by 41% in the protease inhibitor era, and by 81% in the DAA era (P less than .001 for both). Hepatocellular carcinoma rates also rose during the protease inhibitor and DAA eras.
“Further reductions in [wait-listing] are anticipated with increased testing, linkage to care, and access to DAA therapy,” Dr. Flemming and her coauthors wrote in their study abstract.
Dr. Flemming reported no relevant financial disclosures. Several coauthors reported financial ties to pharmaceutical companies that market DAAs.
[email protected]
On Twitter @karioakes
The rate of wait-listing for liver transplants for patients with hepatitis C and decompensated cirrhosis has decreased by over 30% since the entry of direct-acting antiviral (DAA) therapy and now equals the wait-list rate for nonalcoholic steatohepatitis, according to an abstract of a study that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.
Using the U.S. Scientific Registry of Transplant Recipients (SRTR), Jennifer Flemming, MD, and her coauthors developed a cohort of 47,591 adults who were wait-listed for liver transplant because of HCV or hepatitis B virus infection (HBV), or for nonalcoholic steatohepatitis (NASH).
Dr. Flemming, professor of gastroenterology at Queens University, Kingston, Ont., examined trends in liver transplant wait-listing between 2003 and 2015. The time period was divided into the “interferon era,” from 2003 to 2010, the “protease inhibitor era,” from 2011 to 2013, and the “DAA era,” from 2014 to 2015.
Examining annual standardized incidence rates of wait-listing, Dr. Flemming and her collaborators found that wait-listing for HCV patients with decompensated cirrhosis dropped by 5% during the protease inhibitor era, and by 32% in the DAA era (P = .004 and P less than .001, respectively).
Wait-listing for HBV also dropped, by 17% in the protease inhibitor era and by 24% in the DAA era (P = .002 and P less than .001, respectively). For NASH patients, conversely, wait-listing increased by 41% in the protease inhibitor era, and by 81% in the DAA era (P less than .001 for both). Hepatocellular carcinoma rates also rose during the protease inhibitor and DAA eras.
“Further reductions in [wait-listing] are anticipated with increased testing, linkage to care, and access to DAA therapy,” Dr. Flemming and her coauthors wrote in their study abstract.
Dr. Flemming reported no relevant financial disclosures. Several coauthors reported financial ties to pharmaceutical companies that market DAAs.
[email protected]
On Twitter @karioakes
The rate of wait-listing for liver transplants for patients with hepatitis C and decompensated cirrhosis has decreased by over 30% since the entry of direct-acting antiviral (DAA) therapy and now equals the wait-list rate for nonalcoholic steatohepatitis, according to an abstract of a study that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.
Using the U.S. Scientific Registry of Transplant Recipients (SRTR), Jennifer Flemming, MD, and her coauthors developed a cohort of 47,591 adults who were wait-listed for liver transplant because of HCV or hepatitis B virus infection (HBV), or for nonalcoholic steatohepatitis (NASH).
Dr. Flemming, professor of gastroenterology at Queens University, Kingston, Ont., examined trends in liver transplant wait-listing between 2003 and 2015. The time period was divided into the “interferon era,” from 2003 to 2010, the “protease inhibitor era,” from 2011 to 2013, and the “DAA era,” from 2014 to 2015.
Examining annual standardized incidence rates of wait-listing, Dr. Flemming and her collaborators found that wait-listing for HCV patients with decompensated cirrhosis dropped by 5% during the protease inhibitor era, and by 32% in the DAA era (P = .004 and P less than .001, respectively).
Wait-listing for HBV also dropped, by 17% in the protease inhibitor era and by 24% in the DAA era (P = .002 and P less than .001, respectively). For NASH patients, conversely, wait-listing increased by 41% in the protease inhibitor era, and by 81% in the DAA era (P less than .001 for both). Hepatocellular carcinoma rates also rose during the protease inhibitor and DAA eras.
“Further reductions in [wait-listing] are anticipated with increased testing, linkage to care, and access to DAA therapy,” Dr. Flemming and her coauthors wrote in their study abstract.
Dr. Flemming reported no relevant financial disclosures. Several coauthors reported financial ties to pharmaceutical companies that market DAAs.
[email protected]
On Twitter @karioakes
FROM THE LIVER MEETING 2016
Most infective endocarditis calls for early surgery
CHICAGO - Turning to surgery earlier in infective endocarditis may hold the key to a cure for some patients. Upcoming guidelines for surgical treatment of infective endocarditis lend evidence-based support to early surgical intervention in this high-mortality condition.
“Infective endocarditis is the most severe and potentially devastating complication for heart valve disease,” said Joseph Coselli, MD, in a presentation that reviewed current trends in incidence of infective endocarditis (IE) and laid out a rationale and strategy for early surgical intervention in some patients.
“Untreated infective endocarditis is universally fatal,” said Dr. Coselli. Even with current treatments, however, overall mortality for infective endocarditis is 20%-25%, he said.
Speaking at the joint AATS-ACC Heart Valve Summit, Dr. Coselli, chief of the division of cardiothoracic surgery at Baylor College of Medicine, Houston, reviewed the key points in the upcoming guideline and the evidence that backs up the guidelines.
Dr. Coselli served on the writing committee for the 2016 AATS consensus guidelines for the surgical treatment of infective endocarditis; the guidelines are currently in press.
The guidelines propose that “at the time of surgery, the patient should be on an effective antimicrobial regimen to which the causative agent is sensitive,” he said. This is a level I recommendation, as is the recommendation that the surgeon should understand the pathology as well as possible before the procedure. Usually, say the guidelines, this is obtained by means of a transesophageal echocardiogram (TEE), assigning level I status to this recommendation as well.
According to the guidelines, patients with IE who may be surgical candidates during their hospitalization, regardless of whether their antimicrobial course is complete, include those who present with valve dysfunction that results in symptoms of heart failure. Surgery should also be considered in patients with left-sided IE with S. aureus, fungi, or other highly resistant organisms as the causative pathogen. If heart block, an aortic or annular abscess, or destructive penetrating lesions are present, surgery is also indicated. Finally, the guidelines recommend considering surgery if patients have persistent bacteremia or fevers at 5 to 7 days after initiation of appropriate antimicrobial therapy. All of these are class I indications in the upcoming guidelines, he said.
The patient who has relapsing infection, defined by the guidelines as recurrent bacteremia “after a complete course of appropriate antibiotics and subsequently negative blood culture,” who has no other identifiable source of infection, may also be a candidate.
Given the dearth of randomized trials in the area, no recommendation for intervention is backed by a level of evidence greater than B, said Dr. Coselli. And knowledge gaps persist in many areas, such as the appropriate timing of surgery in IE when there are neurological complications. Also, he said, “embolism risk needs to be better understood.” Imaging improvements would help guide decision-making, as would better data about contemporary rates of IE relapse and recurrence, said Dr. Coselli.
Though these surgeries should be done at centers that can field a complete team, and by experience valve surgeons, early intervention may be a key to success: “Operate before a devastating complication occurs,” said Dr. Coselli. “Understand what you see; don’t be afraid of radical debridement, and master alternative options to reconstruction” depending on the heart’s appearance in the OR, he said.
Surgeons can run into trouble in IE cases if they wait too long. “A patient who’s already had an embolic stroke may be too sick,” said Dr. Coselli. Insensitive organisms and ineffective antimicrobial therapy set the patient up for recurrent IE or treatment failure as well.
Having guidance for surgical intervention is important because cardiologists and surgeons will be seeing more infective endocarditis patients as heroin and other illicit intravenous drug use continues to rise, said Dr. Coselli. IE in intravenous drug users now accounts for up to 30% of all patients who seek treatment for IE, he said, citing a study that tracked characteristics of endocarditis patients undergoing surgery at a single institution from 2002-2014 (J Thorac Cardiovasc Surg. 2016 Sep;152:832-41). Incidence in intravenous drug users can range to 2,000 cases per 100,000 patient-years, he said.
The study, conducted by Joon Bum Kim, MD, PhD, and his colleagues at Massachusetts General and Brigham and Women’s hospitals, both in Boston, followed 436 patients with IE, 78 of whom were intravenous drug users (IVDUs) at the time of diagnosis. Overall, the IVDUs were younger (mean age, 36 plus or minus 10 years) when compared with the non-IVDU group (mean age, 58 plus or minus 14 years; P less than 0.001). The non-IVDU cohort were also significantly more likely to have hypertension and diabetes, but less likely to smoke. However, IVDUs were more likely to have embolic events, and to have right-sided valve involvement.
Though early mortality was better in the IVDU group post-surgically, late complications, including reinfection and reoperation, were significantly more likely to occur in the IVDUs, with reinfection more than four times as frequent in IVDUs (aggregate valve-related complications, 41% in IVDUs vs. 10% in non-IVDUs; P = 0.001).
Despite the additional morbidity seen in IVDU-associated endocarditis, the 10-year survival rate was virtually identical between the two groups.
For many IE patients, said Dr. Coselli, “the arguments against surgery have lost strength.” Active systemic infections are treatable, sicker patients can be operated on earlier, and surgeons will gain experience with this sometimes technically challenging surgery, he said. Finally, Dr. Coselli said, even though the best available data support early surgical intervention in select IE patients, “final cure of IE is always the result of antimicrobial treatment and the patient’s own defense.”
[email protected]
On Twitter @karioakes
CHICAGO - Turning to surgery earlier in infective endocarditis may hold the key to a cure for some patients. Upcoming guidelines for surgical treatment of infective endocarditis lend evidence-based support to early surgical intervention in this high-mortality condition.
“Infective endocarditis is the most severe and potentially devastating complication for heart valve disease,” said Joseph Coselli, MD, in a presentation that reviewed current trends in incidence of infective endocarditis (IE) and laid out a rationale and strategy for early surgical intervention in some patients.
“Untreated infective endocarditis is universally fatal,” said Dr. Coselli. Even with current treatments, however, overall mortality for infective endocarditis is 20%-25%, he said.
Speaking at the joint AATS-ACC Heart Valve Summit, Dr. Coselli, chief of the division of cardiothoracic surgery at Baylor College of Medicine, Houston, reviewed the key points in the upcoming guideline and the evidence that backs up the guidelines.
Dr. Coselli served on the writing committee for the 2016 AATS consensus guidelines for the surgical treatment of infective endocarditis; the guidelines are currently in press.
The guidelines propose that “at the time of surgery, the patient should be on an effective antimicrobial regimen to which the causative agent is sensitive,” he said. This is a level I recommendation, as is the recommendation that the surgeon should understand the pathology as well as possible before the procedure. Usually, say the guidelines, this is obtained by means of a transesophageal echocardiogram (TEE), assigning level I status to this recommendation as well.
According to the guidelines, patients with IE who may be surgical candidates during their hospitalization, regardless of whether their antimicrobial course is complete, include those who present with valve dysfunction that results in symptoms of heart failure. Surgery should also be considered in patients with left-sided IE with S. aureus, fungi, or other highly resistant organisms as the causative pathogen. If heart block, an aortic or annular abscess, or destructive penetrating lesions are present, surgery is also indicated. Finally, the guidelines recommend considering surgery if patients have persistent bacteremia or fevers at 5 to 7 days after initiation of appropriate antimicrobial therapy. All of these are class I indications in the upcoming guidelines, he said.
The patient who has relapsing infection, defined by the guidelines as recurrent bacteremia “after a complete course of appropriate antibiotics and subsequently negative blood culture,” who has no other identifiable source of infection, may also be a candidate.
Given the dearth of randomized trials in the area, no recommendation for intervention is backed by a level of evidence greater than B, said Dr. Coselli. And knowledge gaps persist in many areas, such as the appropriate timing of surgery in IE when there are neurological complications. Also, he said, “embolism risk needs to be better understood.” Imaging improvements would help guide decision-making, as would better data about contemporary rates of IE relapse and recurrence, said Dr. Coselli.
Though these surgeries should be done at centers that can field a complete team, and by experience valve surgeons, early intervention may be a key to success: “Operate before a devastating complication occurs,” said Dr. Coselli. “Understand what you see; don’t be afraid of radical debridement, and master alternative options to reconstruction” depending on the heart’s appearance in the OR, he said.
Surgeons can run into trouble in IE cases if they wait too long. “A patient who’s already had an embolic stroke may be too sick,” said Dr. Coselli. Insensitive organisms and ineffective antimicrobial therapy set the patient up for recurrent IE or treatment failure as well.
Having guidance for surgical intervention is important because cardiologists and surgeons will be seeing more infective endocarditis patients as heroin and other illicit intravenous drug use continues to rise, said Dr. Coselli. IE in intravenous drug users now accounts for up to 30% of all patients who seek treatment for IE, he said, citing a study that tracked characteristics of endocarditis patients undergoing surgery at a single institution from 2002-2014 (J Thorac Cardiovasc Surg. 2016 Sep;152:832-41). Incidence in intravenous drug users can range to 2,000 cases per 100,000 patient-years, he said.
The study, conducted by Joon Bum Kim, MD, PhD, and his colleagues at Massachusetts General and Brigham and Women’s hospitals, both in Boston, followed 436 patients with IE, 78 of whom were intravenous drug users (IVDUs) at the time of diagnosis. Overall, the IVDUs were younger (mean age, 36 plus or minus 10 years) when compared with the non-IVDU group (mean age, 58 plus or minus 14 years; P less than 0.001). The non-IVDU cohort were also significantly more likely to have hypertension and diabetes, but less likely to smoke. However, IVDUs were more likely to have embolic events, and to have right-sided valve involvement.
Though early mortality was better in the IVDU group post-surgically, late complications, including reinfection and reoperation, were significantly more likely to occur in the IVDUs, with reinfection more than four times as frequent in IVDUs (aggregate valve-related complications, 41% in IVDUs vs. 10% in non-IVDUs; P = 0.001).
Despite the additional morbidity seen in IVDU-associated endocarditis, the 10-year survival rate was virtually identical between the two groups.
For many IE patients, said Dr. Coselli, “the arguments against surgery have lost strength.” Active systemic infections are treatable, sicker patients can be operated on earlier, and surgeons will gain experience with this sometimes technically challenging surgery, he said. Finally, Dr. Coselli said, even though the best available data support early surgical intervention in select IE patients, “final cure of IE is always the result of antimicrobial treatment and the patient’s own defense.”
[email protected]
On Twitter @karioakes
CHICAGO - Turning to surgery earlier in infective endocarditis may hold the key to a cure for some patients. Upcoming guidelines for surgical treatment of infective endocarditis lend evidence-based support to early surgical intervention in this high-mortality condition.
“Infective endocarditis is the most severe and potentially devastating complication for heart valve disease,” said Joseph Coselli, MD, in a presentation that reviewed current trends in incidence of infective endocarditis (IE) and laid out a rationale and strategy for early surgical intervention in some patients.
“Untreated infective endocarditis is universally fatal,” said Dr. Coselli. Even with current treatments, however, overall mortality for infective endocarditis is 20%-25%, he said.
Speaking at the joint AATS-ACC Heart Valve Summit, Dr. Coselli, chief of the division of cardiothoracic surgery at Baylor College of Medicine, Houston, reviewed the key points in the upcoming guideline and the evidence that backs up the guidelines.
Dr. Coselli served on the writing committee for the 2016 AATS consensus guidelines for the surgical treatment of infective endocarditis; the guidelines are currently in press.
The guidelines propose that “at the time of surgery, the patient should be on an effective antimicrobial regimen to which the causative agent is sensitive,” he said. This is a level I recommendation, as is the recommendation that the surgeon should understand the pathology as well as possible before the procedure. Usually, say the guidelines, this is obtained by means of a transesophageal echocardiogram (TEE), assigning level I status to this recommendation as well.
According to the guidelines, patients with IE who may be surgical candidates during their hospitalization, regardless of whether their antimicrobial course is complete, include those who present with valve dysfunction that results in symptoms of heart failure. Surgery should also be considered in patients with left-sided IE with S. aureus, fungi, or other highly resistant organisms as the causative pathogen. If heart block, an aortic or annular abscess, or destructive penetrating lesions are present, surgery is also indicated. Finally, the guidelines recommend considering surgery if patients have persistent bacteremia or fevers at 5 to 7 days after initiation of appropriate antimicrobial therapy. All of these are class I indications in the upcoming guidelines, he said.
The patient who has relapsing infection, defined by the guidelines as recurrent bacteremia “after a complete course of appropriate antibiotics and subsequently negative blood culture,” who has no other identifiable source of infection, may also be a candidate.
Given the dearth of randomized trials in the area, no recommendation for intervention is backed by a level of evidence greater than B, said Dr. Coselli. And knowledge gaps persist in many areas, such as the appropriate timing of surgery in IE when there are neurological complications. Also, he said, “embolism risk needs to be better understood.” Imaging improvements would help guide decision-making, as would better data about contemporary rates of IE relapse and recurrence, said Dr. Coselli.
Though these surgeries should be done at centers that can field a complete team, and by experience valve surgeons, early intervention may be a key to success: “Operate before a devastating complication occurs,” said Dr. Coselli. “Understand what you see; don’t be afraid of radical debridement, and master alternative options to reconstruction” depending on the heart’s appearance in the OR, he said.
Surgeons can run into trouble in IE cases if they wait too long. “A patient who’s already had an embolic stroke may be too sick,” said Dr. Coselli. Insensitive organisms and ineffective antimicrobial therapy set the patient up for recurrent IE or treatment failure as well.
Having guidance for surgical intervention is important because cardiologists and surgeons will be seeing more infective endocarditis patients as heroin and other illicit intravenous drug use continues to rise, said Dr. Coselli. IE in intravenous drug users now accounts for up to 30% of all patients who seek treatment for IE, he said, citing a study that tracked characteristics of endocarditis patients undergoing surgery at a single institution from 2002-2014 (J Thorac Cardiovasc Surg. 2016 Sep;152:832-41). Incidence in intravenous drug users can range to 2,000 cases per 100,000 patient-years, he said.
The study, conducted by Joon Bum Kim, MD, PhD, and his colleagues at Massachusetts General and Brigham and Women’s hospitals, both in Boston, followed 436 patients with IE, 78 of whom were intravenous drug users (IVDUs) at the time of diagnosis. Overall, the IVDUs were younger (mean age, 36 plus or minus 10 years) when compared with the non-IVDU group (mean age, 58 plus or minus 14 years; P less than 0.001). The non-IVDU cohort were also significantly more likely to have hypertension and diabetes, but less likely to smoke. However, IVDUs were more likely to have embolic events, and to have right-sided valve involvement.
Though early mortality was better in the IVDU group post-surgically, late complications, including reinfection and reoperation, were significantly more likely to occur in the IVDUs, with reinfection more than four times as frequent in IVDUs (aggregate valve-related complications, 41% in IVDUs vs. 10% in non-IVDUs; P = 0.001).
Despite the additional morbidity seen in IVDU-associated endocarditis, the 10-year survival rate was virtually identical between the two groups.
For many IE patients, said Dr. Coselli, “the arguments against surgery have lost strength.” Active systemic infections are treatable, sicker patients can be operated on earlier, and surgeons will gain experience with this sometimes technically challenging surgery, he said. Finally, Dr. Coselli said, even though the best available data support early surgical intervention in select IE patients, “final cure of IE is always the result of antimicrobial treatment and the patient’s own defense.”
[email protected]
On Twitter @karioakes
EXPERT ANALYSIS FROM THE HEART VALVE SUMMIT 2016
Lyme disease spirochete helps babesiosis gain a foothold
BOSTON – The spirochete that causes Lyme disease in humans may be lending a helping hand to the weaker protozoan that causes babesiosis, escalating the rate of human babesiosis cases in regions where both are endemic.
Peter Krause, MD, a research scientist in epidemiology, medicine, and pediatrics at Yale University School of Public Health, New Haven, Conn., reviewed what’s known about babesiosis–Lyme disease coinfections at the annual meeting of the American Society for Microbiology.
Understanding the entire cycle is necessary, he said, because the effects of coinfection will be different depending on the stage of the cycle, and upon the coinfection pathogens.
Over the course of many years, Dr. Krause and his collaborators have used an interdisciplinary, multi-modal approach to try to understand the interplay between these pathogens, their hosts, and environmental, demographic, and ecologic factors.
One arm of their research has taken them to the lab, where they have modeled coinfection and transmission of Borrelia burgdorferi and Babesia microti from their reservoir host, the white-footed mouse (Peromyscus leucopus), to the vector, the deer tick (Ixodes scapularis), which can transmit both diseases to humans.
In an experimental design that mimicked the natural reservoir-vector ecology, Dr. Krause and his collaborators first infected mice with 5 to 10 nymphal ticks, to approximate the average number of ticks that feed on an individual mouse in the wild. The researchers then tracked the effect of coinfection on transmission of each pathogen to ticks during the larval feeds, finding that B. burgdorferi increased B. microti parasitemia in mice who were coinfected. Coinfection also increases B. microti transmission from mice to ticks. This effect happens at least partly because of the increased parasitemia, Dr. Krause said.
The downstream effect on humans is to increase the risk of babesiosis for those who live in regions where both B. microti and B. burgdorferi are endemic, Dr. Krause said.
B. microti is less “ecologically fit” than B. burgdorferi, Dr. Krause said, noting that there are more ticks and humans infected with the latter, as well as more reservoir mice carrying B. burgdorferi. Also, the rate of geographic expansion is more rapid for B. burgdorferi. “B. microti is only endemic in areas where B. burgdorferi is already endemic; it may not be ‘fit’ enough to establish endemic sites on its own,” Dr. Krause said.
The increased rate of B. microti transmission via ticks from mice, if the mice are coinfected with B. burgdorferi, may help explain the greater-than-expected rate of babesiosis in humans in areas of New England where coinfection is common. “This paradox might be explained by the enhancement of B. microti survival and spread by the coinfecting presence of Borrelia burgdorferi,” Dr. Krause said.
This naturalistic experiment has ecological implications in terms of the human impact as well: “Coinfection may help enhance geographic spread of B. microti to new areas,” Dr. Krause said.
Clinicians in geographic areas where both pathogens are endemic should maintain a high level of suspicion for coinfection, especially for the most ill patients. “Anaplasmosis and/or babesiosis coinfection increases the severity of Lyme disease,” Dr. Krause said. “Health care workers should consider anaplasmosis and/or babesiosis coinfection in Lyme disease patients who have more severe illness or who do not respond to antibiotic therapy.”
Understanding the complex interspecies interplay will be increasingly important as more cases of tick-borne illness are seen, Dr. Krause concluded. “Research on coinfections acquired from Ixodes scapularis has just begun.”
Dr. Krause reported no relevant conflicts of interest.
[email protected]
On Twitter @karioakes
BOSTON – The spirochete that causes Lyme disease in humans may be lending a helping hand to the weaker protozoan that causes babesiosis, escalating the rate of human babesiosis cases in regions where both are endemic.
Peter Krause, MD, a research scientist in epidemiology, medicine, and pediatrics at Yale University School of Public Health, New Haven, Conn., reviewed what’s known about babesiosis–Lyme disease coinfections at the annual meeting of the American Society for Microbiology.
Understanding the entire cycle is necessary, he said, because the effects of coinfection will be different depending on the stage of the cycle, and upon the coinfection pathogens.
Over the course of many years, Dr. Krause and his collaborators have used an interdisciplinary, multi-modal approach to try to understand the interplay between these pathogens, their hosts, and environmental, demographic, and ecologic factors.
One arm of their research has taken them to the lab, where they have modeled coinfection and transmission of Borrelia burgdorferi and Babesia microti from their reservoir host, the white-footed mouse (Peromyscus leucopus), to the vector, the deer tick (Ixodes scapularis), which can transmit both diseases to humans.
In an experimental design that mimicked the natural reservoir-vector ecology, Dr. Krause and his collaborators first infected mice with 5 to 10 nymphal ticks, to approximate the average number of ticks that feed on an individual mouse in the wild. The researchers then tracked the effect of coinfection on transmission of each pathogen to ticks during the larval feeds, finding that B. burgdorferi increased B. microti parasitemia in mice who were coinfected. Coinfection also increases B. microti transmission from mice to ticks. This effect happens at least partly because of the increased parasitemia, Dr. Krause said.
The downstream effect on humans is to increase the risk of babesiosis for those who live in regions where both B. microti and B. burgdorferi are endemic, Dr. Krause said.
B. microti is less “ecologically fit” than B. burgdorferi, Dr. Krause said, noting that there are more ticks and humans infected with the latter, as well as more reservoir mice carrying B. burgdorferi. Also, the rate of geographic expansion is more rapid for B. burgdorferi. “B. microti is only endemic in areas where B. burgdorferi is already endemic; it may not be ‘fit’ enough to establish endemic sites on its own,” Dr. Krause said.
The increased rate of B. microti transmission via ticks from mice, if the mice are coinfected with B. burgdorferi, may help explain the greater-than-expected rate of babesiosis in humans in areas of New England where coinfection is common. “This paradox might be explained by the enhancement of B. microti survival and spread by the coinfecting presence of Borrelia burgdorferi,” Dr. Krause said.
This naturalistic experiment has ecological implications in terms of the human impact as well: “Coinfection may help enhance geographic spread of B. microti to new areas,” Dr. Krause said.
Clinicians in geographic areas where both pathogens are endemic should maintain a high level of suspicion for coinfection, especially for the most ill patients. “Anaplasmosis and/or babesiosis coinfection increases the severity of Lyme disease,” Dr. Krause said. “Health care workers should consider anaplasmosis and/or babesiosis coinfection in Lyme disease patients who have more severe illness or who do not respond to antibiotic therapy.”
Understanding the complex interspecies interplay will be increasingly important as more cases of tick-borne illness are seen, Dr. Krause concluded. “Research on coinfections acquired from Ixodes scapularis has just begun.”
Dr. Krause reported no relevant conflicts of interest.
[email protected]
On Twitter @karioakes
BOSTON – The spirochete that causes Lyme disease in humans may be lending a helping hand to the weaker protozoan that causes babesiosis, escalating the rate of human babesiosis cases in regions where both are endemic.
Peter Krause, MD, a research scientist in epidemiology, medicine, and pediatrics at Yale University School of Public Health, New Haven, Conn., reviewed what’s known about babesiosis–Lyme disease coinfections at the annual meeting of the American Society for Microbiology.
Understanding the entire cycle is necessary, he said, because the effects of coinfection will be different depending on the stage of the cycle, and upon the coinfection pathogens.
Over the course of many years, Dr. Krause and his collaborators have used an interdisciplinary, multi-modal approach to try to understand the interplay between these pathogens, their hosts, and environmental, demographic, and ecologic factors.
One arm of their research has taken them to the lab, where they have modeled coinfection and transmission of Borrelia burgdorferi and Babesia microti from their reservoir host, the white-footed mouse (Peromyscus leucopus), to the vector, the deer tick (Ixodes scapularis), which can transmit both diseases to humans.
In an experimental design that mimicked the natural reservoir-vector ecology, Dr. Krause and his collaborators first infected mice with 5 to 10 nymphal ticks, to approximate the average number of ticks that feed on an individual mouse in the wild. The researchers then tracked the effect of coinfection on transmission of each pathogen to ticks during the larval feeds, finding that B. burgdorferi increased B. microti parasitemia in mice who were coinfected. Coinfection also increases B. microti transmission from mice to ticks. This effect happens at least partly because of the increased parasitemia, Dr. Krause said.
The downstream effect on humans is to increase the risk of babesiosis for those who live in regions where both B. microti and B. burgdorferi are endemic, Dr. Krause said.
B. microti is less “ecologically fit” than B. burgdorferi, Dr. Krause said, noting that there are more ticks and humans infected with the latter, as well as more reservoir mice carrying B. burgdorferi. Also, the rate of geographic expansion is more rapid for B. burgdorferi. “B. microti is only endemic in areas where B. burgdorferi is already endemic; it may not be ‘fit’ enough to establish endemic sites on its own,” Dr. Krause said.
The increased rate of B. microti transmission via ticks from mice, if the mice are coinfected with B. burgdorferi, may help explain the greater-than-expected rate of babesiosis in humans in areas of New England where coinfection is common. “This paradox might be explained by the enhancement of B. microti survival and spread by the coinfecting presence of Borrelia burgdorferi,” Dr. Krause said.
This naturalistic experiment has ecological implications in terms of the human impact as well: “Coinfection may help enhance geographic spread of B. microti to new areas,” Dr. Krause said.
Clinicians in geographic areas where both pathogens are endemic should maintain a high level of suspicion for coinfection, especially for the most ill patients. “Anaplasmosis and/or babesiosis coinfection increases the severity of Lyme disease,” Dr. Krause said. “Health care workers should consider anaplasmosis and/or babesiosis coinfection in Lyme disease patients who have more severe illness or who do not respond to antibiotic therapy.”
Understanding the complex interspecies interplay will be increasingly important as more cases of tick-borne illness are seen, Dr. Krause concluded. “Research on coinfections acquired from Ixodes scapularis has just begun.”
Dr. Krause reported no relevant conflicts of interest.
[email protected]
On Twitter @karioakes
EXPERT ANALYSIS FROM ASM 2016
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.
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.
In lupus, optimize non-immunosuppressives to dial back prednisone
LAS VEGAS – For patients with mild to moderate systemic lupus erythematosus, don’t go above six milligrams of prednisone daily, because the treatment is likely to be worse than the disease in the long run, said Michelle Petri, MD.
Speaking at the annual Perspectives in Rheumatic Diseases presented by Global Academy for Medical Education, Dr. Petri shared evidence-backed clinical pearls to help rheumatologists dial in good disease control for their systemic lupus erythematosus (SLE) patients without turning to too much prednisone.
Prednisone is also an independent risk factor for cardiovascular events, with dose-dependent effects, she said. She referred to a 2012 study she coauthored (Am J Epidemiol. 2012 Oct;176[8]:708-19) that found an age-adjusted cardiovascular event rate ratio of 2.4 when patients took 10-19 mg of prednisone daily (95% confidence interval [CI], 1.5-3.8; P = .0002). When the daily prednisone dose was over 20 mg, the rate ratio was 5.1 (95% CI, 3.1-8.4; P less than .0001).
Since it’s so important to minimize prednisone exposure, rheumatologists should be familiar with the full toolkit of non-immunosuppressive immunomodulators, and understand how to help patients assess risks and benefits of various treatments.“Non-immunosuppressive immunomodulators can control mild to moderate systemic lupus, helping to avoid steroids,” Dr. Petri said.
Hydroxychloroquine, when used as background therapy, has proved to have multiple benefits. Not only are flares reduced, but organ damage is reduced, lipids improve, fewer clots occur, and seizures are prevented, she said. There’s also an overall improvement in survival with hydroxychloroquine. In lupus nephritis, “continuing hydroxychloroquine improves complete response rates with mycophenolate mofetil,” Dr. Petri said.
Concerns about hydroxychloroquine-related retinopathy sometimes stand in the way of its use as background therapy, so Dr. Petri encouraged rheumatologists to have a realistic risk-benefit assessment. Higher risk for retinopathy is associated with higher dosing (greater than 6.5 mg/kg of hydroxychloroquine or 3 mg/kg of chloroquine); a higher fat body habitus, unless dosing is appropriately adjusted; the presence of renal disease or concomitant retinal disease; and age over 60.
Newer imaging techniques may sacrifice specificity for very high sensitivity in detecting hydroxychloroquine-related retinopathy, Dr. Petri said. High-speed ultra-high resolution optical coherence tomography (hsUHR-OCT) and multifocal electroretinography (mfERG) are imaging techniques that can detect hydroxychloroquine-related retinopathy, but should be reserved for patients with SLE who actually have visual symptoms, she said. Dr. Petri cited a study of 15 patients who were taking hydroxychloroquine, and 6 age-matched controls with normal visual function. All underwent visual field testing, mfERG, and hsUHR-OCT. The study “was unable to find an asymptomatic patient with evidence of definite damage on hsUHR-OCT” as well as mfERG, she said (Arch Ophthalmol. 2007 Jun;125[6]:775-80).
Vitamin D supplementation gives a modest boost to overall disease control and also affords some renal protection, Dr. Petri said. She was the lead author on a 2013 study that showed that a 20-unit increase in 25-hydroxy vitamin D was associated with reduced global disease severity scores, as well as a 21% reduction in the odds of having a SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score of 5 or more, and a 15% decrease in the odds of having a urine protein to creatinine ratio greater than 0.5 (Arthritis Rheum. 2013 Jul;65[7]:1865-71).
When it comes to vitamin D, more matters, Dr. Petri said. “Go above 40 [ng/mL] on vitamin D,” she said, noting that there may be pleiotropic cardiovascular and hematologic benefits as well.
Though dehydroepiandrosterone (DHEA) is not approved by the Food and Drug Administration to treat SLE, 200 mg of DHEA daily helped women with active SLE improve or stabilize disease activity, and also helped 51% of women in one study reduce prednisone to less than 7.5 mg daily, compared with 29% of women taking placebo (P = .03) (Arthritis Rheum. 2002 Jul;46[7]:1820-9). There’s also “mild protection against bone loss,” Dr. Petri said.
Dr. Petri reported receiving research grants and serving as a consultant to several pharmaceutical companies. Global Academy for Medical Education and this news organization are owned by the same parent company.
[email protected]
On Twitter @karioakes
LAS VEGAS – For patients with mild to moderate systemic lupus erythematosus, don’t go above six milligrams of prednisone daily, because the treatment is likely to be worse than the disease in the long run, said Michelle Petri, MD.
Speaking at the annual Perspectives in Rheumatic Diseases presented by Global Academy for Medical Education, Dr. Petri shared evidence-backed clinical pearls to help rheumatologists dial in good disease control for their systemic lupus erythematosus (SLE) patients without turning to too much prednisone.
Prednisone is also an independent risk factor for cardiovascular events, with dose-dependent effects, she said. She referred to a 2012 study she coauthored (Am J Epidemiol. 2012 Oct;176[8]:708-19) that found an age-adjusted cardiovascular event rate ratio of 2.4 when patients took 10-19 mg of prednisone daily (95% confidence interval [CI], 1.5-3.8; P = .0002). When the daily prednisone dose was over 20 mg, the rate ratio was 5.1 (95% CI, 3.1-8.4; P less than .0001).
Since it’s so important to minimize prednisone exposure, rheumatologists should be familiar with the full toolkit of non-immunosuppressive immunomodulators, and understand how to help patients assess risks and benefits of various treatments.“Non-immunosuppressive immunomodulators can control mild to moderate systemic lupus, helping to avoid steroids,” Dr. Petri said.
Hydroxychloroquine, when used as background therapy, has proved to have multiple benefits. Not only are flares reduced, but organ damage is reduced, lipids improve, fewer clots occur, and seizures are prevented, she said. There’s also an overall improvement in survival with hydroxychloroquine. In lupus nephritis, “continuing hydroxychloroquine improves complete response rates with mycophenolate mofetil,” Dr. Petri said.
Concerns about hydroxychloroquine-related retinopathy sometimes stand in the way of its use as background therapy, so Dr. Petri encouraged rheumatologists to have a realistic risk-benefit assessment. Higher risk for retinopathy is associated with higher dosing (greater than 6.5 mg/kg of hydroxychloroquine or 3 mg/kg of chloroquine); a higher fat body habitus, unless dosing is appropriately adjusted; the presence of renal disease or concomitant retinal disease; and age over 60.
Newer imaging techniques may sacrifice specificity for very high sensitivity in detecting hydroxychloroquine-related retinopathy, Dr. Petri said. High-speed ultra-high resolution optical coherence tomography (hsUHR-OCT) and multifocal electroretinography (mfERG) are imaging techniques that can detect hydroxychloroquine-related retinopathy, but should be reserved for patients with SLE who actually have visual symptoms, she said. Dr. Petri cited a study of 15 patients who were taking hydroxychloroquine, and 6 age-matched controls with normal visual function. All underwent visual field testing, mfERG, and hsUHR-OCT. The study “was unable to find an asymptomatic patient with evidence of definite damage on hsUHR-OCT” as well as mfERG, she said (Arch Ophthalmol. 2007 Jun;125[6]:775-80).
Vitamin D supplementation gives a modest boost to overall disease control and also affords some renal protection, Dr. Petri said. She was the lead author on a 2013 study that showed that a 20-unit increase in 25-hydroxy vitamin D was associated with reduced global disease severity scores, as well as a 21% reduction in the odds of having a SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score of 5 or more, and a 15% decrease in the odds of having a urine protein to creatinine ratio greater than 0.5 (Arthritis Rheum. 2013 Jul;65[7]:1865-71).
When it comes to vitamin D, more matters, Dr. Petri said. “Go above 40 [ng/mL] on vitamin D,” she said, noting that there may be pleiotropic cardiovascular and hematologic benefits as well.
Though dehydroepiandrosterone (DHEA) is not approved by the Food and Drug Administration to treat SLE, 200 mg of DHEA daily helped women with active SLE improve or stabilize disease activity, and also helped 51% of women in one study reduce prednisone to less than 7.5 mg daily, compared with 29% of women taking placebo (P = .03) (Arthritis Rheum. 2002 Jul;46[7]:1820-9). There’s also “mild protection against bone loss,” Dr. Petri said.
Dr. Petri reported receiving research grants and serving as a consultant to several pharmaceutical companies. Global Academy for Medical Education and this news organization are owned by the same parent company.
[email protected]
On Twitter @karioakes
LAS VEGAS – For patients with mild to moderate systemic lupus erythematosus, don’t go above six milligrams of prednisone daily, because the treatment is likely to be worse than the disease in the long run, said Michelle Petri, MD.
Speaking at the annual Perspectives in Rheumatic Diseases presented by Global Academy for Medical Education, Dr. Petri shared evidence-backed clinical pearls to help rheumatologists dial in good disease control for their systemic lupus erythematosus (SLE) patients without turning to too much prednisone.
Prednisone is also an independent risk factor for cardiovascular events, with dose-dependent effects, she said. She referred to a 2012 study she coauthored (Am J Epidemiol. 2012 Oct;176[8]:708-19) that found an age-adjusted cardiovascular event rate ratio of 2.4 when patients took 10-19 mg of prednisone daily (95% confidence interval [CI], 1.5-3.8; P = .0002). When the daily prednisone dose was over 20 mg, the rate ratio was 5.1 (95% CI, 3.1-8.4; P less than .0001).
Since it’s so important to minimize prednisone exposure, rheumatologists should be familiar with the full toolkit of non-immunosuppressive immunomodulators, and understand how to help patients assess risks and benefits of various treatments.“Non-immunosuppressive immunomodulators can control mild to moderate systemic lupus, helping to avoid steroids,” Dr. Petri said.
Hydroxychloroquine, when used as background therapy, has proved to have multiple benefits. Not only are flares reduced, but organ damage is reduced, lipids improve, fewer clots occur, and seizures are prevented, she said. There’s also an overall improvement in survival with hydroxychloroquine. In lupus nephritis, “continuing hydroxychloroquine improves complete response rates with mycophenolate mofetil,” Dr. Petri said.
Concerns about hydroxychloroquine-related retinopathy sometimes stand in the way of its use as background therapy, so Dr. Petri encouraged rheumatologists to have a realistic risk-benefit assessment. Higher risk for retinopathy is associated with higher dosing (greater than 6.5 mg/kg of hydroxychloroquine or 3 mg/kg of chloroquine); a higher fat body habitus, unless dosing is appropriately adjusted; the presence of renal disease or concomitant retinal disease; and age over 60.
Newer imaging techniques may sacrifice specificity for very high sensitivity in detecting hydroxychloroquine-related retinopathy, Dr. Petri said. High-speed ultra-high resolution optical coherence tomography (hsUHR-OCT) and multifocal electroretinography (mfERG) are imaging techniques that can detect hydroxychloroquine-related retinopathy, but should be reserved for patients with SLE who actually have visual symptoms, she said. Dr. Petri cited a study of 15 patients who were taking hydroxychloroquine, and 6 age-matched controls with normal visual function. All underwent visual field testing, mfERG, and hsUHR-OCT. The study “was unable to find an asymptomatic patient with evidence of definite damage on hsUHR-OCT” as well as mfERG, she said (Arch Ophthalmol. 2007 Jun;125[6]:775-80).
Vitamin D supplementation gives a modest boost to overall disease control and also affords some renal protection, Dr. Petri said. She was the lead author on a 2013 study that showed that a 20-unit increase in 25-hydroxy vitamin D was associated with reduced global disease severity scores, as well as a 21% reduction in the odds of having a SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score of 5 or more, and a 15% decrease in the odds of having a urine protein to creatinine ratio greater than 0.5 (Arthritis Rheum. 2013 Jul;65[7]:1865-71).
When it comes to vitamin D, more matters, Dr. Petri said. “Go above 40 [ng/mL] on vitamin D,” she said, noting that there may be pleiotropic cardiovascular and hematologic benefits as well.
Though dehydroepiandrosterone (DHEA) is not approved by the Food and Drug Administration to treat SLE, 200 mg of DHEA daily helped women with active SLE improve or stabilize disease activity, and also helped 51% of women in one study reduce prednisone to less than 7.5 mg daily, compared with 29% of women taking placebo (P = .03) (Arthritis Rheum. 2002 Jul;46[7]:1820-9). There’s also “mild protection against bone loss,” Dr. Petri said.
Dr. Petri reported receiving research grants and serving as a consultant to several pharmaceutical companies. Global Academy for Medical Education and this news organization are owned by the same parent company.
[email protected]
On Twitter @karioakes
EXPERT ANALYSIS FROM THE ANNUAL PERSPECTIVES IN RHEUMATIC DISEASES
Be vigilant for restrictive lung disease in RA
LAS VEGAS – Patients with rheumatoid arthritis who have pulmonary symptoms and a restrictive pulmonary function test pattern have a high likelihood for a diagnosis of interstitial lung disease, making it necessary to put it high on the differential and to begin working collaboratively with pulmonologists, according to Jon T. Giles, MD.
Overall, 8%-15% of RA patients will develop clinically significant interstitial lung disease (ILD), although radiographic evidence of ILD can be seen in up to half of RA patients, and in one study about one in four patients had evidence of ILD on CT scanning within 2 years of RA diagnosis. The overall risk for RA patients to develop ILD has been shown to be nine times higher than for matched controls (Arthritis Rheum. 2010 Jun;62[6]:1583-91), Dr. Giles said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Relatively recently discovered risk factors for RA-ILD include higher levels of anti–citrullinated protein antibodies (ACPAs), and particularly antibodies against peptidylarginine deiminase (PAD), an enzyme that catalyzes arginine’s conversion to citrulline. Particularly for ever-smokers, the presence of the PAD3/4XR antibody has been highly correlated (P = .001) with having radiographic evidence of ILD. Besides currently smoking and ever smoking, other wide-ranging risk factors that have been associated with radiographic evidence of ILD include older age, being male, higher disease activity, and current use of prednisone or leflunomide, according to work that Dr. Giles conducted with his colleagues (Ann Rheum Dis. 2014 Aug;73[8]:1487-94).
An “alphabet soup” of ILD subtypes
Though there’s an “alphabet soup” of subtypes of ILD in RA, 90% of RA patients with ILD will have one of two conditions: usual interstitial pneumonitis (RA-UIP) or nonspecific interstitial pneumonitis (RA-NSIP). It’s not entirely clear whether one type of RA-ILD has a survival advantage over the other, Dr. Giles said.
Care for RA patients should include screening for ILD, said Dr. Giles. Physicians should ask about dry cough, dyspnea, and decreased exercise tolerance. Signs of ILD can include diminished oxygen saturation, a cardiac exam consistent with right heart disease, and rales. It’s not clear, he said, whether periodic chest radiographs or pulmonary function testing in asymptomatic RA patients is warranted.
Positive findings should prompt pulmonary function testing to include DLCO (diffusing capacity of lung for carbon monoxide), which may or may not be reduced in patients with clinically significant ILD. However, testing will show a restrictive pattern. A high-resolution chest CT should also be obtained.
Further evaluation should be done collaboratively with pulmonologists, and preferably with an ILD center, said Dr. Giles. A bronchoalveolar lavage and/or a lung biopsy may be considered.
Radiographic features of RA-UIP can include reticulation and honeycombing, predominantly seen in a subpleural and basilar distribution. Traction bronchiectasis may or may not be present. If a biopsy is performed, the histologic presentation of RA-UIP includes subpleural patches of dense fibrosis and honeycombing adjacent to healthy lung tissue; fibroblastic foci may be seen in the fibrotic regions.
In differentiating RA-UIP from interstitial pulmonary fibrosis (IPF), Dr. Giles said that lymphoid hyperplasia with germinal centers and peribronchial lesions are both more common in RA-UIP than in IPF. By contrast, fibroblastic foci are less common in RA-UIP than in IPF.
Sorting out the relationship between the use of disease-modifying antirheumatic drugs and ILD in RA is complicated by “complexities of attribution,” said Dr. Giles, since “RA patients with the most severe or refractory disease are more likely to both be exposed to a great number of RA therapies and higher doses and more combinations, and to have more risk factors for ILD.” Additionally, hypersensitivity pneumonitis can share some features with some subtypes of RA-ILD.
Treatment goals
Beyond maximizing smoking-cessation intervention, which should be done for all currently smoking ILD patients, treatment goals for RA-ILD are “a balancing act,” Dr. Giles said. Immunizations should be up to date for all RA-ILD patients, and any concomitant pulmonary conditions, such as asthma or chronic obstructive pulmonary disorder, should also be optimally treated. An early evaluation for lung transplant is warranted for RA-ILD as well, he said.
If patients are symptomatic, then the goal is symptom reduction, with the extent of radiographically or histologically documented involvement and the rate of decline to be factored into treatment decisions.
Immunosuppressive treatments for RA-ILD, Dr. Giles said, “are not supported by any randomized clinical trials.” However, corticosteroids are often effective for RA-NSIP; “UIP is often not steroid responsive,” he said. Other agents can include azathioprine, which can give a “double whammy” effect by addressing joint and lung disease. However, azathioprine should not be used concurrently with corticosteroids, he said.
Mycophenolate mofetil (CellCept) has known antifibrotic effects, and there have been case reports of improvement in RA-ILD. Cyclophosphamide is also occasionally used. A host of other treatments have been attempted, including the antifibrotics pirfenidone (Esbriet) and nintedanib (Ofev), although these have been studied only in interstitial pulmonary fibrosis, said Dr. Giles. “Treating symptomatic RA-ILD is always a challenge,” he said.
Dr. Giles has been a consultant to Roche/Genentech and Proximagen and has received grant funding from Pfizer.
Global Academy for Medical Education and this news organization are owned by the same parent company.
[email protected]
On Twitter @karioakes
LAS VEGAS – Patients with rheumatoid arthritis who have pulmonary symptoms and a restrictive pulmonary function test pattern have a high likelihood for a diagnosis of interstitial lung disease, making it necessary to put it high on the differential and to begin working collaboratively with pulmonologists, according to Jon T. Giles, MD.
Overall, 8%-15% of RA patients will develop clinically significant interstitial lung disease (ILD), although radiographic evidence of ILD can be seen in up to half of RA patients, and in one study about one in four patients had evidence of ILD on CT scanning within 2 years of RA diagnosis. The overall risk for RA patients to develop ILD has been shown to be nine times higher than for matched controls (Arthritis Rheum. 2010 Jun;62[6]:1583-91), Dr. Giles said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Relatively recently discovered risk factors for RA-ILD include higher levels of anti–citrullinated protein antibodies (ACPAs), and particularly antibodies against peptidylarginine deiminase (PAD), an enzyme that catalyzes arginine’s conversion to citrulline. Particularly for ever-smokers, the presence of the PAD3/4XR antibody has been highly correlated (P = .001) with having radiographic evidence of ILD. Besides currently smoking and ever smoking, other wide-ranging risk factors that have been associated with radiographic evidence of ILD include older age, being male, higher disease activity, and current use of prednisone or leflunomide, according to work that Dr. Giles conducted with his colleagues (Ann Rheum Dis. 2014 Aug;73[8]:1487-94).
An “alphabet soup” of ILD subtypes
Though there’s an “alphabet soup” of subtypes of ILD in RA, 90% of RA patients with ILD will have one of two conditions: usual interstitial pneumonitis (RA-UIP) or nonspecific interstitial pneumonitis (RA-NSIP). It’s not entirely clear whether one type of RA-ILD has a survival advantage over the other, Dr. Giles said.
Care for RA patients should include screening for ILD, said Dr. Giles. Physicians should ask about dry cough, dyspnea, and decreased exercise tolerance. Signs of ILD can include diminished oxygen saturation, a cardiac exam consistent with right heart disease, and rales. It’s not clear, he said, whether periodic chest radiographs or pulmonary function testing in asymptomatic RA patients is warranted.
Positive findings should prompt pulmonary function testing to include DLCO (diffusing capacity of lung for carbon monoxide), which may or may not be reduced in patients with clinically significant ILD. However, testing will show a restrictive pattern. A high-resolution chest CT should also be obtained.
Further evaluation should be done collaboratively with pulmonologists, and preferably with an ILD center, said Dr. Giles. A bronchoalveolar lavage and/or a lung biopsy may be considered.
Radiographic features of RA-UIP can include reticulation and honeycombing, predominantly seen in a subpleural and basilar distribution. Traction bronchiectasis may or may not be present. If a biopsy is performed, the histologic presentation of RA-UIP includes subpleural patches of dense fibrosis and honeycombing adjacent to healthy lung tissue; fibroblastic foci may be seen in the fibrotic regions.
In differentiating RA-UIP from interstitial pulmonary fibrosis (IPF), Dr. Giles said that lymphoid hyperplasia with germinal centers and peribronchial lesions are both more common in RA-UIP than in IPF. By contrast, fibroblastic foci are less common in RA-UIP than in IPF.
Sorting out the relationship between the use of disease-modifying antirheumatic drugs and ILD in RA is complicated by “complexities of attribution,” said Dr. Giles, since “RA patients with the most severe or refractory disease are more likely to both be exposed to a great number of RA therapies and higher doses and more combinations, and to have more risk factors for ILD.” Additionally, hypersensitivity pneumonitis can share some features with some subtypes of RA-ILD.
Treatment goals
Beyond maximizing smoking-cessation intervention, which should be done for all currently smoking ILD patients, treatment goals for RA-ILD are “a balancing act,” Dr. Giles said. Immunizations should be up to date for all RA-ILD patients, and any concomitant pulmonary conditions, such as asthma or chronic obstructive pulmonary disorder, should also be optimally treated. An early evaluation for lung transplant is warranted for RA-ILD as well, he said.
If patients are symptomatic, then the goal is symptom reduction, with the extent of radiographically or histologically documented involvement and the rate of decline to be factored into treatment decisions.
Immunosuppressive treatments for RA-ILD, Dr. Giles said, “are not supported by any randomized clinical trials.” However, corticosteroids are often effective for RA-NSIP; “UIP is often not steroid responsive,” he said. Other agents can include azathioprine, which can give a “double whammy” effect by addressing joint and lung disease. However, azathioprine should not be used concurrently with corticosteroids, he said.
Mycophenolate mofetil (CellCept) has known antifibrotic effects, and there have been case reports of improvement in RA-ILD. Cyclophosphamide is also occasionally used. A host of other treatments have been attempted, including the antifibrotics pirfenidone (Esbriet) and nintedanib (Ofev), although these have been studied only in interstitial pulmonary fibrosis, said Dr. Giles. “Treating symptomatic RA-ILD is always a challenge,” he said.
Dr. Giles has been a consultant to Roche/Genentech and Proximagen and has received grant funding from Pfizer.
Global Academy for Medical Education and this news organization are owned by the same parent company.
[email protected]
On Twitter @karioakes
LAS VEGAS – Patients with rheumatoid arthritis who have pulmonary symptoms and a restrictive pulmonary function test pattern have a high likelihood for a diagnosis of interstitial lung disease, making it necessary to put it high on the differential and to begin working collaboratively with pulmonologists, according to Jon T. Giles, MD.
Overall, 8%-15% of RA patients will develop clinically significant interstitial lung disease (ILD), although radiographic evidence of ILD can be seen in up to half of RA patients, and in one study about one in four patients had evidence of ILD on CT scanning within 2 years of RA diagnosis. The overall risk for RA patients to develop ILD has been shown to be nine times higher than for matched controls (Arthritis Rheum. 2010 Jun;62[6]:1583-91), Dr. Giles said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Relatively recently discovered risk factors for RA-ILD include higher levels of anti–citrullinated protein antibodies (ACPAs), and particularly antibodies against peptidylarginine deiminase (PAD), an enzyme that catalyzes arginine’s conversion to citrulline. Particularly for ever-smokers, the presence of the PAD3/4XR antibody has been highly correlated (P = .001) with having radiographic evidence of ILD. Besides currently smoking and ever smoking, other wide-ranging risk factors that have been associated with radiographic evidence of ILD include older age, being male, higher disease activity, and current use of prednisone or leflunomide, according to work that Dr. Giles conducted with his colleagues (Ann Rheum Dis. 2014 Aug;73[8]:1487-94).
An “alphabet soup” of ILD subtypes
Though there’s an “alphabet soup” of subtypes of ILD in RA, 90% of RA patients with ILD will have one of two conditions: usual interstitial pneumonitis (RA-UIP) or nonspecific interstitial pneumonitis (RA-NSIP). It’s not entirely clear whether one type of RA-ILD has a survival advantage over the other, Dr. Giles said.
Care for RA patients should include screening for ILD, said Dr. Giles. Physicians should ask about dry cough, dyspnea, and decreased exercise tolerance. Signs of ILD can include diminished oxygen saturation, a cardiac exam consistent with right heart disease, and rales. It’s not clear, he said, whether periodic chest radiographs or pulmonary function testing in asymptomatic RA patients is warranted.
Positive findings should prompt pulmonary function testing to include DLCO (diffusing capacity of lung for carbon monoxide), which may or may not be reduced in patients with clinically significant ILD. However, testing will show a restrictive pattern. A high-resolution chest CT should also be obtained.
Further evaluation should be done collaboratively with pulmonologists, and preferably with an ILD center, said Dr. Giles. A bronchoalveolar lavage and/or a lung biopsy may be considered.
Radiographic features of RA-UIP can include reticulation and honeycombing, predominantly seen in a subpleural and basilar distribution. Traction bronchiectasis may or may not be present. If a biopsy is performed, the histologic presentation of RA-UIP includes subpleural patches of dense fibrosis and honeycombing adjacent to healthy lung tissue; fibroblastic foci may be seen in the fibrotic regions.
In differentiating RA-UIP from interstitial pulmonary fibrosis (IPF), Dr. Giles said that lymphoid hyperplasia with germinal centers and peribronchial lesions are both more common in RA-UIP than in IPF. By contrast, fibroblastic foci are less common in RA-UIP than in IPF.
Sorting out the relationship between the use of disease-modifying antirheumatic drugs and ILD in RA is complicated by “complexities of attribution,” said Dr. Giles, since “RA patients with the most severe or refractory disease are more likely to both be exposed to a great number of RA therapies and higher doses and more combinations, and to have more risk factors for ILD.” Additionally, hypersensitivity pneumonitis can share some features with some subtypes of RA-ILD.
Treatment goals
Beyond maximizing smoking-cessation intervention, which should be done for all currently smoking ILD patients, treatment goals for RA-ILD are “a balancing act,” Dr. Giles said. Immunizations should be up to date for all RA-ILD patients, and any concomitant pulmonary conditions, such as asthma or chronic obstructive pulmonary disorder, should also be optimally treated. An early evaluation for lung transplant is warranted for RA-ILD as well, he said.
If patients are symptomatic, then the goal is symptom reduction, with the extent of radiographically or histologically documented involvement and the rate of decline to be factored into treatment decisions.
Immunosuppressive treatments for RA-ILD, Dr. Giles said, “are not supported by any randomized clinical trials.” However, corticosteroids are often effective for RA-NSIP; “UIP is often not steroid responsive,” he said. Other agents can include azathioprine, which can give a “double whammy” effect by addressing joint and lung disease. However, azathioprine should not be used concurrently with corticosteroids, he said.
Mycophenolate mofetil (CellCept) has known antifibrotic effects, and there have been case reports of improvement in RA-ILD. Cyclophosphamide is also occasionally used. A host of other treatments have been attempted, including the antifibrotics pirfenidone (Esbriet) and nintedanib (Ofev), although these have been studied only in interstitial pulmonary fibrosis, said Dr. Giles. “Treating symptomatic RA-ILD is always a challenge,” he said.
Dr. Giles has been a consultant to Roche/Genentech and Proximagen and has received grant funding from Pfizer.
Global Academy for Medical Education and this news organization are owned by the same parent company.
[email protected]
On Twitter @karioakes