Elizabeth Mechcatie

Vedolizumab, an integrin receptor antagonist, has been approved as a treatment for moderate to severe inflammatory bowel disease in adults who have not had an adequate response to one or more standard treatments, the Food and Drug Administration announced on May 20.

Vedolizumab is administered intravenously, and will be marketed as Entyvio by Takeda Pharmaceuticals America. In trials, vedolizumab was administered intravenously at 0, 2, and 6 weeks, followed by once every 8 weeks for maintenance therapy.

Approval was based on five studies of patients who had not had an adequate response to treatment with corticosteroids, immunomodulators, or tumor necrosis factor blockers. In the two studies of about 900 patients with ulcerative colitis, a higher proportion of patients on vedolizumab achieved and maintained a clinical response and a clinical remission; achieved a corticosteroid-free clinical remission; and "as seen during endoscopy, had improved appearance of the colon," compared with patients on placebo, according to the Food and Drug Administration (FDA).

In the three studies of about 1,500 patients with Crohn’s disease, a greater proportion of those treated with vedolizumab achieved a clinical response, clinical remission, and a corticosteroid-free clinical remission, compared with those on placebo.

Headache, joint pain, nausea, and fever were among the most common adverse events associated with treatment. The most serious events included serious infections; hypersensitivity and infusion-related reactions; and hepatotoxicity.

Because natalizumab (Tysabri), another integrin receptor antagonist, approved for treating multiple sclerosis and Crohn’s disease, has been associated with progressive multifocal leukoencephalopathy (PML), a usually fatal infection, patients in vedolizumab studies were closely followed for PML. Although no cases were reported, "there remains uncertainty regarding the risk of PML in patients taking Entyvio," and the FDA is recommending that health care professionals monitor their patients on vedolizumab for "any new onset, or worsening, of neurological signs and symptoms," according to the FDA statement.

Takeda also will conduct a postmarketing study to evaluate the risk of PML associated with vedolizumab.

At a meeting in December 2013, the FDA’s Gastrointestinal Drugs and Drug Safety and Risk Management advisory committees unanimously supported approval of vedolizumab for Crohn’s disease and ulcerative colitis, agreeing that the benefits of vedolizumab outweighed the potential for progressive multifocal encephalopathy and other possible risks. They recommended that safety be closely monitored after approval, monitoring for potential risks including PML and other infections.

Vedolizumab "blocks the interaction of a specific integrin receptor (expressed on circulating inflammatory cells) with a specific protein (expressed on cells in the interior wall of blood vessels), and thereby blocks the migration of those circulating inflammatory cells across those blood vessels and into areas of inflammation in the gastrointestinal tract," according to the FDA statement announcing the approval.

Serious adverse events associated with vedolizumab should be reported to the FDA at 800-332-1088 or www.fda.gov/MedWatch.

emechcatie@frontlinemedcom.com

Vedolizumab, an integrin receptor antagonist, has been approved as a treatment for moderate to severe inflammatory bowel disease in adults who have not had an adequate response to one or more standard treatments, the Food and Drug Administration announced on May 20.

Vedolizumab is administered intravenously, and will be marketed as Entyvio by Takeda Pharmaceuticals America. In trials, vedolizumab was administered intravenously at 0, 2, and 6 weeks, followed by once every 8 weeks for maintenance therapy.

Approval was based on five studies of patients who had not had an adequate response to treatment with corticosteroids, immunomodulators, or tumor necrosis factor blockers. In the two studies of about 900 patients with ulcerative colitis, a higher proportion of patients on vedolizumab achieved and maintained a clinical response and a clinical remission; achieved a corticosteroid-free clinical remission; and "as seen during endoscopy, had improved appearance of the colon," compared with patients on placebo, according to the Food and Drug Administration (FDA).

In the three studies of about 1,500 patients with Crohn’s disease, a greater proportion of those treated with vedolizumab achieved a clinical response, clinical remission, and a corticosteroid-free clinical remission, compared with those on placebo.

Headache, joint pain, nausea, and fever were among the most common adverse events associated with treatment. The most serious events included serious infections; hypersensitivity and infusion-related reactions; and hepatotoxicity.

Because natalizumab (Tysabri), another integrin receptor antagonist, approved for treating multiple sclerosis and Crohn’s disease, has been associated with progressive multifocal leukoencephalopathy (PML), a usually fatal infection, patients in vedolizumab studies were closely followed for PML. Although no cases were reported, "there remains uncertainty regarding the risk of PML in patients taking Entyvio," and the FDA is recommending that health care professionals monitor their patients on vedolizumab for "any new onset, or worsening, of neurological signs and symptoms," according to the FDA statement.

Takeda also will conduct a postmarketing study to evaluate the risk of PML associated with vedolizumab.

At a meeting in December 2013, the FDA’s Gastrointestinal Drugs and Drug Safety and Risk Management advisory committees unanimously supported approval of vedolizumab for Crohn’s disease and ulcerative colitis, agreeing that the benefits of vedolizumab outweighed the potential for progressive multifocal encephalopathy and other possible risks. They recommended that safety be closely monitored after approval, monitoring for potential risks including PML and other infections.

Vedolizumab "blocks the interaction of a specific integrin receptor (expressed on circulating inflammatory cells) with a specific protein (expressed on cells in the interior wall of blood vessels), and thereby blocks the migration of those circulating inflammatory cells across those blood vessels and into areas of inflammation in the gastrointestinal tract," according to the FDA statement announcing the approval.

Serious adverse events associated with vedolizumab should be reported to the FDA at 800-332-1088 or www.fda.gov/MedWatch.

emechcatie@frontlinemedcom.com

Vedolizumab, an integrin receptor antagonist, has been approved as a treatment for moderate to severe inflammatory bowel disease in adults who have not had an adequate response to one or more standard treatments, the Food and Drug Administration announced on May 20.

Vedolizumab is administered intravenously, and will be marketed as Entyvio by Takeda Pharmaceuticals America. In trials, vedolizumab was administered intravenously at 0, 2, and 6 weeks, followed by once every 8 weeks for maintenance therapy.

Approval was based on five studies of patients who had not had an adequate response to treatment with corticosteroids, immunomodulators, or tumor necrosis factor blockers. In the two studies of about 900 patients with ulcerative colitis, a higher proportion of patients on vedolizumab achieved and maintained a clinical response and a clinical remission; achieved a corticosteroid-free clinical remission; and "as seen during endoscopy, had improved appearance of the colon," compared with patients on placebo, according to the Food and Drug Administration (FDA).

In the three studies of about 1,500 patients with Crohn’s disease, a greater proportion of those treated with vedolizumab achieved a clinical response, clinical remission, and a corticosteroid-free clinical remission, compared with those on placebo.

Headache, joint pain, nausea, and fever were among the most common adverse events associated with treatment. The most serious events included serious infections; hypersensitivity and infusion-related reactions; and hepatotoxicity.

Because natalizumab (Tysabri), another integrin receptor antagonist, approved for treating multiple sclerosis and Crohn’s disease, has been associated with progressive multifocal leukoencephalopathy (PML), a usually fatal infection, patients in vedolizumab studies were closely followed for PML. Although no cases were reported, "there remains uncertainty regarding the risk of PML in patients taking Entyvio," and the FDA is recommending that health care professionals monitor their patients on vedolizumab for "any new onset, or worsening, of neurological signs and symptoms," according to the FDA statement.

Takeda also will conduct a postmarketing study to evaluate the risk of PML associated with vedolizumab.

At a meeting in December 2013, the FDA’s Gastrointestinal Drugs and Drug Safety and Risk Management advisory committees unanimously supported approval of vedolizumab for Crohn’s disease and ulcerative colitis, agreeing that the benefits of vedolizumab outweighed the potential for progressive multifocal encephalopathy and other possible risks. They recommended that safety be closely monitored after approval, monitoring for potential risks including PML and other infections.

Vedolizumab "blocks the interaction of a specific integrin receptor (expressed on circulating inflammatory cells) with a specific protein (expressed on cells in the interior wall of blood vessels), and thereby blocks the migration of those circulating inflammatory cells across those blood vessels and into areas of inflammation in the gastrointestinal tract," according to the FDA statement announcing the approval.

Serious adverse events associated with vedolizumab should be reported to the FDA at 800-332-1088 or www.fda.gov/MedWatch.

emechcatie@frontlinemedcom.com

BALTIMORE – A study of patients with intraabdominal infection indicates that a shorter course of antibiotics is as effective as the standard, longer course, leading researchers to recommend a new standard of care.

The rates of recurrent infections and other outcomes were similar in patients with intraabdominal infections treated with antibiotics for 4 days following source control and among those who received a longer course of treatment based on when their clinical symptoms resolved, in a study reported at the annual meeting of the Surgical Infection Society.

The results support the use of the shorter treatment strategy in this setting, said Dr. Robert Sawyer, who presented the results of the study, SIS Multicenter Study of Duration of Antibiotics for Intraabdominal Infection.

Elizabeth Mechcatie/Frontline Medical News

While antibiotics are used as an adjunct to treat intraabdominal infections, the appropriate duration of treatment is not clear, and reducing the time exposed to antibiotics "could be worthwhile," said Dr. Sawyer, professor of surgery and public health sciences and chief of acute care surgery at the University of Virginia, Charlottesville.

The randomized, multicenter, unblinded study compared a shorter vs. a longer course of antibiotic therapy in 518 patients with intraabdominal infections: 4 days in 258 patients or treatment that continued for 2 days after resolution of the patient’s fever, leukocytosis, and ileus, with a maximum of 10 days of treatment in total, in 260 patients. The patients had similar APACHE II scores; their mean age was in the early 50s; and the colon or rectum was the most common source of infection, followed by the appendix and the small bowel. Antibiotics were administered intravenously or orally. Patients with inadequate source control and a high risk of death within 72 hours were excluded.

Within 30 days, the primary outcome – a composite of surgical site infection, recurrent intraabdominal infection, and death – was similar between the two groups, at about 21.7% in the 4-day treatment group vs. 22.7% in the group treated for 2 days after symptoms resolved.

There were no significant differences in the individual endpoints between the two groups. There were also no differences in the composite endpoints in different subgroups, and when those with percutaneous drainage or patients whose source of infection was the appendix were excluded. Among sicker patients with APACHE scores of 10 or higher, there was a numerical benefit favoring those treated for 4 days (22.1% vs. 29.8% among those treated for the longer duration), but the difference was not statistically significant, although it was reassuring, Dr. Sawyer said.

There were no differences between the two groups in the rates of secondary infections or subsequent infection with resistant pathogens or Clostridium difficile, which were secondary endpoints.

Based on these results, "after source control is obtained, we recommend 4 days of antimicrobial therapy for all patients with intraabdominal infections as the new standard of care," Dr. Sawyer concluded.

Although they had positive comments about the study, several members of the audience commented that a larger study would be a better base for a recommendation to change the standard of care.

This study was one of several studies presented at the meeting that addressed the issue of reducing the time on antibiotic therapy in patients with surgical infections.

The study was sponsored by the National Institutes of Health. Dr. Sawyer had no disclosures.

emechcatie@frontlinemedcom.com

BALTIMORE – A study of patients with intraabdominal infection indicates that a shorter course of antibiotics is as effective as the standard, longer course, leading researchers to recommend a new standard of care.

The rates of recurrent infections and other outcomes were similar in patients with intraabdominal infections treated with antibiotics for 4 days following source control and among those who received a longer course of treatment based on when their clinical symptoms resolved, in a study reported at the annual meeting of the Surgical Infection Society.

The results support the use of the shorter treatment strategy in this setting, said Dr. Robert Sawyer, who presented the results of the study, SIS Multicenter Study of Duration of Antibiotics for Intraabdominal Infection.

Elizabeth Mechcatie/Frontline Medical News

While antibiotics are used as an adjunct to treat intraabdominal infections, the appropriate duration of treatment is not clear, and reducing the time exposed to antibiotics "could be worthwhile," said Dr. Sawyer, professor of surgery and public health sciences and chief of acute care surgery at the University of Virginia, Charlottesville.

The randomized, multicenter, unblinded study compared a shorter vs. a longer course of antibiotic therapy in 518 patients with intraabdominal infections: 4 days in 258 patients or treatment that continued for 2 days after resolution of the patient’s fever, leukocytosis, and ileus, with a maximum of 10 days of treatment in total, in 260 patients. The patients had similar APACHE II scores; their mean age was in the early 50s; and the colon or rectum was the most common source of infection, followed by the appendix and the small bowel. Antibiotics were administered intravenously or orally. Patients with inadequate source control and a high risk of death within 72 hours were excluded.

Within 30 days, the primary outcome – a composite of surgical site infection, recurrent intraabdominal infection, and death – was similar between the two groups, at about 21.7% in the 4-day treatment group vs. 22.7% in the group treated for 2 days after symptoms resolved.

There were no significant differences in the individual endpoints between the two groups. There were also no differences in the composite endpoints in different subgroups, and when those with percutaneous drainage or patients whose source of infection was the appendix were excluded. Among sicker patients with APACHE scores of 10 or higher, there was a numerical benefit favoring those treated for 4 days (22.1% vs. 29.8% among those treated for the longer duration), but the difference was not statistically significant, although it was reassuring, Dr. Sawyer said.

There were no differences between the two groups in the rates of secondary infections or subsequent infection with resistant pathogens or Clostridium difficile, which were secondary endpoints.

Based on these results, "after source control is obtained, we recommend 4 days of antimicrobial therapy for all patients with intraabdominal infections as the new standard of care," Dr. Sawyer concluded.

Although they had positive comments about the study, several members of the audience commented that a larger study would be a better base for a recommendation to change the standard of care.

This study was one of several studies presented at the meeting that addressed the issue of reducing the time on antibiotic therapy in patients with surgical infections.

The study was sponsored by the National Institutes of Health. Dr. Sawyer had no disclosures.

emechcatie@frontlinemedcom.com

BALTIMORE – A study of patients with intraabdominal infection indicates that a shorter course of antibiotics is as effective as the standard, longer course, leading researchers to recommend a new standard of care.

The rates of recurrent infections and other outcomes were similar in patients with intraabdominal infections treated with antibiotics for 4 days following source control and among those who received a longer course of treatment based on when their clinical symptoms resolved, in a study reported at the annual meeting of the Surgical Infection Society.

The results support the use of the shorter treatment strategy in this setting, said Dr. Robert Sawyer, who presented the results of the study, SIS Multicenter Study of Duration of Antibiotics for Intraabdominal Infection.

Elizabeth Mechcatie/Frontline Medical News

While antibiotics are used as an adjunct to treat intraabdominal infections, the appropriate duration of treatment is not clear, and reducing the time exposed to antibiotics "could be worthwhile," said Dr. Sawyer, professor of surgery and public health sciences and chief of acute care surgery at the University of Virginia, Charlottesville.

The randomized, multicenter, unblinded study compared a shorter vs. a longer course of antibiotic therapy in 518 patients with intraabdominal infections: 4 days in 258 patients or treatment that continued for 2 days after resolution of the patient’s fever, leukocytosis, and ileus, with a maximum of 10 days of treatment in total, in 260 patients. The patients had similar APACHE II scores; their mean age was in the early 50s; and the colon or rectum was the most common source of infection, followed by the appendix and the small bowel. Antibiotics were administered intravenously or orally. Patients with inadequate source control and a high risk of death within 72 hours were excluded.

Within 30 days, the primary outcome – a composite of surgical site infection, recurrent intraabdominal infection, and death – was similar between the two groups, at about 21.7% in the 4-day treatment group vs. 22.7% in the group treated for 2 days after symptoms resolved.

There were no significant differences in the individual endpoints between the two groups. There were also no differences in the composite endpoints in different subgroups, and when those with percutaneous drainage or patients whose source of infection was the appendix were excluded. Among sicker patients with APACHE scores of 10 or higher, there was a numerical benefit favoring those treated for 4 days (22.1% vs. 29.8% among those treated for the longer duration), but the difference was not statistically significant, although it was reassuring, Dr. Sawyer said.

There were no differences between the two groups in the rates of secondary infections or subsequent infection with resistant pathogens or Clostridium difficile, which were secondary endpoints.

Based on these results, "after source control is obtained, we recommend 4 days of antimicrobial therapy for all patients with intraabdominal infections as the new standard of care," Dr. Sawyer concluded.

Although they had positive comments about the study, several members of the audience commented that a larger study would be a better base for a recommendation to change the standard of care.

This study was one of several studies presented at the meeting that addressed the issue of reducing the time on antibiotic therapy in patients with surgical infections.

The study was sponsored by the National Institutes of Health. Dr. Sawyer had no disclosures.

emechcatie@frontlinemedcom.com

The Food and Drug Administration has decided that more evidence of serelaxin’s efficacy as a treatment for acute heart failure is needed before the drug can be approved in the United States, Novartis Pharmaceuticals announced May 16.

Serelaxin is a recombinant form of human relaxin-2 hormone that is administered in an intravenous infusion over 48 hours. For approval, the company submitted data from the phase III RELAX-AHF study, an international, randomized, placebo-controlled, double-blind study of about 1,100 patients with acute heart failure. At a meeting in March, the FDA’s Cardiovascular and Renal Drugs Advisory Committee agreed there was evidence that serelaxin had a positive effect on worsening heart failure in the study and that the data were promising, but unanimously voted against recommending approval, citing the need for more studies.

"In accordance with the FDA’s advice we will continue to expedite our clinical trial program to build the supporting body of evidence," Tim Wright, global head of development of the company, said in a statement issued by the company. He added that the company was encouraged by the FDA panel’s feedback.

The company is collecting more data on the drug in acute heart failure, which includes the RELAX-AHF-2 study, which will enroll more than 6,300 patients, according to the statement.

The FDA informs companies about nonapproval decisions in complete response letters, which include advice about what would be needed before the drug can be approved. The FDA does not announce these decisions, but companies often announce when these decisions are made.

emechcatie@frontlinemedcom.com

The Food and Drug Administration has decided that more evidence of serelaxin’s efficacy as a treatment for acute heart failure is needed before the drug can be approved in the United States, Novartis Pharmaceuticals announced May 16.

Serelaxin is a recombinant form of human relaxin-2 hormone that is administered in an intravenous infusion over 48 hours. For approval, the company submitted data from the phase III RELAX-AHF study, an international, randomized, placebo-controlled, double-blind study of about 1,100 patients with acute heart failure. At a meeting in March, the FDA’s Cardiovascular and Renal Drugs Advisory Committee agreed there was evidence that serelaxin had a positive effect on worsening heart failure in the study and that the data were promising, but unanimously voted against recommending approval, citing the need for more studies.

"In accordance with the FDA’s advice we will continue to expedite our clinical trial program to build the supporting body of evidence," Tim Wright, global head of development of the company, said in a statement issued by the company. He added that the company was encouraged by the FDA panel’s feedback.

The company is collecting more data on the drug in acute heart failure, which includes the RELAX-AHF-2 study, which will enroll more than 6,300 patients, according to the statement.

The FDA informs companies about nonapproval decisions in complete response letters, which include advice about what would be needed before the drug can be approved. The FDA does not announce these decisions, but companies often announce when these decisions are made.

emechcatie@frontlinemedcom.com

The Food and Drug Administration has decided that more evidence of serelaxin’s efficacy as a treatment for acute heart failure is needed before the drug can be approved in the United States, Novartis Pharmaceuticals announced May 16.

Serelaxin is a recombinant form of human relaxin-2 hormone that is administered in an intravenous infusion over 48 hours. For approval, the company submitted data from the phase III RELAX-AHF study, an international, randomized, placebo-controlled, double-blind study of about 1,100 patients with acute heart failure. At a meeting in March, the FDA’s Cardiovascular and Renal Drugs Advisory Committee agreed there was evidence that serelaxin had a positive effect on worsening heart failure in the study and that the data were promising, but unanimously voted against recommending approval, citing the need for more studies.

"In accordance with the FDA’s advice we will continue to expedite our clinical trial program to build the supporting body of evidence," Tim Wright, global head of development of the company, said in a statement issued by the company. He added that the company was encouraged by the FDA panel’s feedback.

The company is collecting more data on the drug in acute heart failure, which includes the RELAX-AHF-2 study, which will enroll more than 6,300 patients, according to the statement.

The FDA informs companies about nonapproval decisions in complete response letters, which include advice about what would be needed before the drug can be approved. The FDA does not announce these decisions, but companies often announce when these decisions are made.

emechcatie@frontlinemedcom.com

WASHINGTON - A first in transcatheter aortic valve replacement trials, the CoreValve prosthesis was superior to surgical valve replacement in patients with severe aortic stenosis at increased surgical risk, showing a significantly lower risk of mortality 1 year later.

In the U.S. CoreValve High Risk Study, a prospective randomized controlled study of almost 800 patients, the rate of all-cause mortality at 1 year, the primary endpoint, was 14.2% among those in the transcatheter aortic valve replacement (TAVR) group, compared with 19.1% among those in the surgery group, a statistically significant difference that represented a 26% survival benefit at 1 year for the CoreValve, Dr. David H. Adams reported at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

This is the first prospective, randomized study to show superiority for transcatheter valve therapy over surgery, and "there's no study or trial that I'm aware of that's suggested that TAVR patients would have a superior survival outcome," Dr. Adams of Mount Sinai Medical Center, New York, said in an interview. Based on these results, he said he expects that TAVR "will increasingly become the alternative of choice for patients" at this level of risk.

The study was the high-risk arm of the U.S. CoreValve pivotal trial. The CoreValve self-expanding prosthesis was approved in January 2014 by the Food and Drug Administration for use in extreme risk patients, based on the results of the extreme risk cohort of patients. The data from the study in the high-risk trial are being reviewed at the FDA, according to the manufacturer, Medtronic.

The study compared the safety and effectiveness of TAVR with the CoreValve device to surgical valve replacement in 795 patients at 45 U.S. centers. The patients had severe aortic stenosis, had New York Heart Association class II heart failure or higher, and were judged to have at least a 15% risk of death within 30 days after surgery and less than a 50% risk of death or irreversible complications within 30 days after surgery. Their mean age was about age 83 years, almost half were females, most had class NYHA class III HF, and cardiac risk factors included coronary artery disease (in about two-thirds), previous coronary artery bypass surgery (about 30%), a previous MI (about 25%), and almost all had heart failure.

At 1 year, a composite of major adverse cardiovascular and cerebrovascular events (death from any cause, MI, any stroke, or reintervention), a secondary endpoint, was significantly lower among those on TAVR (20.4%) vs. the surgical group (27.3%). The rate of any stroke at 30 days was 4.9% in TAVR patients and 6.2% in the surgical group; and at 1 year, those rates were 8.8% and 12.6%, respectively; neither difference was statistically significant. Major vascular complications and permanent pacemaker implantations were significantly higher in the TAVR group (22.3% at 1 year, vs. 11.3% in the surgical group). In the TAVR group, there were five cases of cardiac perforation; there were no perforations in the surgical group.

Patients are being followed through 5 years. The 2-year mortality data are encouraging, with continued separation of the all-cause mortality curves, although the numbers are still small, Dr. Adams said.

More patients in the trial refused surgical valve replacement after randomization and the mortality rate within 30 days after surgery was 4.5%, which was lower than the rate specified for inclusion in the study, which was 15% or higher, so the patients may have been at a lower risk than planned, he said.

During the discussion, the inevitable comparisons to the results of the Placement of Aortic Transcatheter Valves A (PARTNER A) study were raised. In PARTNER A, which compared the safety and effectiveness of the balloon-expandable SAPIEN Transcatheter Heart Valve to aortic valve replacement surgery in high-risk patients with severe symptomatic aortic stenosis, found no difference in mortality between the two arms and an increase in cerebrovascular events in the TAVR arm.

Dr. Adams said that different characteristics of the device in the two trials are possible explanations as to why the TAVR results were superior to surgery in the CoreValve study, and not in PARTNER A. "The size of the catheter as well as perhaps the self-expanding nature of the device both could help explain that," he said.

While patient risk was assessed differently in the studies, and the Society of Thoracic Surgeons scores of the patients were different, "we're confident these were patients at increased risk for surgery," he added.

The study was published simultaneously in the New England Journal of Medicine on March 29 (2014 March 29 [doi:10.1056/NEJMoa1400590]).

The study is funded by the CoreValve manufacturer, Medtronic. Dr. Adams disclosed receiving grant support from Medtronic during the conduct of the study and other support from Medtronic and Edwards Lifesciences outside the submitted work.

emechcatie@frontlinemedcom.com

WASHINGTON - A first in transcatheter aortic valve replacement trials, the CoreValve prosthesis was superior to surgical valve replacement in patients with severe aortic stenosis at increased surgical risk, showing a significantly lower risk of mortality 1 year later.

In the U.S. CoreValve High Risk Study, a prospective randomized controlled study of almost 800 patients, the rate of all-cause mortality at 1 year, the primary endpoint, was 14.2% among those in the transcatheter aortic valve replacement (TAVR) group, compared with 19.1% among those in the surgery group, a statistically significant difference that represented a 26% survival benefit at 1 year for the CoreValve, Dr. David H. Adams reported at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

This is the first prospective, randomized study to show superiority for transcatheter valve therapy over surgery, and "there's no study or trial that I'm aware of that's suggested that TAVR patients would have a superior survival outcome," Dr. Adams of Mount Sinai Medical Center, New York, said in an interview. Based on these results, he said he expects that TAVR "will increasingly become the alternative of choice for patients" at this level of risk.

The study was the high-risk arm of the U.S. CoreValve pivotal trial. The CoreValve self-expanding prosthesis was approved in January 2014 by the Food and Drug Administration for use in extreme risk patients, based on the results of the extreme risk cohort of patients. The data from the study in the high-risk trial are being reviewed at the FDA, according to the manufacturer, Medtronic.

The study compared the safety and effectiveness of TAVR with the CoreValve device to surgical valve replacement in 795 patients at 45 U.S. centers. The patients had severe aortic stenosis, had New York Heart Association class II heart failure or higher, and were judged to have at least a 15% risk of death within 30 days after surgery and less than a 50% risk of death or irreversible complications within 30 days after surgery. Their mean age was about age 83 years, almost half were females, most had class NYHA class III HF, and cardiac risk factors included coronary artery disease (in about two-thirds), previous coronary artery bypass surgery (about 30%), a previous MI (about 25%), and almost all had heart failure.

At 1 year, a composite of major adverse cardiovascular and cerebrovascular events (death from any cause, MI, any stroke, or reintervention), a secondary endpoint, was significantly lower among those on TAVR (20.4%) vs. the surgical group (27.3%). The rate of any stroke at 30 days was 4.9% in TAVR patients and 6.2% in the surgical group; and at 1 year, those rates were 8.8% and 12.6%, respectively; neither difference was statistically significant. Major vascular complications and permanent pacemaker implantations were significantly higher in the TAVR group (22.3% at 1 year, vs. 11.3% in the surgical group). In the TAVR group, there were five cases of cardiac perforation; there were no perforations in the surgical group.

Patients are being followed through 5 years. The 2-year mortality data are encouraging, with continued separation of the all-cause mortality curves, although the numbers are still small, Dr. Adams said.

More patients in the trial refused surgical valve replacement after randomization and the mortality rate within 30 days after surgery was 4.5%, which was lower than the rate specified for inclusion in the study, which was 15% or higher, so the patients may have been at a lower risk than planned, he said.

During the discussion, the inevitable comparisons to the results of the Placement of Aortic Transcatheter Valves A (PARTNER A) study were raised. In PARTNER A, which compared the safety and effectiveness of the balloon-expandable SAPIEN Transcatheter Heart Valve to aortic valve replacement surgery in high-risk patients with severe symptomatic aortic stenosis, found no difference in mortality between the two arms and an increase in cerebrovascular events in the TAVR arm.

Dr. Adams said that different characteristics of the device in the two trials are possible explanations as to why the TAVR results were superior to surgery in the CoreValve study, and not in PARTNER A. "The size of the catheter as well as perhaps the self-expanding nature of the device both could help explain that," he said.

While patient risk was assessed differently in the studies, and the Society of Thoracic Surgeons scores of the patients were different, "we're confident these were patients at increased risk for surgery," he added.

The study was published simultaneously in the New England Journal of Medicine on March 29 (2014 March 29 [doi:10.1056/NEJMoa1400590]).

The study is funded by the CoreValve manufacturer, Medtronic. Dr. Adams disclosed receiving grant support from Medtronic during the conduct of the study and other support from Medtronic and Edwards Lifesciences outside the submitted work.

emechcatie@frontlinemedcom.com

WASHINGTON - A first in transcatheter aortic valve replacement trials, the CoreValve prosthesis was superior to surgical valve replacement in patients with severe aortic stenosis at increased surgical risk, showing a significantly lower risk of mortality 1 year later.

In the U.S. CoreValve High Risk Study, a prospective randomized controlled study of almost 800 patients, the rate of all-cause mortality at 1 year, the primary endpoint, was 14.2% among those in the transcatheter aortic valve replacement (TAVR) group, compared with 19.1% among those in the surgery group, a statistically significant difference that represented a 26% survival benefit at 1 year for the CoreValve, Dr. David H. Adams reported at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

This is the first prospective, randomized study to show superiority for transcatheter valve therapy over surgery, and "there's no study or trial that I'm aware of that's suggested that TAVR patients would have a superior survival outcome," Dr. Adams of Mount Sinai Medical Center, New York, said in an interview. Based on these results, he said he expects that TAVR "will increasingly become the alternative of choice for patients" at this level of risk.

The study was the high-risk arm of the U.S. CoreValve pivotal trial. The CoreValve self-expanding prosthesis was approved in January 2014 by the Food and Drug Administration for use in extreme risk patients, based on the results of the extreme risk cohort of patients. The data from the study in the high-risk trial are being reviewed at the FDA, according to the manufacturer, Medtronic.

The study compared the safety and effectiveness of TAVR with the CoreValve device to surgical valve replacement in 795 patients at 45 U.S. centers. The patients had severe aortic stenosis, had New York Heart Association class II heart failure or higher, and were judged to have at least a 15% risk of death within 30 days after surgery and less than a 50% risk of death or irreversible complications within 30 days after surgery. Their mean age was about age 83 years, almost half were females, most had class NYHA class III HF, and cardiac risk factors included coronary artery disease (in about two-thirds), previous coronary artery bypass surgery (about 30%), a previous MI (about 25%), and almost all had heart failure.

At 1 year, a composite of major adverse cardiovascular and cerebrovascular events (death from any cause, MI, any stroke, or reintervention), a secondary endpoint, was significantly lower among those on TAVR (20.4%) vs. the surgical group (27.3%). The rate of any stroke at 30 days was 4.9% in TAVR patients and 6.2% in the surgical group; and at 1 year, those rates were 8.8% and 12.6%, respectively; neither difference was statistically significant. Major vascular complications and permanent pacemaker implantations were significantly higher in the TAVR group (22.3% at 1 year, vs. 11.3% in the surgical group). In the TAVR group, there were five cases of cardiac perforation; there were no perforations in the surgical group.

Patients are being followed through 5 years. The 2-year mortality data are encouraging, with continued separation of the all-cause mortality curves, although the numbers are still small, Dr. Adams said.

More patients in the trial refused surgical valve replacement after randomization and the mortality rate within 30 days after surgery was 4.5%, which was lower than the rate specified for inclusion in the study, which was 15% or higher, so the patients may have been at a lower risk than planned, he said.

During the discussion, the inevitable comparisons to the results of the Placement of Aortic Transcatheter Valves A (PARTNER A) study were raised. In PARTNER A, which compared the safety and effectiveness of the balloon-expandable SAPIEN Transcatheter Heart Valve to aortic valve replacement surgery in high-risk patients with severe symptomatic aortic stenosis, found no difference in mortality between the two arms and an increase in cerebrovascular events in the TAVR arm.

Dr. Adams said that different characteristics of the device in the two trials are possible explanations as to why the TAVR results were superior to surgery in the CoreValve study, and not in PARTNER A. "The size of the catheter as well as perhaps the self-expanding nature of the device both could help explain that," he said.

While patient risk was assessed differently in the studies, and the Society of Thoracic Surgeons scores of the patients were different, "we're confident these were patients at increased risk for surgery," he added.

The study was published simultaneously in the New England Journal of Medicine on March 29 (2014 March 29 [doi:10.1056/NEJMoa1400590]).

The study is funded by the CoreValve manufacturer, Medtronic. Dr. Adams disclosed receiving grant support from Medtronic during the conduct of the study and other support from Medtronic and Edwards Lifesciences outside the submitted work.

emechcatie@frontlinemedcom.com

The recommended starting dose for the insomnia drug eszopiclone has been lowered from 2 mg to 1 mg, to address the risk of next-morning impairment associated with the drug, the Food and Drug Administration announced on May 15.

The manufacturer of the drug, marketed as Lunesta, was required to change the starting dose recommendation because of evidence that levels of the drug "in some patients may be high enough the morning after use to impair activities that require alertness, including driving, even if they feel fully awake," the FDA statement said. The recommendation applies to men and women.

If necessary, the 1-mg dose can be increased to 2 mg or 3 mg, "but the higher doses are more likely to result in next-day impairment of driving and other activities that require full alertness," the statement added. The FDA also is advising patients who are on the 2-mg or 3-mg doses to contact their health care providers for advice on how they can continue the drug safely, and is cautioning patients on the 3-mg dose not to drive or engage in other activities "that require complete mental alertness the day after use."

The recommendations are based partly on the results of a study of 91 healthy adults aged 24-40 years, which compared the effects of the 3-mg dose of eszopiclone and placebo, according to the FDA. The use of the 3-mg dose was associated with severe psychomotor and memory impairments in men and women the next morning, 7.5 hours after taking the medication. At recommended doses, impairments in driving skills, memory, and coordination were evident for up to 11 hours after the drug was taken, and "despite these long-lasting effects, patients were often unaware they were impaired," the statement said.

In January 2013, the FDA recommended reducing the dose for sleep medications containing zolpidem, which include Ambien and Ambien (CR), for the same reason.

The safety communication regarding this drug is available here. Serious adverse events associated with this and other insomnia drugs should be reported to the FDA at 800-332-1088 or at the MedWatch website.

emechcatie@frontlinemedcom.com

The recommended starting dose for the insomnia drug eszopiclone has been lowered from 2 mg to 1 mg, to address the risk of next-morning impairment associated with the drug, the Food and Drug Administration announced on May 15.

The manufacturer of the drug, marketed as Lunesta, was required to change the starting dose recommendation because of evidence that levels of the drug "in some patients may be high enough the morning after use to impair activities that require alertness, including driving, even if they feel fully awake," the FDA statement said. The recommendation applies to men and women.

If necessary, the 1-mg dose can be increased to 2 mg or 3 mg, "but the higher doses are more likely to result in next-day impairment of driving and other activities that require full alertness," the statement added. The FDA also is advising patients who are on the 2-mg or 3-mg doses to contact their health care providers for advice on how they can continue the drug safely, and is cautioning patients on the 3-mg dose not to drive or engage in other activities "that require complete mental alertness the day after use."

The recommendations are based partly on the results of a study of 91 healthy adults aged 24-40 years, which compared the effects of the 3-mg dose of eszopiclone and placebo, according to the FDA. The use of the 3-mg dose was associated with severe psychomotor and memory impairments in men and women the next morning, 7.5 hours after taking the medication. At recommended doses, impairments in driving skills, memory, and coordination were evident for up to 11 hours after the drug was taken, and "despite these long-lasting effects, patients were often unaware they were impaired," the statement said.

In January 2013, the FDA recommended reducing the dose for sleep medications containing zolpidem, which include Ambien and Ambien (CR), for the same reason.

The safety communication regarding this drug is available here. Serious adverse events associated with this and other insomnia drugs should be reported to the FDA at 800-332-1088 or at the MedWatch website.

emechcatie@frontlinemedcom.com

The recommended starting dose for the insomnia drug eszopiclone has been lowered from 2 mg to 1 mg, to address the risk of next-morning impairment associated with the drug, the Food and Drug Administration announced on May 15.

The manufacturer of the drug, marketed as Lunesta, was required to change the starting dose recommendation because of evidence that levels of the drug "in some patients may be high enough the morning after use to impair activities that require alertness, including driving, even if they feel fully awake," the FDA statement said. The recommendation applies to men and women.

If necessary, the 1-mg dose can be increased to 2 mg or 3 mg, "but the higher doses are more likely to result in next-day impairment of driving and other activities that require full alertness," the statement added. The FDA also is advising patients who are on the 2-mg or 3-mg doses to contact their health care providers for advice on how they can continue the drug safely, and is cautioning patients on the 3-mg dose not to drive or engage in other activities "that require complete mental alertness the day after use."

The recommendations are based partly on the results of a study of 91 healthy adults aged 24-40 years, which compared the effects of the 3-mg dose of eszopiclone and placebo, according to the FDA. The use of the 3-mg dose was associated with severe psychomotor and memory impairments in men and women the next morning, 7.5 hours after taking the medication. At recommended doses, impairments in driving skills, memory, and coordination were evident for up to 11 hours after the drug was taken, and "despite these long-lasting effects, patients were often unaware they were impaired," the statement said.

In January 2013, the FDA recommended reducing the dose for sleep medications containing zolpidem, which include Ambien and Ambien (CR), for the same reason.

The safety communication regarding this drug is available here. Serious adverse events associated with this and other insomnia drugs should be reported to the FDA at 800-332-1088 or at the MedWatch website.

emechcatie@frontlinemedcom.com

Treatment with canagliflozin was associated with significant weight loss as well as improvements in glycemic control, when compared with placebo in a 26-week, phase III study of nearly 600 patients.

Dr. William Canovatchel of Janssen Pharmaceuticals, the manufacturer of canagliflozin, is presenting these results on May 16 at the annual meeting of the American Association of Clinical Endocrinologists.

In phase III clinical trials, canagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, has been associated with significant weight loss in a variety of patients, he noted. In the phase III randomized, placebo-controlled study, 584 patients with type 2 diabetes who were inadequately treated with diet and exercise were randomized to placebo or canagliflozin (300 mg or 100 mg once a day). The mean age was 55 years, and the patients’ mean hemoglobin A_1c was 8%. Their mean body weight was 191 pounds (86.8 kg).

At 26 weeks, the mean reductions in HbA_1c from baseline (the primary endpoint) among patients on the 100-mg and 300-mg doses of canagliflozin were 0.77% and 1.03%, respectively, compared with an increase of 0.14% among those on placebo. Differences between the drug and placebo were statistically significant.

In addition, those on the 100-mg and 300-mg canagliflozin doses lost a mean of 5.5 pounds (2.5 kg), and 7.5 pounds (3.4 kg), respectively, compared with a mean of 1 pound (0.5 kg) among those on placebo.

Moreover, 71% of those on 100 mg and 84% of those on 300 mg had reductions in both weight and HbA_1c, compared with 28% of those on placebo, according to Dr. Canovatchel.

Genital mycotic infections, urinary tract infections, and those related to osmotic diuresis were among the adverse events associated with canagliflozin, which was generally well tolerated, he said. The drug was associated with a low rate of hypoglycemia.

Canagliflozin (Invokana) was the first SGLT2 inhibitor to be approved in the United States, in March 2013. These agents, taken orally, work by inhibiting SGLT2 that is expressed in the kidney, reducing renal glucose reabsorption, increasing urinary excretion of glucose, and reducing plasma glucose levels.

The study was published last year (Diabetes Obes. Metab. 2013;15:372-82).

Dr. Canovatchel is an employee of Janssen, the manufacturer of canagliflozin.

emechcatie@frontlinemedcom.com

Treatment with canagliflozin was associated with significant weight loss as well as improvements in glycemic control, when compared with placebo in a 26-week, phase III study of nearly 600 patients.

Dr. William Canovatchel of Janssen Pharmaceuticals, the manufacturer of canagliflozin, is presenting these results on May 16 at the annual meeting of the American Association of Clinical Endocrinologists.

In phase III clinical trials, canagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, has been associated with significant weight loss in a variety of patients, he noted. In the phase III randomized, placebo-controlled study, 584 patients with type 2 diabetes who were inadequately treated with diet and exercise were randomized to placebo or canagliflozin (300 mg or 100 mg once a day). The mean age was 55 years, and the patients’ mean hemoglobin A_1c was 8%. Their mean body weight was 191 pounds (86.8 kg).

At 26 weeks, the mean reductions in HbA_1c from baseline (the primary endpoint) among patients on the 100-mg and 300-mg doses of canagliflozin were 0.77% and 1.03%, respectively, compared with an increase of 0.14% among those on placebo. Differences between the drug and placebo were statistically significant.

In addition, those on the 100-mg and 300-mg canagliflozin doses lost a mean of 5.5 pounds (2.5 kg), and 7.5 pounds (3.4 kg), respectively, compared with a mean of 1 pound (0.5 kg) among those on placebo.

Moreover, 71% of those on 100 mg and 84% of those on 300 mg had reductions in both weight and HbA_1c, compared with 28% of those on placebo, according to Dr. Canovatchel.

Genital mycotic infections, urinary tract infections, and those related to osmotic diuresis were among the adverse events associated with canagliflozin, which was generally well tolerated, he said. The drug was associated with a low rate of hypoglycemia.

Canagliflozin (Invokana) was the first SGLT2 inhibitor to be approved in the United States, in March 2013. These agents, taken orally, work by inhibiting SGLT2 that is expressed in the kidney, reducing renal glucose reabsorption, increasing urinary excretion of glucose, and reducing plasma glucose levels.

The study was published last year (Diabetes Obes. Metab. 2013;15:372-82).

Dr. Canovatchel is an employee of Janssen, the manufacturer of canagliflozin.

emechcatie@frontlinemedcom.com

Treatment with canagliflozin was associated with significant weight loss as well as improvements in glycemic control, when compared with placebo in a 26-week, phase III study of nearly 600 patients.

Dr. William Canovatchel of Janssen Pharmaceuticals, the manufacturer of canagliflozin, is presenting these results on May 16 at the annual meeting of the American Association of Clinical Endocrinologists.

In phase III clinical trials, canagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, has been associated with significant weight loss in a variety of patients, he noted. In the phase III randomized, placebo-controlled study, 584 patients with type 2 diabetes who were inadequately treated with diet and exercise were randomized to placebo or canagliflozin (300 mg or 100 mg once a day). The mean age was 55 years, and the patients’ mean hemoglobin A_1c was 8%. Their mean body weight was 191 pounds (86.8 kg).

At 26 weeks, the mean reductions in HbA_1c from baseline (the primary endpoint) among patients on the 100-mg and 300-mg doses of canagliflozin were 0.77% and 1.03%, respectively, compared with an increase of 0.14% among those on placebo. Differences between the drug and placebo were statistically significant.

In addition, those on the 100-mg and 300-mg canagliflozin doses lost a mean of 5.5 pounds (2.5 kg), and 7.5 pounds (3.4 kg), respectively, compared with a mean of 1 pound (0.5 kg) among those on placebo.

Moreover, 71% of those on 100 mg and 84% of those on 300 mg had reductions in both weight and HbA_1c, compared with 28% of those on placebo, according to Dr. Canovatchel.

Genital mycotic infections, urinary tract infections, and those related to osmotic diuresis were among the adverse events associated with canagliflozin, which was generally well tolerated, he said. The drug was associated with a low rate of hypoglycemia.

Canagliflozin (Invokana) was the first SGLT2 inhibitor to be approved in the United States, in March 2013. These agents, taken orally, work by inhibiting SGLT2 that is expressed in the kidney, reducing renal glucose reabsorption, increasing urinary excretion of glucose, and reducing plasma glucose levels.

The study was published last year (Diabetes Obes. Metab. 2013;15:372-82).

Dr. Canovatchel is an employee of Janssen, the manufacturer of canagliflozin.

emechcatie@frontlinemedcom.com

Treatment with saxagliptin was not associated with an increased risk of major adverse cardiovascular events or heart failure in a pooled analysis of 20 studies of patients with type 2 diabetes.

The analysis also found no association with saxagliptin therapy and individual components of the major adverse cardiovascular events (MACE) endpoint, a composite of cardiovascular death, myocardial infarction, and stroke, according to a study being presented at the meeting. The results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists in Las Vegas.

Saxagliptin, a dipeptidyl peptidase–4 (DPP-44) inhibitor taken orally, was approved by the Food and Drug Administration in 2009 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

The study evaluated adjudicated reports of MACE and investigator reports of heart failure associated with saxagliptin in 20 studies of saxagliptin as monotherapy or as add-on therapy in 9,156 patients with type 2 diabetes. Unlike the SAVOR-TIMI 53 study (Saxagliptin Assessment of Vascular Outcomes Recorded in Patient With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) study, published in 2013, which found an increased risk of heart failure hospitalizations in patients with prior CV disease or multiple CV risk factors, the patients with type 2 diabetes enrolled in the 20 studies were at lower risk for CV events.

In the SAVOR-TIMI 53, which evaluated the drug’s cardiovascular safety in more than 16,000 patients with type 2 diabetes and established cardiovascular disease or risk factors for CHD, treatment with saxagliptin was not associated with an increased or reduced risk of ischemic risk for the composite of CV death, MI, or ischemic stroke, the primary endpoint, over a median of 2 years. But it was associated with a significantly greater risk of being hospitalized for heart failure (hazard ratio, 1.27) (N. Engl. J. Med. 2013;369:1317-26). In a January 2014 safety alert, the FDA said that the agency had requested the manufacturer of saxagliptin study “a possible association” between the use of the drug and heart failure, because of the increased risk of heart failure hospitalizations in that study.

In the 20-study analysis, based on 43 MACE reports in patients treated with saxagliptin and 31 MACE reports among controls, the MACE incidence rate (IR) – the number of events per 100 person-years – was 0.85/100 person-years for those on saxagliptin and 1.12/100 person-years for the controls. The IR ratio (the number of reports among saxagliptin-treated patients divided by the number of reports among the controls), was 0.74. The hazard ratio was 0.75, which suggests there is no increased risk of MACE associated with saxagliptin.

In a subset of 11 studies that evaluated saxagliptin as add-on therapy to metformin in 5,171 patients, the incidence rates were similar: 0.79/100 person-years for those on saxagliptin and 0.85/100 person-years for controls, with an IR ratio of 0.93.

In the 20 studies, the components of the MACE endpoint were also not statistically significantly different between those on saxagliptin and controls, and 21 patients on saxagliptin and 18 controls had heart failure, with an IR ratio of 0.55, he said.

Consistent with the SAVOR-TIMI 53 study, which analyzed MACE in patients with type 2 diabetes and cardiovascular disease or multiple cardiovascular risk factors, this 20-trial pooled analysis of patients from the general type 2 diabetes population found that saxagliptin was not associated with an increased risk of MACE or its components, or heart failure.

The pooled results “are somewhat reassuring in that the use of saxagliptin in patients with type 2 diabetes at lower risk for cardiovascular events is not associated with increased MACE risk,” and would have passed the FDA-recommended boundary for unacceptable risk for diabetes drugs (HR, 1.3), Dr. Sanjay Kaul said in an interview. However, he added, “it is disappointing that glycemic control did not translate into a macrovascular benefit, even though a lower risk population was evaluated.”

Moreover, the study “did not yield a sufficient number of heart failure events to reliably adjudicate the risk of heart failure in this patient population,” noted Dr. Kaul, professor of medicine, University of California, Los Angeles, who was not at the meeting. Dr. Kaul was a panelist at the FDA advisory panel meeting that reviewed the cardiovascular safety of rosiglitazone (Avandia) last year.

Three of the five authors are employed by Bristol-Myers Squibb; two are employed by AstraZeneca Dr. Kaul had no relevant disclosures related to saxagliptin; he has disclosures for diabetes agents manufactured by other companies.

Saxagliptin is marketed as Onglyza by AstraZeneca.

emechcatie@frontlinemedcom.com

Treatment with saxagliptin was not associated with an increased risk of major adverse cardiovascular events or heart failure in a pooled analysis of 20 studies of patients with type 2 diabetes.

The analysis also found no association with saxagliptin therapy and individual components of the major adverse cardiovascular events (MACE) endpoint, a composite of cardiovascular death, myocardial infarction, and stroke, according to a study being presented at the meeting. The results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists in Las Vegas.

Saxagliptin, a dipeptidyl peptidase–4 (DPP-44) inhibitor taken orally, was approved by the Food and Drug Administration in 2009 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

The study evaluated adjudicated reports of MACE and investigator reports of heart failure associated with saxagliptin in 20 studies of saxagliptin as monotherapy or as add-on therapy in 9,156 patients with type 2 diabetes. Unlike the SAVOR-TIMI 53 study (Saxagliptin Assessment of Vascular Outcomes Recorded in Patient With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) study, published in 2013, which found an increased risk of heart failure hospitalizations in patients with prior CV disease or multiple CV risk factors, the patients with type 2 diabetes enrolled in the 20 studies were at lower risk for CV events.

In the SAVOR-TIMI 53, which evaluated the drug’s cardiovascular safety in more than 16,000 patients with type 2 diabetes and established cardiovascular disease or risk factors for CHD, treatment with saxagliptin was not associated with an increased or reduced risk of ischemic risk for the composite of CV death, MI, or ischemic stroke, the primary endpoint, over a median of 2 years. But it was associated with a significantly greater risk of being hospitalized for heart failure (hazard ratio, 1.27) (N. Engl. J. Med. 2013;369:1317-26). In a January 2014 safety alert, the FDA said that the agency had requested the manufacturer of saxagliptin study “a possible association” between the use of the drug and heart failure, because of the increased risk of heart failure hospitalizations in that study.

In the 20-study analysis, based on 43 MACE reports in patients treated with saxagliptin and 31 MACE reports among controls, the MACE incidence rate (IR) – the number of events per 100 person-years – was 0.85/100 person-years for those on saxagliptin and 1.12/100 person-years for the controls. The IR ratio (the number of reports among saxagliptin-treated patients divided by the number of reports among the controls), was 0.74. The hazard ratio was 0.75, which suggests there is no increased risk of MACE associated with saxagliptin.

In a subset of 11 studies that evaluated saxagliptin as add-on therapy to metformin in 5,171 patients, the incidence rates were similar: 0.79/100 person-years for those on saxagliptin and 0.85/100 person-years for controls, with an IR ratio of 0.93.

In the 20 studies, the components of the MACE endpoint were also not statistically significantly different between those on saxagliptin and controls, and 21 patients on saxagliptin and 18 controls had heart failure, with an IR ratio of 0.55, he said.

Consistent with the SAVOR-TIMI 53 study, which analyzed MACE in patients with type 2 diabetes and cardiovascular disease or multiple cardiovascular risk factors, this 20-trial pooled analysis of patients from the general type 2 diabetes population found that saxagliptin was not associated with an increased risk of MACE or its components, or heart failure.

The pooled results “are somewhat reassuring in that the use of saxagliptin in patients with type 2 diabetes at lower risk for cardiovascular events is not associated with increased MACE risk,” and would have passed the FDA-recommended boundary for unacceptable risk for diabetes drugs (HR, 1.3), Dr. Sanjay Kaul said in an interview. However, he added, “it is disappointing that glycemic control did not translate into a macrovascular benefit, even though a lower risk population was evaluated.”

Moreover, the study “did not yield a sufficient number of heart failure events to reliably adjudicate the risk of heart failure in this patient population,” noted Dr. Kaul, professor of medicine, University of California, Los Angeles, who was not at the meeting. Dr. Kaul was a panelist at the FDA advisory panel meeting that reviewed the cardiovascular safety of rosiglitazone (Avandia) last year.

Three of the five authors are employed by Bristol-Myers Squibb; two are employed by AstraZeneca Dr. Kaul had no relevant disclosures related to saxagliptin; he has disclosures for diabetes agents manufactured by other companies.

Saxagliptin is marketed as Onglyza by AstraZeneca.

emechcatie@frontlinemedcom.com

Treatment with saxagliptin was not associated with an increased risk of major adverse cardiovascular events or heart failure in a pooled analysis of 20 studies of patients with type 2 diabetes.

The analysis also found no association with saxagliptin therapy and individual components of the major adverse cardiovascular events (MACE) endpoint, a composite of cardiovascular death, myocardial infarction, and stroke, according to a study being presented at the meeting. The results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists in Las Vegas.

Saxagliptin, a dipeptidyl peptidase–4 (DPP-44) inhibitor taken orally, was approved by the Food and Drug Administration in 2009 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

The study evaluated adjudicated reports of MACE and investigator reports of heart failure associated with saxagliptin in 20 studies of saxagliptin as monotherapy or as add-on therapy in 9,156 patients with type 2 diabetes. Unlike the SAVOR-TIMI 53 study (Saxagliptin Assessment of Vascular Outcomes Recorded in Patient With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) study, published in 2013, which found an increased risk of heart failure hospitalizations in patients with prior CV disease or multiple CV risk factors, the patients with type 2 diabetes enrolled in the 20 studies were at lower risk for CV events.

In the SAVOR-TIMI 53, which evaluated the drug’s cardiovascular safety in more than 16,000 patients with type 2 diabetes and established cardiovascular disease or risk factors for CHD, treatment with saxagliptin was not associated with an increased or reduced risk of ischemic risk for the composite of CV death, MI, or ischemic stroke, the primary endpoint, over a median of 2 years. But it was associated with a significantly greater risk of being hospitalized for heart failure (hazard ratio, 1.27) (N. Engl. J. Med. 2013;369:1317-26). In a January 2014 safety alert, the FDA said that the agency had requested the manufacturer of saxagliptin study “a possible association” between the use of the drug and heart failure, because of the increased risk of heart failure hospitalizations in that study.

In the 20-study analysis, based on 43 MACE reports in patients treated with saxagliptin and 31 MACE reports among controls, the MACE incidence rate (IR) – the number of events per 100 person-years – was 0.85/100 person-years for those on saxagliptin and 1.12/100 person-years for the controls. The IR ratio (the number of reports among saxagliptin-treated patients divided by the number of reports among the controls), was 0.74. The hazard ratio was 0.75, which suggests there is no increased risk of MACE associated with saxagliptin.

In a subset of 11 studies that evaluated saxagliptin as add-on therapy to metformin in 5,171 patients, the incidence rates were similar: 0.79/100 person-years for those on saxagliptin and 0.85/100 person-years for controls, with an IR ratio of 0.93.

In the 20 studies, the components of the MACE endpoint were also not statistically significantly different between those on saxagliptin and controls, and 21 patients on saxagliptin and 18 controls had heart failure, with an IR ratio of 0.55, he said.

Consistent with the SAVOR-TIMI 53 study, which analyzed MACE in patients with type 2 diabetes and cardiovascular disease or multiple cardiovascular risk factors, this 20-trial pooled analysis of patients from the general type 2 diabetes population found that saxagliptin was not associated with an increased risk of MACE or its components, or heart failure.

The pooled results “are somewhat reassuring in that the use of saxagliptin in patients with type 2 diabetes at lower risk for cardiovascular events is not associated with increased MACE risk,” and would have passed the FDA-recommended boundary for unacceptable risk for diabetes drugs (HR, 1.3), Dr. Sanjay Kaul said in an interview. However, he added, “it is disappointing that glycemic control did not translate into a macrovascular benefit, even though a lower risk population was evaluated.”

Moreover, the study “did not yield a sufficient number of heart failure events to reliably adjudicate the risk of heart failure in this patient population,” noted Dr. Kaul, professor of medicine, University of California, Los Angeles, who was not at the meeting. Dr. Kaul was a panelist at the FDA advisory panel meeting that reviewed the cardiovascular safety of rosiglitazone (Avandia) last year.

Three of the five authors are employed by Bristol-Myers Squibb; two are employed by AstraZeneca Dr. Kaul had no relevant disclosures related to saxagliptin; he has disclosures for diabetes agents manufactured by other companies.

Saxagliptin is marketed as Onglyza by AstraZeneca.

emechcatie@frontlinemedcom.com

Treatment with empagliflozin, an investigational sodium-glucose cotransporter 2 (SGLT2) inhibitor, was associated with benefits for blood pressure as well as glycemic control in a 3-month study of more than 800 patients with type 2 diabetes and hypertension.

The study results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists, held in Las Vegas, by Dr. Afshin Salsali, an endocrinologist and executive director, diabetes and metabolism, at Boehringer Ingelheim Pharmaceuticals, the manufacturer of the drug.

Since hypertension is common among patients with type 2 diabetes and is associated with diabetes-related complications, a treatment approach that includes control of blood pressure and hyperglycemia might reduce the risk of cardiovascular complications and mortality in these patients, Dr. Salsali said in an interview before the meeting.

In the phase III randomized, controlled study, 823 patients were treated with either 10 mg of empagliflozin (276 patients), 25 mg of empagliflozin (276), or placebo (271), once a day for 12 weeks. At baseline, the patients’ mean seated systolic and diastolic blood pressures were 130-159 mm Hg and 80-99 mm Hg, respectively; their mean age was 60 years; and their mean body mass index was about 33 kg/m², in the obese category.

The two primary endpoints were changes from baseline in hemoglobin A_1c and mean 24-hour systolic blood pressure as measured by ambulatory blood pressure monitoring, at week 12.

At 12 weeks, the mean reductions in HbA_1c from baseline over placebo were 0.62% for those on the 10-mg dose and 0.65% among those on the 25-mg dose, both significant differences. The reductions in mean 24-hour systolic blood pressure were also significant, compared with placebo: They were 3.44 mm Hg with the 10-mg dose and 4.16 mm Hg with the 25-mg dose, according to Dr. Salsali.

In addition, the mean reductions from baseline in 24-hour diastolic blood pressure were significant at week 12, compared with placebo, a secondary endpoint. Those reductions were 1.36 mm Hg for patients on the 10-mg dose and 1.72 mm Hg for those on the 25-mg dose.

About half of the patients in each group reported adverse events. "Events consistent with volume depletion" were reported in one patient on the 10-mg dose of empagliflozin and one in the placebo group.

This study is unique because it utilized the gold standard for monitoring blood pressure to evaluate the effects of the drug on blood pressure, Dr. Salsali said.

Currently, empagliflozin is approved only in Australia, and it is under review in the United States and Europe. In March, Boehringer Ingelheim and Eli Lilly announced that the Food and Drug Administration had issued a complete response letter stating that deficiencies at a site where empagliflozin would be manufactured needed to be resolved before approval. But the FDA has not requested that any new clinical trials be completed for approval, according to the statement issued by Boehringer Ingelheim.

In March, the drug was recommended for approval by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency for treating adults with type 2 diabetes.

In January, the FDA approved the SGLT2 inhibitor dapagliflozin for the treatment of type 2 diabetes. The first drug in this class to be approved in the United States was canagliflozin (Invokana), approved in March 2013. These agents, taken orally, work by inhibiting SGLT2 that is expressed in the kidney, reducing renal glucose reabsorption, increasing urinary excretion of glucose, and reducing plasma glucose levels.

The study was sponsored by Boehringer Ingelheim; Eli Lilly was a collaborator. Dr. Salsali is an employee of Boehringer Ingelheim USA. Other authors of the study included employees of Boehringer Ingelheim, including Boehringer Ingelheim Finland.

emechcatie@frontlinemedcom.com

Treatment with empagliflozin, an investigational sodium-glucose cotransporter 2 (SGLT2) inhibitor, was associated with benefits for blood pressure as well as glycemic control in a 3-month study of more than 800 patients with type 2 diabetes and hypertension.

The study results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists, held in Las Vegas, by Dr. Afshin Salsali, an endocrinologist and executive director, diabetes and metabolism, at Boehringer Ingelheim Pharmaceuticals, the manufacturer of the drug.

Since hypertension is common among patients with type 2 diabetes and is associated with diabetes-related complications, a treatment approach that includes control of blood pressure and hyperglycemia might reduce the risk of cardiovascular complications and mortality in these patients, Dr. Salsali said in an interview before the meeting.

In the phase III randomized, controlled study, 823 patients were treated with either 10 mg of empagliflozin (276 patients), 25 mg of empagliflozin (276), or placebo (271), once a day for 12 weeks. At baseline, the patients’ mean seated systolic and diastolic blood pressures were 130-159 mm Hg and 80-99 mm Hg, respectively; their mean age was 60 years; and their mean body mass index was about 33 kg/m², in the obese category.

The two primary endpoints were changes from baseline in hemoglobin A_1c and mean 24-hour systolic blood pressure as measured by ambulatory blood pressure monitoring, at week 12.

At 12 weeks, the mean reductions in HbA_1c from baseline over placebo were 0.62% for those on the 10-mg dose and 0.65% among those on the 25-mg dose, both significant differences. The reductions in mean 24-hour systolic blood pressure were also significant, compared with placebo: They were 3.44 mm Hg with the 10-mg dose and 4.16 mm Hg with the 25-mg dose, according to Dr. Salsali.

In addition, the mean reductions from baseline in 24-hour diastolic blood pressure were significant at week 12, compared with placebo, a secondary endpoint. Those reductions were 1.36 mm Hg for patients on the 10-mg dose and 1.72 mm Hg for those on the 25-mg dose.

About half of the patients in each group reported adverse events. "Events consistent with volume depletion" were reported in one patient on the 10-mg dose of empagliflozin and one in the placebo group.

This study is unique because it utilized the gold standard for monitoring blood pressure to evaluate the effects of the drug on blood pressure, Dr. Salsali said.

Currently, empagliflozin is approved only in Australia, and it is under review in the United States and Europe. In March, Boehringer Ingelheim and Eli Lilly announced that the Food and Drug Administration had issued a complete response letter stating that deficiencies at a site where empagliflozin would be manufactured needed to be resolved before approval. But the FDA has not requested that any new clinical trials be completed for approval, according to the statement issued by Boehringer Ingelheim.

In March, the drug was recommended for approval by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency for treating adults with type 2 diabetes.

In January, the FDA approved the SGLT2 inhibitor dapagliflozin for the treatment of type 2 diabetes. The first drug in this class to be approved in the United States was canagliflozin (Invokana), approved in March 2013. These agents, taken orally, work by inhibiting SGLT2 that is expressed in the kidney, reducing renal glucose reabsorption, increasing urinary excretion of glucose, and reducing plasma glucose levels.

The study was sponsored by Boehringer Ingelheim; Eli Lilly was a collaborator. Dr. Salsali is an employee of Boehringer Ingelheim USA. Other authors of the study included employees of Boehringer Ingelheim, including Boehringer Ingelheim Finland.

emechcatie@frontlinemedcom.com

Treatment with empagliflozin, an investigational sodium-glucose cotransporter 2 (SGLT2) inhibitor, was associated with benefits for blood pressure as well as glycemic control in a 3-month study of more than 800 patients with type 2 diabetes and hypertension.

The study results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists, held in Las Vegas, by Dr. Afshin Salsali, an endocrinologist and executive director, diabetes and metabolism, at Boehringer Ingelheim Pharmaceuticals, the manufacturer of the drug.

Since hypertension is common among patients with type 2 diabetes and is associated with diabetes-related complications, a treatment approach that includes control of blood pressure and hyperglycemia might reduce the risk of cardiovascular complications and mortality in these patients, Dr. Salsali said in an interview before the meeting.

In the phase III randomized, controlled study, 823 patients were treated with either 10 mg of empagliflozin (276 patients), 25 mg of empagliflozin (276), or placebo (271), once a day for 12 weeks. At baseline, the patients’ mean seated systolic and diastolic blood pressures were 130-159 mm Hg and 80-99 mm Hg, respectively; their mean age was 60 years; and their mean body mass index was about 33 kg/m², in the obese category.

The two primary endpoints were changes from baseline in hemoglobin A_1c and mean 24-hour systolic blood pressure as measured by ambulatory blood pressure monitoring, at week 12.

At 12 weeks, the mean reductions in HbA_1c from baseline over placebo were 0.62% for those on the 10-mg dose and 0.65% among those on the 25-mg dose, both significant differences. The reductions in mean 24-hour systolic blood pressure were also significant, compared with placebo: They were 3.44 mm Hg with the 10-mg dose and 4.16 mm Hg with the 25-mg dose, according to Dr. Salsali.

In addition, the mean reductions from baseline in 24-hour diastolic blood pressure were significant at week 12, compared with placebo, a secondary endpoint. Those reductions were 1.36 mm Hg for patients on the 10-mg dose and 1.72 mm Hg for those on the 25-mg dose.

About half of the patients in each group reported adverse events. "Events consistent with volume depletion" were reported in one patient on the 10-mg dose of empagliflozin and one in the placebo group.

This study is unique because it utilized the gold standard for monitoring blood pressure to evaluate the effects of the drug on blood pressure, Dr. Salsali said.

Currently, empagliflozin is approved only in Australia, and it is under review in the United States and Europe. In March, Boehringer Ingelheim and Eli Lilly announced that the Food and Drug Administration had issued a complete response letter stating that deficiencies at a site where empagliflozin would be manufactured needed to be resolved before approval. But the FDA has not requested that any new clinical trials be completed for approval, according to the statement issued by Boehringer Ingelheim.

In March, the drug was recommended for approval by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency for treating adults with type 2 diabetes.

In January, the FDA approved the SGLT2 inhibitor dapagliflozin for the treatment of type 2 diabetes. The first drug in this class to be approved in the United States was canagliflozin (Invokana), approved in March 2013. These agents, taken orally, work by inhibiting SGLT2 that is expressed in the kidney, reducing renal glucose reabsorption, increasing urinary excretion of glucose, and reducing plasma glucose levels.

The study was sponsored by Boehringer Ingelheim; Eli Lilly was a collaborator. Dr. Salsali is an employee of Boehringer Ingelheim USA. Other authors of the study included employees of Boehringer Ingelheim, including Boehringer Ingelheim Finland.

emechcatie@frontlinemedcom.com

[UPDATED] Current recommendations and labeling regarding the use of dabigatran will not change, based on the results of a large observational cohort study comparing the risks of the direct thrombin inhibitor and warfarin in Medicare recipients, the Food and Drug Administration announced on May 13.

The study, which was completed recently and has not been published, found that dabigatran, compared with warfarin, was associated with a lower risk of ischemic stroke, intracranial hemorrhage, and death, according to the FDA’s statement on the findings. The risk of major gastrointestinal bleeding, however, was higher with dabigatran, and the risk of myocardial infarction was similar in both groups.

The statement points out that other than the MI finding, the results are consistent with the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which found the MI risk was higher among those on dabigatran than with warfarin. Approval of dabigatran in 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF was based on the results of the RE-LY study. Dabigatran is marketed as Pradaxa by Boehringer Ingelheim.

"As a result of our latest findings, we still consider Pradaxa to have a favorable benefit to risk profile and have made no changes to the current label or recommendations for use," the FDA statement said. "Importantly, the new study is based on a much larger and older patient population than those used in FDA’s earlier review of postmarket data, and employed a more sophisticated analytical method to capture and analyze the events of concern."

The study, part of an ongoing review of dabigatran, evaluated the risks of more than 134,000 new users of dabigatran and warfarin, who were over age 65 years and had been diagnosed with atrial fibrillation during the 6 months before the medication was dispensed. The data were from 2010-2012. Patient outcomes were identified in administrative and insurance claims, and the study represented more than 37,500 person-years of follow-up.

The results were as follows, with warfarin as the reference group, and dabigatran results based on the analysis of both approved doses (75 mg and 150 mg) combined:

• For ischemic stroke, the incidence rates (IR) per 1,000 person-years were 11.3 for dabigatran, vs. 13.9 for warfarin (hazard ratio, 0.80).

• For intracranial hemorrhage, the incidence rates were 3.3 for dabigatran, vs. 9.6 for warfarin (HR, 0.34).

• For major GI bleeding, the incidence rates were 34.2 for dabigatran, vs. 26.5 for warfarin (HR, 1.28).

• For acute MI, the incidence rates were 15.7 for dabigatran, vs. 16.9 for warfarin (HR, 0.92).

• For mortality, the incidence rates were 32.6 for dabigatran vs. 37.8 for warfarin (HR, 0.86).

The FDA statement points out that the results for major GI bleeding in this study are different from a previous FDA analysis of about 10,600 new users of dabigatran and warfarin, reported in 2012, which found that GI and intracranial hemorrhage rates were lower among patients treated with dabigatran, compared with those on warfarin. However, that study included patients under age 65 years (64% were older than age 65 years), and this disparity "may reflect the age differences in the two patient populations," the FDA statement said.

In an interview, Dr. Sanjay Kaul, professor of medicine at University of California Los Angeles, said the data in the Medicare study were reassuring, “and indicate that the favorable benefit-risk balance observed in the pre-approval randomized controlled trial, RE-LY, are generalizable in real world clinical practice.”

Without a placebo control, he added, “it is unclear what to make of the MI signal observed in RE-LY, but not in this study.” And while the exact cause of increased GI bleeding remains unclear, Dr. Kaul pointed out that this risk cannot be mitigated by gastroprotective medications such as H2 blockers or proton pump inhibitors, and that “it is best to avoid this medication in patients with history of lower-GI bleeding.”

Dr. Deepak Bhatt, professor of medicine at Harvard University in Boston, also described the results of the FDA study as reassuring. The study provides real world data in a large number of patients that complement and largely mirror the results in RE-LY, he said in an interview.

“I think that all those findings regarding death, stroke, and GI bleeding are all true because they were true in the randomized clinical trial dataset, and it is good to see they also appear to be true in real life clinical practice,” he commented. 

In addition, the data “further support the idea that the novel oral anticoagulants in patients who don’t have contraindications for them, and can afford them, [are] a better option than warfarin,” said Dr. Bhatt, the executive director of Interventional Cardiovascular Programs, at Brigham and Women’s Hospital Heart and Vascular Center, Boston.

He pointed out that overall, the three novel oral anticoagulants – dabigatran and the factor Xa inhibitors, apixaban and rivaroxaban – approved for the nonvalvular AF indication, appear to reduce the risk of stroke and death, “and across the board, they all show significantly less intracranial hemorrhage.”

“The availability of agents that have a lower intracranial hemorrhage risk, such as dabigatran, really is an advantage and will hopefully lead to more patients with atrial fibrillation being appropriately treated, instead of being undertreated  because of fear of bleeding into the brain,” he said. 

The FDA plans to publish the Medicare study and will continue to review the risks of bleeding with anticoagulants.

Dabigatran is now also approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days, and to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

The FDA has issued two previous safety alerts regarding the bleeding risks associated with dabigatran, in 2011 and 2012.

Dr. Kaul is a consultant to Boehringer Ingelheim and has equity interest in Johnson and Johnson. Dr. Bhatt said he has research grants with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi Aventis, and the Medicines Company. He is also on the executive committee for the RE-DUAL PCI trial, a large study comparing dabigatran to warfarin in stented patients with AF, which will be starting soon.

The FDA notice is available here. Serious adverse events associated with dabigatran and warfarin should be reported to the FDA at 800-332-1088 or at MedWatch.

emechcatie@frontlinemedcom.com

[UPDATED] Current recommendations and labeling regarding the use of dabigatran will not change, based on the results of a large observational cohort study comparing the risks of the direct thrombin inhibitor and warfarin in Medicare recipients, the Food and Drug Administration announced on May 13.

The study, which was completed recently and has not been published, found that dabigatran, compared with warfarin, was associated with a lower risk of ischemic stroke, intracranial hemorrhage, and death, according to the FDA’s statement on the findings. The risk of major gastrointestinal bleeding, however, was higher with dabigatran, and the risk of myocardial infarction was similar in both groups.

The statement points out that other than the MI finding, the results are consistent with the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which found the MI risk was higher among those on dabigatran than with warfarin. Approval of dabigatran in 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF was based on the results of the RE-LY study. Dabigatran is marketed as Pradaxa by Boehringer Ingelheim.

"As a result of our latest findings, we still consider Pradaxa to have a favorable benefit to risk profile and have made no changes to the current label or recommendations for use," the FDA statement said. "Importantly, the new study is based on a much larger and older patient population than those used in FDA’s earlier review of postmarket data, and employed a more sophisticated analytical method to capture and analyze the events of concern."

The study, part of an ongoing review of dabigatran, evaluated the risks of more than 134,000 new users of dabigatran and warfarin, who were over age 65 years and had been diagnosed with atrial fibrillation during the 6 months before the medication was dispensed. The data were from 2010-2012. Patient outcomes were identified in administrative and insurance claims, and the study represented more than 37,500 person-years of follow-up.

The results were as follows, with warfarin as the reference group, and dabigatran results based on the analysis of both approved doses (75 mg and 150 mg) combined:

• For ischemic stroke, the incidence rates (IR) per 1,000 person-years were 11.3 for dabigatran, vs. 13.9 for warfarin (hazard ratio, 0.80).

• For intracranial hemorrhage, the incidence rates were 3.3 for dabigatran, vs. 9.6 for warfarin (HR, 0.34).

• For major GI bleeding, the incidence rates were 34.2 for dabigatran, vs. 26.5 for warfarin (HR, 1.28).

• For acute MI, the incidence rates were 15.7 for dabigatran, vs. 16.9 for warfarin (HR, 0.92).

• For mortality, the incidence rates were 32.6 for dabigatran vs. 37.8 for warfarin (HR, 0.86).

The FDA statement points out that the results for major GI bleeding in this study are different from a previous FDA analysis of about 10,600 new users of dabigatran and warfarin, reported in 2012, which found that GI and intracranial hemorrhage rates were lower among patients treated with dabigatran, compared with those on warfarin. However, that study included patients under age 65 years (64% were older than age 65 years), and this disparity "may reflect the age differences in the two patient populations," the FDA statement said.

In an interview, Dr. Sanjay Kaul, professor of medicine at University of California Los Angeles, said the data in the Medicare study were reassuring, “and indicate that the favorable benefit-risk balance observed in the pre-approval randomized controlled trial, RE-LY, are generalizable in real world clinical practice.”

Without a placebo control, he added, “it is unclear what to make of the MI signal observed in RE-LY, but not in this study.” And while the exact cause of increased GI bleeding remains unclear, Dr. Kaul pointed out that this risk cannot be mitigated by gastroprotective medications such as H2 blockers or proton pump inhibitors, and that “it is best to avoid this medication in patients with history of lower-GI bleeding.”

Dr. Deepak Bhatt, professor of medicine at Harvard University in Boston, also described the results of the FDA study as reassuring. The study provides real world data in a large number of patients that complement and largely mirror the results in RE-LY, he said in an interview.

“I think that all those findings regarding death, stroke, and GI bleeding are all true because they were true in the randomized clinical trial dataset, and it is good to see they also appear to be true in real life clinical practice,” he commented. 

In addition, the data “further support the idea that the novel oral anticoagulants in patients who don’t have contraindications for them, and can afford them, [are] a better option than warfarin,” said Dr. Bhatt, the executive director of Interventional Cardiovascular Programs, at Brigham and Women’s Hospital Heart and Vascular Center, Boston.

He pointed out that overall, the three novel oral anticoagulants – dabigatran and the factor Xa inhibitors, apixaban and rivaroxaban – approved for the nonvalvular AF indication, appear to reduce the risk of stroke and death, “and across the board, they all show significantly less intracranial hemorrhage.”

“The availability of agents that have a lower intracranial hemorrhage risk, such as dabigatran, really is an advantage and will hopefully lead to more patients with atrial fibrillation being appropriately treated, instead of being undertreated  because of fear of bleeding into the brain,” he said. 

The FDA plans to publish the Medicare study and will continue to review the risks of bleeding with anticoagulants.

Dabigatran is now also approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days, and to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

The FDA has issued two previous safety alerts regarding the bleeding risks associated with dabigatran, in 2011 and 2012.

Dr. Kaul is a consultant to Boehringer Ingelheim and has equity interest in Johnson and Johnson. Dr. Bhatt said he has research grants with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi Aventis, and the Medicines Company. He is also on the executive committee for the RE-DUAL PCI trial, a large study comparing dabigatran to warfarin in stented patients with AF, which will be starting soon.

The FDA notice is available here. Serious adverse events associated with dabigatran and warfarin should be reported to the FDA at 800-332-1088 or at MedWatch.

emechcatie@frontlinemedcom.com

[UPDATED] Current recommendations and labeling regarding the use of dabigatran will not change, based on the results of a large observational cohort study comparing the risks of the direct thrombin inhibitor and warfarin in Medicare recipients, the Food and Drug Administration announced on May 13.

The study, which was completed recently and has not been published, found that dabigatran, compared with warfarin, was associated with a lower risk of ischemic stroke, intracranial hemorrhage, and death, according to the FDA’s statement on the findings. The risk of major gastrointestinal bleeding, however, was higher with dabigatran, and the risk of myocardial infarction was similar in both groups.

The statement points out that other than the MI finding, the results are consistent with the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which found the MI risk was higher among those on dabigatran than with warfarin. Approval of dabigatran in 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF was based on the results of the RE-LY study. Dabigatran is marketed as Pradaxa by Boehringer Ingelheim.

"As a result of our latest findings, we still consider Pradaxa to have a favorable benefit to risk profile and have made no changes to the current label or recommendations for use," the FDA statement said. "Importantly, the new study is based on a much larger and older patient population than those used in FDA’s earlier review of postmarket data, and employed a more sophisticated analytical method to capture and analyze the events of concern."

The study, part of an ongoing review of dabigatran, evaluated the risks of more than 134,000 new users of dabigatran and warfarin, who were over age 65 years and had been diagnosed with atrial fibrillation during the 6 months before the medication was dispensed. The data were from 2010-2012. Patient outcomes were identified in administrative and insurance claims, and the study represented more than 37,500 person-years of follow-up.

The results were as follows, with warfarin as the reference group, and dabigatran results based on the analysis of both approved doses (75 mg and 150 mg) combined:

• For ischemic stroke, the incidence rates (IR) per 1,000 person-years were 11.3 for dabigatran, vs. 13.9 for warfarin (hazard ratio, 0.80).

• For intracranial hemorrhage, the incidence rates were 3.3 for dabigatran, vs. 9.6 for warfarin (HR, 0.34).

• For major GI bleeding, the incidence rates were 34.2 for dabigatran, vs. 26.5 for warfarin (HR, 1.28).

• For acute MI, the incidence rates were 15.7 for dabigatran, vs. 16.9 for warfarin (HR, 0.92).

• For mortality, the incidence rates were 32.6 for dabigatran vs. 37.8 for warfarin (HR, 0.86).

The FDA statement points out that the results for major GI bleeding in this study are different from a previous FDA analysis of about 10,600 new users of dabigatran and warfarin, reported in 2012, which found that GI and intracranial hemorrhage rates were lower among patients treated with dabigatran, compared with those on warfarin. However, that study included patients under age 65 years (64% were older than age 65 years), and this disparity "may reflect the age differences in the two patient populations," the FDA statement said.

In an interview, Dr. Sanjay Kaul, professor of medicine at University of California Los Angeles, said the data in the Medicare study were reassuring, “and indicate that the favorable benefit-risk balance observed in the pre-approval randomized controlled trial, RE-LY, are generalizable in real world clinical practice.”

Without a placebo control, he added, “it is unclear what to make of the MI signal observed in RE-LY, but not in this study.” And while the exact cause of increased GI bleeding remains unclear, Dr. Kaul pointed out that this risk cannot be mitigated by gastroprotective medications such as H2 blockers or proton pump inhibitors, and that “it is best to avoid this medication in patients with history of lower-GI bleeding.”

Dr. Deepak Bhatt, professor of medicine at Harvard University in Boston, also described the results of the FDA study as reassuring. The study provides real world data in a large number of patients that complement and largely mirror the results in RE-LY, he said in an interview.

“I think that all those findings regarding death, stroke, and GI bleeding are all true because they were true in the randomized clinical trial dataset, and it is good to see they also appear to be true in real life clinical practice,” he commented. 

In addition, the data “further support the idea that the novel oral anticoagulants in patients who don’t have contraindications for them, and can afford them, [are] a better option than warfarin,” said Dr. Bhatt, the executive director of Interventional Cardiovascular Programs, at Brigham and Women’s Hospital Heart and Vascular Center, Boston.

He pointed out that overall, the three novel oral anticoagulants – dabigatran and the factor Xa inhibitors, apixaban and rivaroxaban – approved for the nonvalvular AF indication, appear to reduce the risk of stroke and death, “and across the board, they all show significantly less intracranial hemorrhage.”

“The availability of agents that have a lower intracranial hemorrhage risk, such as dabigatran, really is an advantage and will hopefully lead to more patients with atrial fibrillation being appropriately treated, instead of being undertreated  because of fear of bleeding into the brain,” he said. 

The FDA plans to publish the Medicare study and will continue to review the risks of bleeding with anticoagulants.

Dabigatran is now also approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days, and to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

The FDA has issued two previous safety alerts regarding the bleeding risks associated with dabigatran, in 2011 and 2012.

Dr. Kaul is a consultant to Boehringer Ingelheim and has equity interest in Johnson and Johnson. Dr. Bhatt said he has research grants with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi Aventis, and the Medicines Company. He is also on the executive committee for the RE-DUAL PCI trial, a large study comparing dabigatran to warfarin in stented patients with AF, which will be starting soon.

The FDA notice is available here. Serious adverse events associated with dabigatran and warfarin should be reported to the FDA at 800-332-1088 or at MedWatch.

emechcatie@frontlinemedcom.com

BALTIMORE – Hypoalbuminemia was identified as a significant risk factor for increased mortality and morbidity in obese patients undergoing elective general surgery, in a large study of patients from the ACS National Surgical Quality Improvement Program (NSQIP) database, Dr. Zachary C. Dietch reported at the annual meeting of the Surgical Infection Society.

The results suggest that surgeons may need to be more careful in evaluating protein deficiency in obese patients before surgery, said Dr. Dietch, a surgical resident at the University of Virginia, Charlottesville.

Elizabeth Mechcatie/Frontline Medical News

Protein-calorie deficiency is a well-known risk factor for complications, including infections and other surgical complications, but the risks of protein deficiency in different weight classes have not been well described. And while serum albumin is commonly used as an index for nutritional status and is known to correlate with adverse surgical outcomes, its use "as an index for nutrition status remains controversial," he noted.

But based on the results, "We feel that these risks likely reflect protein deficiency, and we feel that serum albumin appropriately reflects protein status in this population," he commented.

To evaluate the association of preoperative serum albumin and surgical complications by weight class, Dr. Dietch and his associates evaluated 240,000 general elective surgery patients, from the 2011 NSQIP database who had an elective procedure. After excluding certain groups of patients including those with systemic infections, cirrhosis, as well as those who were pregnant and those who had no preoperative albumin results available, they were left with about 86,000 patients.

Of these patients, 2,088 (about 2.4%) had a low serum albumin (below 3.0 g/dL); these patients tended to be older and tended to be in lower weight categories. Of those with hypoalbuminemia, 6.2% had a body mass index of 40 kg/m² and greater and almost 22% had a BMI between 30-39 (a BMI of 30 and greater falls in the obese category), and they had higher rates of comorbidities.

After controlling for factors that included comorbidities, surgical wound classification, operation type and complexity, the interaction of hypoalbuminemia and BMI conferred a statistically significant increase in the risk of mortality among those with a BMI of 40 and above, with an odds ratio of 18.98; and among those with a BMI between 30 and 39, with an odds ratio of 3.14 – when compared with patients in lower weight categories, who had low serum albumin, Dr. Dietch said.

Among those with a BMI of 40 and greater who had hypoalbuminemia, the risk of all complications was significantly increased (OR, 3.13) and the risk of all infectious complications was significantly increased (2.59). The risk of all complications was not significantly increased among those with a BMI of 30-39.

"The impact of protein deficiency on outcomes among patients may not be appreciated by surgeons," he concluded. This was a hypothesis-generating study and future studies "should prospectively investigate preoperative nutritional interventions in at-risk patients regardless of BMI," he added, noting that the next step would be a pilot study.

The limitations of the study included the possibility that the NSQIP data did not capture confounding disease states, and no causal relationship between protein status and surgical complications could be established because of the observational nature of the study, he noted.

In response to an audience member’s comment that a low albumin can be a reflection of a proinflammatory state, Dr. Dietch said that he and his coinvestigators recognized this and attempted to eliminate patients with proinflammatory states, such as those with systemic infections and those with systemic inflammatory response syndrome.

The study was funded by a National Institutes of Health training grant. Dr. Dietch had no disclosures

emechcatie@frontlinemedcom.com

BALTIMORE – Hypoalbuminemia was identified as a significant risk factor for increased mortality and morbidity in obese patients undergoing elective general surgery, in a large study of patients from the ACS National Surgical Quality Improvement Program (NSQIP) database, Dr. Zachary C. Dietch reported at the annual meeting of the Surgical Infection Society.

The results suggest that surgeons may need to be more careful in evaluating protein deficiency in obese patients before surgery, said Dr. Dietch, a surgical resident at the University of Virginia, Charlottesville.

Elizabeth Mechcatie/Frontline Medical News

Protein-calorie deficiency is a well-known risk factor for complications, including infections and other surgical complications, but the risks of protein deficiency in different weight classes have not been well described. And while serum albumin is commonly used as an index for nutritional status and is known to correlate with adverse surgical outcomes, its use "as an index for nutrition status remains controversial," he noted.

But based on the results, "We feel that these risks likely reflect protein deficiency, and we feel that serum albumin appropriately reflects protein status in this population," he commented.

To evaluate the association of preoperative serum albumin and surgical complications by weight class, Dr. Dietch and his associates evaluated 240,000 general elective surgery patients, from the 2011 NSQIP database who had an elective procedure. After excluding certain groups of patients including those with systemic infections, cirrhosis, as well as those who were pregnant and those who had no preoperative albumin results available, they were left with about 86,000 patients.

Of these patients, 2,088 (about 2.4%) had a low serum albumin (below 3.0 g/dL); these patients tended to be older and tended to be in lower weight categories. Of those with hypoalbuminemia, 6.2% had a body mass index of 40 kg/m² and greater and almost 22% had a BMI between 30-39 (a BMI of 30 and greater falls in the obese category), and they had higher rates of comorbidities.

After controlling for factors that included comorbidities, surgical wound classification, operation type and complexity, the interaction of hypoalbuminemia and BMI conferred a statistically significant increase in the risk of mortality among those with a BMI of 40 and above, with an odds ratio of 18.98; and among those with a BMI between 30 and 39, with an odds ratio of 3.14 – when compared with patients in lower weight categories, who had low serum albumin, Dr. Dietch said.

Among those with a BMI of 40 and greater who had hypoalbuminemia, the risk of all complications was significantly increased (OR, 3.13) and the risk of all infectious complications was significantly increased (2.59). The risk of all complications was not significantly increased among those with a BMI of 30-39.

"The impact of protein deficiency on outcomes among patients may not be appreciated by surgeons," he concluded. This was a hypothesis-generating study and future studies "should prospectively investigate preoperative nutritional interventions in at-risk patients regardless of BMI," he added, noting that the next step would be a pilot study.

The limitations of the study included the possibility that the NSQIP data did not capture confounding disease states, and no causal relationship between protein status and surgical complications could be established because of the observational nature of the study, he noted.

In response to an audience member’s comment that a low albumin can be a reflection of a proinflammatory state, Dr. Dietch said that he and his coinvestigators recognized this and attempted to eliminate patients with proinflammatory states, such as those with systemic infections and those with systemic inflammatory response syndrome.

The study was funded by a National Institutes of Health training grant. Dr. Dietch had no disclosures

emechcatie@frontlinemedcom.com

BALTIMORE – Hypoalbuminemia was identified as a significant risk factor for increased mortality and morbidity in obese patients undergoing elective general surgery, in a large study of patients from the ACS National Surgical Quality Improvement Program (NSQIP) database, Dr. Zachary C. Dietch reported at the annual meeting of the Surgical Infection Society.

The results suggest that surgeons may need to be more careful in evaluating protein deficiency in obese patients before surgery, said Dr. Dietch, a surgical resident at the University of Virginia, Charlottesville.

Elizabeth Mechcatie/Frontline Medical News

Protein-calorie deficiency is a well-known risk factor for complications, including infections and other surgical complications, but the risks of protein deficiency in different weight classes have not been well described. And while serum albumin is commonly used as an index for nutritional status and is known to correlate with adverse surgical outcomes, its use "as an index for nutrition status remains controversial," he noted.

But based on the results, "We feel that these risks likely reflect protein deficiency, and we feel that serum albumin appropriately reflects protein status in this population," he commented.

To evaluate the association of preoperative serum albumin and surgical complications by weight class, Dr. Dietch and his associates evaluated 240,000 general elective surgery patients, from the 2011 NSQIP database who had an elective procedure. After excluding certain groups of patients including those with systemic infections, cirrhosis, as well as those who were pregnant and those who had no preoperative albumin results available, they were left with about 86,000 patients.

Of these patients, 2,088 (about 2.4%) had a low serum albumin (below 3.0 g/dL); these patients tended to be older and tended to be in lower weight categories. Of those with hypoalbuminemia, 6.2% had a body mass index of 40 kg/m² and greater and almost 22% had a BMI between 30-39 (a BMI of 30 and greater falls in the obese category), and they had higher rates of comorbidities.

After controlling for factors that included comorbidities, surgical wound classification, operation type and complexity, the interaction of hypoalbuminemia and BMI conferred a statistically significant increase in the risk of mortality among those with a BMI of 40 and above, with an odds ratio of 18.98; and among those with a BMI between 30 and 39, with an odds ratio of 3.14 – when compared with patients in lower weight categories, who had low serum albumin, Dr. Dietch said.

Among those with a BMI of 40 and greater who had hypoalbuminemia, the risk of all complications was significantly increased (OR, 3.13) and the risk of all infectious complications was significantly increased (2.59). The risk of all complications was not significantly increased among those with a BMI of 30-39.

"The impact of protein deficiency on outcomes among patients may not be appreciated by surgeons," he concluded. This was a hypothesis-generating study and future studies "should prospectively investigate preoperative nutritional interventions in at-risk patients regardless of BMI," he added, noting that the next step would be a pilot study.

The limitations of the study included the possibility that the NSQIP data did not capture confounding disease states, and no causal relationship between protein status and surgical complications could be established because of the observational nature of the study, he noted.

In response to an audience member’s comment that a low albumin can be a reflection of a proinflammatory state, Dr. Dietch said that he and his coinvestigators recognized this and attempted to eliminate patients with proinflammatory states, such as those with systemic infections and those with systemic inflammatory response syndrome.

The study was funded by a National Institutes of Health training grant. Dr. Dietch had no disclosures

emechcatie@frontlinemedcom.com