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Heart failure patients with preserved ejection who received an investigational agent LCA696 experienced a significant reduction of NT-proBNP at 12 weeks, compared with those who received valsartan, a randomized, multicenter, phase II trial demonstrated.
In addition, a reduction in left atrial size at 36 weeks was observed in patients in the LCA696 group, compared with those who received the angiotensin receptor blocker, researchers led by Dr. Scott Solomon of the cardiovascular division at Brigham and Women’s Hospital, Boston, reported in a study published online Aug. 26, 2012, in the Lancet. The study was simultaneously presented at the annual congress of the European Society of Cardiology.
"Present treatment of heart failure with preserved ejection fraction remains both symptom based and empiric, with no specific treatment approved for this indication," the researchers wrote. "Although ACE inhibitors and ARBs have been associated with symptom improvement, increased functional capacity, and reduction in admission to hospital in these patients, existing guidelines state that no treatment has convincingly been shown to reduce morbidity or mortality.
In a phase II trial known as PARAMOUNT, Dr. Solomon and his associates at 65 centers in 13 countries set out to assess the efficacy and safety of LCZ696 in 301 heart failure patients with preserved ejection fraction. LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that includes valsartan. The researchers hypothesized that LCA696 works by augmenting the active natriuretic peptides to improve myocardial relaxation and reduce hypertrophy. They recruited patients from November 2009 through March 2011.
Patients were eligible for PARAMOUNT if they were at least 40 years of age, had New York Heart Association class II-III heart failure, a left ventricular ejection fraction (LVEF) of 45% or higher, and an NT-proBNP greater than 400 pg/mL (Lancet 2012 Aug. 26 [http://dx.doi.org/10.1016/S0140-6736(12)61227-6]).
After randomization, 149 patients were started on 50 mg LCZ696 twice daily and 152 were started on 40 mg valsartan twice daily and titrated to their final doses of 200 mg LCZ696 twice daily or 160 mg valsartan twice daily over a period of 2-4 weeks. All patients were treated for 36 weeks; the primary end point was change in NT-proBNP from baseline to 12 weeks. This end point was selected "because raised natriuretic peptide concentrations are associated with adverse outcomes in patients with heart failure, including those with preserved ejection fraction, and reductions in NT-proBNP have been associated with improved outcomes in heart failure," the researchers explained.
Dr. Solomon and his associates reported complete data from 134 patients in the LCZ696 group and 132 patients in the valsartan group. The mean age of patients in both groups was 71 years and more than half (57%) were women. The change in NT-proBNP from baseline to week 12 was significantly reduced in patients in the LCZ696 group (from 783 to 605 pg/mL), compared with patients in the valsartan group (from 862 to 835 pg/mL). This translated into a significant ratio of change between the two treatment groups of 0.77. By week 36, the differences in NT-proBNP between the two groups were no longer significant.
After 36 weeks of treatment, patients in the LCZ696 group experienced significant reductions in left atrial volume and in left atrial dimension, compared with their counterparts in the valsartan group. "Left atrial size has been one of the most powerful predictors of outcome in heart failure, including heart failure with preserved ejection fraction," the researchers wrote. "The reported reduction in left atrial size offers support to the notion that LCZ696 had a sustained physiological benefit to 36 weeks."
LCZ696 was well tolerated and the proportion of patients who experienced one or more serious adverse events was similar between the two groups (15% among those in the LCZ696 group vs. 20% among those in the valsartan group).
Novartis funded the study. Dr. Solomon and six of his coauthors disclosed having received research support from, and have consulted for, Novartis, which is developing LCZ696. Three other coauthors are employed by the company.
The positive signals from PARAMOUNT will surely trigger a definitive trial. However, what will the comparator be? Valsartan, a drug not known to be effective for heart failure with preserved ejection fraction? This comparison would show whether there was an advantage to adding a neprilysin inhibitor, but would not provide evidence that valsartan was useful in patients with heart failure with preserved ejection fraction. ACE inhibitors, which seem to have some effect in disease with preserved ejection fraction? An increase in diuretic dose – perhaps the best method of improving symptoms in a congested patient? Or simply placebo? A placebo-controlled design would be the easiest to interpret, but could be confounded by the widespread use of rennin-angiotensin-aldosterone system antagonists in patients with heart failure with preserved ejection fraction, often for problems such as hypertension and peripheral edema. Such background treatment might not easily be withdrawn, rendering enrollment difficult.
Another trial, in patients with heart failure with reduced ejection fraction and raised plasma natriuretic peptides, will show whether LCZ696 is superior to enalapril. If trials in disease with both preserved and reduced ejection fraction are positive (and use the same comparator), cardiac phenotype could become less important than plasma concentration of natriuretic peptides for management of heart failure. However, if LCZ696 proves ineffective in heart failure with preserved ejection fraction, then more attention should be paid to targeting of comorbid disease, to the individual phenotypes, to the causes underlying disease with preserved ejection fraction, or to the aging process itself, which could be the ultimate determinant of prognosis in these patients.
Dr. John G.F. Cleland and Dr. Andrew L. Clark are with the department of cardiology at Castle Hill Hospital in Kingston-Upon-Hull, United Kingdom. These remarks were adapted from a editorial accompanying the PARAMOUNT report (Lancet 2012 Aug. 26 [ http://dx.doi.org/10.1016/ S0140-6736(12)61349-X ]). Dr. Cleland disclosed that he has received honoraria from Novartis. Dr. Clark stated that he has no relevant financial conflicts of interest.
The positive signals from PARAMOUNT will surely trigger a definitive trial. However, what will the comparator be? Valsartan, a drug not known to be effective for heart failure with preserved ejection fraction? This comparison would show whether there was an advantage to adding a neprilysin inhibitor, but would not provide evidence that valsartan was useful in patients with heart failure with preserved ejection fraction. ACE inhibitors, which seem to have some effect in disease with preserved ejection fraction? An increase in diuretic dose – perhaps the best method of improving symptoms in a congested patient? Or simply placebo? A placebo-controlled design would be the easiest to interpret, but could be confounded by the widespread use of rennin-angiotensin-aldosterone system antagonists in patients with heart failure with preserved ejection fraction, often for problems such as hypertension and peripheral edema. Such background treatment might not easily be withdrawn, rendering enrollment difficult.
Another trial, in patients with heart failure with reduced ejection fraction and raised plasma natriuretic peptides, will show whether LCZ696 is superior to enalapril. If trials in disease with both preserved and reduced ejection fraction are positive (and use the same comparator), cardiac phenotype could become less important than plasma concentration of natriuretic peptides for management of heart failure. However, if LCZ696 proves ineffective in heart failure with preserved ejection fraction, then more attention should be paid to targeting of comorbid disease, to the individual phenotypes, to the causes underlying disease with preserved ejection fraction, or to the aging process itself, which could be the ultimate determinant of prognosis in these patients.
Dr. John G.F. Cleland and Dr. Andrew L. Clark are with the department of cardiology at Castle Hill Hospital in Kingston-Upon-Hull, United Kingdom. These remarks were adapted from a editorial accompanying the PARAMOUNT report (Lancet 2012 Aug. 26 [ http://dx.doi.org/10.1016/ S0140-6736(12)61349-X ]). Dr. Cleland disclosed that he has received honoraria from Novartis. Dr. Clark stated that he has no relevant financial conflicts of interest.
The positive signals from PARAMOUNT will surely trigger a definitive trial. However, what will the comparator be? Valsartan, a drug not known to be effective for heart failure with preserved ejection fraction? This comparison would show whether there was an advantage to adding a neprilysin inhibitor, but would not provide evidence that valsartan was useful in patients with heart failure with preserved ejection fraction. ACE inhibitors, which seem to have some effect in disease with preserved ejection fraction? An increase in diuretic dose – perhaps the best method of improving symptoms in a congested patient? Or simply placebo? A placebo-controlled design would be the easiest to interpret, but could be confounded by the widespread use of rennin-angiotensin-aldosterone system antagonists in patients with heart failure with preserved ejection fraction, often for problems such as hypertension and peripheral edema. Such background treatment might not easily be withdrawn, rendering enrollment difficult.
Another trial, in patients with heart failure with reduced ejection fraction and raised plasma natriuretic peptides, will show whether LCZ696 is superior to enalapril. If trials in disease with both preserved and reduced ejection fraction are positive (and use the same comparator), cardiac phenotype could become less important than plasma concentration of natriuretic peptides for management of heart failure. However, if LCZ696 proves ineffective in heart failure with preserved ejection fraction, then more attention should be paid to targeting of comorbid disease, to the individual phenotypes, to the causes underlying disease with preserved ejection fraction, or to the aging process itself, which could be the ultimate determinant of prognosis in these patients.
Dr. John G.F. Cleland and Dr. Andrew L. Clark are with the department of cardiology at Castle Hill Hospital in Kingston-Upon-Hull, United Kingdom. These remarks were adapted from a editorial accompanying the PARAMOUNT report (Lancet 2012 Aug. 26 [ http://dx.doi.org/10.1016/ S0140-6736(12)61349-X ]). Dr. Cleland disclosed that he has received honoraria from Novartis. Dr. Clark stated that he has no relevant financial conflicts of interest.
Heart failure patients with preserved ejection who received an investigational agent LCA696 experienced a significant reduction of NT-proBNP at 12 weeks, compared with those who received valsartan, a randomized, multicenter, phase II trial demonstrated.
In addition, a reduction in left atrial size at 36 weeks was observed in patients in the LCA696 group, compared with those who received the angiotensin receptor blocker, researchers led by Dr. Scott Solomon of the cardiovascular division at Brigham and Women’s Hospital, Boston, reported in a study published online Aug. 26, 2012, in the Lancet. The study was simultaneously presented at the annual congress of the European Society of Cardiology.
"Present treatment of heart failure with preserved ejection fraction remains both symptom based and empiric, with no specific treatment approved for this indication," the researchers wrote. "Although ACE inhibitors and ARBs have been associated with symptom improvement, increased functional capacity, and reduction in admission to hospital in these patients, existing guidelines state that no treatment has convincingly been shown to reduce morbidity or mortality.
In a phase II trial known as PARAMOUNT, Dr. Solomon and his associates at 65 centers in 13 countries set out to assess the efficacy and safety of LCZ696 in 301 heart failure patients with preserved ejection fraction. LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that includes valsartan. The researchers hypothesized that LCA696 works by augmenting the active natriuretic peptides to improve myocardial relaxation and reduce hypertrophy. They recruited patients from November 2009 through March 2011.
Patients were eligible for PARAMOUNT if they were at least 40 years of age, had New York Heart Association class II-III heart failure, a left ventricular ejection fraction (LVEF) of 45% or higher, and an NT-proBNP greater than 400 pg/mL (Lancet 2012 Aug. 26 [http://dx.doi.org/10.1016/S0140-6736(12)61227-6]).
After randomization, 149 patients were started on 50 mg LCZ696 twice daily and 152 were started on 40 mg valsartan twice daily and titrated to their final doses of 200 mg LCZ696 twice daily or 160 mg valsartan twice daily over a period of 2-4 weeks. All patients were treated for 36 weeks; the primary end point was change in NT-proBNP from baseline to 12 weeks. This end point was selected "because raised natriuretic peptide concentrations are associated with adverse outcomes in patients with heart failure, including those with preserved ejection fraction, and reductions in NT-proBNP have been associated with improved outcomes in heart failure," the researchers explained.
Dr. Solomon and his associates reported complete data from 134 patients in the LCZ696 group and 132 patients in the valsartan group. The mean age of patients in both groups was 71 years and more than half (57%) were women. The change in NT-proBNP from baseline to week 12 was significantly reduced in patients in the LCZ696 group (from 783 to 605 pg/mL), compared with patients in the valsartan group (from 862 to 835 pg/mL). This translated into a significant ratio of change between the two treatment groups of 0.77. By week 36, the differences in NT-proBNP between the two groups were no longer significant.
After 36 weeks of treatment, patients in the LCZ696 group experienced significant reductions in left atrial volume and in left atrial dimension, compared with their counterparts in the valsartan group. "Left atrial size has been one of the most powerful predictors of outcome in heart failure, including heart failure with preserved ejection fraction," the researchers wrote. "The reported reduction in left atrial size offers support to the notion that LCZ696 had a sustained physiological benefit to 36 weeks."
LCZ696 was well tolerated and the proportion of patients who experienced one or more serious adverse events was similar between the two groups (15% among those in the LCZ696 group vs. 20% among those in the valsartan group).
Novartis funded the study. Dr. Solomon and six of his coauthors disclosed having received research support from, and have consulted for, Novartis, which is developing LCZ696. Three other coauthors are employed by the company.
Heart failure patients with preserved ejection who received an investigational agent LCA696 experienced a significant reduction of NT-proBNP at 12 weeks, compared with those who received valsartan, a randomized, multicenter, phase II trial demonstrated.
In addition, a reduction in left atrial size at 36 weeks was observed in patients in the LCA696 group, compared with those who received the angiotensin receptor blocker, researchers led by Dr. Scott Solomon of the cardiovascular division at Brigham and Women’s Hospital, Boston, reported in a study published online Aug. 26, 2012, in the Lancet. The study was simultaneously presented at the annual congress of the European Society of Cardiology.
"Present treatment of heart failure with preserved ejection fraction remains both symptom based and empiric, with no specific treatment approved for this indication," the researchers wrote. "Although ACE inhibitors and ARBs have been associated with symptom improvement, increased functional capacity, and reduction in admission to hospital in these patients, existing guidelines state that no treatment has convincingly been shown to reduce morbidity or mortality.
In a phase II trial known as PARAMOUNT, Dr. Solomon and his associates at 65 centers in 13 countries set out to assess the efficacy and safety of LCZ696 in 301 heart failure patients with preserved ejection fraction. LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that includes valsartan. The researchers hypothesized that LCA696 works by augmenting the active natriuretic peptides to improve myocardial relaxation and reduce hypertrophy. They recruited patients from November 2009 through March 2011.
Patients were eligible for PARAMOUNT if they were at least 40 years of age, had New York Heart Association class II-III heart failure, a left ventricular ejection fraction (LVEF) of 45% or higher, and an NT-proBNP greater than 400 pg/mL (Lancet 2012 Aug. 26 [http://dx.doi.org/10.1016/S0140-6736(12)61227-6]).
After randomization, 149 patients were started on 50 mg LCZ696 twice daily and 152 were started on 40 mg valsartan twice daily and titrated to their final doses of 200 mg LCZ696 twice daily or 160 mg valsartan twice daily over a period of 2-4 weeks. All patients were treated for 36 weeks; the primary end point was change in NT-proBNP from baseline to 12 weeks. This end point was selected "because raised natriuretic peptide concentrations are associated with adverse outcomes in patients with heart failure, including those with preserved ejection fraction, and reductions in NT-proBNP have been associated with improved outcomes in heart failure," the researchers explained.
Dr. Solomon and his associates reported complete data from 134 patients in the LCZ696 group and 132 patients in the valsartan group. The mean age of patients in both groups was 71 years and more than half (57%) were women. The change in NT-proBNP from baseline to week 12 was significantly reduced in patients in the LCZ696 group (from 783 to 605 pg/mL), compared with patients in the valsartan group (from 862 to 835 pg/mL). This translated into a significant ratio of change between the two treatment groups of 0.77. By week 36, the differences in NT-proBNP between the two groups were no longer significant.
After 36 weeks of treatment, patients in the LCZ696 group experienced significant reductions in left atrial volume and in left atrial dimension, compared with their counterparts in the valsartan group. "Left atrial size has been one of the most powerful predictors of outcome in heart failure, including heart failure with preserved ejection fraction," the researchers wrote. "The reported reduction in left atrial size offers support to the notion that LCZ696 had a sustained physiological benefit to 36 weeks."
LCZ696 was well tolerated and the proportion of patients who experienced one or more serious adverse events was similar between the two groups (15% among those in the LCZ696 group vs. 20% among those in the valsartan group).
Novartis funded the study. Dr. Solomon and six of his coauthors disclosed having received research support from, and have consulted for, Novartis, which is developing LCZ696. Three other coauthors are employed by the company.
FROM THE LANCET
Major Finding: The change in NT-proBNP from baseline to week 12 was significantly reduced in patients in the LCZ696 group (from 783 to 605 pg/mL), compared with patients in the valsartan group (from 862 to 835 pg/mL). This translated into a ratio of change of 0.77.
Data Source: Data are from a phase II randomized trial of 301 heart failure patients with preserved ejection fraction that compared the angiotensin receptor neprilysin inhibitor LCZ696 with valsartan.
Disclosures: Novartis funded the study. Dr. Solomon and six of his coauthors disclosed having received research support from, and have consulted for, Novartis. Three other coauthors are employed by the company.