Heart Failure

SILVER SPRING, MD.– Alogliptin’s cardiovascular risk profile is acceptably safe for high-risk patients with type 2 diabetes, a Food and Drug Administration advisory panel has unanimously agreed.

At a meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee on April 14, panelists reviewed the results of the results of a large cardiovascular outcomes study of the dipeptidyl peptidase-4 (DPP-4) inhibitor, the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study, an international, randomized, double-blind, placebo-controlled trial of about 5,400 people with type 2 diabetes and established cardiovascular disease.

The FDA is requiring CV outcomes trials for all type 2 diabetes drugs, including those in development, and issued a guidance for industry for these trials in December 2008, which states that the trials should evaluate the major adverse cardiovascular event (MACE) incidence in patients at increased risk for CVD and that a 30% or greater excess CV risk over placebo should be excluded to meet the criteria for acceptable CV safety.

Alogliptin, marketed as Nesina by Takeda Pharmaceutical USA, was approved in January 2013. It also is combined with metformin (Kazano) and with pioglitazone (Oseni). The EXAMINE study, which was underway at the time of approval, enrolled people who had an acute coronary syndrome event (acute MI or unstable angina requiring hospitalization) within 15-90 days of enrollment.

Over a median follow-up of 1.5 years, there was no increase in the MACE composite endpoint of CV death, nonfatal MI, and nonfatal stroke among those on alogliptin (11.3%), compared with those on placebo (11.8%), for a hazard ratio of 0.96 – meeting the FDA criteria for CV safety (N. Engl. J. Med. 2013;369:1327-35).

Some of the issues raised with the study included a lower-than-planned proportion of patients enrolled in the United States and Canada – less than 16% of the total – and a subgroup analysis showing that, in the North American patients, the MACE rate among those on alogliptin was elevated compared with placebo (HR, 1.28). The FDA reviewers said that the North American population had some characteristics that might explain this difference.

Another finding discussed was the higher number of hospitalizations for heart failure in patients on alogliptin (106) than for those on placebo (89), for a rate of 2.6 vs. 2.3 cases per 100 patient-years (HR, 1.19), according to the FDA. In the CV outcomes study of another DPP-4 inhibitor, saxagliptin, which the panel reviewed earlier in the day, there was a similar signal for an increased risk of heart failure hospitalizations associated with the drug.

Panelists, however, said they were not convinced that the geographic differences represented a real effect, which they said could be due to chance and did not affect the overall results – although they would have preferred to have more people from the United States enrolled in the study. Panelists also were not overly concerned about the risk of heart failure, but they pointed out that the risk of heart failure risk should be monitored in patients on the drug because of the signal seen with saxagliptin. Several panelists said that they suspected that heart failure may turn out to be a class effect. CV outcomes trials for the two other approved DPP-4 inhibitors – sitagliptin (Januvia) and linagliptin (Tradjenta) – are ongoing.

“It’s clear that the trial achieved its primary objective in a manner consistent with the 2008 guidelines,” said one of the panelists, Dr. Thomas Wang, director of the division of cardiovascular medicine at Vanderbilt University, Nashville, Tenn. Although there were some limitations of the study, such as the low proportion of U.S. participants and the relatively short duration of follow-up, “these limitations do not come close to negating the conclusion” regarding the cardiovascular risk profile, he commented.

In another vote, 13 of the 16 panelists said that the new safety information should be added to the alogliptin prescribing information. “This trial represented a huge effort and we know a lot about the outcomes related to this drug now,” and that information should be included in the label, said one of the panelists, Dr. Susan Heckbert, professor in the department of epidemiology, University of Washington, Seattle.

Three panelists voted not to add any information to the label. The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest

emechcatie@frontlinemedcom.com

SILVER SPRING, MD.– Alogliptin’s cardiovascular risk profile is acceptably safe for high-risk patients with type 2 diabetes, a Food and Drug Administration advisory panel has unanimously agreed.

At a meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee on April 14, panelists reviewed the results of the results of a large cardiovascular outcomes study of the dipeptidyl peptidase-4 (DPP-4) inhibitor, the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study, an international, randomized, double-blind, placebo-controlled trial of about 5,400 people with type 2 diabetes and established cardiovascular disease.

The FDA is requiring CV outcomes trials for all type 2 diabetes drugs, including those in development, and issued a guidance for industry for these trials in December 2008, which states that the trials should evaluate the major adverse cardiovascular event (MACE) incidence in patients at increased risk for CVD and that a 30% or greater excess CV risk over placebo should be excluded to meet the criteria for acceptable CV safety.

Alogliptin, marketed as Nesina by Takeda Pharmaceutical USA, was approved in January 2013. It also is combined with metformin (Kazano) and with pioglitazone (Oseni). The EXAMINE study, which was underway at the time of approval, enrolled people who had an acute coronary syndrome event (acute MI or unstable angina requiring hospitalization) within 15-90 days of enrollment.

Over a median follow-up of 1.5 years, there was no increase in the MACE composite endpoint of CV death, nonfatal MI, and nonfatal stroke among those on alogliptin (11.3%), compared with those on placebo (11.8%), for a hazard ratio of 0.96 – meeting the FDA criteria for CV safety (N. Engl. J. Med. 2013;369:1327-35).

Some of the issues raised with the study included a lower-than-planned proportion of patients enrolled in the United States and Canada – less than 16% of the total – and a subgroup analysis showing that, in the North American patients, the MACE rate among those on alogliptin was elevated compared with placebo (HR, 1.28). The FDA reviewers said that the North American population had some characteristics that might explain this difference.

Another finding discussed was the higher number of hospitalizations for heart failure in patients on alogliptin (106) than for those on placebo (89), for a rate of 2.6 vs. 2.3 cases per 100 patient-years (HR, 1.19), according to the FDA. In the CV outcomes study of another DPP-4 inhibitor, saxagliptin, which the panel reviewed earlier in the day, there was a similar signal for an increased risk of heart failure hospitalizations associated with the drug.

Panelists, however, said they were not convinced that the geographic differences represented a real effect, which they said could be due to chance and did not affect the overall results – although they would have preferred to have more people from the United States enrolled in the study. Panelists also were not overly concerned about the risk of heart failure, but they pointed out that the risk of heart failure risk should be monitored in patients on the drug because of the signal seen with saxagliptin. Several panelists said that they suspected that heart failure may turn out to be a class effect. CV outcomes trials for the two other approved DPP-4 inhibitors – sitagliptin (Januvia) and linagliptin (Tradjenta) – are ongoing.

“It’s clear that the trial achieved its primary objective in a manner consistent with the 2008 guidelines,” said one of the panelists, Dr. Thomas Wang, director of the division of cardiovascular medicine at Vanderbilt University, Nashville, Tenn. Although there were some limitations of the study, such as the low proportion of U.S. participants and the relatively short duration of follow-up, “these limitations do not come close to negating the conclusion” regarding the cardiovascular risk profile, he commented.

In another vote, 13 of the 16 panelists said that the new safety information should be added to the alogliptin prescribing information. “This trial represented a huge effort and we know a lot about the outcomes related to this drug now,” and that information should be included in the label, said one of the panelists, Dr. Susan Heckbert, professor in the department of epidemiology, University of Washington, Seattle.

Three panelists voted not to add any information to the label. The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest

emechcatie@frontlinemedcom.com

SILVER SPRING, MD.– Alogliptin’s cardiovascular risk profile is acceptably safe for high-risk patients with type 2 diabetes, a Food and Drug Administration advisory panel has unanimously agreed.

At a meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee on April 14, panelists reviewed the results of the results of a large cardiovascular outcomes study of the dipeptidyl peptidase-4 (DPP-4) inhibitor, the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study, an international, randomized, double-blind, placebo-controlled trial of about 5,400 people with type 2 diabetes and established cardiovascular disease.

The FDA is requiring CV outcomes trials for all type 2 diabetes drugs, including those in development, and issued a guidance for industry for these trials in December 2008, which states that the trials should evaluate the major adverse cardiovascular event (MACE) incidence in patients at increased risk for CVD and that a 30% or greater excess CV risk over placebo should be excluded to meet the criteria for acceptable CV safety.

Alogliptin, marketed as Nesina by Takeda Pharmaceutical USA, was approved in January 2013. It also is combined with metformin (Kazano) and with pioglitazone (Oseni). The EXAMINE study, which was underway at the time of approval, enrolled people who had an acute coronary syndrome event (acute MI or unstable angina requiring hospitalization) within 15-90 days of enrollment.

Over a median follow-up of 1.5 years, there was no increase in the MACE composite endpoint of CV death, nonfatal MI, and nonfatal stroke among those on alogliptin (11.3%), compared with those on placebo (11.8%), for a hazard ratio of 0.96 – meeting the FDA criteria for CV safety (N. Engl. J. Med. 2013;369:1327-35).

Some of the issues raised with the study included a lower-than-planned proportion of patients enrolled in the United States and Canada – less than 16% of the total – and a subgroup analysis showing that, in the North American patients, the MACE rate among those on alogliptin was elevated compared with placebo (HR, 1.28). The FDA reviewers said that the North American population had some characteristics that might explain this difference.

Another finding discussed was the higher number of hospitalizations for heart failure in patients on alogliptin (106) than for those on placebo (89), for a rate of 2.6 vs. 2.3 cases per 100 patient-years (HR, 1.19), according to the FDA. In the CV outcomes study of another DPP-4 inhibitor, saxagliptin, which the panel reviewed earlier in the day, there was a similar signal for an increased risk of heart failure hospitalizations associated with the drug.

Panelists, however, said they were not convinced that the geographic differences represented a real effect, which they said could be due to chance and did not affect the overall results – although they would have preferred to have more people from the United States enrolled in the study. Panelists also were not overly concerned about the risk of heart failure, but they pointed out that the risk of heart failure risk should be monitored in patients on the drug because of the signal seen with saxagliptin. Several panelists said that they suspected that heart failure may turn out to be a class effect. CV outcomes trials for the two other approved DPP-4 inhibitors – sitagliptin (Januvia) and linagliptin (Tradjenta) – are ongoing.

“It’s clear that the trial achieved its primary objective in a manner consistent with the 2008 guidelines,” said one of the panelists, Dr. Thomas Wang, director of the division of cardiovascular medicine at Vanderbilt University, Nashville, Tenn. Although there were some limitations of the study, such as the low proportion of U.S. participants and the relatively short duration of follow-up, “these limitations do not come close to negating the conclusion” regarding the cardiovascular risk profile, he commented.

In another vote, 13 of the 16 panelists said that the new safety information should be added to the alogliptin prescribing information. “This trial represented a huge effort and we know a lot about the outcomes related to this drug now,” and that information should be included in the label, said one of the panelists, Dr. Susan Heckbert, professor in the department of epidemiology, University of Washington, Seattle.

Three panelists voted not to add any information to the label. The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest

emechcatie@frontlinemedcom.com

SAN DIEGO – Congestion secondary to advanced heart failure appears to cause type 2 diabetes in a significant subgroup of patients, based on suggestive findings from a series of recently reported studies, Dr. Maya Guglin said during an interview at the annual meeting of the American College of Cardiology.

Dr. Guglin reviewed convergent findings from several groups of patients who received left ventricular assist devices to treat advanced heart failure. The analyses all showed that many, though not a majority, of those patients also had type 2 diabetes. Soon after patients received an assist device, the type 2 diabetes uniformly improved – and in many cases, glycemic control normalized.

Dr. Guglin, who has named this condition “cardiogenic diabetes,” said that reducing congestion with an assist device or with diuretic treatment seems the best way to both reduce congestion and improve or resolve the diabetes.

Those treatments will “improve quality of life, reduce hospital admissions for heart failure, and also improve the course of diabetes,” said Dr. Guglin, professor of medicine and medical director of the ventricular assist device program at the University of Kentucky in Lexington.

Dr. Guglin had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

SAN DIEGO – Congestion secondary to advanced heart failure appears to cause type 2 diabetes in a significant subgroup of patients, based on suggestive findings from a series of recently reported studies, Dr. Maya Guglin said during an interview at the annual meeting of the American College of Cardiology.

Dr. Guglin reviewed convergent findings from several groups of patients who received left ventricular assist devices to treat advanced heart failure. The analyses all showed that many, though not a majority, of those patients also had type 2 diabetes. Soon after patients received an assist device, the type 2 diabetes uniformly improved – and in many cases, glycemic control normalized.

Dr. Guglin, who has named this condition “cardiogenic diabetes,” said that reducing congestion with an assist device or with diuretic treatment seems the best way to both reduce congestion and improve or resolve the diabetes.

Those treatments will “improve quality of life, reduce hospital admissions for heart failure, and also improve the course of diabetes,” said Dr. Guglin, professor of medicine and medical director of the ventricular assist device program at the University of Kentucky in Lexington.

Dr. Guglin had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

SAN DIEGO – Congestion secondary to advanced heart failure appears to cause type 2 diabetes in a significant subgroup of patients, based on suggestive findings from a series of recently reported studies, Dr. Maya Guglin said during an interview at the annual meeting of the American College of Cardiology.

Dr. Guglin reviewed convergent findings from several groups of patients who received left ventricular assist devices to treat advanced heart failure. The analyses all showed that many, though not a majority, of those patients also had type 2 diabetes. Soon after patients received an assist device, the type 2 diabetes uniformly improved – and in many cases, glycemic control normalized.

Dr. Guglin, who has named this condition “cardiogenic diabetes,” said that reducing congestion with an assist device or with diuretic treatment seems the best way to both reduce congestion and improve or resolve the diabetes.

Those treatments will “improve quality of life, reduce hospital admissions for heart failure, and also improve the course of diabetes,” said Dr. Guglin, professor of medicine and medical director of the ventricular assist device program at the University of Kentucky in Lexington.

Dr. Guglin had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

SILVER SPRING, MD.– Results of a large postmarketing study evaluating the cardiovascular safety of saxagliptin in a high-risk population provided reassuring evidence about the drug’s overall cardiovascular risk, although a signal for heart failure hospitalizations associated with the drug was a concern, according to a Food and Drug Administration advisory panel.

At a meeting on April 14, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1, with one abstention, that the results of the SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus) trial showed that the use of saxagliptin in patients with type 2 diabetes had an acceptable cardiovascular risk profile. However, the panelists were concerned about the signal for an increased risk of hospitalizations for heart failure associated with saxagliptin in the study, which they agreed should be studied further. Nearly all of the panelists also voted that the safety data, including the heart failure finding and an imbalance in all-cause mortality among those on saxagliptin arm of the study, be added to the drug’s prescribing information.

Deepak Chitnis/Frontline Medical News

Approved in 2009, saxagliptin, a dipeptidyl peptidase–4 (DPP4) inhibitor, is indicated “as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings” and is marketed as Onglyza by AstraZeneca. A fixed-dose combination of saxagliptin with extended-release metformin (Kombiglyze XR) was approved in 2010. The FDA panel votes apply to both products.

The FDA is requiring that manufacturers conduct CV outcomes trials for all type 2 diabetes drugs in patients at high risk for cardiovascular disease (CVD), and in December 2008, issued a guidance document for industry, outlining the requirements for these studies, which included showing that the CVD risk, based on a major adverse cardiovascular event (MACE) endpoint, is not increased by more than 30% compared to placebo.

AstraZeneca conducted SAVOR, a prospective, randomized, double-blind, placebo-controlled study of nearly 16,500 people with type 2 diabetes, who had or were at risk of CVD, comparing saxagliptin to placebo, on top of standard treatment (N. Engl. J. Med. 2013;369:1317-26). After a median follow-up of about 2 years, the incidence of MACE (a composite of cardiovascular death, nonfatal MI, and nonfatal ischemic stroke) was identical in both groups, at 7.4%, with a hazard ratio of 1.0, meeting the FDA criteria for cardiovascular safety as outlined in the guidance, according to the company. Saxagliptin was not superior to placebo in reducing the MACE events, another primary objective of the study.

Unexpectedly, hospitalization for heart failure (HF), a component of the secondary composite endpoint, was increased among those treated with saxagliptin (hazard ratio, 1.27). There was also a “numerical imbalance” in all-cause mortality between groups, with 17 deaths in the saxagliptin patients vs. 11 in the placebo group (HR, 1.11).

However, deaths caused by heart failure were balanced between those on saxagliptin and those on placebo, and no possible mechanism for the HF finding could be identified, according to AstraZeneca, which is planning a mechanistic study to evaluate the effects of saxagliptin on volume, neurohormonal changes, and cardiac function. The company has proposed that the HF finding be addressed by adding this information to the prescribing information.

The cardiovascular safety results were reassuring, said Dr. Morris Schambelan, a panelist and professor emeritus of medicine in the division of endocrinology at the University of California, San Francisco, but like others on the committee, added that he believes the heart failure signal was real and that providing clinicians with information in the drug’s label to help predict those at higher risk in would be helpful.

Several panelists were somewhat concerned about the all-cause mortality finding, which is a strong endpoint, and therefore cannot be ruled out, they said. But they also pointed out that follow-up was relatively short for a drug that is used long term and that the results should be applied cautiously to patients at lower risk than were those enrolled in the trial.

The FDA usually follows the recommendations of its advisory panel members. Panelists had no relevant disclosures.

CV outcomes trials for other approved DPP4 inhibitors approved for type 2 diabetes – sitagliptin (Januvia) and linagliptin (Tradjenta) – are ongoing. The panel review of the CV outcomes trial for another DPP4 inhibitor approved, alogliptin (Nesina), followed the meeting on saxagliptin.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD.– Results of a large postmarketing study evaluating the cardiovascular safety of saxagliptin in a high-risk population provided reassuring evidence about the drug’s overall cardiovascular risk, although a signal for heart failure hospitalizations associated with the drug was a concern, according to a Food and Drug Administration advisory panel.

At a meeting on April 14, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1, with one abstention, that the results of the SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus) trial showed that the use of saxagliptin in patients with type 2 diabetes had an acceptable cardiovascular risk profile. However, the panelists were concerned about the signal for an increased risk of hospitalizations for heart failure associated with saxagliptin in the study, which they agreed should be studied further. Nearly all of the panelists also voted that the safety data, including the heart failure finding and an imbalance in all-cause mortality among those on saxagliptin arm of the study, be added to the drug’s prescribing information.

Deepak Chitnis/Frontline Medical News

Approved in 2009, saxagliptin, a dipeptidyl peptidase–4 (DPP4) inhibitor, is indicated “as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings” and is marketed as Onglyza by AstraZeneca. A fixed-dose combination of saxagliptin with extended-release metformin (Kombiglyze XR) was approved in 2010. The FDA panel votes apply to both products.

The FDA is requiring that manufacturers conduct CV outcomes trials for all type 2 diabetes drugs in patients at high risk for cardiovascular disease (CVD), and in December 2008, issued a guidance document for industry, outlining the requirements for these studies, which included showing that the CVD risk, based on a major adverse cardiovascular event (MACE) endpoint, is not increased by more than 30% compared to placebo.

AstraZeneca conducted SAVOR, a prospective, randomized, double-blind, placebo-controlled study of nearly 16,500 people with type 2 diabetes, who had or were at risk of CVD, comparing saxagliptin to placebo, on top of standard treatment (N. Engl. J. Med. 2013;369:1317-26). After a median follow-up of about 2 years, the incidence of MACE (a composite of cardiovascular death, nonfatal MI, and nonfatal ischemic stroke) was identical in both groups, at 7.4%, with a hazard ratio of 1.0, meeting the FDA criteria for cardiovascular safety as outlined in the guidance, according to the company. Saxagliptin was not superior to placebo in reducing the MACE events, another primary objective of the study.

Unexpectedly, hospitalization for heart failure (HF), a component of the secondary composite endpoint, was increased among those treated with saxagliptin (hazard ratio, 1.27). There was also a “numerical imbalance” in all-cause mortality between groups, with 17 deaths in the saxagliptin patients vs. 11 in the placebo group (HR, 1.11).

However, deaths caused by heart failure were balanced between those on saxagliptin and those on placebo, and no possible mechanism for the HF finding could be identified, according to AstraZeneca, which is planning a mechanistic study to evaluate the effects of saxagliptin on volume, neurohormonal changes, and cardiac function. The company has proposed that the HF finding be addressed by adding this information to the prescribing information.

The cardiovascular safety results were reassuring, said Dr. Morris Schambelan, a panelist and professor emeritus of medicine in the division of endocrinology at the University of California, San Francisco, but like others on the committee, added that he believes the heart failure signal was real and that providing clinicians with information in the drug’s label to help predict those at higher risk in would be helpful.

Several panelists were somewhat concerned about the all-cause mortality finding, which is a strong endpoint, and therefore cannot be ruled out, they said. But they also pointed out that follow-up was relatively short for a drug that is used long term and that the results should be applied cautiously to patients at lower risk than were those enrolled in the trial.

The FDA usually follows the recommendations of its advisory panel members. Panelists had no relevant disclosures.

CV outcomes trials for other approved DPP4 inhibitors approved for type 2 diabetes – sitagliptin (Januvia) and linagliptin (Tradjenta) – are ongoing. The panel review of the CV outcomes trial for another DPP4 inhibitor approved, alogliptin (Nesina), followed the meeting on saxagliptin.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD.– Results of a large postmarketing study evaluating the cardiovascular safety of saxagliptin in a high-risk population provided reassuring evidence about the drug’s overall cardiovascular risk, although a signal for heart failure hospitalizations associated with the drug was a concern, according to a Food and Drug Administration advisory panel.

At a meeting on April 14, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1, with one abstention, that the results of the SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus) trial showed that the use of saxagliptin in patients with type 2 diabetes had an acceptable cardiovascular risk profile. However, the panelists were concerned about the signal for an increased risk of hospitalizations for heart failure associated with saxagliptin in the study, which they agreed should be studied further. Nearly all of the panelists also voted that the safety data, including the heart failure finding and an imbalance in all-cause mortality among those on saxagliptin arm of the study, be added to the drug’s prescribing information.

Deepak Chitnis/Frontline Medical News

Approved in 2009, saxagliptin, a dipeptidyl peptidase–4 (DPP4) inhibitor, is indicated “as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings” and is marketed as Onglyza by AstraZeneca. A fixed-dose combination of saxagliptin with extended-release metformin (Kombiglyze XR) was approved in 2010. The FDA panel votes apply to both products.

The FDA is requiring that manufacturers conduct CV outcomes trials for all type 2 diabetes drugs in patients at high risk for cardiovascular disease (CVD), and in December 2008, issued a guidance document for industry, outlining the requirements for these studies, which included showing that the CVD risk, based on a major adverse cardiovascular event (MACE) endpoint, is not increased by more than 30% compared to placebo.

AstraZeneca conducted SAVOR, a prospective, randomized, double-blind, placebo-controlled study of nearly 16,500 people with type 2 diabetes, who had or were at risk of CVD, comparing saxagliptin to placebo, on top of standard treatment (N. Engl. J. Med. 2013;369:1317-26). After a median follow-up of about 2 years, the incidence of MACE (a composite of cardiovascular death, nonfatal MI, and nonfatal ischemic stroke) was identical in both groups, at 7.4%, with a hazard ratio of 1.0, meeting the FDA criteria for cardiovascular safety as outlined in the guidance, according to the company. Saxagliptin was not superior to placebo in reducing the MACE events, another primary objective of the study.

Unexpectedly, hospitalization for heart failure (HF), a component of the secondary composite endpoint, was increased among those treated with saxagliptin (hazard ratio, 1.27). There was also a “numerical imbalance” in all-cause mortality between groups, with 17 deaths in the saxagliptin patients vs. 11 in the placebo group (HR, 1.11).

However, deaths caused by heart failure were balanced between those on saxagliptin and those on placebo, and no possible mechanism for the HF finding could be identified, according to AstraZeneca, which is planning a mechanistic study to evaluate the effects of saxagliptin on volume, neurohormonal changes, and cardiac function. The company has proposed that the HF finding be addressed by adding this information to the prescribing information.

The cardiovascular safety results were reassuring, said Dr. Morris Schambelan, a panelist and professor emeritus of medicine in the division of endocrinology at the University of California, San Francisco, but like others on the committee, added that he believes the heart failure signal was real and that providing clinicians with information in the drug’s label to help predict those at higher risk in would be helpful.

Several panelists were somewhat concerned about the all-cause mortality finding, which is a strong endpoint, and therefore cannot be ruled out, they said. But they also pointed out that follow-up was relatively short for a drug that is used long term and that the results should be applied cautiously to patients at lower risk than were those enrolled in the trial.

The FDA usually follows the recommendations of its advisory panel members. Panelists had no relevant disclosures.

CV outcomes trials for other approved DPP4 inhibitors approved for type 2 diabetes – sitagliptin (Januvia) and linagliptin (Tradjenta) – are ongoing. The panel review of the CV outcomes trial for another DPP4 inhibitor approved, alogliptin (Nesina), followed the meeting on saxagliptin.

emechcatie@frontlinemedcom.com

SAN DIEGO – A series of reports in 2014 from several independent groups implicated heart failure as a trigger of type 2 diabetes; findings from several of the analyses also suggested that relief of congestion can result in rapid resolution of the diabetes.

The best way to manage new-onset diabetes in heart failure patients is to “minimize the congestion,” and to “try to achieve as good control of the heart failure as possible,” said Dr. Maya Guglin during a talk at the annual meeting of the American College of Cardiology, in which she laid out the evidence for this newly recognized form of type 2 diabetes. In a review she published in 2014, Dr. Guglin coined the term “cardiogenic diabetes” to describe the condition (Heart Fail. Rev. 2014;19:595-602).

Dr. Guglin traced the data trail for cardiogenic diabetes starting in a 2011 retrospective study of 15 patients with advanced heart failure who received a left ventricular assist device (LVAD) at Columbia University in New York (Eur. J. Heart Fail. 2011;13:195-9). These 15, about a third of the 43 total LVAD recipients at Columbia at the time, had been diagnosed with type 2 diabetes for an average of 6 years before receiving the device. Just before they got their device, their average hemoglobin A_1c (HbA_1c) level was 7.7%, and their average fasting plasma glucose level was 158 mg/dL. An average of 4 months later, their mean HbA_1c had dropped to 6%, and their mean fasting glucose had fallen to 104 mg/dL. Six patients were completely off any diabetes medication. All this occurred while patients had a small increase in their body mass index, which Dr. Guglin attributed to their better physical condition and improved appetite.

Last year, another four reports appeared from four independent, U.S. heart failure groups with results that mirrored the Columbia experience. Dr. Guglin and her associates at the University of Kentucky, Lexington, reported their experience with 50 patients who received an LVAD during 2002-2012 and had type 2 diabetes just before they received a device, with an average HbA_1c of 7.6%. Three months after LVAD placement, their average HbA_1c had dropped to 5.7%, and 9-12 months after device placement, their average HbA_1c level was 5.3% (ASAIO J. 2014;60:290-3). As in the Columbia series, these improvements in hyperglycemia occurred without any significant change in body mass index.

Dr. Guglin also cited similar findings in 50 LVAD patients treated at the University of Rochester (N.Y.)(ASAIO J. 2014;60:675-80), 28 LVAD patients at Penn State Medical College in Hershey, Pa. (Heart Surg. Forum 2014;17:E98-102), and 66 LVAD patients from the University of Illinois in Chicago (Eur. J. Heart Fail. 2014;16:1120-4). In these reports type 2 diabetes existed in roughly a quarter to a third of patients with advanced heart failure who qualified for an LVAD just prior to the time they received the device.

Dr. Guglin also cited two epidemiologic analyses with complementary findings on the risk for incident diabetes faced by heart failure patients. She and her associates reviewed data from 3,165 elderly Americans free from diabetes enrolled in the Cardiovascular Health Study. This cohort included 80 patients with heart failure and 3,085 without heart failure. During 3-4 years of follow-up, 6% of the heart failure patients developed new-onset diabetes, and an additional 10% developed new-onset impaired fasting glucose. In contrast, these incidence rates were 1.5% and 5%, respectively, in the enrollees without heart failure at baseline. In an analysis that controlled for several demographic and biomedical factors, heart failure linked with a statistically significant, 2.4-fold increased risk for the development of diabetes (Cardiology 2014;129:84-92).

And a Danish nationwide cohort study of more than 99,000 residents discharged from a first-time hospitalization for heart failure during 1997-2010 showed a statistically significant link between heart failure severity and an increased rate of development of incident diabetes using diuretic treatment dosage as a surrogate measure of heart failure severity (Diabetologia 2014;57:1595-1600).

The apparent impact of LVAD placement on type 2 diabetes contrasts with what happens in patients who receive a heart transplant, where this association has not been seen. Dr. Guglin suggested that may be because of the immunosuppression with steroids that heart transplant recipients receive, treatment that also prevents diabetes resolution, she said.

“It all boils down to congestion,” Dr. Guglin said in an interview. “Control congestion as much as possible to control the diabetes.”

Dr. Guglin had no relevant financial disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

SAN DIEGO – A series of reports in 2014 from several independent groups implicated heart failure as a trigger of type 2 diabetes; findings from several of the analyses also suggested that relief of congestion can result in rapid resolution of the diabetes.

The best way to manage new-onset diabetes in heart failure patients is to “minimize the congestion,” and to “try to achieve as good control of the heart failure as possible,” said Dr. Maya Guglin during a talk at the annual meeting of the American College of Cardiology, in which she laid out the evidence for this newly recognized form of type 2 diabetes. In a review she published in 2014, Dr. Guglin coined the term “cardiogenic diabetes” to describe the condition (Heart Fail. Rev. 2014;19:595-602).

Dr. Guglin traced the data trail for cardiogenic diabetes starting in a 2011 retrospective study of 15 patients with advanced heart failure who received a left ventricular assist device (LVAD) at Columbia University in New York (Eur. J. Heart Fail. 2011;13:195-9). These 15, about a third of the 43 total LVAD recipients at Columbia at the time, had been diagnosed with type 2 diabetes for an average of 6 years before receiving the device. Just before they got their device, their average hemoglobin A_1c (HbA_1c) level was 7.7%, and their average fasting plasma glucose level was 158 mg/dL. An average of 4 months later, their mean HbA_1c had dropped to 6%, and their mean fasting glucose had fallen to 104 mg/dL. Six patients were completely off any diabetes medication. All this occurred while patients had a small increase in their body mass index, which Dr. Guglin attributed to their better physical condition and improved appetite.

Last year, another four reports appeared from four independent, U.S. heart failure groups with results that mirrored the Columbia experience. Dr. Guglin and her associates at the University of Kentucky, Lexington, reported their experience with 50 patients who received an LVAD during 2002-2012 and had type 2 diabetes just before they received a device, with an average HbA_1c of 7.6%. Three months after LVAD placement, their average HbA_1c had dropped to 5.7%, and 9-12 months after device placement, their average HbA_1c level was 5.3% (ASAIO J. 2014;60:290-3). As in the Columbia series, these improvements in hyperglycemia occurred without any significant change in body mass index.

Dr. Guglin also cited similar findings in 50 LVAD patients treated at the University of Rochester (N.Y.)(ASAIO J. 2014;60:675-80), 28 LVAD patients at Penn State Medical College in Hershey, Pa. (Heart Surg. Forum 2014;17:E98-102), and 66 LVAD patients from the University of Illinois in Chicago (Eur. J. Heart Fail. 2014;16:1120-4). In these reports type 2 diabetes existed in roughly a quarter to a third of patients with advanced heart failure who qualified for an LVAD just prior to the time they received the device.

Dr. Guglin also cited two epidemiologic analyses with complementary findings on the risk for incident diabetes faced by heart failure patients. She and her associates reviewed data from 3,165 elderly Americans free from diabetes enrolled in the Cardiovascular Health Study. This cohort included 80 patients with heart failure and 3,085 without heart failure. During 3-4 years of follow-up, 6% of the heart failure patients developed new-onset diabetes, and an additional 10% developed new-onset impaired fasting glucose. In contrast, these incidence rates were 1.5% and 5%, respectively, in the enrollees without heart failure at baseline. In an analysis that controlled for several demographic and biomedical factors, heart failure linked with a statistically significant, 2.4-fold increased risk for the development of diabetes (Cardiology 2014;129:84-92).

And a Danish nationwide cohort study of more than 99,000 residents discharged from a first-time hospitalization for heart failure during 1997-2010 showed a statistically significant link between heart failure severity and an increased rate of development of incident diabetes using diuretic treatment dosage as a surrogate measure of heart failure severity (Diabetologia 2014;57:1595-1600).

The apparent impact of LVAD placement on type 2 diabetes contrasts with what happens in patients who receive a heart transplant, where this association has not been seen. Dr. Guglin suggested that may be because of the immunosuppression with steroids that heart transplant recipients receive, treatment that also prevents diabetes resolution, she said.

“It all boils down to congestion,” Dr. Guglin said in an interview. “Control congestion as much as possible to control the diabetes.”

Dr. Guglin had no relevant financial disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

SAN DIEGO – A series of reports in 2014 from several independent groups implicated heart failure as a trigger of type 2 diabetes; findings from several of the analyses also suggested that relief of congestion can result in rapid resolution of the diabetes.

The best way to manage new-onset diabetes in heart failure patients is to “minimize the congestion,” and to “try to achieve as good control of the heart failure as possible,” said Dr. Maya Guglin during a talk at the annual meeting of the American College of Cardiology, in which she laid out the evidence for this newly recognized form of type 2 diabetes. In a review she published in 2014, Dr. Guglin coined the term “cardiogenic diabetes” to describe the condition (Heart Fail. Rev. 2014;19:595-602).

Dr. Guglin traced the data trail for cardiogenic diabetes starting in a 2011 retrospective study of 15 patients with advanced heart failure who received a left ventricular assist device (LVAD) at Columbia University in New York (Eur. J. Heart Fail. 2011;13:195-9). These 15, about a third of the 43 total LVAD recipients at Columbia at the time, had been diagnosed with type 2 diabetes for an average of 6 years before receiving the device. Just before they got their device, their average hemoglobin A_1c (HbA_1c) level was 7.7%, and their average fasting plasma glucose level was 158 mg/dL. An average of 4 months later, their mean HbA_1c had dropped to 6%, and their mean fasting glucose had fallen to 104 mg/dL. Six patients were completely off any diabetes medication. All this occurred while patients had a small increase in their body mass index, which Dr. Guglin attributed to their better physical condition and improved appetite.

Last year, another four reports appeared from four independent, U.S. heart failure groups with results that mirrored the Columbia experience. Dr. Guglin and her associates at the University of Kentucky, Lexington, reported their experience with 50 patients who received an LVAD during 2002-2012 and had type 2 diabetes just before they received a device, with an average HbA_1c of 7.6%. Three months after LVAD placement, their average HbA_1c had dropped to 5.7%, and 9-12 months after device placement, their average HbA_1c level was 5.3% (ASAIO J. 2014;60:290-3). As in the Columbia series, these improvements in hyperglycemia occurred without any significant change in body mass index.

Dr. Guglin also cited similar findings in 50 LVAD patients treated at the University of Rochester (N.Y.)(ASAIO J. 2014;60:675-80), 28 LVAD patients at Penn State Medical College in Hershey, Pa. (Heart Surg. Forum 2014;17:E98-102), and 66 LVAD patients from the University of Illinois in Chicago (Eur. J. Heart Fail. 2014;16:1120-4). In these reports type 2 diabetes existed in roughly a quarter to a third of patients with advanced heart failure who qualified for an LVAD just prior to the time they received the device.

Dr. Guglin also cited two epidemiologic analyses with complementary findings on the risk for incident diabetes faced by heart failure patients. She and her associates reviewed data from 3,165 elderly Americans free from diabetes enrolled in the Cardiovascular Health Study. This cohort included 80 patients with heart failure and 3,085 without heart failure. During 3-4 years of follow-up, 6% of the heart failure patients developed new-onset diabetes, and an additional 10% developed new-onset impaired fasting glucose. In contrast, these incidence rates were 1.5% and 5%, respectively, in the enrollees without heart failure at baseline. In an analysis that controlled for several demographic and biomedical factors, heart failure linked with a statistically significant, 2.4-fold increased risk for the development of diabetes (Cardiology 2014;129:84-92).

And a Danish nationwide cohort study of more than 99,000 residents discharged from a first-time hospitalization for heart failure during 1997-2010 showed a statistically significant link between heart failure severity and an increased rate of development of incident diabetes using diuretic treatment dosage as a surrogate measure of heart failure severity (Diabetologia 2014;57:1595-1600).

The apparent impact of LVAD placement on type 2 diabetes contrasts with what happens in patients who receive a heart transplant, where this association has not been seen. Dr. Guglin suggested that may be because of the immunosuppression with steroids that heart transplant recipients receive, treatment that also prevents diabetes resolution, she said.

“It all boils down to congestion,” Dr. Guglin said in an interview. “Control congestion as much as possible to control the diabetes.”

Dr. Guglin had no relevant financial disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

SAN DIEGO – Beefing up a sick left ventricle via a set of injections of an inert alginate hydrogel resulted in significantly improved functional capacity, compared with optimal medical therapy through 6 months of follow-up in patients with advanced heart failure in the randomized AUGMENT-HF trial.

Investigators also noted “an interesting and striking reduction” in hospitalizations for worsening heart failure in the group that received left ventricular (LV) augmentation with the material, known as Algisyl-LVR, Dr. Stefan D. Anker reported at the annual meeting of the American College of Cardiology.

Bruce Jancin/Frontline Medical News

Indeed, among 78 patients with advanced heart failure randomized to hydrogel injections plus optimal medical therapy or to optimal medical therapy alone, there were 14 hospitalizations for worsening heart failure in eight controls, compared with 5 hospitalizations in four patients in the LV augmentation group. The between-group difference is large, but the number of hospitalizations is still small. AUGMENT-HF will continue for 2 years of follow-up.

“This gives us hope for the future,” said Dr. Anker, professor of cardiology and cachexia research at Charité Medical School, Berlin.

In addition, based upon the favorable 6-month study results, planning is underway for a larger, pivotal phase III U.S. trial of Algisyl-LVR, classified as a medical device, to start later this year.

At present, surgeons implant the hydrogel through a minithoracotomy. The procedure involves 10-20 injections totaling 4-5 mL of the inert, permanent material, which is placed as a ring of beads along a circumferential line at the left ventricular midwall.

“We make the wall thicker and the cavity of the ventricle a little smaller, thereby reducing wall stress. We basically try to change the physics of the pump action of the heart to improve patient status and perhaps patient outcome,” Dr. Anker explained.

Surgeons say it’s an easily learned procedure. The surgical morbidity and mortality seen in AUGMENT-HF were deemed acceptable by investigators and the study sponsor, so this new therapy will initially be developed as a surgical procedure. But it’s certainly a treatment that lends itself to delivery by percutaneous catheter in the future, according to the cardiologist.

Study participants had moderate to severe heart failure, with an average LV ejection fraction of 25%. Most were New York Heart Association (NYHA) functional class III.

The primary study endpoint was change in peak oxygen uptake (VO₂) at 6 months from a baseline of 12.2 mL/kg/min. The value improved to 13.5 mL/kg/min in the LV augmentation group, compared with 12.4 mL/kg/min in controls, a between-group difference that Dr. Anker characterized as clinically relevant. He noted that one of the study’s strengths was that each peak VO₂ result was the average of two tests performed on the same occasion, a method that markedly improves test reproducibility.

Also, 6-minute walk distance improved in the LV augmentation group by a mean of 84.7 meters from a baseline 280 meters, while decreasing by 15.4 meters in controls.

“This is quite a positive result rarely seen with other therapies. For everybody involved, this was a very positive finding,” Dr. Anker said.

Among controls, NYHC class stayed steady over the course of 6 months while showing a 0.9-class improvement in the LV augmentation group.

Heart failure etiology – ischemic versus nonischemic – had no bearing on LV augmentation’s effectiveness. Baseline 6-minute walk distance did, though. Patients with a baseline walk distance of less than 287 meters experienced a much larger treatment effect: a mean 2.42 mL/kg/min greater improvement from baseline to 6 months with LV augmentation than in controls, as compared with a nonsignificant 0.4 mL/kg/min advantage among patients who covered more than 287 meters at baseline.

The mean procedure time was 80 minutes, with 190 minutes of anesthesia time. Patients spent an average of 2 days in the ICU.

Three deaths occurred in the surgical group within the first 30 days. Excluding the index hospitalization, there were 22 major adverse cardiovascular events in the control group and 9 in the LV augmentation group. Among these were three cardiovascular deaths in each study arm, for a total of six deaths through 6 months in the LV augmentation patients. However, with additional study follow-up beyond the 6 months presented at ACC 15, mortality has evened out in the two groups, according to Dr. Anker. Sustained ventricular tachycardia occurred in four controls and one patient who received LV augmentation. Several audience members expressed surprise at the low arrhythmia rate in the LV augmentation group, but Dr. Anker’s coinvestigator Dr. Douglas L. Mann explained that the implantation doesn’t create an isthmus, thus there is no nidus for arrhythmia formation.

“No arrhythmia signal has been seen. There is actually a reduction in both atrial and ventricular arrhythmias,” said Dr. Mann, professor of internal medicine and chief of the division of cardiovascular medicine at Washington University in St. Louis.

The AUGMENT-HF trial was sponsored by LoneStar Heart. Dr. Anker reported having no financial relationship with LoneStar, although he serves as a consultant to half a dozen other health care companies.

bjancin@frontlinemedcom.com

SAN DIEGO – Beefing up a sick left ventricle via a set of injections of an inert alginate hydrogel resulted in significantly improved functional capacity, compared with optimal medical therapy through 6 months of follow-up in patients with advanced heart failure in the randomized AUGMENT-HF trial.

Investigators also noted “an interesting and striking reduction” in hospitalizations for worsening heart failure in the group that received left ventricular (LV) augmentation with the material, known as Algisyl-LVR, Dr. Stefan D. Anker reported at the annual meeting of the American College of Cardiology.

Bruce Jancin/Frontline Medical News

Indeed, among 78 patients with advanced heart failure randomized to hydrogel injections plus optimal medical therapy or to optimal medical therapy alone, there were 14 hospitalizations for worsening heart failure in eight controls, compared with 5 hospitalizations in four patients in the LV augmentation group. The between-group difference is large, but the number of hospitalizations is still small. AUGMENT-HF will continue for 2 years of follow-up.

“This gives us hope for the future,” said Dr. Anker, professor of cardiology and cachexia research at Charité Medical School, Berlin.

In addition, based upon the favorable 6-month study results, planning is underway for a larger, pivotal phase III U.S. trial of Algisyl-LVR, classified as a medical device, to start later this year.

At present, surgeons implant the hydrogel through a minithoracotomy. The procedure involves 10-20 injections totaling 4-5 mL of the inert, permanent material, which is placed as a ring of beads along a circumferential line at the left ventricular midwall.

“We make the wall thicker and the cavity of the ventricle a little smaller, thereby reducing wall stress. We basically try to change the physics of the pump action of the heart to improve patient status and perhaps patient outcome,” Dr. Anker explained.

Surgeons say it’s an easily learned procedure. The surgical morbidity and mortality seen in AUGMENT-HF were deemed acceptable by investigators and the study sponsor, so this new therapy will initially be developed as a surgical procedure. But it’s certainly a treatment that lends itself to delivery by percutaneous catheter in the future, according to the cardiologist.

Study participants had moderate to severe heart failure, with an average LV ejection fraction of 25%. Most were New York Heart Association (NYHA) functional class III.

The primary study endpoint was change in peak oxygen uptake (VO₂) at 6 months from a baseline of 12.2 mL/kg/min. The value improved to 13.5 mL/kg/min in the LV augmentation group, compared with 12.4 mL/kg/min in controls, a between-group difference that Dr. Anker characterized as clinically relevant. He noted that one of the study’s strengths was that each peak VO₂ result was the average of two tests performed on the same occasion, a method that markedly improves test reproducibility.

Also, 6-minute walk distance improved in the LV augmentation group by a mean of 84.7 meters from a baseline 280 meters, while decreasing by 15.4 meters in controls.

“This is quite a positive result rarely seen with other therapies. For everybody involved, this was a very positive finding,” Dr. Anker said.

Among controls, NYHC class stayed steady over the course of 6 months while showing a 0.9-class improvement in the LV augmentation group.

Heart failure etiology – ischemic versus nonischemic – had no bearing on LV augmentation’s effectiveness. Baseline 6-minute walk distance did, though. Patients with a baseline walk distance of less than 287 meters experienced a much larger treatment effect: a mean 2.42 mL/kg/min greater improvement from baseline to 6 months with LV augmentation than in controls, as compared with a nonsignificant 0.4 mL/kg/min advantage among patients who covered more than 287 meters at baseline.

The mean procedure time was 80 minutes, with 190 minutes of anesthesia time. Patients spent an average of 2 days in the ICU.

Three deaths occurred in the surgical group within the first 30 days. Excluding the index hospitalization, there were 22 major adverse cardiovascular events in the control group and 9 in the LV augmentation group. Among these were three cardiovascular deaths in each study arm, for a total of six deaths through 6 months in the LV augmentation patients. However, with additional study follow-up beyond the 6 months presented at ACC 15, mortality has evened out in the two groups, according to Dr. Anker. Sustained ventricular tachycardia occurred in four controls and one patient who received LV augmentation. Several audience members expressed surprise at the low arrhythmia rate in the LV augmentation group, but Dr. Anker’s coinvestigator Dr. Douglas L. Mann explained that the implantation doesn’t create an isthmus, thus there is no nidus for arrhythmia formation.

“No arrhythmia signal has been seen. There is actually a reduction in both atrial and ventricular arrhythmias,” said Dr. Mann, professor of internal medicine and chief of the division of cardiovascular medicine at Washington University in St. Louis.

The AUGMENT-HF trial was sponsored by LoneStar Heart. Dr. Anker reported having no financial relationship with LoneStar, although he serves as a consultant to half a dozen other health care companies.

bjancin@frontlinemedcom.com

SAN DIEGO – Beefing up a sick left ventricle via a set of injections of an inert alginate hydrogel resulted in significantly improved functional capacity, compared with optimal medical therapy through 6 months of follow-up in patients with advanced heart failure in the randomized AUGMENT-HF trial.

Investigators also noted “an interesting and striking reduction” in hospitalizations for worsening heart failure in the group that received left ventricular (LV) augmentation with the material, known as Algisyl-LVR, Dr. Stefan D. Anker reported at the annual meeting of the American College of Cardiology.

Bruce Jancin/Frontline Medical News

Indeed, among 78 patients with advanced heart failure randomized to hydrogel injections plus optimal medical therapy or to optimal medical therapy alone, there were 14 hospitalizations for worsening heart failure in eight controls, compared with 5 hospitalizations in four patients in the LV augmentation group. The between-group difference is large, but the number of hospitalizations is still small. AUGMENT-HF will continue for 2 years of follow-up.

“This gives us hope for the future,” said Dr. Anker, professor of cardiology and cachexia research at Charité Medical School, Berlin.

In addition, based upon the favorable 6-month study results, planning is underway for a larger, pivotal phase III U.S. trial of Algisyl-LVR, classified as a medical device, to start later this year.

At present, surgeons implant the hydrogel through a minithoracotomy. The procedure involves 10-20 injections totaling 4-5 mL of the inert, permanent material, which is placed as a ring of beads along a circumferential line at the left ventricular midwall.

“We make the wall thicker and the cavity of the ventricle a little smaller, thereby reducing wall stress. We basically try to change the physics of the pump action of the heart to improve patient status and perhaps patient outcome,” Dr. Anker explained.

Surgeons say it’s an easily learned procedure. The surgical morbidity and mortality seen in AUGMENT-HF were deemed acceptable by investigators and the study sponsor, so this new therapy will initially be developed as a surgical procedure. But it’s certainly a treatment that lends itself to delivery by percutaneous catheter in the future, according to the cardiologist.

Study participants had moderate to severe heart failure, with an average LV ejection fraction of 25%. Most were New York Heart Association (NYHA) functional class III.

The primary study endpoint was change in peak oxygen uptake (VO₂) at 6 months from a baseline of 12.2 mL/kg/min. The value improved to 13.5 mL/kg/min in the LV augmentation group, compared with 12.4 mL/kg/min in controls, a between-group difference that Dr. Anker characterized as clinically relevant. He noted that one of the study’s strengths was that each peak VO₂ result was the average of two tests performed on the same occasion, a method that markedly improves test reproducibility.

Also, 6-minute walk distance improved in the LV augmentation group by a mean of 84.7 meters from a baseline 280 meters, while decreasing by 15.4 meters in controls.

“This is quite a positive result rarely seen with other therapies. For everybody involved, this was a very positive finding,” Dr. Anker said.

Among controls, NYHC class stayed steady over the course of 6 months while showing a 0.9-class improvement in the LV augmentation group.

Heart failure etiology – ischemic versus nonischemic – had no bearing on LV augmentation’s effectiveness. Baseline 6-minute walk distance did, though. Patients with a baseline walk distance of less than 287 meters experienced a much larger treatment effect: a mean 2.42 mL/kg/min greater improvement from baseline to 6 months with LV augmentation than in controls, as compared with a nonsignificant 0.4 mL/kg/min advantage among patients who covered more than 287 meters at baseline.

The mean procedure time was 80 minutes, with 190 minutes of anesthesia time. Patients spent an average of 2 days in the ICU.

Three deaths occurred in the surgical group within the first 30 days. Excluding the index hospitalization, there were 22 major adverse cardiovascular events in the control group and 9 in the LV augmentation group. Among these were three cardiovascular deaths in each study arm, for a total of six deaths through 6 months in the LV augmentation patients. However, with additional study follow-up beyond the 6 months presented at ACC 15, mortality has evened out in the two groups, according to Dr. Anker. Sustained ventricular tachycardia occurred in four controls and one patient who received LV augmentation. Several audience members expressed surprise at the low arrhythmia rate in the LV augmentation group, but Dr. Anker’s coinvestigator Dr. Douglas L. Mann explained that the implantation doesn’t create an isthmus, thus there is no nidus for arrhythmia formation.

“No arrhythmia signal has been seen. There is actually a reduction in both atrial and ventricular arrhythmias,” said Dr. Mann, professor of internal medicine and chief of the division of cardiovascular medicine at Washington University in St. Louis.

The AUGMENT-HF trial was sponsored by LoneStar Heart. Dr. Anker reported having no financial relationship with LoneStar, although he serves as a consultant to half a dozen other health care companies.

bjancin@frontlinemedcom.com

SAN DIEGO – Patients with major depressive disorder and heart failure with reduced ejection fraction fared no better with a selective serotonin reuptake inhibitor than with placebo in terms of heart failure outcomes or improved psychological well being in MOOD-HF, the first large randomized trial to examine the issue.

“MOOD-HF does not provide a rationale for the use of escitalopram in patients with systolic heart failure and comorbid depression. MOOD-HF suggests, however, that optimal heart failure management resulting in improved signs and symptoms might possibly be a means to ameliorate comorbid depression,” Dr. Christiane E. Angermann said at the annual meeting of the American College of Cardiology.

Moreover, exploratory secondary analysis suggested “a very subtle long-term effect of the antidepressant that may not be so favorable” in patients with more severe heart failure, she added.

“It seems that some of our patients take antidepressants in vain, and we should care more about the heart failure medications,” said Dr. Angermann, chairman of the MOOD-HF trial and director of clinical research at the Comprehensive Heart Failure Center at the University of Wurzburg (Germany).

MOOD-HF was an ambitious clinical trial conducted at 16 German academic medical centers. The study began with the screening – via the Patient Health Questionnaire–9 – of more than 11,000 patients who had heart failure with reduced ejection fraction. A psychiatrist using the Structured Clinical Interview for Depression eventually diagnosed a subgroup as having major depressive disorder. Ultimately, 372 patients with an average left ventricular ejection fraction of 35% were randomized in double-blind fashion to escitalopram (Lexapro) or placebo for a planned 24 months.

The study rationale stemmed from the well-established finding that depression is three to five times more common in heart failure patients than in the general population, and that the severity of depression in these patients shows a dose-response relationship with their risks of all-cause mortality and heart failure hospitalization. The primary study hypothesis in MOOD-HF was that treating the comorbid depression would result in a reduced risk of all-cause mortality and unplanned hospitalization for any cause.

“Never before had an ethics committee been persuaded to allow patients with major depressive disorder to be on a placebo for 2 years,” said Dr. Angermann. “It took a lot of discussion with the psychiatrists, addressing whether these were depressed patients with comorbid heart failure or patients with heart failure and comorbid depression. We ended up agreeing that since these patients mostly die from heart failure, therefore this is the main disease. And since there was no evidence from other cardiovascular studies that antidepressants were of use, we were allowed to do the study,” she explained.

The trial was halted early for futility at the request of the data safety monitoring board after a median of 18 months. At that point, the primary composite endpoint of death or unplanned hospitalization had occurred in 116 patients in the escitalopram group and 119 on placebo.

A key secondary endpoint – improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) at 12 weeks – was also a virtual dead heat. From a baseline score of 21, both the escitalopram and placebo groups showed a clinically meaningful improvement of roughly 9 points. The improvement in MADRS scores in the control group piqued investigators’ interest because no psychotherapy or counseling was involved in the trial.

The target dose of escitalopram was 20 mg/day, with uptitration to that goal taking place over the first 12 weeks. The mean dose of the antidepressant at week 12 was 13.7 mg/day. During the course of the study, however, the target dose dropped to 10 mg/day in patients over age 65 in accordance with updated regulatory guidance regarding possible proarrhythmic QTc prolongation in older patients. As it turned out, QTc prolongation was not an issue in MOOD-HF. Indeed, there was no difference between the two groups in terms of any serious adverse events. Adherence to the study medication was good, Dr. Angermann continued.

While the dose of escitalopram was being uptitrated during the first 12 weeks, so was guideline-directed medical therapy for heart failure in both study arms. The patients improved from being at 56% of the recommended dose of ACE inhibitor/angiotensin receptor blocker therapy at baseline to 64%, and from 58% of the target dose of beta-blocker therapy to 63%. That, rather than the antidepressant, appeared to be responsible for the improvement in heart failure, she said.

Both study arms showed similar improvements over time in New York Heart Association functional class and left ventricular ejection fraction. But levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) – an important biomarker of heart failure severity – improved only in the placebo-treated controls. The same held true for reduction in left ventricular end diastolic diameter.

“This suggests a somewhat attenuated improvement in heart failure in the escitalopram group,” the cardiologist observed.

The investigators conducted a post hoc analysis to generate a hypothesis-generating risk score for the primary outcome. One point each was given for age greater than 62.6 years, a baseline NT-proBNP level in excess of 807 ng/L, a heart rate greater than 68 bpm, being New York Heart Association class III/IV, and having a left ventricular end diastolic diameter in excess of 59 mm. These were thresholds that identified patients in the top half of the study population for each of these variables.

In patients with a risk score of 0-2, escitalopram was associated with a highly significant 33% reduction in the risk of death or unplanned hospitalization compared with placebo. However, in patients with a score of 3-5, the escitalopram group had a 52% greater risk of the primary endpoint than controls.

“This suggests a heterogeneous pathophysiology and an impact of individual disease profiles on the effects of the study medication,” Dr. Angermann said.

MOOD-HF was funded chiefly by the German Ministry of Education and Research and the University of Wurzburg. Lundbeck provided the escitalopram gratis. Dr. Angermann reported serving as a consultant to ResMed, Novartis, and Vifor and receiving research grants from Lundbeck, Alere, and Boehringer Ingelheim.

bjancin@frontlinemedcom.com

SAN DIEGO – Patients with major depressive disorder and heart failure with reduced ejection fraction fared no better with a selective serotonin reuptake inhibitor than with placebo in terms of heart failure outcomes or improved psychological well being in MOOD-HF, the first large randomized trial to examine the issue.

“MOOD-HF does not provide a rationale for the use of escitalopram in patients with systolic heart failure and comorbid depression. MOOD-HF suggests, however, that optimal heart failure management resulting in improved signs and symptoms might possibly be a means to ameliorate comorbid depression,” Dr. Christiane E. Angermann said at the annual meeting of the American College of Cardiology.

Moreover, exploratory secondary analysis suggested “a very subtle long-term effect of the antidepressant that may not be so favorable” in patients with more severe heart failure, she added.

“It seems that some of our patients take antidepressants in vain, and we should care more about the heart failure medications,” said Dr. Angermann, chairman of the MOOD-HF trial and director of clinical research at the Comprehensive Heart Failure Center at the University of Wurzburg (Germany).

MOOD-HF was an ambitious clinical trial conducted at 16 German academic medical centers. The study began with the screening – via the Patient Health Questionnaire–9 – of more than 11,000 patients who had heart failure with reduced ejection fraction. A psychiatrist using the Structured Clinical Interview for Depression eventually diagnosed a subgroup as having major depressive disorder. Ultimately, 372 patients with an average left ventricular ejection fraction of 35% were randomized in double-blind fashion to escitalopram (Lexapro) or placebo for a planned 24 months.

The study rationale stemmed from the well-established finding that depression is three to five times more common in heart failure patients than in the general population, and that the severity of depression in these patients shows a dose-response relationship with their risks of all-cause mortality and heart failure hospitalization. The primary study hypothesis in MOOD-HF was that treating the comorbid depression would result in a reduced risk of all-cause mortality and unplanned hospitalization for any cause.

“Never before had an ethics committee been persuaded to allow patients with major depressive disorder to be on a placebo for 2 years,” said Dr. Angermann. “It took a lot of discussion with the psychiatrists, addressing whether these were depressed patients with comorbid heart failure or patients with heart failure and comorbid depression. We ended up agreeing that since these patients mostly die from heart failure, therefore this is the main disease. And since there was no evidence from other cardiovascular studies that antidepressants were of use, we were allowed to do the study,” she explained.

The trial was halted early for futility at the request of the data safety monitoring board after a median of 18 months. At that point, the primary composite endpoint of death or unplanned hospitalization had occurred in 116 patients in the escitalopram group and 119 on placebo.

A key secondary endpoint – improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) at 12 weeks – was also a virtual dead heat. From a baseline score of 21, both the escitalopram and placebo groups showed a clinically meaningful improvement of roughly 9 points. The improvement in MADRS scores in the control group piqued investigators’ interest because no psychotherapy or counseling was involved in the trial.

The target dose of escitalopram was 20 mg/day, with uptitration to that goal taking place over the first 12 weeks. The mean dose of the antidepressant at week 12 was 13.7 mg/day. During the course of the study, however, the target dose dropped to 10 mg/day in patients over age 65 in accordance with updated regulatory guidance regarding possible proarrhythmic QTc prolongation in older patients. As it turned out, QTc prolongation was not an issue in MOOD-HF. Indeed, there was no difference between the two groups in terms of any serious adverse events. Adherence to the study medication was good, Dr. Angermann continued.

While the dose of escitalopram was being uptitrated during the first 12 weeks, so was guideline-directed medical therapy for heart failure in both study arms. The patients improved from being at 56% of the recommended dose of ACE inhibitor/angiotensin receptor blocker therapy at baseline to 64%, and from 58% of the target dose of beta-blocker therapy to 63%. That, rather than the antidepressant, appeared to be responsible for the improvement in heart failure, she said.

Both study arms showed similar improvements over time in New York Heart Association functional class and left ventricular ejection fraction. But levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) – an important biomarker of heart failure severity – improved only in the placebo-treated controls. The same held true for reduction in left ventricular end diastolic diameter.

“This suggests a somewhat attenuated improvement in heart failure in the escitalopram group,” the cardiologist observed.

The investigators conducted a post hoc analysis to generate a hypothesis-generating risk score for the primary outcome. One point each was given for age greater than 62.6 years, a baseline NT-proBNP level in excess of 807 ng/L, a heart rate greater than 68 bpm, being New York Heart Association class III/IV, and having a left ventricular end diastolic diameter in excess of 59 mm. These were thresholds that identified patients in the top half of the study population for each of these variables.

In patients with a risk score of 0-2, escitalopram was associated with a highly significant 33% reduction in the risk of death or unplanned hospitalization compared with placebo. However, in patients with a score of 3-5, the escitalopram group had a 52% greater risk of the primary endpoint than controls.

“This suggests a heterogeneous pathophysiology and an impact of individual disease profiles on the effects of the study medication,” Dr. Angermann said.

MOOD-HF was funded chiefly by the German Ministry of Education and Research and the University of Wurzburg. Lundbeck provided the escitalopram gratis. Dr. Angermann reported serving as a consultant to ResMed, Novartis, and Vifor and receiving research grants from Lundbeck, Alere, and Boehringer Ingelheim.

bjancin@frontlinemedcom.com

SAN DIEGO – Patients with major depressive disorder and heart failure with reduced ejection fraction fared no better with a selective serotonin reuptake inhibitor than with placebo in terms of heart failure outcomes or improved psychological well being in MOOD-HF, the first large randomized trial to examine the issue.

“MOOD-HF does not provide a rationale for the use of escitalopram in patients with systolic heart failure and comorbid depression. MOOD-HF suggests, however, that optimal heart failure management resulting in improved signs and symptoms might possibly be a means to ameliorate comorbid depression,” Dr. Christiane E. Angermann said at the annual meeting of the American College of Cardiology.

Moreover, exploratory secondary analysis suggested “a very subtle long-term effect of the antidepressant that may not be so favorable” in patients with more severe heart failure, she added.

“It seems that some of our patients take antidepressants in vain, and we should care more about the heart failure medications,” said Dr. Angermann, chairman of the MOOD-HF trial and director of clinical research at the Comprehensive Heart Failure Center at the University of Wurzburg (Germany).

MOOD-HF was an ambitious clinical trial conducted at 16 German academic medical centers. The study began with the screening – via the Patient Health Questionnaire–9 – of more than 11,000 patients who had heart failure with reduced ejection fraction. A psychiatrist using the Structured Clinical Interview for Depression eventually diagnosed a subgroup as having major depressive disorder. Ultimately, 372 patients with an average left ventricular ejection fraction of 35% were randomized in double-blind fashion to escitalopram (Lexapro) or placebo for a planned 24 months.

The study rationale stemmed from the well-established finding that depression is three to five times more common in heart failure patients than in the general population, and that the severity of depression in these patients shows a dose-response relationship with their risks of all-cause mortality and heart failure hospitalization. The primary study hypothesis in MOOD-HF was that treating the comorbid depression would result in a reduced risk of all-cause mortality and unplanned hospitalization for any cause.

“Never before had an ethics committee been persuaded to allow patients with major depressive disorder to be on a placebo for 2 years,” said Dr. Angermann. “It took a lot of discussion with the psychiatrists, addressing whether these were depressed patients with comorbid heart failure or patients with heart failure and comorbid depression. We ended up agreeing that since these patients mostly die from heart failure, therefore this is the main disease. And since there was no evidence from other cardiovascular studies that antidepressants were of use, we were allowed to do the study,” she explained.

The trial was halted early for futility at the request of the data safety monitoring board after a median of 18 months. At that point, the primary composite endpoint of death or unplanned hospitalization had occurred in 116 patients in the escitalopram group and 119 on placebo.

A key secondary endpoint – improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) at 12 weeks – was also a virtual dead heat. From a baseline score of 21, both the escitalopram and placebo groups showed a clinically meaningful improvement of roughly 9 points. The improvement in MADRS scores in the control group piqued investigators’ interest because no psychotherapy or counseling was involved in the trial.

The target dose of escitalopram was 20 mg/day, with uptitration to that goal taking place over the first 12 weeks. The mean dose of the antidepressant at week 12 was 13.7 mg/day. During the course of the study, however, the target dose dropped to 10 mg/day in patients over age 65 in accordance with updated regulatory guidance regarding possible proarrhythmic QTc prolongation in older patients. As it turned out, QTc prolongation was not an issue in MOOD-HF. Indeed, there was no difference between the two groups in terms of any serious adverse events. Adherence to the study medication was good, Dr. Angermann continued.

While the dose of escitalopram was being uptitrated during the first 12 weeks, so was guideline-directed medical therapy for heart failure in both study arms. The patients improved from being at 56% of the recommended dose of ACE inhibitor/angiotensin receptor blocker therapy at baseline to 64%, and from 58% of the target dose of beta-blocker therapy to 63%. That, rather than the antidepressant, appeared to be responsible for the improvement in heart failure, she said.

Both study arms showed similar improvements over time in New York Heart Association functional class and left ventricular ejection fraction. But levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) – an important biomarker of heart failure severity – improved only in the placebo-treated controls. The same held true for reduction in left ventricular end diastolic diameter.

“This suggests a somewhat attenuated improvement in heart failure in the escitalopram group,” the cardiologist observed.

The investigators conducted a post hoc analysis to generate a hypothesis-generating risk score for the primary outcome. One point each was given for age greater than 62.6 years, a baseline NT-proBNP level in excess of 807 ng/L, a heart rate greater than 68 bpm, being New York Heart Association class III/IV, and having a left ventricular end diastolic diameter in excess of 59 mm. These were thresholds that identified patients in the top half of the study population for each of these variables.

In patients with a risk score of 0-2, escitalopram was associated with a highly significant 33% reduction in the risk of death or unplanned hospitalization compared with placebo. However, in patients with a score of 3-5, the escitalopram group had a 52% greater risk of the primary endpoint than controls.

“This suggests a heterogeneous pathophysiology and an impact of individual disease profiles on the effects of the study medication,” Dr. Angermann said.

MOOD-HF was funded chiefly by the German Ministry of Education and Research and the University of Wurzburg. Lundbeck provided the escitalopram gratis. Dr. Angermann reported serving as a consultant to ResMed, Novartis, and Vifor and receiving research grants from Lundbeck, Alere, and Boehringer Ingelheim.

bjancin@frontlinemedcom.com

SAN DIEGO – Percutaneous pulmonary artery denervation for the treatment of pulmonary arterial hypertension safely resulted in significantly greater improvement in functional capacity and hemodynamics compared with medication, in a controlled before-and-after study.

A particularly noteworthy secondary finding in the study was that rehospitalizations during the first 6 months after pulmonary artery denervation (PADN) occurred just one-third as frequently as in the 6-month preprocedural period on standard medications, Dr. Shao-Liang Chen said at the annual meeting of the American College of Cardiology.

He and his coinvestigators, including Dr. Gregg W. Stone of Columbia University in New York, developed a percutaneous catheter-based method of destroying the pulmonary baroreceptor structure located at the bifurcation area of the middle pulmonary artery. Along the way, they redefined the understanding of the pathogenesis of pulmonary artery hypertension (PAH) by demonstrating that local sympathetic nerve activity plays a pivotal role in modulating the elevations of mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR), which are the disease hallmarks.

Dr. Chen and coinvestigators previously reported the first-in-man study of PADN, which demonstrated safety and short-term efficacy (J. Am. Coll. Cardiol. 2013;62:1092-100). At ACC 15, Dr. Chen presented the findings of the new PADN-2 study, which expands upon the first study by including more patients and longer and more comprehensive follow-up.

The study comprised 28 patients with PAH, including 11 with idiopathic PAH and 8 with pulmonary hypertension caused by left ventricular disease. All of them underwent medication washout followed by right heart catheterization and echocardiography for baseline off-drug hemodynamic measurements as well as a 6-minute walk distance test of their functional capacity. Then they went back on medications for 6 months, after which they underwent repeat testing. Then their medications were discontinued and they underwent PADN. Six months after the procedure, still off medications, they were retested once again.

The primary study endpoint was change in 6-minute walk distance. After 6 months of medication it improved from 361 to 373 meters, a modest 3.9% gain over off-drug baseline. In contrast, 6-minute walk distance grew from 358 to 423 meters 6 months after PADN, a clinically important 23.9% improvement, reported Dr. Chen, a cardiologist at First Hospital of Nanjing (China) Medical University.

Multiple secondary hemodynamic endpoints also showed significantly greater improvement with PADN than medical therapy.

Twelve predefined clinical events – mostly involving worsening PAH – occurred during medical management, compared with three in the 6 months following PADN.

In addition, there were 12 hospitalizations during the 6 months on medical management compared with only 4 after the same patients underwent PADN. Health care costs averaged $35,000 per patient during the 6-month study period on medication compared with $6,000 per patient in the first 6 months after PADN.

There were no deaths, aneurysms, access site hematomas, or thrombotic events during either study period.

Further randomized, controlled trials are planned to explore the possibility that the benefits seen in the PADN-2 trial will result in reduced mortality in patients with PAH, according to Dr. Chen.

The PADN-2 trial was sponsored by Nanjing Medical University. Dr. Chen reported serving as a consultant to MicroPort.

bjancin@frontlinemedcom.com

SAN DIEGO – Percutaneous pulmonary artery denervation for the treatment of pulmonary arterial hypertension safely resulted in significantly greater improvement in functional capacity and hemodynamics compared with medication, in a controlled before-and-after study.

A particularly noteworthy secondary finding in the study was that rehospitalizations during the first 6 months after pulmonary artery denervation (PADN) occurred just one-third as frequently as in the 6-month preprocedural period on standard medications, Dr. Shao-Liang Chen said at the annual meeting of the American College of Cardiology.

He and his coinvestigators, including Dr. Gregg W. Stone of Columbia University in New York, developed a percutaneous catheter-based method of destroying the pulmonary baroreceptor structure located at the bifurcation area of the middle pulmonary artery. Along the way, they redefined the understanding of the pathogenesis of pulmonary artery hypertension (PAH) by demonstrating that local sympathetic nerve activity plays a pivotal role in modulating the elevations of mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR), which are the disease hallmarks.

Dr. Chen and coinvestigators previously reported the first-in-man study of PADN, which demonstrated safety and short-term efficacy (J. Am. Coll. Cardiol. 2013;62:1092-100). At ACC 15, Dr. Chen presented the findings of the new PADN-2 study, which expands upon the first study by including more patients and longer and more comprehensive follow-up.

The study comprised 28 patients with PAH, including 11 with idiopathic PAH and 8 with pulmonary hypertension caused by left ventricular disease. All of them underwent medication washout followed by right heart catheterization and echocardiography for baseline off-drug hemodynamic measurements as well as a 6-minute walk distance test of their functional capacity. Then they went back on medications for 6 months, after which they underwent repeat testing. Then their medications were discontinued and they underwent PADN. Six months after the procedure, still off medications, they were retested once again.

The primary study endpoint was change in 6-minute walk distance. After 6 months of medication it improved from 361 to 373 meters, a modest 3.9% gain over off-drug baseline. In contrast, 6-minute walk distance grew from 358 to 423 meters 6 months after PADN, a clinically important 23.9% improvement, reported Dr. Chen, a cardiologist at First Hospital of Nanjing (China) Medical University.

Multiple secondary hemodynamic endpoints also showed significantly greater improvement with PADN than medical therapy.

Twelve predefined clinical events – mostly involving worsening PAH – occurred during medical management, compared with three in the 6 months following PADN.

In addition, there were 12 hospitalizations during the 6 months on medical management compared with only 4 after the same patients underwent PADN. Health care costs averaged $35,000 per patient during the 6-month study period on medication compared with $6,000 per patient in the first 6 months after PADN.

There were no deaths, aneurysms, access site hematomas, or thrombotic events during either study period.

Further randomized, controlled trials are planned to explore the possibility that the benefits seen in the PADN-2 trial will result in reduced mortality in patients with PAH, according to Dr. Chen.

The PADN-2 trial was sponsored by Nanjing Medical University. Dr. Chen reported serving as a consultant to MicroPort.

bjancin@frontlinemedcom.com

SAN DIEGO – Percutaneous pulmonary artery denervation for the treatment of pulmonary arterial hypertension safely resulted in significantly greater improvement in functional capacity and hemodynamics compared with medication, in a controlled before-and-after study.

A particularly noteworthy secondary finding in the study was that rehospitalizations during the first 6 months after pulmonary artery denervation (PADN) occurred just one-third as frequently as in the 6-month preprocedural period on standard medications, Dr. Shao-Liang Chen said at the annual meeting of the American College of Cardiology.

He and his coinvestigators, including Dr. Gregg W. Stone of Columbia University in New York, developed a percutaneous catheter-based method of destroying the pulmonary baroreceptor structure located at the bifurcation area of the middle pulmonary artery. Along the way, they redefined the understanding of the pathogenesis of pulmonary artery hypertension (PAH) by demonstrating that local sympathetic nerve activity plays a pivotal role in modulating the elevations of mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR), which are the disease hallmarks.

Dr. Chen and coinvestigators previously reported the first-in-man study of PADN, which demonstrated safety and short-term efficacy (J. Am. Coll. Cardiol. 2013;62:1092-100). At ACC 15, Dr. Chen presented the findings of the new PADN-2 study, which expands upon the first study by including more patients and longer and more comprehensive follow-up.

The study comprised 28 patients with PAH, including 11 with idiopathic PAH and 8 with pulmonary hypertension caused by left ventricular disease. All of them underwent medication washout followed by right heart catheterization and echocardiography for baseline off-drug hemodynamic measurements as well as a 6-minute walk distance test of their functional capacity. Then they went back on medications for 6 months, after which they underwent repeat testing. Then their medications were discontinued and they underwent PADN. Six months after the procedure, still off medications, they were retested once again.

The primary study endpoint was change in 6-minute walk distance. After 6 months of medication it improved from 361 to 373 meters, a modest 3.9% gain over off-drug baseline. In contrast, 6-minute walk distance grew from 358 to 423 meters 6 months after PADN, a clinically important 23.9% improvement, reported Dr. Chen, a cardiologist at First Hospital of Nanjing (China) Medical University.

Multiple secondary hemodynamic endpoints also showed significantly greater improvement with PADN than medical therapy.

Twelve predefined clinical events – mostly involving worsening PAH – occurred during medical management, compared with three in the 6 months following PADN.

In addition, there were 12 hospitalizations during the 6 months on medical management compared with only 4 after the same patients underwent PADN. Health care costs averaged $35,000 per patient during the 6-month study period on medication compared with $6,000 per patient in the first 6 months after PADN.

There were no deaths, aneurysms, access site hematomas, or thrombotic events during either study period.

Further randomized, controlled trials are planned to explore the possibility that the benefits seen in the PADN-2 trial will result in reduced mortality in patients with PAH, according to Dr. Chen.

The PADN-2 trial was sponsored by Nanjing Medical University. Dr. Chen reported serving as a consultant to MicroPort.

bjancin@frontlinemedcom.com