Elizabeth Mechcatie

The novel oral anticoagulant dabigatran has been approved for treating and reducing the risk of recurrence of deep venous thrombosis and pulmonary embolism, based on the results of four phase III studies, the manufacturer announced on April 7.

Specifically, the approved indications are 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 dose is administered twice a day.

This is the second approval for dabigatran, a direct thrombin inhibitor marketed as Pradaxa by Boehringer-Ingelheim Pharmaceuticals. It was initially approved in 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Approval was based on four international phase III studies, according to a statement issued by the company.

The studies are the RE-COVER and RE-COVER II trials and the RE-MEDY and RE-SONATE trials.

Dabigatran is approved with a medication guide, and the prescribing information includes a boxed warning about the increased risk of thrombotic events and spinal/epidural hematoma when it is prematurely discontinued.

The updated prescribing information is available here. Serious adverse events associated with dabigatran should be reported to the Food and Drug Administration’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch.

[email protected]

The novel oral anticoagulant dabigatran has been approved for treating and reducing the risk of recurrence of deep venous thrombosis and pulmonary embolism, based on the results of four phase III studies, the manufacturer announced on April 7.

Specifically, the approved indications are 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 dose is administered twice a day.

This is the second approval for dabigatran, a direct thrombin inhibitor marketed as Pradaxa by Boehringer-Ingelheim Pharmaceuticals. It was initially approved in 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Approval was based on four international phase III studies, according to a statement issued by the company.

The studies are the RE-COVER and RE-COVER II trials and the RE-MEDY and RE-SONATE trials.

Dabigatran is approved with a medication guide, and the prescribing information includes a boxed warning about the increased risk of thrombotic events and spinal/epidural hematoma when it is prematurely discontinued.

The updated prescribing information is available here. Serious adverse events associated with dabigatran should be reported to the Food and Drug Administration’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch.

[email protected]

The novel oral anticoagulant dabigatran has been approved for treating and reducing the risk of recurrence of deep venous thrombosis and pulmonary embolism, based on the results of four phase III studies, the manufacturer announced on April 7.

Specifically, the approved indications are 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 dose is administered twice a day.

This is the second approval for dabigatran, a direct thrombin inhibitor marketed as Pradaxa by Boehringer-Ingelheim Pharmaceuticals. It was initially approved in 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Approval was based on four international phase III studies, according to a statement issued by the company.

The studies are the RE-COVER and RE-COVER II trials and the RE-MEDY and RE-SONATE trials.

Dabigatran is approved with a medication guide, and the prescribing information includes a boxed warning about the increased risk of thrombotic events and spinal/epidural hematoma when it is prematurely discontinued.

The updated prescribing information is available here. Serious adverse events associated with dabigatran should be reported to the Food and Drug Administration’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch.

[email protected]

HYATTSVILLE, MD. – Inhaled insulin will probably become available as a treatment option again, with a Food and Drug Administration advisory panel’s recommendation to approve an orally administered dry powder recombinant insulin formulation for the treatment of both type 1 and type 2 diabetes.

At a meeting on April 1, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1 that the safety and efficacy data for the inhaled insulin, delivered with an inhaler, supported approval for treatment of adults with type 1 diabetes; they voted 14-0 that the data supported approval for treatment of adults with type 2 diabetes. Panelists had unresolved concerns about safety, including the potential for lung cancer and adverse pulmonary effects, acute bronchospasm in people with asthma, and deteriorating pulmonary function over time, which they said should be closely monitored after approval.

Panelists also pointed out that the results of phase III trials indicated that the inhaled insulin product was not as effective as traditional insulin, and that it would not be appropriate for all patients with type 1 and type 2 diabetes. They did note, however, that there was a need for more treatment options and that an inhaled insulin could be useful for certain groups of patients, such as elderly or disabled patients who have physical impairments and have difficulties with injectable insulin and patients who refuse to use needles – and when a dose of insulin is needed to lower blood glucose between meals.

The proposed indication for the Technosphere insulin inhalation system – which provides insulin in cartridges, delivered with the "Gen2" inhaler – is to improve glycemic control in adults with type 1 or type 2 diabetes. The system’s rapid-acting insulin works faster and has a shorter duration of action than regular human insulin or rapid-acting analog insulins, according to the manufacturer, MannKind Corp.

It is administered immediately before or within the first 20 minutes of starting a meal and is used with basal insulin in patients with type 1 diabetes, and it can be used with oral glucose-lowering medications or basal insulin in patients with type 2 diabetes, according to the company, which plans to market the product as Afrezza if approved.

The orally inhaled insulin marketed as Exubera was approved by the FDA in January 2006 for treating adults with type 1 and 2 diabetes, but Pfizer took it off the market in 2007 because of poor sales.

The FDA rejected the approval of the MannKind inhaled insulin twice before because of issues with efficacy and the device, and it asked the company to conduct two new phase III studies with a new inhaler.

In the study of patients with type 1 diabetes, those treated with Afrezza had a mean 0.20–percentage point drop in HbA_1c from baseline at 24 weeks, compared with a 0.42–percentage point drop among those on insulin aspart. In the study of patients with type 2 diabetes who were on metformin or at least two other oral diabetes drugs, those treated with Afrezza had a mean 0.84–percentage point drop in HbA_1c from baseline, compared with 0.41 at 24 weeks in those on placebo. In trials, the most common adverse events were a dry, transient cough and transient changes in pulmonary function. Lung cancer rates were similar to what would be expected in the general population, according to the company. Hypoglycemia was slightly lower among those on Afrezza in both studies.

There have been four lung cancers in patients treated with Afrezza in clinical trials, including two cases in patients with no smoking history. Since the product delivers a high level of insulin to the lungs, and insulin may activate growth receptors in the lungs, the panel agreed this was a significant issue that should be followed in postmarketing studies. The company has proposed a prospective observational registry of patients to track the incidence of primary lung cancers, as well as other malignancies and serious pulmonary, allergic, and hypoglycemic events that require medical intervention. Labeling would recommend that spirometry be done every 6 months during treatment.

Voting for approval, panel chair Dr. Robert Smith, professor of medicine at Brown University, Providence, R.I., said that inhaled insulin "represents a drug that will serve some patients that are not effectively served by currently available forms of insulin." The data about the potentially serious adverse effects "were not strong enough that I feel it is imperative to resolve those questions" before marketing, he added, but stressed that these safety issues, including the potential for lung cancer and deteriorating lung function, are "very, very important to follow up."

The panelist who voted against approval for type 1diabetes, Dr. David Cooke, clinical director of the division of pediatric endocrinology at Johns Hopkins University, Baltimore, said he was concerned that the risks outweighed the benefits in this group of patients, particularly because of the potential increased risk of cancer. But he said he was more confident about the risk-benefit profile for patients with type 2 diabetes because they would not be exposed to the drug for as long as patients with type 1 diabetes, and that the inhaled insulin may provide some type 2 patients who might otherwise put off taking insulin with a more acceptable and effective option.

The FDA is expected to make a decision on approval by April 15. The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts. Occasionally, a panelist is given a waiver but not at this meeting.

[email protected]

HYATTSVILLE, MD. – Inhaled insulin will probably become available as a treatment option again, with a Food and Drug Administration advisory panel’s recommendation to approve an orally administered dry powder recombinant insulin formulation for the treatment of both type 1 and type 2 diabetes.

At a meeting on April 1, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1 that the safety and efficacy data for the inhaled insulin, delivered with an inhaler, supported approval for treatment of adults with type 1 diabetes; they voted 14-0 that the data supported approval for treatment of adults with type 2 diabetes. Panelists had unresolved concerns about safety, including the potential for lung cancer and adverse pulmonary effects, acute bronchospasm in people with asthma, and deteriorating pulmonary function over time, which they said should be closely monitored after approval.

Panelists also pointed out that the results of phase III trials indicated that the inhaled insulin product was not as effective as traditional insulin, and that it would not be appropriate for all patients with type 1 and type 2 diabetes. They did note, however, that there was a need for more treatment options and that an inhaled insulin could be useful for certain groups of patients, such as elderly or disabled patients who have physical impairments and have difficulties with injectable insulin and patients who refuse to use needles – and when a dose of insulin is needed to lower blood glucose between meals.

The proposed indication for the Technosphere insulin inhalation system – which provides insulin in cartridges, delivered with the "Gen2" inhaler – is to improve glycemic control in adults with type 1 or type 2 diabetes. The system’s rapid-acting insulin works faster and has a shorter duration of action than regular human insulin or rapid-acting analog insulins, according to the manufacturer, MannKind Corp.

It is administered immediately before or within the first 20 minutes of starting a meal and is used with basal insulin in patients with type 1 diabetes, and it can be used with oral glucose-lowering medications or basal insulin in patients with type 2 diabetes, according to the company, which plans to market the product as Afrezza if approved.

The orally inhaled insulin marketed as Exubera was approved by the FDA in January 2006 for treating adults with type 1 and 2 diabetes, but Pfizer took it off the market in 2007 because of poor sales.

The FDA rejected the approval of the MannKind inhaled insulin twice before because of issues with efficacy and the device, and it asked the company to conduct two new phase III studies with a new inhaler.

In the study of patients with type 1 diabetes, those treated with Afrezza had a mean 0.20–percentage point drop in HbA_1c from baseline at 24 weeks, compared with a 0.42–percentage point drop among those on insulin aspart. In the study of patients with type 2 diabetes who were on metformin or at least two other oral diabetes drugs, those treated with Afrezza had a mean 0.84–percentage point drop in HbA_1c from baseline, compared with 0.41 at 24 weeks in those on placebo. In trials, the most common adverse events were a dry, transient cough and transient changes in pulmonary function. Lung cancer rates were similar to what would be expected in the general population, according to the company. Hypoglycemia was slightly lower among those on Afrezza in both studies.

There have been four lung cancers in patients treated with Afrezza in clinical trials, including two cases in patients with no smoking history. Since the product delivers a high level of insulin to the lungs, and insulin may activate growth receptors in the lungs, the panel agreed this was a significant issue that should be followed in postmarketing studies. The company has proposed a prospective observational registry of patients to track the incidence of primary lung cancers, as well as other malignancies and serious pulmonary, allergic, and hypoglycemic events that require medical intervention. Labeling would recommend that spirometry be done every 6 months during treatment.

Voting for approval, panel chair Dr. Robert Smith, professor of medicine at Brown University, Providence, R.I., said that inhaled insulin "represents a drug that will serve some patients that are not effectively served by currently available forms of insulin." The data about the potentially serious adverse effects "were not strong enough that I feel it is imperative to resolve those questions" before marketing, he added, but stressed that these safety issues, including the potential for lung cancer and deteriorating lung function, are "very, very important to follow up."

The panelist who voted against approval for type 1diabetes, Dr. David Cooke, clinical director of the division of pediatric endocrinology at Johns Hopkins University, Baltimore, said he was concerned that the risks outweighed the benefits in this group of patients, particularly because of the potential increased risk of cancer. But he said he was more confident about the risk-benefit profile for patients with type 2 diabetes because they would not be exposed to the drug for as long as patients with type 1 diabetes, and that the inhaled insulin may provide some type 2 patients who might otherwise put off taking insulin with a more acceptable and effective option.

The FDA is expected to make a decision on approval by April 15. The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts. Occasionally, a panelist is given a waiver but not at this meeting.

[email protected]

HYATTSVILLE, MD. – Inhaled insulin will probably become available as a treatment option again, with a Food and Drug Administration advisory panel’s recommendation to approve an orally administered dry powder recombinant insulin formulation for the treatment of both type 1 and type 2 diabetes.

At a meeting on April 1, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1 that the safety and efficacy data for the inhaled insulin, delivered with an inhaler, supported approval for treatment of adults with type 1 diabetes; they voted 14-0 that the data supported approval for treatment of adults with type 2 diabetes. Panelists had unresolved concerns about safety, including the potential for lung cancer and adverse pulmonary effects, acute bronchospasm in people with asthma, and deteriorating pulmonary function over time, which they said should be closely monitored after approval.

Panelists also pointed out that the results of phase III trials indicated that the inhaled insulin product was not as effective as traditional insulin, and that it would not be appropriate for all patients with type 1 and type 2 diabetes. They did note, however, that there was a need for more treatment options and that an inhaled insulin could be useful for certain groups of patients, such as elderly or disabled patients who have physical impairments and have difficulties with injectable insulin and patients who refuse to use needles – and when a dose of insulin is needed to lower blood glucose between meals.

The proposed indication for the Technosphere insulin inhalation system – which provides insulin in cartridges, delivered with the "Gen2" inhaler – is to improve glycemic control in adults with type 1 or type 2 diabetes. The system’s rapid-acting insulin works faster and has a shorter duration of action than regular human insulin or rapid-acting analog insulins, according to the manufacturer, MannKind Corp.

It is administered immediately before or within the first 20 minutes of starting a meal and is used with basal insulin in patients with type 1 diabetes, and it can be used with oral glucose-lowering medications or basal insulin in patients with type 2 diabetes, according to the company, which plans to market the product as Afrezza if approved.

The orally inhaled insulin marketed as Exubera was approved by the FDA in January 2006 for treating adults with type 1 and 2 diabetes, but Pfizer took it off the market in 2007 because of poor sales.

The FDA rejected the approval of the MannKind inhaled insulin twice before because of issues with efficacy and the device, and it asked the company to conduct two new phase III studies with a new inhaler.

In the study of patients with type 1 diabetes, those treated with Afrezza had a mean 0.20–percentage point drop in HbA_1c from baseline at 24 weeks, compared with a 0.42–percentage point drop among those on insulin aspart. In the study of patients with type 2 diabetes who were on metformin or at least two other oral diabetes drugs, those treated with Afrezza had a mean 0.84–percentage point drop in HbA_1c from baseline, compared with 0.41 at 24 weeks in those on placebo. In trials, the most common adverse events were a dry, transient cough and transient changes in pulmonary function. Lung cancer rates were similar to what would be expected in the general population, according to the company. Hypoglycemia was slightly lower among those on Afrezza in both studies.

There have been four lung cancers in patients treated with Afrezza in clinical trials, including two cases in patients with no smoking history. Since the product delivers a high level of insulin to the lungs, and insulin may activate growth receptors in the lungs, the panel agreed this was a significant issue that should be followed in postmarketing studies. The company has proposed a prospective observational registry of patients to track the incidence of primary lung cancers, as well as other malignancies and serious pulmonary, allergic, and hypoglycemic events that require medical intervention. Labeling would recommend that spirometry be done every 6 months during treatment.

Voting for approval, panel chair Dr. Robert Smith, professor of medicine at Brown University, Providence, R.I., said that inhaled insulin "represents a drug that will serve some patients that are not effectively served by currently available forms of insulin." The data about the potentially serious adverse effects "were not strong enough that I feel it is imperative to resolve those questions" before marketing, he added, but stressed that these safety issues, including the potential for lung cancer and deteriorating lung function, are "very, very important to follow up."

The panelist who voted against approval for type 1diabetes, Dr. David Cooke, clinical director of the division of pediatric endocrinology at Johns Hopkins University, Baltimore, said he was concerned that the risks outweighed the benefits in this group of patients, particularly because of the potential increased risk of cancer. But he said he was more confident about the risk-benefit profile for patients with type 2 diabetes because they would not be exposed to the drug for as long as patients with type 1 diabetes, and that the inhaled insulin may provide some type 2 patients who might otherwise put off taking insulin with a more acceptable and effective option.

The FDA is expected to make a decision on approval by April 15. The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts. Occasionally, a panelist is given a waiver but not at this meeting.

[email protected]

A hand-held autoinjector that delivers a single dose of naloxone to be used in cases of suspected or known opioid overdoses has been approved by the Food and Drug Administration.

The treatment "is the first combination drug-device product designed to deliver a dose of naloxone for administration outside of a health care setting," said Dr. Bob Rappaport, director of the Division of Anesthesia, Analgesia, and Addiction Products in the FDA’s Center for Drug Evaluation and Research. "Making this product available could save lives by facilitating earlier use of the drug in emergency situations," he added in an FDA statement announcing the approval April 3.

The product’s application was granted priority review status by the agency and reviewed in only 15 weeks, FDA Commissioner Margaret A. Hamburg said in a separate statement.

The autoinjector will be marketed by kaléo, Inc., under the trade name Evzio. It can be administered subcutaneously or intramuscularly, and is intended to be administered by family members or caregivers in cases of suspected overdoses, the statement said. As with automated defibrillators, verbal instructions and visual clues regarding how to use the device are provided when activated. A trainer device is included with the product for people to become familiar with how to use the device.

The FDA statement notes that deaths due to drug overdoses are currently the leading cause of fatal injuries in the United States, and that in 2013, the Centers for Disease Control and Prevention reported that drug overdose deaths had increased steadily over 10 years.

While naloxone is the standard treatment for overdoses, it has been available for administration only with syringes by health care professionals.

The product is expected to be available though major pharmacies this summer, according to a kaléo statement announcing the approval.

[email protected]

A hand-held autoinjector that delivers a single dose of naloxone to be used in cases of suspected or known opioid overdoses has been approved by the Food and Drug Administration.

The treatment "is the first combination drug-device product designed to deliver a dose of naloxone for administration outside of a health care setting," said Dr. Bob Rappaport, director of the Division of Anesthesia, Analgesia, and Addiction Products in the FDA’s Center for Drug Evaluation and Research. "Making this product available could save lives by facilitating earlier use of the drug in emergency situations," he added in an FDA statement announcing the approval April 3.

The product’s application was granted priority review status by the agency and reviewed in only 15 weeks, FDA Commissioner Margaret A. Hamburg said in a separate statement.

The autoinjector will be marketed by kaléo, Inc., under the trade name Evzio. It can be administered subcutaneously or intramuscularly, and is intended to be administered by family members or caregivers in cases of suspected overdoses, the statement said. As with automated defibrillators, verbal instructions and visual clues regarding how to use the device are provided when activated. A trainer device is included with the product for people to become familiar with how to use the device.

The FDA statement notes that deaths due to drug overdoses are currently the leading cause of fatal injuries in the United States, and that in 2013, the Centers for Disease Control and Prevention reported that drug overdose deaths had increased steadily over 10 years.

While naloxone is the standard treatment for overdoses, it has been available for administration only with syringes by health care professionals.

The product is expected to be available though major pharmacies this summer, according to a kaléo statement announcing the approval.

[email protected]

A hand-held autoinjector that delivers a single dose of naloxone to be used in cases of suspected or known opioid overdoses has been approved by the Food and Drug Administration.

The treatment "is the first combination drug-device product designed to deliver a dose of naloxone for administration outside of a health care setting," said Dr. Bob Rappaport, director of the Division of Anesthesia, Analgesia, and Addiction Products in the FDA’s Center for Drug Evaluation and Research. "Making this product available could save lives by facilitating earlier use of the drug in emergency situations," he added in an FDA statement announcing the approval April 3.

The product’s application was granted priority review status by the agency and reviewed in only 15 weeks, FDA Commissioner Margaret A. Hamburg said in a separate statement.

The autoinjector will be marketed by kaléo, Inc., under the trade name Evzio. It can be administered subcutaneously or intramuscularly, and is intended to be administered by family members or caregivers in cases of suspected overdoses, the statement said. As with automated defibrillators, verbal instructions and visual clues regarding how to use the device are provided when activated. A trainer device is included with the product for people to become familiar with how to use the device.

The FDA statement notes that deaths due to drug overdoses are currently the leading cause of fatal injuries in the United States, and that in 2013, the Centers for Disease Control and Prevention reported that drug overdose deaths had increased steadily over 10 years.

While naloxone is the standard treatment for overdoses, it has been available for administration only with syringes by health care professionals.

The product is expected to be available though major pharmacies this summer, according to a kaléo statement announcing the approval.

[email protected]

WASHINGTON – Administering methylprednisolone to patients undergoing cardiac surgery with cardiopulmonary bypass did not reduce the risks of death or major morbidity at 30 days, but was associated with an increased risk of early postoperative myocardial infarction, in a randomized controlled trial of about 7,500 high-risk surgical patients.

Based on the results of the study, the Steroids in Cardiac Surgery (SIRS) trial, "methylprednisolone should not be administered prophylactically to high-risk patients undergoing cardiac surgery" with cardiopulmonary bypass, Dr. Richard Whitlock said at the annual meeting of the American College of Cardiology.

SIRS, a randomized controlled study, evaluated the effects of prophylactic steroids in patients undergoing cardiac surgery with cardiopulmonary bypass in 18 countries in North and South America, Europe, the Middle East, and Asia. The study addressed whether the use of prophylactic steroids can attenuate the "intense inflammatory response" that occurs with cardiopulmonary bypass and is associated with adverse outcomes, said Dr. Whitlock, a cardiac surgeon at McMaster University, Hamilton, Ont., and lead investigator in the study.

Whether this approach results in improved outcomes has been unclear, he said. A recent meta-analysis of 44 small studies suggested that steroids have clinical benefits in this setting, and this use of methylprednisolone is standard practice in many European countries. And although it is not used as extensively in the United States, it is still standard care at some U.S. centers, he noted.

In SIRS, patients were randomized to 500 mg methylprednisolone, administered intravenously during surgery (3,755 patients) or placebo (3,752). Patients were considered high risk; their mean age was 67 years, two-thirds were male, and their mean EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 7.1. Only one patient, who was in the treatment group, was lost to follow-up.

There were no significant differences between the two groups in the two primary endpoints: total mortality at 30 days and the combined endpoint of total mortality, stroke, MI, renal failure, or respiratory failure within 30 days. The results were consistent across different subgroups, including sex, diabetes status, age, EuroSCORE, type of surgery and duration of cardiopulmonary bypass.

However, significantly more patients in the treatment group had an MI – mostly early – after surgery (500 vs. 408 in the placebo group), an increased risk of 22%, which was statistically significant.

The use of methylprednisolone was not associated with an altered risk of other stroke, new renal failure, or respiratory failure, or other outcomes measured, including transfusion requirements, new-onset atrial fibrillation, length of ICU or hospital stay, surgical site infections, delirium, or GI complications, Dr. Whitlock said.

When asked about a possible mechanism behind the SIRS results, Dr. Whitlock said that one possible explanation could be that since one of the important early recovery strategies after myocardial injury is movement of glucose into cells, and insulin requirements increase in the steroid-treated patients, "it is possible that we’re inducing insulin resistance: Thereby, glucose is not entering the myocyte for the recovery phase after the ischemic insult." While that is plausible, he added, "we really don’t have the answer. What is important is the signal is clear, it’s clear across all subgroups, and it is a prognostically important increase."

Dr. Amit Khera, director of the preventive cardiology program at UT Southwestern Medical Center, Dallas, commented that SIRS was a definitive study, and this use of methylprednisolone, at least at higher doses, "should not be a strategy we should pursue."

The SIRS trial was conducted by the Population Health Research Institute at the Hamilton Health Sciences and McMaster University during 2007-2014 and was funded with grants from the Canadian Institutes for Health Research and the Canadian Network and Centre for Trials Internationally. Dr. Whitlock said he had no relevant financial disclosures.

[email protected]

WASHINGTON – Administering methylprednisolone to patients undergoing cardiac surgery with cardiopulmonary bypass did not reduce the risks of death or major morbidity at 30 days, but was associated with an increased risk of early postoperative myocardial infarction, in a randomized controlled trial of about 7,500 high-risk surgical patients.

Based on the results of the study, the Steroids in Cardiac Surgery (SIRS) trial, "methylprednisolone should not be administered prophylactically to high-risk patients undergoing cardiac surgery" with cardiopulmonary bypass, Dr. Richard Whitlock said at the annual meeting of the American College of Cardiology.

SIRS, a randomized controlled study, evaluated the effects of prophylactic steroids in patients undergoing cardiac surgery with cardiopulmonary bypass in 18 countries in North and South America, Europe, the Middle East, and Asia. The study addressed whether the use of prophylactic steroids can attenuate the "intense inflammatory response" that occurs with cardiopulmonary bypass and is associated with adverse outcomes, said Dr. Whitlock, a cardiac surgeon at McMaster University, Hamilton, Ont., and lead investigator in the study.

Whether this approach results in improved outcomes has been unclear, he said. A recent meta-analysis of 44 small studies suggested that steroids have clinical benefits in this setting, and this use of methylprednisolone is standard practice in many European countries. And although it is not used as extensively in the United States, it is still standard care at some U.S. centers, he noted.

In SIRS, patients were randomized to 500 mg methylprednisolone, administered intravenously during surgery (3,755 patients) or placebo (3,752). Patients were considered high risk; their mean age was 67 years, two-thirds were male, and their mean EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 7.1. Only one patient, who was in the treatment group, was lost to follow-up.

There were no significant differences between the two groups in the two primary endpoints: total mortality at 30 days and the combined endpoint of total mortality, stroke, MI, renal failure, or respiratory failure within 30 days. The results were consistent across different subgroups, including sex, diabetes status, age, EuroSCORE, type of surgery and duration of cardiopulmonary bypass.

However, significantly more patients in the treatment group had an MI – mostly early – after surgery (500 vs. 408 in the placebo group), an increased risk of 22%, which was statistically significant.

The use of methylprednisolone was not associated with an altered risk of other stroke, new renal failure, or respiratory failure, or other outcomes measured, including transfusion requirements, new-onset atrial fibrillation, length of ICU or hospital stay, surgical site infections, delirium, or GI complications, Dr. Whitlock said.

When asked about a possible mechanism behind the SIRS results, Dr. Whitlock said that one possible explanation could be that since one of the important early recovery strategies after myocardial injury is movement of glucose into cells, and insulin requirements increase in the steroid-treated patients, "it is possible that we’re inducing insulin resistance: Thereby, glucose is not entering the myocyte for the recovery phase after the ischemic insult." While that is plausible, he added, "we really don’t have the answer. What is important is the signal is clear, it’s clear across all subgroups, and it is a prognostically important increase."

Dr. Amit Khera, director of the preventive cardiology program at UT Southwestern Medical Center, Dallas, commented that SIRS was a definitive study, and this use of methylprednisolone, at least at higher doses, "should not be a strategy we should pursue."

The SIRS trial was conducted by the Population Health Research Institute at the Hamilton Health Sciences and McMaster University during 2007-2014 and was funded with grants from the Canadian Institutes for Health Research and the Canadian Network and Centre for Trials Internationally. Dr. Whitlock said he had no relevant financial disclosures.

[email protected]

WASHINGTON – Administering methylprednisolone to patients undergoing cardiac surgery with cardiopulmonary bypass did not reduce the risks of death or major morbidity at 30 days, but was associated with an increased risk of early postoperative myocardial infarction, in a randomized controlled trial of about 7,500 high-risk surgical patients.

Based on the results of the study, the Steroids in Cardiac Surgery (SIRS) trial, "methylprednisolone should not be administered prophylactically to high-risk patients undergoing cardiac surgery" with cardiopulmonary bypass, Dr. Richard Whitlock said at the annual meeting of the American College of Cardiology.

SIRS, a randomized controlled study, evaluated the effects of prophylactic steroids in patients undergoing cardiac surgery with cardiopulmonary bypass in 18 countries in North and South America, Europe, the Middle East, and Asia. The study addressed whether the use of prophylactic steroids can attenuate the "intense inflammatory response" that occurs with cardiopulmonary bypass and is associated with adverse outcomes, said Dr. Whitlock, a cardiac surgeon at McMaster University, Hamilton, Ont., and lead investigator in the study.

Whether this approach results in improved outcomes has been unclear, he said. A recent meta-analysis of 44 small studies suggested that steroids have clinical benefits in this setting, and this use of methylprednisolone is standard practice in many European countries. And although it is not used as extensively in the United States, it is still standard care at some U.S. centers, he noted.

In SIRS, patients were randomized to 500 mg methylprednisolone, administered intravenously during surgery (3,755 patients) or placebo (3,752). Patients were considered high risk; their mean age was 67 years, two-thirds were male, and their mean EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 7.1. Only one patient, who was in the treatment group, was lost to follow-up.

There were no significant differences between the two groups in the two primary endpoints: total mortality at 30 days and the combined endpoint of total mortality, stroke, MI, renal failure, or respiratory failure within 30 days. The results were consistent across different subgroups, including sex, diabetes status, age, EuroSCORE, type of surgery and duration of cardiopulmonary bypass.

However, significantly more patients in the treatment group had an MI – mostly early – after surgery (500 vs. 408 in the placebo group), an increased risk of 22%, which was statistically significant.

The use of methylprednisolone was not associated with an altered risk of other stroke, new renal failure, or respiratory failure, or other outcomes measured, including transfusion requirements, new-onset atrial fibrillation, length of ICU or hospital stay, surgical site infections, delirium, or GI complications, Dr. Whitlock said.

When asked about a possible mechanism behind the SIRS results, Dr. Whitlock said that one possible explanation could be that since one of the important early recovery strategies after myocardial injury is movement of glucose into cells, and insulin requirements increase in the steroid-treated patients, "it is possible that we’re inducing insulin resistance: Thereby, glucose is not entering the myocyte for the recovery phase after the ischemic insult." While that is plausible, he added, "we really don’t have the answer. What is important is the signal is clear, it’s clear across all subgroups, and it is a prognostically important increase."

Dr. Amit Khera, director of the preventive cardiology program at UT Southwestern Medical Center, Dallas, commented that SIRS was a definitive study, and this use of methylprednisolone, at least at higher doses, "should not be a strategy we should pursue."

The SIRS trial was conducted by the Population Health Research Institute at the Hamilton Health Sciences and McMaster University during 2007-2014 and was funded with grants from the Canadian Institutes for Health Research and the Canadian Network and Centre for Trials Internationally. Dr. Whitlock said he had no relevant financial disclosures.

[email protected]

HYATTSVILLE, MD. – Inhaled insulin will probably become available as a treatment option again, with a Food and Drug Administration advisory panel’s recommendation to approve an orally administered dry powder recombinant insulin formulation for the treatment of both type 1 and type 2 diabetes.

At a meeting on April 1, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1 that the safety and efficacy data for the inhaled insulin, delivered with an inhaler, supported approval for treatment of adults with type 1 diabetes; they voted 14-0 that the data supported approval for treatment of adults with type 2 diabetes. Panelists had unresolved concerns about safety, including the potential for lung cancer and adverse pulmonary effects, acute bronchospasm in people with asthma, and deteriorating pulmonary function over time, which they said should be closely monitored after approval.

Courtesy MannKind Corp

Panelists also pointed out that the results of phase III trials indicated that the inhaled insulin product was not as effective as traditional insulin, and that it would not be appropriate for all patients with type 1 and type 2 diabetes. They did note, however, that there was a need for more treatment options and that an inhaled insulin could be useful for certain groups of patients, such as elderly or disabled patients who have physical impairments and have difficulties with injectable insulin and patients who refuse to use needles – and when a dose of insulin is needed to lower blood glucose between meals.

The proposed indication for the Technosphere insulin inhalation system – which provides insulin in cartridges, delivered with the "Gen2" inhaler – is to improve glycemic control in adults with type 1 or type 2 diabetes. The system’s rapid-acting insulin works faster and has a shorter duration of action than regular human insulin or rapid-acting analog insulins, according to the manufacturer, MannKind Corp.

It is administered immediately before or within the first 20 minutes of starting a meal and is used with basal insulin in patients with type 1 diabetes, and it can be used with oral glucose-lowering medications or basal insulin in patients with type 2 diabetes, according to the company, which plans to market the product as Afrezza if approved.

The orally inhaled insulin marketed as Exubera was approved by the FDA in January 2006 for treating adults with type 1 and 2 diabetes, but Pfizer took it off the market in 2007 because of poor sales.

The FDA rejected the approval of the MannKind inhaled insulin twice before because of issues with efficacy and the device, and it asked the company to conduct two new phase III studies with a new inhaler.

In the study of patients with type 1 diabetes, those treated with Afrezza had a mean 0.20–percentage point drop in HbA_1c from baseline at 24 weeks, compared with a 0.42–percentage point drop among those on insulin aspart. In the study of patients with type 2 diabetes who were on metformin or at least two other oral diabetes drugs, those treated with Afrezza had a mean 0.84–percentage point drop in HbA_1c from baseline, compared with 0.41 at 24 weeks in those on placebo. In trials, the most common adverse events were a dry, transient cough and transient changes in pulmonary function. Lung cancer rates were similar to what would be expected in the general population, according to the company. Hypoglycemia was slightly lower among those on Afrezza in both studies.

There have been four lung cancers in patients treated with Afrezza in clinical trials, including two cases in patients with no smoking history. Since the product delivers a high level of insulin to the lungs, and insulin may activate growth receptors in the lungs, the panel agreed this was a significant issue that should be followed in postmarketing studies. The company has proposed a prospective observational registry of patients to track the incidence of primary lung cancers, as well as other malignancies and serious pulmonary, allergic, and hypoglycemic events that require medical intervention. Labeling would recommend that spirometry be done every 6 months during treatment.

Voting for approval, panel chair Dr. Robert Smith, professor of medicine at Brown University, Providence, R.I., said that inhaled insulin "represents a drug that will serve some patients that are not effectively served by currently available forms of insulin." The data about the potentially serious adverse effects "were not strong enough that I feel it is imperative to resolve those questions" before marketing, he added, but stressed that these safety issues, including the potential for lung cancer and deteriorating lung function, are "very, very important to follow up."

The panelist who voted against approval for type 1diabetes, Dr. David Cooke, clinical director of the division of pediatric endocrinology at Johns Hopkins University, Baltimore, said he was concerned that the risks outweighed the benefits in this group of patients, particularly because of the potential increased risk of cancer. But he said he was more confident about the risk-benefit profile for patients with type 2 diabetes because they would not be exposed to the drug for as long as patients with type 1 diabetes, and that the inhaled insulin may provide some type 2 patients who might otherwise put off taking insulin with a more acceptable and effective option.

The FDA extended the date for completing the review by three months, so the agency can fully review additional information requested from the company, according to a MannKind statement issued April 7.

This article was updated April 7, 2014.

[email protected]

HYATTSVILLE, MD. – Inhaled insulin will probably become available as a treatment option again, with a Food and Drug Administration advisory panel’s recommendation to approve an orally administered dry powder recombinant insulin formulation for the treatment of both type 1 and type 2 diabetes.

At a meeting on April 1, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1 that the safety and efficacy data for the inhaled insulin, delivered with an inhaler, supported approval for treatment of adults with type 1 diabetes; they voted 14-0 that the data supported approval for treatment of adults with type 2 diabetes. Panelists had unresolved concerns about safety, including the potential for lung cancer and adverse pulmonary effects, acute bronchospasm in people with asthma, and deteriorating pulmonary function over time, which they said should be closely monitored after approval.

Courtesy MannKind Corp

Panelists also pointed out that the results of phase III trials indicated that the inhaled insulin product was not as effective as traditional insulin, and that it would not be appropriate for all patients with type 1 and type 2 diabetes. They did note, however, that there was a need for more treatment options and that an inhaled insulin could be useful for certain groups of patients, such as elderly or disabled patients who have physical impairments and have difficulties with injectable insulin and patients who refuse to use needles – and when a dose of insulin is needed to lower blood glucose between meals.

The proposed indication for the Technosphere insulin inhalation system – which provides insulin in cartridges, delivered with the "Gen2" inhaler – is to improve glycemic control in adults with type 1 or type 2 diabetes. The system’s rapid-acting insulin works faster and has a shorter duration of action than regular human insulin or rapid-acting analog insulins, according to the manufacturer, MannKind Corp.

It is administered immediately before or within the first 20 minutes of starting a meal and is used with basal insulin in patients with type 1 diabetes, and it can be used with oral glucose-lowering medications or basal insulin in patients with type 2 diabetes, according to the company, which plans to market the product as Afrezza if approved.

The orally inhaled insulin marketed as Exubera was approved by the FDA in January 2006 for treating adults with type 1 and 2 diabetes, but Pfizer took it off the market in 2007 because of poor sales.

The FDA rejected the approval of the MannKind inhaled insulin twice before because of issues with efficacy and the device, and it asked the company to conduct two new phase III studies with a new inhaler.

In the study of patients with type 1 diabetes, those treated with Afrezza had a mean 0.20–percentage point drop in HbA_1c from baseline at 24 weeks, compared with a 0.42–percentage point drop among those on insulin aspart. In the study of patients with type 2 diabetes who were on metformin or at least two other oral diabetes drugs, those treated with Afrezza had a mean 0.84–percentage point drop in HbA_1c from baseline, compared with 0.41 at 24 weeks in those on placebo. In trials, the most common adverse events were a dry, transient cough and transient changes in pulmonary function. Lung cancer rates were similar to what would be expected in the general population, according to the company. Hypoglycemia was slightly lower among those on Afrezza in both studies.

There have been four lung cancers in patients treated with Afrezza in clinical trials, including two cases in patients with no smoking history. Since the product delivers a high level of insulin to the lungs, and insulin may activate growth receptors in the lungs, the panel agreed this was a significant issue that should be followed in postmarketing studies. The company has proposed a prospective observational registry of patients to track the incidence of primary lung cancers, as well as other malignancies and serious pulmonary, allergic, and hypoglycemic events that require medical intervention. Labeling would recommend that spirometry be done every 6 months during treatment.

Voting for approval, panel chair Dr. Robert Smith, professor of medicine at Brown University, Providence, R.I., said that inhaled insulin "represents a drug that will serve some patients that are not effectively served by currently available forms of insulin." The data about the potentially serious adverse effects "were not strong enough that I feel it is imperative to resolve those questions" before marketing, he added, but stressed that these safety issues, including the potential for lung cancer and deteriorating lung function, are "very, very important to follow up."

The panelist who voted against approval for type 1diabetes, Dr. David Cooke, clinical director of the division of pediatric endocrinology at Johns Hopkins University, Baltimore, said he was concerned that the risks outweighed the benefits in this group of patients, particularly because of the potential increased risk of cancer. But he said he was more confident about the risk-benefit profile for patients with type 2 diabetes because they would not be exposed to the drug for as long as patients with type 1 diabetes, and that the inhaled insulin may provide some type 2 patients who might otherwise put off taking insulin with a more acceptable and effective option.

The FDA extended the date for completing the review by three months, so the agency can fully review additional information requested from the company, according to a MannKind statement issued April 7.

This article was updated April 7, 2014.

[email protected]

HYATTSVILLE, MD. – Inhaled insulin will probably become available as a treatment option again, with a Food and Drug Administration advisory panel’s recommendation to approve an orally administered dry powder recombinant insulin formulation for the treatment of both type 1 and type 2 diabetes.

At a meeting on April 1, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1 that the safety and efficacy data for the inhaled insulin, delivered with an inhaler, supported approval for treatment of adults with type 1 diabetes; they voted 14-0 that the data supported approval for treatment of adults with type 2 diabetes. Panelists had unresolved concerns about safety, including the potential for lung cancer and adverse pulmonary effects, acute bronchospasm in people with asthma, and deteriorating pulmonary function over time, which they said should be closely monitored after approval.

Courtesy MannKind Corp

Panelists also pointed out that the results of phase III trials indicated that the inhaled insulin product was not as effective as traditional insulin, and that it would not be appropriate for all patients with type 1 and type 2 diabetes. They did note, however, that there was a need for more treatment options and that an inhaled insulin could be useful for certain groups of patients, such as elderly or disabled patients who have physical impairments and have difficulties with injectable insulin and patients who refuse to use needles – and when a dose of insulin is needed to lower blood glucose between meals.

The proposed indication for the Technosphere insulin inhalation system – which provides insulin in cartridges, delivered with the "Gen2" inhaler – is to improve glycemic control in adults with type 1 or type 2 diabetes. The system’s rapid-acting insulin works faster and has a shorter duration of action than regular human insulin or rapid-acting analog insulins, according to the manufacturer, MannKind Corp.

It is administered immediately before or within the first 20 minutes of starting a meal and is used with basal insulin in patients with type 1 diabetes, and it can be used with oral glucose-lowering medications or basal insulin in patients with type 2 diabetes, according to the company, which plans to market the product as Afrezza if approved.

The orally inhaled insulin marketed as Exubera was approved by the FDA in January 2006 for treating adults with type 1 and 2 diabetes, but Pfizer took it off the market in 2007 because of poor sales.

The FDA rejected the approval of the MannKind inhaled insulin twice before because of issues with efficacy and the device, and it asked the company to conduct two new phase III studies with a new inhaler.

In the study of patients with type 1 diabetes, those treated with Afrezza had a mean 0.20–percentage point drop in HbA_1c from baseline at 24 weeks, compared with a 0.42–percentage point drop among those on insulin aspart. In the study of patients with type 2 diabetes who were on metformin or at least two other oral diabetes drugs, those treated with Afrezza had a mean 0.84–percentage point drop in HbA_1c from baseline, compared with 0.41 at 24 weeks in those on placebo. In trials, the most common adverse events were a dry, transient cough and transient changes in pulmonary function. Lung cancer rates were similar to what would be expected in the general population, according to the company. Hypoglycemia was slightly lower among those on Afrezza in both studies.

There have been four lung cancers in patients treated with Afrezza in clinical trials, including two cases in patients with no smoking history. Since the product delivers a high level of insulin to the lungs, and insulin may activate growth receptors in the lungs, the panel agreed this was a significant issue that should be followed in postmarketing studies. The company has proposed a prospective observational registry of patients to track the incidence of primary lung cancers, as well as other malignancies and serious pulmonary, allergic, and hypoglycemic events that require medical intervention. Labeling would recommend that spirometry be done every 6 months during treatment.

Voting for approval, panel chair Dr. Robert Smith, professor of medicine at Brown University, Providence, R.I., said that inhaled insulin "represents a drug that will serve some patients that are not effectively served by currently available forms of insulin." The data about the potentially serious adverse effects "were not strong enough that I feel it is imperative to resolve those questions" before marketing, he added, but stressed that these safety issues, including the potential for lung cancer and deteriorating lung function, are "very, very important to follow up."

The panelist who voted against approval for type 1diabetes, Dr. David Cooke, clinical director of the division of pediatric endocrinology at Johns Hopkins University, Baltimore, said he was concerned that the risks outweighed the benefits in this group of patients, particularly because of the potential increased risk of cancer. But he said he was more confident about the risk-benefit profile for patients with type 2 diabetes because they would not be exposed to the drug for as long as patients with type 1 diabetes, and that the inhaled insulin may provide some type 2 patients who might otherwise put off taking insulin with a more acceptable and effective option.

The FDA extended the date for completing the review by three months, so the agency can fully review additional information requested from the company, according to a MannKind statement issued April 7.

This article was updated April 7, 2014.

[email protected]

WASHINGTON – Bariatric surgery combined with intensive medical therapy had a significantly greater impact on glycemic control, compared with medical therapy alone, in a 3-year study of overweight and obese people with uncontrolled type 2 diabetes – providing evidence supporting the durability of the beneficial effects of surgery beyond 1 year.

In the study of 137 patients, who all received intensive medical therapy, 37.5% of patients who had a gastric bypass and 24.5% of those who had a sleeve-gastrectomy had achieved the primary endpoint, a hemoglobin A_1c of 6% or lower, 3 years after surgery, compared with 5% of those who had received medical therapy alone, Dr. Sangeeta Kashyap said on March 31 at the annual meeting of the American College of Cardiology.

"Many surgical patients achieved this control without the use of any diabetic medications, particularly insulin; metabolic syndrome components improved, and quality of life was enhanced," said Dr. Kashyap, an endocrinologist at the Cleveland Clinic, where the study was conducted.

In addition, about two-thirds (65%) of those in the surgery groups met the American Diabetes Association HbA_1c goal of 7% or less, compared with 40% of those in the medical group, she added.

These are the 3-year results of the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. The 1-year results of STAMPEDE are among the data that have shown intensive medical therapy and surgery can result in the remission of type 2 diabetes, but the durability of these effects have been unclear.

STAMPEDE is an investigator-initiated study that enrolled 150 overweight or obese middle-aged adults who had had type 2 diabetes for an average of 8.3 years and HbA_1c levels above 7% (mean baseline level was 9.3%) and a body mass index of 27-43 kg/m² (mean baseline BMI was 36); their mean age was 48 years, two-thirds were white, 68% were women, and 43% required insulin. One-third had a BMI under 35, below the current National Institutes of Health guideline for bariatric surgery.

After randomization to intensive medical therapy alone or a Roux-en-Y gastric bypass or sleeve gastrectomy plus intensive medical therapy, treatment was adjusted every 3 months for the first 2 years, then every 6 months, aiming for a HbA_1c of 6% or less. The results were based on the 137 patients who completed 3 years of follow-up.

Significantly more patients in the surgery groups achieved the primary endpoint at 3 years without diabetes medications: 35.4% in the bypass group and 20.4% in the sleeve group, compared with none of those on medical therapy. "Virtually all" of those in the gastric bypass group met the primary endpoint without the use of insulin, Dr. Kashyap noted.

Relapses of glycemic control, defined as those who met the primary endpoint at 12 months but not at 3 years, occurred in the bypass group (24%) but were higher in the sleeve group (50%) and in the medical therapy group (80%).

Other benefits identified at 3 years included improved measures of HDL and triglycerides in the surgery group, compared with the medical therapy group. There were no differences in changes in blood pressure or in LDL levels; or, at 2 years, no differences between carotid intimal medial thickness measures in the three groups. But there was a substantial decrease in the medications used for blood pressure and cholesterol in the surgery groups: At 3 years, about 40% of the patients in the two surgery groups were not taking any cardiovascular medications, vs. only 2% of those in the medical therapy group.

Those in the two surgery groups also had more favorable effects on secondary endpoints that included body weight, use of glucose-lowering medications, and quality of life, compared with the intensive medical therapy group. Those in the bypass group showed improvements in five of eight quality of life measures, including physical function and less body pain, and those in the sleeve gastrectomy group has improvements in two of the eight measures, compared with no improvements among those on medical therapy.

Dr. Kashyap said that being able to take fewer medications per day and mobility and physical function improvements in the significant number of patients with osteoarthritis contributed to the improved quality of life in the surgery patients.

There were no procedure-related deaths, and other than four patients in the surgery groups who required additional surgery in the first year, none needed surgery after that time, and there were no deaths or life-threatening complications in the three groups of patients.

Dr. Kashyap pointed out that bariatric surgery is considered optimal for people who are heavier than a proportion of the patients in this study, but in the study, people who might not normally be considered for bariatric surgery experienced significant benefits. Often an underused intervention in medicine, bariatric surgery "should be considered a treatment option for patients with uncontrolled type 2 diabetes with moderate to severe obesity," Dr. Kashyap concluded.

The size of the study was one of the limitations, and larger studies are needed to determine if this approach is associated with benefits on cardiovascular events and complications, she added.

The 3-year STAMPEDE results were published concurrently with the presentation in the New England Journal of Medicine (doi:10.1056/NEJMoa1401329).

The investigator-initiated study received funding from Ethicon, the Cleveland Clinic, LifeScan, and the National Institutes of Health. Dr. Kashyap had no disclosures.

[email protected]

WASHINGTON – Bariatric surgery combined with intensive medical therapy had a significantly greater impact on glycemic control, compared with medical therapy alone, in a 3-year study of overweight and obese people with uncontrolled type 2 diabetes – providing evidence supporting the durability of the beneficial effects of surgery beyond 1 year.

In the study of 137 patients, who all received intensive medical therapy, 37.5% of patients who had a gastric bypass and 24.5% of those who had a sleeve-gastrectomy had achieved the primary endpoint, a hemoglobin A_1c of 6% or lower, 3 years after surgery, compared with 5% of those who had received medical therapy alone, Dr. Sangeeta Kashyap said on March 31 at the annual meeting of the American College of Cardiology.

"Many surgical patients achieved this control without the use of any diabetic medications, particularly insulin; metabolic syndrome components improved, and quality of life was enhanced," said Dr. Kashyap, an endocrinologist at the Cleveland Clinic, where the study was conducted.

In addition, about two-thirds (65%) of those in the surgery groups met the American Diabetes Association HbA_1c goal of 7% or less, compared with 40% of those in the medical group, she added.

These are the 3-year results of the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. The 1-year results of STAMPEDE are among the data that have shown intensive medical therapy and surgery can result in the remission of type 2 diabetes, but the durability of these effects have been unclear.

STAMPEDE is an investigator-initiated study that enrolled 150 overweight or obese middle-aged adults who had had type 2 diabetes for an average of 8.3 years and HbA_1c levels above 7% (mean baseline level was 9.3%) and a body mass index of 27-43 kg/m² (mean baseline BMI was 36); their mean age was 48 years, two-thirds were white, 68% were women, and 43% required insulin. One-third had a BMI under 35, below the current National Institutes of Health guideline for bariatric surgery.

After randomization to intensive medical therapy alone or a Roux-en-Y gastric bypass or sleeve gastrectomy plus intensive medical therapy, treatment was adjusted every 3 months for the first 2 years, then every 6 months, aiming for a HbA_1c of 6% or less. The results were based on the 137 patients who completed 3 years of follow-up.

Significantly more patients in the surgery groups achieved the primary endpoint at 3 years without diabetes medications: 35.4% in the bypass group and 20.4% in the sleeve group, compared with none of those on medical therapy. "Virtually all" of those in the gastric bypass group met the primary endpoint without the use of insulin, Dr. Kashyap noted.

Relapses of glycemic control, defined as those who met the primary endpoint at 12 months but not at 3 years, occurred in the bypass group (24%) but were higher in the sleeve group (50%) and in the medical therapy group (80%).

Other benefits identified at 3 years included improved measures of HDL and triglycerides in the surgery group, compared with the medical therapy group. There were no differences in changes in blood pressure or in LDL levels; or, at 2 years, no differences between carotid intimal medial thickness measures in the three groups. But there was a substantial decrease in the medications used for blood pressure and cholesterol in the surgery groups: At 3 years, about 40% of the patients in the two surgery groups were not taking any cardiovascular medications, vs. only 2% of those in the medical therapy group.

Those in the two surgery groups also had more favorable effects on secondary endpoints that included body weight, use of glucose-lowering medications, and quality of life, compared with the intensive medical therapy group. Those in the bypass group showed improvements in five of eight quality of life measures, including physical function and less body pain, and those in the sleeve gastrectomy group has improvements in two of the eight measures, compared with no improvements among those on medical therapy.

Dr. Kashyap said that being able to take fewer medications per day and mobility and physical function improvements in the significant number of patients with osteoarthritis contributed to the improved quality of life in the surgery patients.

There were no procedure-related deaths, and other than four patients in the surgery groups who required additional surgery in the first year, none needed surgery after that time, and there were no deaths or life-threatening complications in the three groups of patients.

Dr. Kashyap pointed out that bariatric surgery is considered optimal for people who are heavier than a proportion of the patients in this study, but in the study, people who might not normally be considered for bariatric surgery experienced significant benefits. Often an underused intervention in medicine, bariatric surgery "should be considered a treatment option for patients with uncontrolled type 2 diabetes with moderate to severe obesity," Dr. Kashyap concluded.

The size of the study was one of the limitations, and larger studies are needed to determine if this approach is associated with benefits on cardiovascular events and complications, she added.

The 3-year STAMPEDE results were published concurrently with the presentation in the New England Journal of Medicine (doi:10.1056/NEJMoa1401329).

The investigator-initiated study received funding from Ethicon, the Cleveland Clinic, LifeScan, and the National Institutes of Health. Dr. Kashyap had no disclosures.

[email protected]

WASHINGTON – Bariatric surgery combined with intensive medical therapy had a significantly greater impact on glycemic control, compared with medical therapy alone, in a 3-year study of overweight and obese people with uncontrolled type 2 diabetes – providing evidence supporting the durability of the beneficial effects of surgery beyond 1 year.

In the study of 137 patients, who all received intensive medical therapy, 37.5% of patients who had a gastric bypass and 24.5% of those who had a sleeve-gastrectomy had achieved the primary endpoint, a hemoglobin A_1c of 6% or lower, 3 years after surgery, compared with 5% of those who had received medical therapy alone, Dr. Sangeeta Kashyap said on March 31 at the annual meeting of the American College of Cardiology.

"Many surgical patients achieved this control without the use of any diabetic medications, particularly insulin; metabolic syndrome components improved, and quality of life was enhanced," said Dr. Kashyap, an endocrinologist at the Cleveland Clinic, where the study was conducted.

In addition, about two-thirds (65%) of those in the surgery groups met the American Diabetes Association HbA_1c goal of 7% or less, compared with 40% of those in the medical group, she added.

These are the 3-year results of the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. The 1-year results of STAMPEDE are among the data that have shown intensive medical therapy and surgery can result in the remission of type 2 diabetes, but the durability of these effects have been unclear.

STAMPEDE is an investigator-initiated study that enrolled 150 overweight or obese middle-aged adults who had had type 2 diabetes for an average of 8.3 years and HbA_1c levels above 7% (mean baseline level was 9.3%) and a body mass index of 27-43 kg/m² (mean baseline BMI was 36); their mean age was 48 years, two-thirds were white, 68% were women, and 43% required insulin. One-third had a BMI under 35, below the current National Institutes of Health guideline for bariatric surgery.

After randomization to intensive medical therapy alone or a Roux-en-Y gastric bypass or sleeve gastrectomy plus intensive medical therapy, treatment was adjusted every 3 months for the first 2 years, then every 6 months, aiming for a HbA_1c of 6% or less. The results were based on the 137 patients who completed 3 years of follow-up.

Significantly more patients in the surgery groups achieved the primary endpoint at 3 years without diabetes medications: 35.4% in the bypass group and 20.4% in the sleeve group, compared with none of those on medical therapy. "Virtually all" of those in the gastric bypass group met the primary endpoint without the use of insulin, Dr. Kashyap noted.

Relapses of glycemic control, defined as those who met the primary endpoint at 12 months but not at 3 years, occurred in the bypass group (24%) but were higher in the sleeve group (50%) and in the medical therapy group (80%).

Other benefits identified at 3 years included improved measures of HDL and triglycerides in the surgery group, compared with the medical therapy group. There were no differences in changes in blood pressure or in LDL levels; or, at 2 years, no differences between carotid intimal medial thickness measures in the three groups. But there was a substantial decrease in the medications used for blood pressure and cholesterol in the surgery groups: At 3 years, about 40% of the patients in the two surgery groups were not taking any cardiovascular medications, vs. only 2% of those in the medical therapy group.

Those in the two surgery groups also had more favorable effects on secondary endpoints that included body weight, use of glucose-lowering medications, and quality of life, compared with the intensive medical therapy group. Those in the bypass group showed improvements in five of eight quality of life measures, including physical function and less body pain, and those in the sleeve gastrectomy group has improvements in two of the eight measures, compared with no improvements among those on medical therapy.

Dr. Kashyap said that being able to take fewer medications per day and mobility and physical function improvements in the significant number of patients with osteoarthritis contributed to the improved quality of life in the surgery patients.

There were no procedure-related deaths, and other than four patients in the surgery groups who required additional surgery in the first year, none needed surgery after that time, and there were no deaths or life-threatening complications in the three groups of patients.

Dr. Kashyap pointed out that bariatric surgery is considered optimal for people who are heavier than a proportion of the patients in this study, but in the study, people who might not normally be considered for bariatric surgery experienced significant benefits. Often an underused intervention in medicine, bariatric surgery "should be considered a treatment option for patients with uncontrolled type 2 diabetes with moderate to severe obesity," Dr. Kashyap concluded.

The size of the study was one of the limitations, and larger studies are needed to determine if this approach is associated with benefits on cardiovascular events and complications, she added.

The 3-year STAMPEDE results were published concurrently with the presentation in the New England Journal of Medicine (doi:10.1056/NEJMoa1401329).

The investigator-initiated study received funding from Ethicon, the Cleveland Clinic, LifeScan, and the National Institutes of Health. Dr. Kashyap had no disclosures.

[email protected]

WASHINGTON – Early treatment with cardiac-resynchronization therapy with a defibrillator showed a significant survival benefit in patients with mild heart failure, left ventricular dysfunction, and left bundle-branch block, but no benefit was seen among those who did not have bundle-branch block.

In this long-term follow-up analysis of the MADIT-CRT trial, there was a trend toward increased all-cause mortality among those who did not have left bundle-branch block, said Dr. Ilan Goldenberg of the Israeli Association for Cardiovascular Trials and Tel Aviv (Israel) University at the annual meeting of the American College of Cardiology. MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy) followed 1,692 surviving patients for a median of 5.6 years, as the first phase, and 854 patients enrolled in registries in the United States and elsewhere, as the second phase, and the data were merged. The primary endpoint was death from any cause.

The results indicate that in patients with mild heart failure (HF) symptoms, left ventricular dysfunction, and left bundle-branch block (LBBB), "early intervention with cardiac resynchronization therapy is associated with a significant long-term survival benefit, whereas currently, there is no evidence for any clinical benefit associated with cardiac resynchronization therapy in mild heart failure patients" without LBBB, he concluded.

In the original study, treatment with a cardiac resynchronization therapy–defibrillator (CRT-D) was associated with a significant 34% reduction in the risk of nonfatal HF events or all-cause mortality over a median 2.4 years follow-up. But the effect of the device on risk of all-cause mortality was neutral, possibly because of the short-term follow-up, so whether treatment could affect long-term survival in this population was unclear, he pointed out. Benefit in the original trial appeared to be restricted to patients with LBBB, he added.

In the long-term study, 7 years after enrollment, cumulative all-cause mortality in those with LBBB was 18% among those patients treated with CRT-D, compared with 29% among those who received defibrillator therapy alone, a statistically significant difference that represented a 41% reduced risk. The separation in event rates appeared after 1 year and continued for 7 years. Based on this difference in survival, nine patients would need to be treated with CRT-D to save one life over 7 years, Dr. Goldenberg said. The survival benefit was present regardless of age, sex, HF functional class I or II, baseline ejection fractions or cardiac volume, or QRS duration.

In patients with LBBB, treatment was also associated with a "pronounced" risk reduction of 62% in heart failure events, with benefits that started to appear after enrollment and continued through follow-up, and a significant 55% reduction in the combined endpoint of heart failure and death.

"In contrast, among patients without LBBB, we see that even after multivariate adjustment, there was no evidence for any clinical benefit associated with cardiac resynchronization therapy, with even a trend to a 57% increased risk of all-cause mortality" in patients without LBBB. In contrast, in patients who did not have left bundle-branch block, "there was no evidence for any clinical benefit associated with cardiac resynchronization therapy during long-term follow-up," for all-cause mortality and for nonfatal HF events, Dr. Goldenberg said.

The earlier results were published in 2009 (N. Engl. J. Med. 2009;361:1329-38).

The current study was published simultaneously with its presentation in the New England Journal of Medicine (2014, March 30 [doi:10.1056/NEJMoa1401426]).

The study was funded by unrestricted research grants from Boston Scientific to the University of Rochester, N.Y., and the Israeli Association for Cardiovascular Trials. Dr. Goldenberg disclosed having received grant support from Boston Scientific outside of this study.

[email protected]

WASHINGTON – Early treatment with cardiac-resynchronization therapy with a defibrillator showed a significant survival benefit in patients with mild heart failure, left ventricular dysfunction, and left bundle-branch block, but no benefit was seen among those who did not have bundle-branch block.

In this long-term follow-up analysis of the MADIT-CRT trial, there was a trend toward increased all-cause mortality among those who did not have left bundle-branch block, said Dr. Ilan Goldenberg of the Israeli Association for Cardiovascular Trials and Tel Aviv (Israel) University at the annual meeting of the American College of Cardiology. MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy) followed 1,692 surviving patients for a median of 5.6 years, as the first phase, and 854 patients enrolled in registries in the United States and elsewhere, as the second phase, and the data were merged. The primary endpoint was death from any cause.

The results indicate that in patients with mild heart failure (HF) symptoms, left ventricular dysfunction, and left bundle-branch block (LBBB), "early intervention with cardiac resynchronization therapy is associated with a significant long-term survival benefit, whereas currently, there is no evidence for any clinical benefit associated with cardiac resynchronization therapy in mild heart failure patients" without LBBB, he concluded.

In the original study, treatment with a cardiac resynchronization therapy–defibrillator (CRT-D) was associated with a significant 34% reduction in the risk of nonfatal HF events or all-cause mortality over a median 2.4 years follow-up. But the effect of the device on risk of all-cause mortality was neutral, possibly because of the short-term follow-up, so whether treatment could affect long-term survival in this population was unclear, he pointed out. Benefit in the original trial appeared to be restricted to patients with LBBB, he added.

In the long-term study, 7 years after enrollment, cumulative all-cause mortality in those with LBBB was 18% among those patients treated with CRT-D, compared with 29% among those who received defibrillator therapy alone, a statistically significant difference that represented a 41% reduced risk. The separation in event rates appeared after 1 year and continued for 7 years. Based on this difference in survival, nine patients would need to be treated with CRT-D to save one life over 7 years, Dr. Goldenberg said. The survival benefit was present regardless of age, sex, HF functional class I or II, baseline ejection fractions or cardiac volume, or QRS duration.

In patients with LBBB, treatment was also associated with a "pronounced" risk reduction of 62% in heart failure events, with benefits that started to appear after enrollment and continued through follow-up, and a significant 55% reduction in the combined endpoint of heart failure and death.

"In contrast, among patients without LBBB, we see that even after multivariate adjustment, there was no evidence for any clinical benefit associated with cardiac resynchronization therapy, with even a trend to a 57% increased risk of all-cause mortality" in patients without LBBB. In contrast, in patients who did not have left bundle-branch block, "there was no evidence for any clinical benefit associated with cardiac resynchronization therapy during long-term follow-up," for all-cause mortality and for nonfatal HF events, Dr. Goldenberg said.

The earlier results were published in 2009 (N. Engl. J. Med. 2009;361:1329-38).

The current study was published simultaneously with its presentation in the New England Journal of Medicine (2014, March 30 [doi:10.1056/NEJMoa1401426]).

The study was funded by unrestricted research grants from Boston Scientific to the University of Rochester, N.Y., and the Israeli Association for Cardiovascular Trials. Dr. Goldenberg disclosed having received grant support from Boston Scientific outside of this study.

[email protected]

WASHINGTON – Early treatment with cardiac-resynchronization therapy with a defibrillator showed a significant survival benefit in patients with mild heart failure, left ventricular dysfunction, and left bundle-branch block, but no benefit was seen among those who did not have bundle-branch block.

In this long-term follow-up analysis of the MADIT-CRT trial, there was a trend toward increased all-cause mortality among those who did not have left bundle-branch block, said Dr. Ilan Goldenberg of the Israeli Association for Cardiovascular Trials and Tel Aviv (Israel) University at the annual meeting of the American College of Cardiology. MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy) followed 1,692 surviving patients for a median of 5.6 years, as the first phase, and 854 patients enrolled in registries in the United States and elsewhere, as the second phase, and the data were merged. The primary endpoint was death from any cause.

The results indicate that in patients with mild heart failure (HF) symptoms, left ventricular dysfunction, and left bundle-branch block (LBBB), "early intervention with cardiac resynchronization therapy is associated with a significant long-term survival benefit, whereas currently, there is no evidence for any clinical benefit associated with cardiac resynchronization therapy in mild heart failure patients" without LBBB, he concluded.

In the original study, treatment with a cardiac resynchronization therapy–defibrillator (CRT-D) was associated with a significant 34% reduction in the risk of nonfatal HF events or all-cause mortality over a median 2.4 years follow-up. But the effect of the device on risk of all-cause mortality was neutral, possibly because of the short-term follow-up, so whether treatment could affect long-term survival in this population was unclear, he pointed out. Benefit in the original trial appeared to be restricted to patients with LBBB, he added.

In the long-term study, 7 years after enrollment, cumulative all-cause mortality in those with LBBB was 18% among those patients treated with CRT-D, compared with 29% among those who received defibrillator therapy alone, a statistically significant difference that represented a 41% reduced risk. The separation in event rates appeared after 1 year and continued for 7 years. Based on this difference in survival, nine patients would need to be treated with CRT-D to save one life over 7 years, Dr. Goldenberg said. The survival benefit was present regardless of age, sex, HF functional class I or II, baseline ejection fractions or cardiac volume, or QRS duration.

In patients with LBBB, treatment was also associated with a "pronounced" risk reduction of 62% in heart failure events, with benefits that started to appear after enrollment and continued through follow-up, and a significant 55% reduction in the combined endpoint of heart failure and death.

"In contrast, among patients without LBBB, we see that even after multivariate adjustment, there was no evidence for any clinical benefit associated with cardiac resynchronization therapy, with even a trend to a 57% increased risk of all-cause mortality" in patients without LBBB. In contrast, in patients who did not have left bundle-branch block, "there was no evidence for any clinical benefit associated with cardiac resynchronization therapy during long-term follow-up," for all-cause mortality and for nonfatal HF events, Dr. Goldenberg said.

The earlier results were published in 2009 (N. Engl. J. Med. 2009;361:1329-38).

The current study was published simultaneously with its presentation in the New England Journal of Medicine (2014, March 30 [doi:10.1056/NEJMoa1401426]).

The study was funded by unrestricted research grants from Boston Scientific to the University of Rochester, N.Y., and the Israeli Association for Cardiovascular Trials. Dr. Goldenberg disclosed having received grant support from Boston Scientific outside of this study.

[email protected]

WASHINGTON – Patients with acute heart failure who were discharged on an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker were significantly less likely to be readmitted to the hospital within 30 days of discharge than patients who were not prescribed these drugs, in a retrospective study of Medicare beneficiaries.

Using data from the Alabama Heart Failure Project, the study looked at hospital readmission rates in 1,348 patients with acute decompensated heart failure and an ejection fraction under 45%, discharged from 106 hospitals in the United States. Their mean age was 75 years, they had similar renal function, they were on various baseline cardiac medications, and they had no contraindications for angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) treatment. Of these patients, 734 were prescribed one of these drugs before discharge.

Nick Piegari/Frontline Medical News

The heart failure readmission and all-cause mortality rates were significantly higher among those who were not started on an ACE inhibitor or ARB before discharge: The 30-day heart failure readmission rate was 14% among those who did not receive an ACE inhibitor or ARB, compared with 7% of those who did – a 48% reduced risk, said Dr. Kumar Sanam, a heart failure fellow at the University of Alabama, Birmingham, at the annual meeting of the American College of Cardiology.

The all-cause readmission rate within 30 days among patients discharged without an ACE inhibitor or ARB was also significantly higher, at 24%, compared with 18% of those discharged with an ACE or an ARB, a relative risk reduction of 26%. The risk of all-cause mortality was reduced by 44% among those prescribed an ACE inhibitor or ARB, Dr. Sanam said.

Under the Affordable Care Act, hospitals will be penalized for above-average, all-cause 30-day readmission rates, he noted, and these findings highlight how the use of treatment recommended in evidence-based guidelines "could be used to reduce a costly health care problem," in the United States, Dr. Sanam said. An estimated one in four patients hospitalized with heart failure return to the hospital within 30 days, and heart failure is the most common cause of 30-day all-cause readmissions, he noted.

Dr. Sanam had no disclosures.

[email protected]

WASHINGTON – Patients with acute heart failure who were discharged on an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker were significantly less likely to be readmitted to the hospital within 30 days of discharge than patients who were not prescribed these drugs, in a retrospective study of Medicare beneficiaries.

Using data from the Alabama Heart Failure Project, the study looked at hospital readmission rates in 1,348 patients with acute decompensated heart failure and an ejection fraction under 45%, discharged from 106 hospitals in the United States. Their mean age was 75 years, they had similar renal function, they were on various baseline cardiac medications, and they had no contraindications for angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) treatment. Of these patients, 734 were prescribed one of these drugs before discharge.

Nick Piegari/Frontline Medical News

The heart failure readmission and all-cause mortality rates were significantly higher among those who were not started on an ACE inhibitor or ARB before discharge: The 30-day heart failure readmission rate was 14% among those who did not receive an ACE inhibitor or ARB, compared with 7% of those who did – a 48% reduced risk, said Dr. Kumar Sanam, a heart failure fellow at the University of Alabama, Birmingham, at the annual meeting of the American College of Cardiology.

The all-cause readmission rate within 30 days among patients discharged without an ACE inhibitor or ARB was also significantly higher, at 24%, compared with 18% of those discharged with an ACE or an ARB, a relative risk reduction of 26%. The risk of all-cause mortality was reduced by 44% among those prescribed an ACE inhibitor or ARB, Dr. Sanam said.

Under the Affordable Care Act, hospitals will be penalized for above-average, all-cause 30-day readmission rates, he noted, and these findings highlight how the use of treatment recommended in evidence-based guidelines "could be used to reduce a costly health care problem," in the United States, Dr. Sanam said. An estimated one in four patients hospitalized with heart failure return to the hospital within 30 days, and heart failure is the most common cause of 30-day all-cause readmissions, he noted.

Dr. Sanam had no disclosures.

[email protected]

WASHINGTON – Patients with acute heart failure who were discharged on an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker were significantly less likely to be readmitted to the hospital within 30 days of discharge than patients who were not prescribed these drugs, in a retrospective study of Medicare beneficiaries.

Using data from the Alabama Heart Failure Project, the study looked at hospital readmission rates in 1,348 patients with acute decompensated heart failure and an ejection fraction under 45%, discharged from 106 hospitals in the United States. Their mean age was 75 years, they had similar renal function, they were on various baseline cardiac medications, and they had no contraindications for angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) treatment. Of these patients, 734 were prescribed one of these drugs before discharge.

Nick Piegari/Frontline Medical News

The heart failure readmission and all-cause mortality rates were significantly higher among those who were not started on an ACE inhibitor or ARB before discharge: The 30-day heart failure readmission rate was 14% among those who did not receive an ACE inhibitor or ARB, compared with 7% of those who did – a 48% reduced risk, said Dr. Kumar Sanam, a heart failure fellow at the University of Alabama, Birmingham, at the annual meeting of the American College of Cardiology.

The all-cause readmission rate within 30 days among patients discharged without an ACE inhibitor or ARB was also significantly higher, at 24%, compared with 18% of those discharged with an ACE or an ARB, a relative risk reduction of 26%. The risk of all-cause mortality was reduced by 44% among those prescribed an ACE inhibitor or ARB, Dr. Sanam said.

Under the Affordable Care Act, hospitals will be penalized for above-average, all-cause 30-day readmission rates, he noted, and these findings highlight how the use of treatment recommended in evidence-based guidelines "could be used to reduce a costly health care problem," in the United States, Dr. Sanam said. An estimated one in four patients hospitalized with heart failure return to the hospital within 30 days, and heart failure is the most common cause of 30-day all-cause readmissions, he noted.

Dr. Sanam had no disclosures.

[email protected]

WASHINGTON, D.C. – Heart failure patients discharged on inexpensive, guideline-recommended drugs were half as likely to be readmitted for the condition within* 30 days, compared with those who weren’t given the drugs, according to a study of the Alabama Heart Failure Project that used Medicare data.

Dr. Kumar Sanam, an advanced heart failure fellow at the University of Alabama, Birmingham, presented the study at the annual meeting of the American College of Cardiology, and sat down with us to discuss the take-home implications of the study.

[email protected]

*CORRECTION, 4/22/2014: An earlier version of this story misstated the follow-up period.

WASHINGTON, D.C. – Heart failure patients discharged on inexpensive, guideline-recommended drugs were half as likely to be readmitted for the condition within* 30 days, compared with those who weren’t given the drugs, according to a study of the Alabama Heart Failure Project that used Medicare data.

Dr. Kumar Sanam, an advanced heart failure fellow at the University of Alabama, Birmingham, presented the study at the annual meeting of the American College of Cardiology, and sat down with us to discuss the take-home implications of the study.

[email protected]

*CORRECTION, 4/22/2014: An earlier version of this story misstated the follow-up period.

WASHINGTON, D.C. – Heart failure patients discharged on inexpensive, guideline-recommended drugs were half as likely to be readmitted for the condition within* 30 days, compared with those who weren’t given the drugs, according to a study of the Alabama Heart Failure Project that used Medicare data.

Dr. Kumar Sanam, an advanced heart failure fellow at the University of Alabama, Birmingham, presented the study at the annual meeting of the American College of Cardiology, and sat down with us to discuss the take-home implications of the study.

[email protected]

*CORRECTION, 4/22/2014: An earlier version of this story misstated the follow-up period.

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

his 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. Of the procedure-related outcomes, 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.

Nick Piegari/Frontline Medical News

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 at the meeting.

Among the study limitations was that 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.

[email protected]

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

his 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. Of the procedure-related outcomes, 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.

Nick Piegari/Frontline Medical News

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 at the meeting.

Among the study limitations was that 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.

[email protected]

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

his 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. Of the procedure-related outcomes, 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.

Nick Piegari/Frontline Medical News

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 at the meeting.

Among the study limitations was that 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.

[email protected]