Heart Failure

First-line combination therapy with ambrisentan and tadalafil cut the rate of clinical events in pulmonary arterial hypertension (PAH) by half, compared with monotherapy using either drug, in an international phase 3-4 clinical trial reported online Aug. 27 in the New England Journal of Medicine.

Ambrisentan, a selective endothelin-A-receptor antagonist, and tadalafil, a phosphodiesterase type 5 inhibitor, target different intracellular pathways known to have dysfunctional signaling in PAH, so researchers expected them to have an additive effect when combined. The study findings support the rationale of targeting multiple affected pathways early in the course of PAH, rather than following the traditional approach of sequentially adding newer agents to established background therapy, said Dr. Nazzareno Galie of the department of experimental, diagnostic, and specialty medicine, University of Bologna (Italy), and his associates.

The 4-year, industry-sponsored trial involved 500 adults treated at 120 medical centers in 14 countries for PAH with World Health Organization functional class II or III symptoms. It included patients whose disorder was idiopathic; hereditary; or associated with connective tissue disease, drugs or toxins, stable HIV infection, or repaired congenital heart defects.

The mean age of participants was 54.4 years, and 78% were women. The mean pulmonary artery pressure was 48.7 mm Hg, and mean 6-minute walk distance was 353 m at baseline. A total of 253 patients were randomly assigned to receive oral, once-daily combination therapy, 126 to receive ambrisentan plus placebo, and 121 to receive tadalafil plus placebo. They were assessed at monthly intervals during the 24-week treatment period and were allowed to continue therapy indefinitely. The mean duration of use of the study medication was 517 days. Patients were followed up a final time 1 month after taking their last dose of study medication.

The primary efficacy endpoint was the first event of clinical failure, which was a composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term treatment response. Only 18% of the combination-therapy group reached this endpoint, compared with 34% of the ambrisentan group, 28% of the tadalafil group, and 31% of the pooled-monotherapy group. The hazard ratios for the primary endpoint were 0.50 for the combination therapy versus pooled monotherapy, 0.48 for combination therapy versus ambrisentan alone, and 0.53 for combination therapy versus tadalafil alone.

This treatment benefit was mainly driven by one component of the combined endpoint: The rate of hospitalization for worsening PAH was three times higher with the two monotherapies (12%) than with combination therapy (4%). Improvement in the secondary endpoints of change in N-terminal pro–brain natriuretic peptide level, the percentage of participants with a satisfactory treatment response, and change in 6-minute walk distance all significantly favored the combination therapy, Dr. Galie and his associates said (N Engl J Med. 2015 Aug 27. doi: 10.1056/NEJMoa1413687).It is important to note, however, that “despite improvements in a variety of factors with combination therapy, we found no significant difference in WHO functional class among the study groups at week 24,” they wrote.

The combination of ambrisentan and tadalafil produced more adverse effects than either monotherapy, but the rate of discontinuation of a study drug and the rate of serious adverse events were similar across the three study groups. The most frequent adverse effects were peripheral edema, headache, nasal congestion, and anemia.

The AMBITION study was funded by Gilead Sciences and GlaxoSmithKline, which designed the trial, collected and analyzed the data, and wrote the report in conjunction with the authors. Gilead Sciences, GlaxoSmithKline, and Eli Lilly provided the study drugs. Dr. Galie reported receiving grants and personal fees from GlaxoSmithKline, Actelion, Bayer, and Pfizer; his associates reported ties to numerous industry sources.

First-line combination therapy with ambrisentan and tadalafil cut the rate of clinical events in pulmonary arterial hypertension (PAH) by half, compared with monotherapy using either drug, in an international phase 3-4 clinical trial reported online Aug. 27 in the New England Journal of Medicine.

Ambrisentan, a selective endothelin-A-receptor antagonist, and tadalafil, a phosphodiesterase type 5 inhibitor, target different intracellular pathways known to have dysfunctional signaling in PAH, so researchers expected them to have an additive effect when combined. The study findings support the rationale of targeting multiple affected pathways early in the course of PAH, rather than following the traditional approach of sequentially adding newer agents to established background therapy, said Dr. Nazzareno Galie of the department of experimental, diagnostic, and specialty medicine, University of Bologna (Italy), and his associates.

The 4-year, industry-sponsored trial involved 500 adults treated at 120 medical centers in 14 countries for PAH with World Health Organization functional class II or III symptoms. It included patients whose disorder was idiopathic; hereditary; or associated with connective tissue disease, drugs or toxins, stable HIV infection, or repaired congenital heart defects.

The mean age of participants was 54.4 years, and 78% were women. The mean pulmonary artery pressure was 48.7 mm Hg, and mean 6-minute walk distance was 353 m at baseline. A total of 253 patients were randomly assigned to receive oral, once-daily combination therapy, 126 to receive ambrisentan plus placebo, and 121 to receive tadalafil plus placebo. They were assessed at monthly intervals during the 24-week treatment period and were allowed to continue therapy indefinitely. The mean duration of use of the study medication was 517 days. Patients were followed up a final time 1 month after taking their last dose of study medication.

The primary efficacy endpoint was the first event of clinical failure, which was a composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term treatment response. Only 18% of the combination-therapy group reached this endpoint, compared with 34% of the ambrisentan group, 28% of the tadalafil group, and 31% of the pooled-monotherapy group. The hazard ratios for the primary endpoint were 0.50 for the combination therapy versus pooled monotherapy, 0.48 for combination therapy versus ambrisentan alone, and 0.53 for combination therapy versus tadalafil alone.

This treatment benefit was mainly driven by one component of the combined endpoint: The rate of hospitalization for worsening PAH was three times higher with the two monotherapies (12%) than with combination therapy (4%). Improvement in the secondary endpoints of change in N-terminal pro–brain natriuretic peptide level, the percentage of participants with a satisfactory treatment response, and change in 6-minute walk distance all significantly favored the combination therapy, Dr. Galie and his associates said (N Engl J Med. 2015 Aug 27. doi: 10.1056/NEJMoa1413687).It is important to note, however, that “despite improvements in a variety of factors with combination therapy, we found no significant difference in WHO functional class among the study groups at week 24,” they wrote.

The combination of ambrisentan and tadalafil produced more adverse effects than either monotherapy, but the rate of discontinuation of a study drug and the rate of serious adverse events were similar across the three study groups. The most frequent adverse effects were peripheral edema, headache, nasal congestion, and anemia.

The AMBITION study was funded by Gilead Sciences and GlaxoSmithKline, which designed the trial, collected and analyzed the data, and wrote the report in conjunction with the authors. Gilead Sciences, GlaxoSmithKline, and Eli Lilly provided the study drugs. Dr. Galie reported receiving grants and personal fees from GlaxoSmithKline, Actelion, Bayer, and Pfizer; his associates reported ties to numerous industry sources.

First-line combination therapy with ambrisentan and tadalafil cut the rate of clinical events in pulmonary arterial hypertension (PAH) by half, compared with monotherapy using either drug, in an international phase 3-4 clinical trial reported online Aug. 27 in the New England Journal of Medicine.

Ambrisentan, a selective endothelin-A-receptor antagonist, and tadalafil, a phosphodiesterase type 5 inhibitor, target different intracellular pathways known to have dysfunctional signaling in PAH, so researchers expected them to have an additive effect when combined. The study findings support the rationale of targeting multiple affected pathways early in the course of PAH, rather than following the traditional approach of sequentially adding newer agents to established background therapy, said Dr. Nazzareno Galie of the department of experimental, diagnostic, and specialty medicine, University of Bologna (Italy), and his associates.

The 4-year, industry-sponsored trial involved 500 adults treated at 120 medical centers in 14 countries for PAH with World Health Organization functional class II or III symptoms. It included patients whose disorder was idiopathic; hereditary; or associated with connective tissue disease, drugs or toxins, stable HIV infection, or repaired congenital heart defects.

The mean age of participants was 54.4 years, and 78% were women. The mean pulmonary artery pressure was 48.7 mm Hg, and mean 6-minute walk distance was 353 m at baseline. A total of 253 patients were randomly assigned to receive oral, once-daily combination therapy, 126 to receive ambrisentan plus placebo, and 121 to receive tadalafil plus placebo. They were assessed at monthly intervals during the 24-week treatment period and were allowed to continue therapy indefinitely. The mean duration of use of the study medication was 517 days. Patients were followed up a final time 1 month after taking their last dose of study medication.

The primary efficacy endpoint was the first event of clinical failure, which was a composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term treatment response. Only 18% of the combination-therapy group reached this endpoint, compared with 34% of the ambrisentan group, 28% of the tadalafil group, and 31% of the pooled-monotherapy group. The hazard ratios for the primary endpoint were 0.50 for the combination therapy versus pooled monotherapy, 0.48 for combination therapy versus ambrisentan alone, and 0.53 for combination therapy versus tadalafil alone.

This treatment benefit was mainly driven by one component of the combined endpoint: The rate of hospitalization for worsening PAH was three times higher with the two monotherapies (12%) than with combination therapy (4%). Improvement in the secondary endpoints of change in N-terminal pro–brain natriuretic peptide level, the percentage of participants with a satisfactory treatment response, and change in 6-minute walk distance all significantly favored the combination therapy, Dr. Galie and his associates said (N Engl J Med. 2015 Aug 27. doi: 10.1056/NEJMoa1413687).It is important to note, however, that “despite improvements in a variety of factors with combination therapy, we found no significant difference in WHO functional class among the study groups at week 24,” they wrote.

The combination of ambrisentan and tadalafil produced more adverse effects than either monotherapy, but the rate of discontinuation of a study drug and the rate of serious adverse events were similar across the three study groups. The most frequent adverse effects were peripheral edema, headache, nasal congestion, and anemia.

The AMBITION study was funded by Gilead Sciences and GlaxoSmithKline, which designed the trial, collected and analyzed the data, and wrote the report in conjunction with the authors. Gilead Sciences, GlaxoSmithKline, and Eli Lilly provided the study drugs. Dr. Galie reported receiving grants and personal fees from GlaxoSmithKline, Actelion, Bayer, and Pfizer; his associates reported ties to numerous industry sources.

A longitudinal cohort study shows a U-shaped relationship between total physical activity and heart failure risk in men.

The 15-year study of 33,012 men, average age 60 years at baseline, showed that those who engaged in the highest levels and intensity of total physical activity had a 31% greater risk of heart failure than did those in the median activity category.

©Thinkstock.com

However, men who undertook the lowest levels of physical activity had up to a 69% greater risk of heart failure compared to the median activity group, according to the results, published online Aug. 12 in JACC: Heart Failure.

“The U-shaped relationship between exercise levels and the likelihood of subsequent heart failure is a unique finding and will stimulate further research in the important field of prevention,” said Dr. Christopher O’Connor, editor-in-chief of JACC: Heart Failure, who was not involved in the study.

The questionnaire-based study involved of 3,609 heart failure events, which included 3,190 first events of heart failure hospitalizations and 419 deaths from heart failure.

The study authors assigned intensity scores – defined as metabolic equivalents (MET) hours/day – to each type of physical activity, then calculated a total daily physical activity score for each individual by multiplying the intensity scores by reported duration of each activity.

Watching TV, reading, and sleep were assigned the lowest intensity MET scores, walking or bicycling were in the mid-range, and exercise was assigned the highest MET scores.

Walking or bicycling at least 20 minutes a day were associated with the greatest reductions in the risk of heart failure – 21% – compared to not walking or biking, and this type and level of activity was linked to an 8-month delay in the onset of heart failure among those who engaged in it.

The investigators also found no differences between the two groups in terms of age or education level, and the exclusion of study participants who developed heart failure in the 3 first years of follow-up did not impact results.

“When examining long-term behavior regarding walking or biking and HF [heart failure] risk, the results suggested that more recent active behavior in this PA [physical activity] domain may be more important for HF protection than past PA levels,” wrote Dr. Iffat Rahman and colleagues at the Karolinska Institute, Stockholm.

Exercising for more than 1 hour per week was linked with a 14% reduction in risk, but work occupation, household work, and physical inactivity did not affect heart failure risk (JACC Heart Fail. 2015 Aug 12. doi:10.1016/j.jchf.2015.05.006).

While previous studies have shown that lower levels of physical activity increase the risk of heart failure, the authors said this was the first to show an increase in risk among individuals who undertake very high levels of physical activity.

“It is possible that substantial increase of pumping of blood by the heart could damage the cardiac muscle fibers causing damage in the myocardium,” the authors wrote.

“Moreover, adverse cardiovascular outcomes could potentially be attributed to increased oxidative stress, arterial stiffness, and coronary artery calcification.”

A similar study looking at the relationship between physical activity and heart failure in women did not find an increased risk with very high levels of physical activity, suggesting a differential effect between men and women.

There were no conflicts of interest declared.

A longitudinal cohort study shows a U-shaped relationship between total physical activity and heart failure risk in men.

The 15-year study of 33,012 men, average age 60 years at baseline, showed that those who engaged in the highest levels and intensity of total physical activity had a 31% greater risk of heart failure than did those in the median activity category.

©Thinkstock.com

However, men who undertook the lowest levels of physical activity had up to a 69% greater risk of heart failure compared to the median activity group, according to the results, published online Aug. 12 in JACC: Heart Failure.

“The U-shaped relationship between exercise levels and the likelihood of subsequent heart failure is a unique finding and will stimulate further research in the important field of prevention,” said Dr. Christopher O’Connor, editor-in-chief of JACC: Heart Failure, who was not involved in the study.

The questionnaire-based study involved of 3,609 heart failure events, which included 3,190 first events of heart failure hospitalizations and 419 deaths from heart failure.

The study authors assigned intensity scores – defined as metabolic equivalents (MET) hours/day – to each type of physical activity, then calculated a total daily physical activity score for each individual by multiplying the intensity scores by reported duration of each activity.

Watching TV, reading, and sleep were assigned the lowest intensity MET scores, walking or bicycling were in the mid-range, and exercise was assigned the highest MET scores.

Walking or bicycling at least 20 minutes a day were associated with the greatest reductions in the risk of heart failure – 21% – compared to not walking or biking, and this type and level of activity was linked to an 8-month delay in the onset of heart failure among those who engaged in it.

The investigators also found no differences between the two groups in terms of age or education level, and the exclusion of study participants who developed heart failure in the 3 first years of follow-up did not impact results.

“When examining long-term behavior regarding walking or biking and HF [heart failure] risk, the results suggested that more recent active behavior in this PA [physical activity] domain may be more important for HF protection than past PA levels,” wrote Dr. Iffat Rahman and colleagues at the Karolinska Institute, Stockholm.

Exercising for more than 1 hour per week was linked with a 14% reduction in risk, but work occupation, household work, and physical inactivity did not affect heart failure risk (JACC Heart Fail. 2015 Aug 12. doi:10.1016/j.jchf.2015.05.006).

While previous studies have shown that lower levels of physical activity increase the risk of heart failure, the authors said this was the first to show an increase in risk among individuals who undertake very high levels of physical activity.

“It is possible that substantial increase of pumping of blood by the heart could damage the cardiac muscle fibers causing damage in the myocardium,” the authors wrote.

“Moreover, adverse cardiovascular outcomes could potentially be attributed to increased oxidative stress, arterial stiffness, and coronary artery calcification.”

A similar study looking at the relationship between physical activity and heart failure in women did not find an increased risk with very high levels of physical activity, suggesting a differential effect between men and women.

There were no conflicts of interest declared.

A longitudinal cohort study shows a U-shaped relationship between total physical activity and heart failure risk in men.

The 15-year study of 33,012 men, average age 60 years at baseline, showed that those who engaged in the highest levels and intensity of total physical activity had a 31% greater risk of heart failure than did those in the median activity category.

©Thinkstock.com

However, men who undertook the lowest levels of physical activity had up to a 69% greater risk of heart failure compared to the median activity group, according to the results, published online Aug. 12 in JACC: Heart Failure.

“The U-shaped relationship between exercise levels and the likelihood of subsequent heart failure is a unique finding and will stimulate further research in the important field of prevention,” said Dr. Christopher O’Connor, editor-in-chief of JACC: Heart Failure, who was not involved in the study.

The questionnaire-based study involved of 3,609 heart failure events, which included 3,190 first events of heart failure hospitalizations and 419 deaths from heart failure.

The study authors assigned intensity scores – defined as metabolic equivalents (MET) hours/day – to each type of physical activity, then calculated a total daily physical activity score for each individual by multiplying the intensity scores by reported duration of each activity.

Watching TV, reading, and sleep were assigned the lowest intensity MET scores, walking or bicycling were in the mid-range, and exercise was assigned the highest MET scores.

Walking or bicycling at least 20 minutes a day were associated with the greatest reductions in the risk of heart failure – 21% – compared to not walking or biking, and this type and level of activity was linked to an 8-month delay in the onset of heart failure among those who engaged in it.

The investigators also found no differences between the two groups in terms of age or education level, and the exclusion of study participants who developed heart failure in the 3 first years of follow-up did not impact results.

“When examining long-term behavior regarding walking or biking and HF [heart failure] risk, the results suggested that more recent active behavior in this PA [physical activity] domain may be more important for HF protection than past PA levels,” wrote Dr. Iffat Rahman and colleagues at the Karolinska Institute, Stockholm.

Exercising for more than 1 hour per week was linked with a 14% reduction in risk, but work occupation, household work, and physical inactivity did not affect heart failure risk (JACC Heart Fail. 2015 Aug 12. doi:10.1016/j.jchf.2015.05.006).

While previous studies have shown that lower levels of physical activity increase the risk of heart failure, the authors said this was the first to show an increase in risk among individuals who undertake very high levels of physical activity.

“It is possible that substantial increase of pumping of blood by the heart could damage the cardiac muscle fibers causing damage in the myocardium,” the authors wrote.

“Moreover, adverse cardiovascular outcomes could potentially be attributed to increased oxidative stress, arterial stiffness, and coronary artery calcification.”

A similar study looking at the relationship between physical activity and heart failure in women did not find an increased risk with very high levels of physical activity, suggesting a differential effect between men and women.

There were no conflicts of interest declared.

An abnormal troponin T level of 14 ng/L or higher, as measured using a high-sensitivity assay, doubles the risk of cardiovascular events and death among patients who have stable ischemic heart disease and type 2 diabetes, according to a report published online Aug. 13 in the New England Journal of Medicine.

Moreover, an increase of more than 25% in troponin T level during the course of 1 year predicts a worse outcome than do stable or decreasing troponin T levels in this patient population, significantly increasing the rates of death from cardiovascular causes, MI, or stroke. These findings “raise the possibility that serial measurements of troponin concentration may improve its prognostic value, and that persistently elevated and increasing troponin concentrations may be the best predictor of adverse outcomes,” said Dr. Brendan M. Everett of the divisions of cardiovascular medicine and preventive medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston.

These findings have particular significance because the prevalence of elevated troponin T was fully 40% in this study, noted Dr. Everett and his associates.

To examine the possible relationship between elevated troponin T and adverse cardiovascular outcomes in patients who had both stable ischemic heart disease and diabetes, the investigators performed a post hoc analysis of data gathered in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) clinical trial, which compared outcomes between patients who underwent preventive percutaneous coronary intervention or CABG plus intensive medical therapy against those who received intensive medical therapy alone.

For their ancillary study, Dr. Everett and his colleagues focused on 2,285 of these participants who had high-sensitivity assays to measure very low cardiac troponin levels in plasma samples and who were followed for a mean of 5 years. At baseline, 897 (40%) of these patients had troponin T levels of 14 ng/L or higher, the current cutoff point for both men and women.

The 5-year incidence of the composite outcome of death from cardiovascular causes, MI, or stroke was 27.1% in patients with elevated troponin T at baseline, compared with 12.9% in those with normal troponin T. The between-groups differences in each of the individual components of this composite outcome were of similar magnitude, as were the between-group differences in the secondary outcomes of death from any cause and heart failure (N Engl J Med. 2015 Aug 13 [doi:10.1056/NEJMoa1415921]).

This association remained robust after the data were adjusted to account for numerous potentially confounding factors such as traditional CV risk factors, a history of MI, a history of heart failure, the severity of diabetes, glomerular filtration rate, ECG abnormalities, the number of coronary lesions, and the presence of an abnormal ejection fraction.

In a further analysis that divided patients into five groups according to their troponin T levels, adverse event rates were substantially higher than average only in the highest two categories: 14.0-23.0 ng/L and 23.0 ng/L and higher.

In another analysis, the investigators assessed outcomes in a subgroup of 1,984 participants who underwent troponin T testing both at baseline and 1 year later. Patients whose levels increased by more than 25% during that year – about 7% of this subgroup – showed significantly increased risk of all adverse outcomes, compared with patients whose troponin T levels either remained stable or decreased.

Prompt revascularization via percutaneous coronary intervention or coronary artery bypass surgery did not lower the risk of any adverse outcomes in patients who had elevated troponin T. It is therefore crucial that the troponin T assay, already in widespread use, not be used to justify revascularization procedures, the researchers wrote. At least on the basis of this study’s findings, such procedures appear to offer little benefit, they noted.

The National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and Roche Diagnostics supported the study. Dr. Everett reported ties with Roche, Novartis, and Genzyme; his associates reported ties to numerous industry sources.

An abnormal troponin T level of 14 ng/L or higher, as measured using a high-sensitivity assay, doubles the risk of cardiovascular events and death among patients who have stable ischemic heart disease and type 2 diabetes, according to a report published online Aug. 13 in the New England Journal of Medicine.

Moreover, an increase of more than 25% in troponin T level during the course of 1 year predicts a worse outcome than do stable or decreasing troponin T levels in this patient population, significantly increasing the rates of death from cardiovascular causes, MI, or stroke. These findings “raise the possibility that serial measurements of troponin concentration may improve its prognostic value, and that persistently elevated and increasing troponin concentrations may be the best predictor of adverse outcomes,” said Dr. Brendan M. Everett of the divisions of cardiovascular medicine and preventive medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston.

These findings have particular significance because the prevalence of elevated troponin T was fully 40% in this study, noted Dr. Everett and his associates.

To examine the possible relationship between elevated troponin T and adverse cardiovascular outcomes in patients who had both stable ischemic heart disease and diabetes, the investigators performed a post hoc analysis of data gathered in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) clinical trial, which compared outcomes between patients who underwent preventive percutaneous coronary intervention or CABG plus intensive medical therapy against those who received intensive medical therapy alone.

For their ancillary study, Dr. Everett and his colleagues focused on 2,285 of these participants who had high-sensitivity assays to measure very low cardiac troponin levels in plasma samples and who were followed for a mean of 5 years. At baseline, 897 (40%) of these patients had troponin T levels of 14 ng/L or higher, the current cutoff point for both men and women.

The 5-year incidence of the composite outcome of death from cardiovascular causes, MI, or stroke was 27.1% in patients with elevated troponin T at baseline, compared with 12.9% in those with normal troponin T. The between-groups differences in each of the individual components of this composite outcome were of similar magnitude, as were the between-group differences in the secondary outcomes of death from any cause and heart failure (N Engl J Med. 2015 Aug 13 [doi:10.1056/NEJMoa1415921]).

This association remained robust after the data were adjusted to account for numerous potentially confounding factors such as traditional CV risk factors, a history of MI, a history of heart failure, the severity of diabetes, glomerular filtration rate, ECG abnormalities, the number of coronary lesions, and the presence of an abnormal ejection fraction.

In a further analysis that divided patients into five groups according to their troponin T levels, adverse event rates were substantially higher than average only in the highest two categories: 14.0-23.0 ng/L and 23.0 ng/L and higher.

In another analysis, the investigators assessed outcomes in a subgroup of 1,984 participants who underwent troponin T testing both at baseline and 1 year later. Patients whose levels increased by more than 25% during that year – about 7% of this subgroup – showed significantly increased risk of all adverse outcomes, compared with patients whose troponin T levels either remained stable or decreased.

Prompt revascularization via percutaneous coronary intervention or coronary artery bypass surgery did not lower the risk of any adverse outcomes in patients who had elevated troponin T. It is therefore crucial that the troponin T assay, already in widespread use, not be used to justify revascularization procedures, the researchers wrote. At least on the basis of this study’s findings, such procedures appear to offer little benefit, they noted.

The National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and Roche Diagnostics supported the study. Dr. Everett reported ties with Roche, Novartis, and Genzyme; his associates reported ties to numerous industry sources.

An abnormal troponin T level of 14 ng/L or higher, as measured using a high-sensitivity assay, doubles the risk of cardiovascular events and death among patients who have stable ischemic heart disease and type 2 diabetes, according to a report published online Aug. 13 in the New England Journal of Medicine.

Moreover, an increase of more than 25% in troponin T level during the course of 1 year predicts a worse outcome than do stable or decreasing troponin T levels in this patient population, significantly increasing the rates of death from cardiovascular causes, MI, or stroke. These findings “raise the possibility that serial measurements of troponin concentration may improve its prognostic value, and that persistently elevated and increasing troponin concentrations may be the best predictor of adverse outcomes,” said Dr. Brendan M. Everett of the divisions of cardiovascular medicine and preventive medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston.

These findings have particular significance because the prevalence of elevated troponin T was fully 40% in this study, noted Dr. Everett and his associates.

To examine the possible relationship between elevated troponin T and adverse cardiovascular outcomes in patients who had both stable ischemic heart disease and diabetes, the investigators performed a post hoc analysis of data gathered in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) clinical trial, which compared outcomes between patients who underwent preventive percutaneous coronary intervention or CABG plus intensive medical therapy against those who received intensive medical therapy alone.

For their ancillary study, Dr. Everett and his colleagues focused on 2,285 of these participants who had high-sensitivity assays to measure very low cardiac troponin levels in plasma samples and who were followed for a mean of 5 years. At baseline, 897 (40%) of these patients had troponin T levels of 14 ng/L or higher, the current cutoff point for both men and women.

The 5-year incidence of the composite outcome of death from cardiovascular causes, MI, or stroke was 27.1% in patients with elevated troponin T at baseline, compared with 12.9% in those with normal troponin T. The between-groups differences in each of the individual components of this composite outcome were of similar magnitude, as were the between-group differences in the secondary outcomes of death from any cause and heart failure (N Engl J Med. 2015 Aug 13 [doi:10.1056/NEJMoa1415921]).

This association remained robust after the data were adjusted to account for numerous potentially confounding factors such as traditional CV risk factors, a history of MI, a history of heart failure, the severity of diabetes, glomerular filtration rate, ECG abnormalities, the number of coronary lesions, and the presence of an abnormal ejection fraction.

In a further analysis that divided patients into five groups according to their troponin T levels, adverse event rates were substantially higher than average only in the highest two categories: 14.0-23.0 ng/L and 23.0 ng/L and higher.

In another analysis, the investigators assessed outcomes in a subgroup of 1,984 participants who underwent troponin T testing both at baseline and 1 year later. Patients whose levels increased by more than 25% during that year – about 7% of this subgroup – showed significantly increased risk of all adverse outcomes, compared with patients whose troponin T levels either remained stable or decreased.

Prompt revascularization via percutaneous coronary intervention or coronary artery bypass surgery did not lower the risk of any adverse outcomes in patients who had elevated troponin T. It is therefore crucial that the troponin T assay, already in widespread use, not be used to justify revascularization procedures, the researchers wrote. At least on the basis of this study’s findings, such procedures appear to offer little benefit, they noted.

The National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and Roche Diagnostics supported the study. Dr. Everett reported ties with Roche, Novartis, and Genzyme; his associates reported ties to numerous industry sources.

Inpatient mortality for pneumonia, acute MI, heart failure, and stroke each fell significantly from 2002 to 2012, the Agency for Healthcare Research and Quality reported.

Over that period, mortality among adults hospitalized with pneumonia went from 65 per 1,000 admissions to 35.8 per 1,000 for a drop of 45% – largest of the four high-volume conditions. Corresponding declines for the others were 41% for acute MI, 29% for heart failure, and 27% for stroke, the AHRQ noted.

Since “death following discharge from a hospital is not reflected in these data,” the report said, measures of inpatient mortality “can reflect both improvements in health care and shifts in where end-of-life care takes place over time.”

The estimates in the report are based on data from the Nationwide Inpatient Sample (2002-2011) and State Inpatient Databases (2012).

rfranki@frontlinemedcom.com

Inpatient mortality for pneumonia, acute MI, heart failure, and stroke each fell significantly from 2002 to 2012, the Agency for Healthcare Research and Quality reported.

Over that period, mortality among adults hospitalized with pneumonia went from 65 per 1,000 admissions to 35.8 per 1,000 for a drop of 45% – largest of the four high-volume conditions. Corresponding declines for the others were 41% for acute MI, 29% for heart failure, and 27% for stroke, the AHRQ noted.

Since “death following discharge from a hospital is not reflected in these data,” the report said, measures of inpatient mortality “can reflect both improvements in health care and shifts in where end-of-life care takes place over time.”

The estimates in the report are based on data from the Nationwide Inpatient Sample (2002-2011) and State Inpatient Databases (2012).

rfranki@frontlinemedcom.com

Inpatient mortality for pneumonia, acute MI, heart failure, and stroke each fell significantly from 2002 to 2012, the Agency for Healthcare Research and Quality reported.

Over that period, mortality among adults hospitalized with pneumonia went from 65 per 1,000 admissions to 35.8 per 1,000 for a drop of 45% – largest of the four high-volume conditions. Corresponding declines for the others were 41% for acute MI, 29% for heart failure, and 27% for stroke, the AHRQ noted.

Since “death following discharge from a hospital is not reflected in these data,” the report said, measures of inpatient mortality “can reflect both improvements in health care and shifts in where end-of-life care takes place over time.”

The estimates in the report are based on data from the Nationwide Inpatient Sample (2002-2011) and State Inpatient Databases (2012).

rfranki@frontlinemedcom.com

In the one-quarter of heart failure patients who receive an implantable cardioverter defibrillator for primary prevention and whose left ventricular ejection fraction improves more than 35%, both mortality and appropriate ICD shocks are decreased, according to a report published online July 27 in Journal of the American College of Cardiology.

This raises the question of whether such patients’ risk for sudden cardiac death still warrants replacement of the ICD generator years later, especially among those whose devices have never needed to deliver a shock, said Yiyi Zhang, Ph.D., of the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, and her associates.

© janulla/Thinkstock

To examine this issue, the investigators analyzed data from PROSE-ICD (Prospective Observational Study of Implantable Cardioverter-Defibrillators), in which patients with systolic heart failure received primary-prevention ICDs at four U.S. cardiology centers after an initial LVEF assessment. For their study, Dr. Zhang and her associates focused on 538 of these study participants whose LVEF was reassessed at least once during roughly 5 years of follow-up.

About 57% of the study subjects were white and 70% were men. The average age at baseline was 59 years.

LVEF improved after ICD implantation in 215 (40%) of the participants, including 134 patients (25%) in whom it improved to greater than 35%. These patients were at significantly reduced risk of all-cause mortality and of requiring ICD shocks, compared with patients whose LVEF was either unchanged (47%) or decreased (13%) after ICD implantation, the investigators said. In a Cox regression model adjusted for age, sex, race, baseline LVEF, and stratified by enrollment center, the hazard ratio for all-cause mortality was 0.31, and that for an appropriate shock was 0.33 (J. Am. Coll. Cardiol. 2015 July 27 [doi:10.1016/j.jacc.2015.05.057]).

The mode of death could not be determined in many cases because records were unreliable for patients who died out of hospital, so the researchers couldn’t examine any association between LVEF changes and cardiac-specific mortality.

These study results are consistent with those of several previous studies, Dr. Zhang and her associates noted.

“Findings from our study indicate that repeated LVEF assessment after ICD implantation can provide additional prognostic information and may also allow for more informed decision making regarding ICD generator replacement, especially in patients whose LVEF improved significantly,” they said.

Further studies in larger populations that have more frequent LVEF reassessments are needed to establish whether ICD generator replacement has a positive or negative impact on this patient population, and to better guide clinicians in deciding whether ICD generator replacement should be deferred in individual patients, the investigators added.

In the one-quarter of heart failure patients who receive an implantable cardioverter defibrillator for primary prevention and whose left ventricular ejection fraction improves more than 35%, both mortality and appropriate ICD shocks are decreased, according to a report published online July 27 in Journal of the American College of Cardiology.

This raises the question of whether such patients’ risk for sudden cardiac death still warrants replacement of the ICD generator years later, especially among those whose devices have never needed to deliver a shock, said Yiyi Zhang, Ph.D., of the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, and her associates.

© janulla/Thinkstock

To examine this issue, the investigators analyzed data from PROSE-ICD (Prospective Observational Study of Implantable Cardioverter-Defibrillators), in which patients with systolic heart failure received primary-prevention ICDs at four U.S. cardiology centers after an initial LVEF assessment. For their study, Dr. Zhang and her associates focused on 538 of these study participants whose LVEF was reassessed at least once during roughly 5 years of follow-up.

About 57% of the study subjects were white and 70% were men. The average age at baseline was 59 years.

LVEF improved after ICD implantation in 215 (40%) of the participants, including 134 patients (25%) in whom it improved to greater than 35%. These patients were at significantly reduced risk of all-cause mortality and of requiring ICD shocks, compared with patients whose LVEF was either unchanged (47%) or decreased (13%) after ICD implantation, the investigators said. In a Cox regression model adjusted for age, sex, race, baseline LVEF, and stratified by enrollment center, the hazard ratio for all-cause mortality was 0.31, and that for an appropriate shock was 0.33 (J. Am. Coll. Cardiol. 2015 July 27 [doi:10.1016/j.jacc.2015.05.057]).

The mode of death could not be determined in many cases because records were unreliable for patients who died out of hospital, so the researchers couldn’t examine any association between LVEF changes and cardiac-specific mortality.

These study results are consistent with those of several previous studies, Dr. Zhang and her associates noted.

“Findings from our study indicate that repeated LVEF assessment after ICD implantation can provide additional prognostic information and may also allow for more informed decision making regarding ICD generator replacement, especially in patients whose LVEF improved significantly,” they said.

Further studies in larger populations that have more frequent LVEF reassessments are needed to establish whether ICD generator replacement has a positive or negative impact on this patient population, and to better guide clinicians in deciding whether ICD generator replacement should be deferred in individual patients, the investigators added.

In the one-quarter of heart failure patients who receive an implantable cardioverter defibrillator for primary prevention and whose left ventricular ejection fraction improves more than 35%, both mortality and appropriate ICD shocks are decreased, according to a report published online July 27 in Journal of the American College of Cardiology.

This raises the question of whether such patients’ risk for sudden cardiac death still warrants replacement of the ICD generator years later, especially among those whose devices have never needed to deliver a shock, said Yiyi Zhang, Ph.D., of the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, and her associates.

© janulla/Thinkstock

To examine this issue, the investigators analyzed data from PROSE-ICD (Prospective Observational Study of Implantable Cardioverter-Defibrillators), in which patients with systolic heart failure received primary-prevention ICDs at four U.S. cardiology centers after an initial LVEF assessment. For their study, Dr. Zhang and her associates focused on 538 of these study participants whose LVEF was reassessed at least once during roughly 5 years of follow-up.

About 57% of the study subjects were white and 70% were men. The average age at baseline was 59 years.

LVEF improved after ICD implantation in 215 (40%) of the participants, including 134 patients (25%) in whom it improved to greater than 35%. These patients were at significantly reduced risk of all-cause mortality and of requiring ICD shocks, compared with patients whose LVEF was either unchanged (47%) or decreased (13%) after ICD implantation, the investigators said. In a Cox regression model adjusted for age, sex, race, baseline LVEF, and stratified by enrollment center, the hazard ratio for all-cause mortality was 0.31, and that for an appropriate shock was 0.33 (J. Am. Coll. Cardiol. 2015 July 27 [doi:10.1016/j.jacc.2015.05.057]).

The mode of death could not be determined in many cases because records were unreliable for patients who died out of hospital, so the researchers couldn’t examine any association between LVEF changes and cardiac-specific mortality.

These study results are consistent with those of several previous studies, Dr. Zhang and her associates noted.

“Findings from our study indicate that repeated LVEF assessment after ICD implantation can provide additional prognostic information and may also allow for more informed decision making regarding ICD generator replacement, especially in patients whose LVEF improved significantly,” they said.

Further studies in larger populations that have more frequent LVEF reassessments are needed to establish whether ICD generator replacement has a positive or negative impact on this patient population, and to better guide clinicians in deciding whether ICD generator replacement should be deferred in individual patients, the investigators added.

Patiromer, an orally administered potassium-binding polymer, significantly decreased serum potassium in adults who had diabetic kidney disease with hyperkalemia in a phase II study funded by and conducted with the manufacturer.

Patiromer consists of tiny, smooth beads in a liquid suspension and works by binding potassium throughout the GI tract, allowing it to be excreted in the feces. After preliminary studies demonstrated the agent’s usefulness in reducing hyperkalemia for up to 12 weeks in high-risk patients, researchers performed this open-label, uncontrolled trial to determine optimal dosing and to assess its longer-term safety. The findings were reported online July 14 in JAMA.

All four doses of patiromer studied significantly reduced serum potassium, beginning within 48 hours of the initial dose and continuing through all 52 weeks of treatment. The proportion of patients whose potassium levels reached target range at all scheduled visits ranged from 83% to 93% in those who had mild hyperkalemia at baseline and from 77% to 95% in those who had moderate hyperkalemia at baseline. Hyperkalemia quickly reappeared when patiromer treatment ended, reverting to baseline levels, wrote Dr. George L. Bakris of the ASH Comprehensive Hypertension Center, division of endocrinology, diabetes, and metabolism, University of Chicago, and his associates.

Study participants were 222 white patients with mild and 84 with moderate hyperkalemia (mean age, 66 years). All had type 2 diabetes and hypertension, and approximately one-third had heart failure; 65% had stage 3 and 22% had stage 4 chronic kidney disease (CKD), All were taking an ACE inhibitor, an angiotensin II receptor blocker, or both, with or without spironolactone. At 48 medical centers in five European countries, they were randomly assigned to receive one of four doses of patiromer that could be titrated up or down as needed for 4 weeks. Patients then entered an 8-week treatment phase, after which they continued maintenance therapy for a further 40 weeks (JAMA 2015 July 14 [doi:10.1001/jama.2015.7446]).

The optimal doses of patiromer were found to be the two lowest doses assessed in this study, 8.4 g daily and 16.8 g daily, which significantly decreased serum potassium without provoking hypokalemia. These doses will now be tested in a phase III study.

The most frequent treatment-related adverse events in the phase II study were nonsevere hypomagnesemia (7.2%), constipation (4.6%), and diarrhea (2.7%). A total of 28 patients (9.2%) developed at least one adverse event prompting them to discontinue patiromer, including worsening of CKD (which was considered unrelated to treatment), hypokalemia (5 patients), and one hypertensive crisis (also unrelated to treatment). No dose-related edema was noted, and there were no clinically relevant changes in serum calcium or phosphate levels.

Patiromer, an orally administered potassium-binding polymer, significantly decreased serum potassium in adults who had diabetic kidney disease with hyperkalemia in a phase II study funded by and conducted with the manufacturer.

Patiromer consists of tiny, smooth beads in a liquid suspension and works by binding potassium throughout the GI tract, allowing it to be excreted in the feces. After preliminary studies demonstrated the agent’s usefulness in reducing hyperkalemia for up to 12 weeks in high-risk patients, researchers performed this open-label, uncontrolled trial to determine optimal dosing and to assess its longer-term safety. The findings were reported online July 14 in JAMA.

All four doses of patiromer studied significantly reduced serum potassium, beginning within 48 hours of the initial dose and continuing through all 52 weeks of treatment. The proportion of patients whose potassium levels reached target range at all scheduled visits ranged from 83% to 93% in those who had mild hyperkalemia at baseline and from 77% to 95% in those who had moderate hyperkalemia at baseline. Hyperkalemia quickly reappeared when patiromer treatment ended, reverting to baseline levels, wrote Dr. George L. Bakris of the ASH Comprehensive Hypertension Center, division of endocrinology, diabetes, and metabolism, University of Chicago, and his associates.

Study participants were 222 white patients with mild and 84 with moderate hyperkalemia (mean age, 66 years). All had type 2 diabetes and hypertension, and approximately one-third had heart failure; 65% had stage 3 and 22% had stage 4 chronic kidney disease (CKD), All were taking an ACE inhibitor, an angiotensin II receptor blocker, or both, with or without spironolactone. At 48 medical centers in five European countries, they were randomly assigned to receive one of four doses of patiromer that could be titrated up or down as needed for 4 weeks. Patients then entered an 8-week treatment phase, after which they continued maintenance therapy for a further 40 weeks (JAMA 2015 July 14 [doi:10.1001/jama.2015.7446]).

The optimal doses of patiromer were found to be the two lowest doses assessed in this study, 8.4 g daily and 16.8 g daily, which significantly decreased serum potassium without provoking hypokalemia. These doses will now be tested in a phase III study.

The most frequent treatment-related adverse events in the phase II study were nonsevere hypomagnesemia (7.2%), constipation (4.6%), and diarrhea (2.7%). A total of 28 patients (9.2%) developed at least one adverse event prompting them to discontinue patiromer, including worsening of CKD (which was considered unrelated to treatment), hypokalemia (5 patients), and one hypertensive crisis (also unrelated to treatment). No dose-related edema was noted, and there were no clinically relevant changes in serum calcium or phosphate levels.

Patiromer, an orally administered potassium-binding polymer, significantly decreased serum potassium in adults who had diabetic kidney disease with hyperkalemia in a phase II study funded by and conducted with the manufacturer.

Patiromer consists of tiny, smooth beads in a liquid suspension and works by binding potassium throughout the GI tract, allowing it to be excreted in the feces. After preliminary studies demonstrated the agent’s usefulness in reducing hyperkalemia for up to 12 weeks in high-risk patients, researchers performed this open-label, uncontrolled trial to determine optimal dosing and to assess its longer-term safety. The findings were reported online July 14 in JAMA.

All four doses of patiromer studied significantly reduced serum potassium, beginning within 48 hours of the initial dose and continuing through all 52 weeks of treatment. The proportion of patients whose potassium levels reached target range at all scheduled visits ranged from 83% to 93% in those who had mild hyperkalemia at baseline and from 77% to 95% in those who had moderate hyperkalemia at baseline. Hyperkalemia quickly reappeared when patiromer treatment ended, reverting to baseline levels, wrote Dr. George L. Bakris of the ASH Comprehensive Hypertension Center, division of endocrinology, diabetes, and metabolism, University of Chicago, and his associates.

Study participants were 222 white patients with mild and 84 with moderate hyperkalemia (mean age, 66 years). All had type 2 diabetes and hypertension, and approximately one-third had heart failure; 65% had stage 3 and 22% had stage 4 chronic kidney disease (CKD), All were taking an ACE inhibitor, an angiotensin II receptor blocker, or both, with or without spironolactone. At 48 medical centers in five European countries, they were randomly assigned to receive one of four doses of patiromer that could be titrated up or down as needed for 4 weeks. Patients then entered an 8-week treatment phase, after which they continued maintenance therapy for a further 40 weeks (JAMA 2015 July 14 [doi:10.1001/jama.2015.7446]).

The optimal doses of patiromer were found to be the two lowest doses assessed in this study, 8.4 g daily and 16.8 g daily, which significantly decreased serum potassium without provoking hypokalemia. These doses will now be tested in a phase III study.

The most frequent treatment-related adverse events in the phase II study were nonsevere hypomagnesemia (7.2%), constipation (4.6%), and diarrhea (2.7%). A total of 28 patients (9.2%) developed at least one adverse event prompting them to discontinue patiromer, including worsening of CKD (which was considered unrelated to treatment), hypokalemia (5 patients), and one hypertensive crisis (also unrelated to treatment). No dose-related edema was noted, and there were no clinically relevant changes in serum calcium or phosphate levels.

A combination of a new drug, sacubitril, a neprilysin inhibitor, and the angiotensin receptor blocker valsartan has been approved for treating heart failure, providing what experts are describing as a major advance in the treatment of heart failure.

The approval, announced by the Food and Drug Administration on July 7, was based on the results of the PARADIGM-HF study of about 8,400 patients with class II-IV heart failure and an ejection fraction of 40% or less. The study showed that the combination reduced the risk of cardiovascular death and hospitalization for heart failure by 20% and reduced the risk for all-cause mortality by 16%, compared with enalapril, with a favorable adverse event profile.

The approved indication for sacubitril-valsartan is to “reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure [New York Heart Association class II-IV] and reduced ejection fraction,” according to the prescribing information. The indications section includes the statement that it “is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB [angiotensin II receptor blocker].” It is contraindicated for use with ACE inhibitors, and when patients on an ACE inhibitor are switched to this drug a washout period of 36 hours before starting treatment is recommended.

Previously called LCZ696, the combination tablet formulation will be marketed by Novartis as Entresto, and will be available in three dosage strengths of sacubitril-valsartan: 24/26 mg, 49/51 mg, and 97/103 mg; in published studies of the combination, these doses are referred to as 50 mg, 100 mg, and 200 mg, respectively. The target dose is 97/103 mg twice a day.

“Many of us see this as a real sea change in heart failure management; we’re all eager to start using this new medicine in our patients, and I think clinicians will very rapidly get a feel for this drug,” Dr. Scott D. Solomon, professor of medicine, Harvard Medical School, Boston, and one of the authors of the study, said in an interview. Referring to the trial results, he noted that for at least 10 years, there has not been a new drug for heart failure that has had this impact on mortality, “so this is really quite an extraordinary finding.”

The availability of a new drug class, a neprilysin inhibitor, “opens up a new chapter in our treatment of heart failure,” said Dr. Mariell Jessup, professor of medicine at the University of Pennsylvania, Philadelphia, who was not involved in the study. “I’m very excited that we now have this new drug for use in our patients,” she said, pointing out that with the exception of ivabradine (Corlanor), approved in April, there has not been a new type of drug approved for heart failure in a long time.

Neprilysin is an endopeptidase that degrades several endogenous vasoactive peptides. Sacubitril “inhibits the breakdown of natriuretic peptides, among other vasoactive compounds, so the drug simultaneously blocks one of the neurohormonal systems that is abnormally activated in the setting of heart failure, and it also augments one of the neurohormonal systems that can be beneficial in patients with heart failure,” said Dr. Solomon, who is also director of noninvasive cardiology at Brigham and Women’s Hospital, Boston.

In PARADIGM-HF, conducted to determine if sacubitril-valsartan was superior to treatment with an ACE inhibitor, the recognized standard treatment for heart failure, a composite of death from cardiovascular causes or a first hospitalization for heart failure (the primary outcome), was 21.8% among those randomized to the combination vs. 26.5% of those on enalapril after a median 27-month follow-up, a highly statistically significant difference that represented a 20% reduced risk over the comparator (N. Engl. J. Med. 371:993-1004). A 20% reduced risk over enalapril was seen for the two components individually in the study, which was stopped early because of the magnitude of the effect over enalapril at a dose of the ACE inhibitor that the investigators pointed out had been shown to reduce mortality, compared with placebo.

Hypotension and nonserious cases of angioedema were higher among those on sacubitril-valsartan, while renal impairment, hyperkalemia, and cough were higher in the enalapril-treated patients.

As with ACE inhibitors, there is a small risk for angioedema, and while the number of cases was low in the study, physicians need to be aware of this issue, Dr. Solomon said. “To use this effectively, patients who are on ACE inhibitors or ARBs will need to be stopped, given 36 hours to wash out, and then started on this new agent,” he said.

In an interview, Dr. Jessup said that she hopes that physicians approach this new drug with the same caution they have with other drugs for patients with systolic heart failure and encouraged clinicians to carefully read the study and familiarize themselves with the prescribing information. Patients should not be taken off an ACE inhibitor and immediately switched to Entresto, she said.

She referred to the “famous” Canadian study that identified a significant increase in spironolactone prescriptions and in the rates of hyperkalemia and hyperkalemia-associated deaths after the positive Randomized Aldactone Evaluation Study (RALES) results were published in 1999 (N. Engl. J. Med. 2004;351:543-51). After the study, which found significant improvements in morbidity and mortality in patients with severe heart failure, was published, “physicians immediately started to put their patients on spironolactone and there was a spike in hyperkalemia and in deaths,” she noted.

The Entresto label includes a boxed warning about the risk of fetal toxicity, and the FDA statement recommends that health care professionals counsel patients about the risks to an unborn baby. One of the company’s postmarketing requirements is to conduct an epidemiologic study evaluating the incidence of angioedema in black patients treated with the combination, compared with another drug, according to the FDA’s approval letter.

The PARADIGM-HF results were reported in August 2014 at the European Society of Cardiology annual meeting in Barcelona. Dr. Solomon said that a large international study evaluating Entresto in patients with heart failure and preserved ejection fraction is currently underway.

The cost per day of Entresto is $12.50 (the wholesale acquisition cost), and the company anticipates that the product will be available in most pharmacies within weeks of the approval date, according to a Novartis spokesperson.

Valsartan, approved in 2001, is marketed as Diovan by Novartis and is available in generic form from Ranbaxy.

The PARADIGM-HF trial was funded by Novartis. Dr. Solomon, a member of the executive committee for the study, has received research support from Novartis for the conduct of this and other studies, and has served as a consultant to the company. Dr. Jessup had no related disclosures.

emechcatie@frontlinemedcom.com

A combination of a new drug, sacubitril, a neprilysin inhibitor, and the angiotensin receptor blocker valsartan has been approved for treating heart failure, providing what experts are describing as a major advance in the treatment of heart failure.

The approval, announced by the Food and Drug Administration on July 7, was based on the results of the PARADIGM-HF study of about 8,400 patients with class II-IV heart failure and an ejection fraction of 40% or less. The study showed that the combination reduced the risk of cardiovascular death and hospitalization for heart failure by 20% and reduced the risk for all-cause mortality by 16%, compared with enalapril, with a favorable adverse event profile.

The approved indication for sacubitril-valsartan is to “reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure [New York Heart Association class II-IV] and reduced ejection fraction,” according to the prescribing information. The indications section includes the statement that it “is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB [angiotensin II receptor blocker].” It is contraindicated for use with ACE inhibitors, and when patients on an ACE inhibitor are switched to this drug a washout period of 36 hours before starting treatment is recommended.

Previously called LCZ696, the combination tablet formulation will be marketed by Novartis as Entresto, and will be available in three dosage strengths of sacubitril-valsartan: 24/26 mg, 49/51 mg, and 97/103 mg; in published studies of the combination, these doses are referred to as 50 mg, 100 mg, and 200 mg, respectively. The target dose is 97/103 mg twice a day.

“Many of us see this as a real sea change in heart failure management; we’re all eager to start using this new medicine in our patients, and I think clinicians will very rapidly get a feel for this drug,” Dr. Scott D. Solomon, professor of medicine, Harvard Medical School, Boston, and one of the authors of the study, said in an interview. Referring to the trial results, he noted that for at least 10 years, there has not been a new drug for heart failure that has had this impact on mortality, “so this is really quite an extraordinary finding.”

The availability of a new drug class, a neprilysin inhibitor, “opens up a new chapter in our treatment of heart failure,” said Dr. Mariell Jessup, professor of medicine at the University of Pennsylvania, Philadelphia, who was not involved in the study. “I’m very excited that we now have this new drug for use in our patients,” she said, pointing out that with the exception of ivabradine (Corlanor), approved in April, there has not been a new type of drug approved for heart failure in a long time.

Neprilysin is an endopeptidase that degrades several endogenous vasoactive peptides. Sacubitril “inhibits the breakdown of natriuretic peptides, among other vasoactive compounds, so the drug simultaneously blocks one of the neurohormonal systems that is abnormally activated in the setting of heart failure, and it also augments one of the neurohormonal systems that can be beneficial in patients with heart failure,” said Dr. Solomon, who is also director of noninvasive cardiology at Brigham and Women’s Hospital, Boston.

In PARADIGM-HF, conducted to determine if sacubitril-valsartan was superior to treatment with an ACE inhibitor, the recognized standard treatment for heart failure, a composite of death from cardiovascular causes or a first hospitalization for heart failure (the primary outcome), was 21.8% among those randomized to the combination vs. 26.5% of those on enalapril after a median 27-month follow-up, a highly statistically significant difference that represented a 20% reduced risk over the comparator (N. Engl. J. Med. 371:993-1004). A 20% reduced risk over enalapril was seen for the two components individually in the study, which was stopped early because of the magnitude of the effect over enalapril at a dose of the ACE inhibitor that the investigators pointed out had been shown to reduce mortality, compared with placebo.

Hypotension and nonserious cases of angioedema were higher among those on sacubitril-valsartan, while renal impairment, hyperkalemia, and cough were higher in the enalapril-treated patients.

As with ACE inhibitors, there is a small risk for angioedema, and while the number of cases was low in the study, physicians need to be aware of this issue, Dr. Solomon said. “To use this effectively, patients who are on ACE inhibitors or ARBs will need to be stopped, given 36 hours to wash out, and then started on this new agent,” he said.

In an interview, Dr. Jessup said that she hopes that physicians approach this new drug with the same caution they have with other drugs for patients with systolic heart failure and encouraged clinicians to carefully read the study and familiarize themselves with the prescribing information. Patients should not be taken off an ACE inhibitor and immediately switched to Entresto, she said.

She referred to the “famous” Canadian study that identified a significant increase in spironolactone prescriptions and in the rates of hyperkalemia and hyperkalemia-associated deaths after the positive Randomized Aldactone Evaluation Study (RALES) results were published in 1999 (N. Engl. J. Med. 2004;351:543-51). After the study, which found significant improvements in morbidity and mortality in patients with severe heart failure, was published, “physicians immediately started to put their patients on spironolactone and there was a spike in hyperkalemia and in deaths,” she noted.

The Entresto label includes a boxed warning about the risk of fetal toxicity, and the FDA statement recommends that health care professionals counsel patients about the risks to an unborn baby. One of the company’s postmarketing requirements is to conduct an epidemiologic study evaluating the incidence of angioedema in black patients treated with the combination, compared with another drug, according to the FDA’s approval letter.

The PARADIGM-HF results were reported in August 2014 at the European Society of Cardiology annual meeting in Barcelona. Dr. Solomon said that a large international study evaluating Entresto in patients with heart failure and preserved ejection fraction is currently underway.

The cost per day of Entresto is $12.50 (the wholesale acquisition cost), and the company anticipates that the product will be available in most pharmacies within weeks of the approval date, according to a Novartis spokesperson.

Valsartan, approved in 2001, is marketed as Diovan by Novartis and is available in generic form from Ranbaxy.

The PARADIGM-HF trial was funded by Novartis. Dr. Solomon, a member of the executive committee for the study, has received research support from Novartis for the conduct of this and other studies, and has served as a consultant to the company. Dr. Jessup had no related disclosures.

emechcatie@frontlinemedcom.com

A combination of a new drug, sacubitril, a neprilysin inhibitor, and the angiotensin receptor blocker valsartan has been approved for treating heart failure, providing what experts are describing as a major advance in the treatment of heart failure.

The approval, announced by the Food and Drug Administration on July 7, was based on the results of the PARADIGM-HF study of about 8,400 patients with class II-IV heart failure and an ejection fraction of 40% or less. The study showed that the combination reduced the risk of cardiovascular death and hospitalization for heart failure by 20% and reduced the risk for all-cause mortality by 16%, compared with enalapril, with a favorable adverse event profile.

The approved indication for sacubitril-valsartan is to “reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure [New York Heart Association class II-IV] and reduced ejection fraction,” according to the prescribing information. The indications section includes the statement that it “is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB [angiotensin II receptor blocker].” It is contraindicated for use with ACE inhibitors, and when patients on an ACE inhibitor are switched to this drug a washout period of 36 hours before starting treatment is recommended.

Previously called LCZ696, the combination tablet formulation will be marketed by Novartis as Entresto, and will be available in three dosage strengths of sacubitril-valsartan: 24/26 mg, 49/51 mg, and 97/103 mg; in published studies of the combination, these doses are referred to as 50 mg, 100 mg, and 200 mg, respectively. The target dose is 97/103 mg twice a day.

“Many of us see this as a real sea change in heart failure management; we’re all eager to start using this new medicine in our patients, and I think clinicians will very rapidly get a feel for this drug,” Dr. Scott D. Solomon, professor of medicine, Harvard Medical School, Boston, and one of the authors of the study, said in an interview. Referring to the trial results, he noted that for at least 10 years, there has not been a new drug for heart failure that has had this impact on mortality, “so this is really quite an extraordinary finding.”

The availability of a new drug class, a neprilysin inhibitor, “opens up a new chapter in our treatment of heart failure,” said Dr. Mariell Jessup, professor of medicine at the University of Pennsylvania, Philadelphia, who was not involved in the study. “I’m very excited that we now have this new drug for use in our patients,” she said, pointing out that with the exception of ivabradine (Corlanor), approved in April, there has not been a new type of drug approved for heart failure in a long time.

Neprilysin is an endopeptidase that degrades several endogenous vasoactive peptides. Sacubitril “inhibits the breakdown of natriuretic peptides, among other vasoactive compounds, so the drug simultaneously blocks one of the neurohormonal systems that is abnormally activated in the setting of heart failure, and it also augments one of the neurohormonal systems that can be beneficial in patients with heart failure,” said Dr. Solomon, who is also director of noninvasive cardiology at Brigham and Women’s Hospital, Boston.

In PARADIGM-HF, conducted to determine if sacubitril-valsartan was superior to treatment with an ACE inhibitor, the recognized standard treatment for heart failure, a composite of death from cardiovascular causes or a first hospitalization for heart failure (the primary outcome), was 21.8% among those randomized to the combination vs. 26.5% of those on enalapril after a median 27-month follow-up, a highly statistically significant difference that represented a 20% reduced risk over the comparator (N. Engl. J. Med. 371:993-1004). A 20% reduced risk over enalapril was seen for the two components individually in the study, which was stopped early because of the magnitude of the effect over enalapril at a dose of the ACE inhibitor that the investigators pointed out had been shown to reduce mortality, compared with placebo.

Hypotension and nonserious cases of angioedema were higher among those on sacubitril-valsartan, while renal impairment, hyperkalemia, and cough were higher in the enalapril-treated patients.

As with ACE inhibitors, there is a small risk for angioedema, and while the number of cases was low in the study, physicians need to be aware of this issue, Dr. Solomon said. “To use this effectively, patients who are on ACE inhibitors or ARBs will need to be stopped, given 36 hours to wash out, and then started on this new agent,” he said.

In an interview, Dr. Jessup said that she hopes that physicians approach this new drug with the same caution they have with other drugs for patients with systolic heart failure and encouraged clinicians to carefully read the study and familiarize themselves with the prescribing information. Patients should not be taken off an ACE inhibitor and immediately switched to Entresto, she said.

She referred to the “famous” Canadian study that identified a significant increase in spironolactone prescriptions and in the rates of hyperkalemia and hyperkalemia-associated deaths after the positive Randomized Aldactone Evaluation Study (RALES) results were published in 1999 (N. Engl. J. Med. 2004;351:543-51). After the study, which found significant improvements in morbidity and mortality in patients with severe heart failure, was published, “physicians immediately started to put their patients on spironolactone and there was a spike in hyperkalemia and in deaths,” she noted.

The Entresto label includes a boxed warning about the risk of fetal toxicity, and the FDA statement recommends that health care professionals counsel patients about the risks to an unborn baby. One of the company’s postmarketing requirements is to conduct an epidemiologic study evaluating the incidence of angioedema in black patients treated with the combination, compared with another drug, according to the FDA’s approval letter.

The PARADIGM-HF results were reported in August 2014 at the European Society of Cardiology annual meeting in Barcelona. Dr. Solomon said that a large international study evaluating Entresto in patients with heart failure and preserved ejection fraction is currently underway.

The cost per day of Entresto is $12.50 (the wholesale acquisition cost), and the company anticipates that the product will be available in most pharmacies within weeks of the approval date, according to a Novartis spokesperson.

Valsartan, approved in 2001, is marketed as Diovan by Novartis and is available in generic form from Ranbaxy.

The PARADIGM-HF trial was funded by Novartis. Dr. Solomon, a member of the executive committee for the study, has received research support from Novartis for the conduct of this and other studies, and has served as a consultant to the company. Dr. Jessup had no related disclosures.

emechcatie@frontlinemedcom.com

The nature of U.S. transcatheter aortic valve replacement (TAVR) shifted dramatically in mid-June when the Food and Drug Administration, in two separate actions timed just days apart, approved marketing of next-generation models for the only two transcatheter aortic valve replacement systems on the U.S. market.

For inoperable or high-risk patients in came the Edwards Sapien 3 and the CoreValve Evolut R systems, and out went the Sapien XT and the original CoreValve. In the process the transcatheter aortic valve replacement (TAVR) procedures available to American patients on a routine basis became smaller – meaning more likely to use transfemoral approaches, less likely to cause substantial paravalvular leak, less likely to cause stroke, and in the case of the Evolut system also became repositionable and less likely to result in the need for a pacemaker.

With approvals of these two latest-generation devices, in both cases based on follow-up data of only 30 days, “we have really expanded the types of patients who can be treated with TAVR in the U.S., and we can do it with better products and get better outcomes. I am thrilled this technology will be available to patients,” said Dr. Jeffrey J. Popma, a lead investigator for the Evolut U.S. pivotal trial and professor of medicine at Harvard University in Boston.

Mitchel L. Zoler/Frontline Medical News

The pair of approvals were also notable as clear demonstration that the FDA was willing to base its decisions on 30-day follow-up data, a step closer to the approval model it applies to heart valves placed using open surgery. Perhaps most attention-grabbing of all, the FDA based its approval of the Evolut system on data from a total of 151 patients, with 60 coming from the ex-U.S. trial designed to secure a CE mark in Europe, and the other 91 patients the first ones enrolled in what was designed to be the U.S. pivotal trial for Evolut, with a planned enrollment of 250 patients that had almost fully filled by mid-June.

“This was a really good week for the FDA,” said Dr. Popma. “The FDA approved devices with reasonable assurance of safety and efficacy but without the burden of requiring 1 or more years follow-up. We are seeing a changed FDA,” he declared in an interview.

Although the full dataset for all 151 patients that the FDA used to approve the self-expanding Evolut system has not yet been released, investigators from the U.S. trial say data from their first 91 patients looked similar to the 60 patients in the CE trial, the results of which appeared in a poster in March at the annual scientific sessions of the American College of Cardiology.

The CE trial enrolled 60 symptomatic extreme- or high-risk patients at six centers in Australia, New Zealand, and the United Kingdom, who averaged 83 years old and had an average Society of Thoracic Surgeons predicted mortality estimate of 7%. Fifty-nine of the 60 patients (98%) had their TAVR done via the transfemoral route, and during 30-day follow-up no patients died and none had a stroke. The researchers identified a moderate or severe paravalvular leak in 3% of patients after 30 days, and 12% of patients had a new need for a pacemaker. By comparison, in the CoreValve pivotal trial for the first-generation version of this self-expanding valve, death occurred in 3% of patients after 30 days, major strokes in 4%, moderate or severe paravalvular leaks occurred in 9%, and 20% of patients by that point had required placement of a new pacemaker (N. Engl. J. Med. 2014;370:1790-8).

The striking reductions in more severe paravalvular leaks and in the need for a pacemaker likely related at least in part to the ability to reposition the Evolut valve during placement as long as the valve was not more than 80% deployed and as long as retrieval was not attempted more than three times.

Repositioning is “huge” said Dr. Mathew R. Williams, chief of adult cardiac surgery and director of interventional cardiology at New York University, and one of two lead investigators on the U.S. CoreValve Evolut R pivotal trial. “We don’t need to use it most of the time, but having that ability reduces stress and helps make the operator more comfortable,” he said in an interview. The more optimized positioning allowed by the recapture feature likely helped minimize both paravalvular leaks and the valve’s ability to trigger an arrhythmia and need for pacing. In the CE trial the operator used the repositioning function in 15 patients (25%) for a total of 22 repositioning events.

Like Dr. Popma, Dr. Williams welcomed the June 17 approval of the Sapien 3 TAVR system, based on 30-day outcomes from all 583 patients enrolled in the U.S. pivotal trial. Results from that study became public last March in a late-breaker report at the American College of Cardiology meeting.

Mitchel L. Zoler/Frontline Medical News

Sapien 3 treatment of high-risk, symptomatic patients, who averaged 83 years old and had a STS predicted mortality rate of 8.6%, resulted in a 2% mortality rate, a 1.5% stroke rate, a 3% rate of moderate or severe paravalvular leaks, and 13% of patients had a new need for a pacemaker, Dr. Susheel Kodali reported when he presented these data in March. Trial investigators were able to place the Sapien 3 aortic valve via a transfemoral approach in 491 of the 583 patients (84%) enrolled in the study. The adverse outcomes with Sapien 3 contrasted with rates for the prior Sapien XT TAVR system of 3.5% for 30-day mortality, 4.3% for strokes, and a 24% rate of moderate or severe paravalvular leak, said Dr. Kodali, director of the heart valve program at Columbia University in New York.

While the Sapien 3 and Evolut systems appeared to produce roughly similar outcomes for parameters like 30-day mortality, stroke, and paravalvular leak rates, with both systems outperforming what they displaced, the Evolut has two important differences, compared with Sapien 3. First, the Evolut is slightly smaller, with the ability to traverse arteries as narrow as 5 mm, whereas the minimum vessel size for Sapien 3 passage is 5.5 mm; second, Evolute is repositionable, while Sapien 3 is not.

The CoreValve Evolut R trials were sponsored by Medtronic. Dr. Popma has received research grants from and served as a speaker on behalf of Medtronic. He has also been a speaker for Abbott Vascular, Boston Scientific, Covidien, Cook Medical, and Direct Flow Medical and has received research support from five other companies. Dr. Williams has been a consultant to and received research support from Medtronic and has also been a consultant to Edwards and Direct Flow Medical. The Sapien 3 trial was sponsored by Edwards. Dr. Kodali has received research support from Edwards, has an equity interest in Thubrikar Aortic Valve, has received honoraria from St. Jude, and has served on the steering committee for trials sponsored by Claret Medical and Meril.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The nature of U.S. transcatheter aortic valve replacement (TAVR) shifted dramatically in mid-June when the Food and Drug Administration, in two separate actions timed just days apart, approved marketing of next-generation models for the only two transcatheter aortic valve replacement systems on the U.S. market.

For inoperable or high-risk patients in came the Edwards Sapien 3 and the CoreValve Evolut R systems, and out went the Sapien XT and the original CoreValve. In the process the transcatheter aortic valve replacement (TAVR) procedures available to American patients on a routine basis became smaller – meaning more likely to use transfemoral approaches, less likely to cause substantial paravalvular leak, less likely to cause stroke, and in the case of the Evolut system also became repositionable and less likely to result in the need for a pacemaker.

With approvals of these two latest-generation devices, in both cases based on follow-up data of only 30 days, “we have really expanded the types of patients who can be treated with TAVR in the U.S., and we can do it with better products and get better outcomes. I am thrilled this technology will be available to patients,” said Dr. Jeffrey J. Popma, a lead investigator for the Evolut U.S. pivotal trial and professor of medicine at Harvard University in Boston.

Mitchel L. Zoler/Frontline Medical News

The pair of approvals were also notable as clear demonstration that the FDA was willing to base its decisions on 30-day follow-up data, a step closer to the approval model it applies to heart valves placed using open surgery. Perhaps most attention-grabbing of all, the FDA based its approval of the Evolut system on data from a total of 151 patients, with 60 coming from the ex-U.S. trial designed to secure a CE mark in Europe, and the other 91 patients the first ones enrolled in what was designed to be the U.S. pivotal trial for Evolut, with a planned enrollment of 250 patients that had almost fully filled by mid-June.

“This was a really good week for the FDA,” said Dr. Popma. “The FDA approved devices with reasonable assurance of safety and efficacy but without the burden of requiring 1 or more years follow-up. We are seeing a changed FDA,” he declared in an interview.

Although the full dataset for all 151 patients that the FDA used to approve the self-expanding Evolut system has not yet been released, investigators from the U.S. trial say data from their first 91 patients looked similar to the 60 patients in the CE trial, the results of which appeared in a poster in March at the annual scientific sessions of the American College of Cardiology.

The CE trial enrolled 60 symptomatic extreme- or high-risk patients at six centers in Australia, New Zealand, and the United Kingdom, who averaged 83 years old and had an average Society of Thoracic Surgeons predicted mortality estimate of 7%. Fifty-nine of the 60 patients (98%) had their TAVR done via the transfemoral route, and during 30-day follow-up no patients died and none had a stroke. The researchers identified a moderate or severe paravalvular leak in 3% of patients after 30 days, and 12% of patients had a new need for a pacemaker. By comparison, in the CoreValve pivotal trial for the first-generation version of this self-expanding valve, death occurred in 3% of patients after 30 days, major strokes in 4%, moderate or severe paravalvular leaks occurred in 9%, and 20% of patients by that point had required placement of a new pacemaker (N. Engl. J. Med. 2014;370:1790-8).

The striking reductions in more severe paravalvular leaks and in the need for a pacemaker likely related at least in part to the ability to reposition the Evolut valve during placement as long as the valve was not more than 80% deployed and as long as retrieval was not attempted more than three times.

Repositioning is “huge” said Dr. Mathew R. Williams, chief of adult cardiac surgery and director of interventional cardiology at New York University, and one of two lead investigators on the U.S. CoreValve Evolut R pivotal trial. “We don’t need to use it most of the time, but having that ability reduces stress and helps make the operator more comfortable,” he said in an interview. The more optimized positioning allowed by the recapture feature likely helped minimize both paravalvular leaks and the valve’s ability to trigger an arrhythmia and need for pacing. In the CE trial the operator used the repositioning function in 15 patients (25%) for a total of 22 repositioning events.

Like Dr. Popma, Dr. Williams welcomed the June 17 approval of the Sapien 3 TAVR system, based on 30-day outcomes from all 583 patients enrolled in the U.S. pivotal trial. Results from that study became public last March in a late-breaker report at the American College of Cardiology meeting.

Mitchel L. Zoler/Frontline Medical News

Sapien 3 treatment of high-risk, symptomatic patients, who averaged 83 years old and had a STS predicted mortality rate of 8.6%, resulted in a 2% mortality rate, a 1.5% stroke rate, a 3% rate of moderate or severe paravalvular leaks, and 13% of patients had a new need for a pacemaker, Dr. Susheel Kodali reported when he presented these data in March. Trial investigators were able to place the Sapien 3 aortic valve via a transfemoral approach in 491 of the 583 patients (84%) enrolled in the study. The adverse outcomes with Sapien 3 contrasted with rates for the prior Sapien XT TAVR system of 3.5% for 30-day mortality, 4.3% for strokes, and a 24% rate of moderate or severe paravalvular leak, said Dr. Kodali, director of the heart valve program at Columbia University in New York.

While the Sapien 3 and Evolut systems appeared to produce roughly similar outcomes for parameters like 30-day mortality, stroke, and paravalvular leak rates, with both systems outperforming what they displaced, the Evolut has two important differences, compared with Sapien 3. First, the Evolut is slightly smaller, with the ability to traverse arteries as narrow as 5 mm, whereas the minimum vessel size for Sapien 3 passage is 5.5 mm; second, Evolute is repositionable, while Sapien 3 is not.

The CoreValve Evolut R trials were sponsored by Medtronic. Dr. Popma has received research grants from and served as a speaker on behalf of Medtronic. He has also been a speaker for Abbott Vascular, Boston Scientific, Covidien, Cook Medical, and Direct Flow Medical and has received research support from five other companies. Dr. Williams has been a consultant to and received research support from Medtronic and has also been a consultant to Edwards and Direct Flow Medical. The Sapien 3 trial was sponsored by Edwards. Dr. Kodali has received research support from Edwards, has an equity interest in Thubrikar Aortic Valve, has received honoraria from St. Jude, and has served on the steering committee for trials sponsored by Claret Medical and Meril.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The nature of U.S. transcatheter aortic valve replacement (TAVR) shifted dramatically in mid-June when the Food and Drug Administration, in two separate actions timed just days apart, approved marketing of next-generation models for the only two transcatheter aortic valve replacement systems on the U.S. market.

For inoperable or high-risk patients in came the Edwards Sapien 3 and the CoreValve Evolut R systems, and out went the Sapien XT and the original CoreValve. In the process the transcatheter aortic valve replacement (TAVR) procedures available to American patients on a routine basis became smaller – meaning more likely to use transfemoral approaches, less likely to cause substantial paravalvular leak, less likely to cause stroke, and in the case of the Evolut system also became repositionable and less likely to result in the need for a pacemaker.

With approvals of these two latest-generation devices, in both cases based on follow-up data of only 30 days, “we have really expanded the types of patients who can be treated with TAVR in the U.S., and we can do it with better products and get better outcomes. I am thrilled this technology will be available to patients,” said Dr. Jeffrey J. Popma, a lead investigator for the Evolut U.S. pivotal trial and professor of medicine at Harvard University in Boston.

Mitchel L. Zoler/Frontline Medical News

The pair of approvals were also notable as clear demonstration that the FDA was willing to base its decisions on 30-day follow-up data, a step closer to the approval model it applies to heart valves placed using open surgery. Perhaps most attention-grabbing of all, the FDA based its approval of the Evolut system on data from a total of 151 patients, with 60 coming from the ex-U.S. trial designed to secure a CE mark in Europe, and the other 91 patients the first ones enrolled in what was designed to be the U.S. pivotal trial for Evolut, with a planned enrollment of 250 patients that had almost fully filled by mid-June.

“This was a really good week for the FDA,” said Dr. Popma. “The FDA approved devices with reasonable assurance of safety and efficacy but without the burden of requiring 1 or more years follow-up. We are seeing a changed FDA,” he declared in an interview.

Although the full dataset for all 151 patients that the FDA used to approve the self-expanding Evolut system has not yet been released, investigators from the U.S. trial say data from their first 91 patients looked similar to the 60 patients in the CE trial, the results of which appeared in a poster in March at the annual scientific sessions of the American College of Cardiology.

The CE trial enrolled 60 symptomatic extreme- or high-risk patients at six centers in Australia, New Zealand, and the United Kingdom, who averaged 83 years old and had an average Society of Thoracic Surgeons predicted mortality estimate of 7%. Fifty-nine of the 60 patients (98%) had their TAVR done via the transfemoral route, and during 30-day follow-up no patients died and none had a stroke. The researchers identified a moderate or severe paravalvular leak in 3% of patients after 30 days, and 12% of patients had a new need for a pacemaker. By comparison, in the CoreValve pivotal trial for the first-generation version of this self-expanding valve, death occurred in 3% of patients after 30 days, major strokes in 4%, moderate or severe paravalvular leaks occurred in 9%, and 20% of patients by that point had required placement of a new pacemaker (N. Engl. J. Med. 2014;370:1790-8).

The striking reductions in more severe paravalvular leaks and in the need for a pacemaker likely related at least in part to the ability to reposition the Evolut valve during placement as long as the valve was not more than 80% deployed and as long as retrieval was not attempted more than three times.

Repositioning is “huge” said Dr. Mathew R. Williams, chief of adult cardiac surgery and director of interventional cardiology at New York University, and one of two lead investigators on the U.S. CoreValve Evolut R pivotal trial. “We don’t need to use it most of the time, but having that ability reduces stress and helps make the operator more comfortable,” he said in an interview. The more optimized positioning allowed by the recapture feature likely helped minimize both paravalvular leaks and the valve’s ability to trigger an arrhythmia and need for pacing. In the CE trial the operator used the repositioning function in 15 patients (25%) for a total of 22 repositioning events.

Like Dr. Popma, Dr. Williams welcomed the June 17 approval of the Sapien 3 TAVR system, based on 30-day outcomes from all 583 patients enrolled in the U.S. pivotal trial. Results from that study became public last March in a late-breaker report at the American College of Cardiology meeting.

Mitchel L. Zoler/Frontline Medical News

Sapien 3 treatment of high-risk, symptomatic patients, who averaged 83 years old and had a STS predicted mortality rate of 8.6%, resulted in a 2% mortality rate, a 1.5% stroke rate, a 3% rate of moderate or severe paravalvular leaks, and 13% of patients had a new need for a pacemaker, Dr. Susheel Kodali reported when he presented these data in March. Trial investigators were able to place the Sapien 3 aortic valve via a transfemoral approach in 491 of the 583 patients (84%) enrolled in the study. The adverse outcomes with Sapien 3 contrasted with rates for the prior Sapien XT TAVR system of 3.5% for 30-day mortality, 4.3% for strokes, and a 24% rate of moderate or severe paravalvular leak, said Dr. Kodali, director of the heart valve program at Columbia University in New York.

While the Sapien 3 and Evolut systems appeared to produce roughly similar outcomes for parameters like 30-day mortality, stroke, and paravalvular leak rates, with both systems outperforming what they displaced, the Evolut has two important differences, compared with Sapien 3. First, the Evolut is slightly smaller, with the ability to traverse arteries as narrow as 5 mm, whereas the minimum vessel size for Sapien 3 passage is 5.5 mm; second, Evolute is repositionable, while Sapien 3 is not.

The CoreValve Evolut R trials were sponsored by Medtronic. Dr. Popma has received research grants from and served as a speaker on behalf of Medtronic. He has also been a speaker for Abbott Vascular, Boston Scientific, Covidien, Cook Medical, and Direct Flow Medical and has received research support from five other companies. Dr. Williams has been a consultant to and received research support from Medtronic and has also been a consultant to Edwards and Direct Flow Medical. The Sapien 3 trial was sponsored by Edwards. Dr. Kodali has received research support from Edwards, has an equity interest in Thubrikar Aortic Valve, has received honoraria from St. Jude, and has served on the steering committee for trials sponsored by Claret Medical and Meril.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler