Trial explores ranolazine in pulmonary hypertension-linked heart failure

CHICAGO – The antianginal drug ranolazine improved hemodynamics and functional status in patients with pulmonary hypertension associated with heart failure with preserved ejection fraction in a proof-of-concept trial of just 10 patients.

Six months of twice-daily ranolazine (Ranexa) decreased baseline mean pulmonary arterial pressure (PAP) by 41% and mean pulmonary capillary wedge pressure (PCWP) by 40% in this hard-to-treat population.

Half of the patients improved from World Health Organization functional class III to II, and no patient deteriorated.

"This pilot study suggests ranolazine might be a promising treatment for pulmonary hypertension associated with heart failure with preserved EF [ejection fraction]," Dr. Harrison Farber said during a late-breaking abstract session at the annual meeting of the American College of Chest Physicians.

Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF) is an increasingly common condition, but currently no effective treatment exists for HFpEF alone or PH associated with it. Disappointing results were reported earlier this year for sildenafil (Viagra) in patients with diastolic heart failure in the RELAX trial.

"This pilot study suggests ranolazine might be a promising treatment for pulmonary hypertension associated with heart failure with preserved EF [ejection fraction]..."

Ranolazine is approved for the treatment of chronic angina, and was selected because animal and human data suggest it reduces left ventricular wall stiffness and mechanical dysfunction in conditions associated with diastolic dysfunction, said Dr. Farber, director of the pulmonary hypertension center, Boston University.

To ensure patients in the single-center, open-label, prospective, non–placebo controlled trial truly had HFpEF, entry criteria were fairly strict. They included left ventricular ejection fraction (LVEF) greater than 50% by echocardiogram, mean PAP of at least 25 mm Hg, PCWP between 18 mm Hg and 30 mm Hg, and a pulmonary arterial diastolic pressure-PCWP gradient of 10 mm Hg or less.

The eight women and two men received twice-daily ranolazine 500 mg, titrated to 1,000 mg twice daily, as tolerated. Their mean age was 63 years, mean body mass index 41.6 kg/m², and 80% had diabetes.

At 6 months, mean PAP dropped from 39 mm Hg to 23 mm Hg, mean PCWP from 22 mm Hg to 13 mm HG, and 6-minute walk distances increased from 286 meters to 319 meters, Dr. Farber said.

"Seven of the subjects have actually continued ranolazine for a year or greater and the 6-minute-walk and functional class improvements have actually been maintained to this point," he said.

No significant changes were seen in cardiac index, pulmonary vascular resistance, echocardiogram parameters, brain natriuretic peptide, N-terminal pro-BNP, or troponin.

There was, however, a significant reduction in LV mass at 6 months on blinded MRI evaluation, and a trend for improved right ventricular ejection fraction and decrease in RV mass, he said.

Session comoderator Dr. Namita Sood with Ohio State University in Columbus congratulated the authors on "a courageous study" in an understudied population and asked whether the drop in PAP and PCWP was a consequence of improved LV and diastolic dysfunction or whether ranolazine may have a direct effect on pulmonary vasculature.

Dr. Farber responded, "To be honest, the answer is I don’t know, but since the two were sort of in concert, my guess would be – although it was a small study and I can’t tell you for sure – it was more of an effect on the left ventricle and a concomitant drop in the pulmonary pressures."

Some audience members questioned whether the investigators targeted the right population since patients did not appear to be sufficiently diuresed at entry. Dr. Farber said the exploratory analysis was done to determine if a signal was present and that tighter controls would be needed if they go forward. Diuretics were not controlled in the 10 patients, although no dramatic changes in doses occurred. No patients were on nitrates.

One patient discontinued treatment because of the worsening of an existing symptomatic bradyarrhythmia. Otherwise, the drug was well tolerated, with the only other side effect being headache that went away in the first week of treatment, he said.

Dr. Farber and his coauthors reported grant support from Gilead Sciences, which makes ranolazine.

[email protected]

This article was updated 11/7/13.

CHICAGO – The antianginal drug ranolazine improved hemodynamics and functional status in patients with pulmonary hypertension associated with heart failure with preserved ejection fraction in a proof-of-concept trial of just 10 patients.

Six months of twice-daily ranolazine (Ranexa) decreased baseline mean pulmonary arterial pressure (PAP) by 41% and mean pulmonary capillary wedge pressure (PCWP) by 40% in this hard-to-treat population.

Half of the patients improved from World Health Organization functional class III to II, and no patient deteriorated.

"This pilot study suggests ranolazine might be a promising treatment for pulmonary hypertension associated with heart failure with preserved EF [ejection fraction]," Dr. Harrison Farber said during a late-breaking abstract session at the annual meeting of the American College of Chest Physicians.

Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF) is an increasingly common condition, but currently no effective treatment exists for HFpEF alone or PH associated with it. Disappointing results were reported earlier this year for sildenafil (Viagra) in patients with diastolic heart failure in the RELAX trial.

"This pilot study suggests ranolazine might be a promising treatment for pulmonary hypertension associated with heart failure with preserved EF [ejection fraction]..."

Ranolazine is approved for the treatment of chronic angina, and was selected because animal and human data suggest it reduces left ventricular wall stiffness and mechanical dysfunction in conditions associated with diastolic dysfunction, said Dr. Farber, director of the pulmonary hypertension center, Boston University.

To ensure patients in the single-center, open-label, prospective, non–placebo controlled trial truly had HFpEF, entry criteria were fairly strict. They included left ventricular ejection fraction (LVEF) greater than 50% by echocardiogram, mean PAP of at least 25 mm Hg, PCWP between 18 mm Hg and 30 mm Hg, and a pulmonary arterial diastolic pressure-PCWP gradient of 10 mm Hg or less.

The eight women and two men received twice-daily ranolazine 500 mg, titrated to 1,000 mg twice daily, as tolerated. Their mean age was 63 years, mean body mass index 41.6 kg/m², and 80% had diabetes.

At 6 months, mean PAP dropped from 39 mm Hg to 23 mm Hg, mean PCWP from 22 mm Hg to 13 mm HG, and 6-minute walk distances increased from 286 meters to 319 meters, Dr. Farber said.

"Seven of the subjects have actually continued ranolazine for a year or greater and the 6-minute-walk and functional class improvements have actually been maintained to this point," he said.

No significant changes were seen in cardiac index, pulmonary vascular resistance, echocardiogram parameters, brain natriuretic peptide, N-terminal pro-BNP, or troponin.

There was, however, a significant reduction in LV mass at 6 months on blinded MRI evaluation, and a trend for improved right ventricular ejection fraction and decrease in RV mass, he said.

Session comoderator Dr. Namita Sood with Ohio State University in Columbus congratulated the authors on "a courageous study" in an understudied population and asked whether the drop in PAP and PCWP was a consequence of improved LV and diastolic dysfunction or whether ranolazine may have a direct effect on pulmonary vasculature.

Dr. Farber responded, "To be honest, the answer is I don’t know, but since the two were sort of in concert, my guess would be – although it was a small study and I can’t tell you for sure – it was more of an effect on the left ventricle and a concomitant drop in the pulmonary pressures."

Some audience members questioned whether the investigators targeted the right population since patients did not appear to be sufficiently diuresed at entry. Dr. Farber said the exploratory analysis was done to determine if a signal was present and that tighter controls would be needed if they go forward. Diuretics were not controlled in the 10 patients, although no dramatic changes in doses occurred. No patients were on nitrates.

One patient discontinued treatment because of the worsening of an existing symptomatic bradyarrhythmia. Otherwise, the drug was well tolerated, with the only other side effect being headache that went away in the first week of treatment, he said.

Dr. Farber and his coauthors reported grant support from Gilead Sciences, which makes ranolazine.

[email protected]

This article was updated 11/7/13.

CHICAGO – The antianginal drug ranolazine improved hemodynamics and functional status in patients with pulmonary hypertension associated with heart failure with preserved ejection fraction in a proof-of-concept trial of just 10 patients.

Six months of twice-daily ranolazine (Ranexa) decreased baseline mean pulmonary arterial pressure (PAP) by 41% and mean pulmonary capillary wedge pressure (PCWP) by 40% in this hard-to-treat population.

Half of the patients improved from World Health Organization functional class III to II, and no patient deteriorated.

"This pilot study suggests ranolazine might be a promising treatment for pulmonary hypertension associated with heart failure with preserved EF [ejection fraction]," Dr. Harrison Farber said during a late-breaking abstract session at the annual meeting of the American College of Chest Physicians.

Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF) is an increasingly common condition, but currently no effective treatment exists for HFpEF alone or PH associated with it. Disappointing results were reported earlier this year for sildenafil (Viagra) in patients with diastolic heart failure in the RELAX trial.

"This pilot study suggests ranolazine might be a promising treatment for pulmonary hypertension associated with heart failure with preserved EF [ejection fraction]..."

Ranolazine is approved for the treatment of chronic angina, and was selected because animal and human data suggest it reduces left ventricular wall stiffness and mechanical dysfunction in conditions associated with diastolic dysfunction, said Dr. Farber, director of the pulmonary hypertension center, Boston University.

To ensure patients in the single-center, open-label, prospective, non–placebo controlled trial truly had HFpEF, entry criteria were fairly strict. They included left ventricular ejection fraction (LVEF) greater than 50% by echocardiogram, mean PAP of at least 25 mm Hg, PCWP between 18 mm Hg and 30 mm Hg, and a pulmonary arterial diastolic pressure-PCWP gradient of 10 mm Hg or less.

The eight women and two men received twice-daily ranolazine 500 mg, titrated to 1,000 mg twice daily, as tolerated. Their mean age was 63 years, mean body mass index 41.6 kg/m², and 80% had diabetes.

At 6 months, mean PAP dropped from 39 mm Hg to 23 mm Hg, mean PCWP from 22 mm Hg to 13 mm HG, and 6-minute walk distances increased from 286 meters to 319 meters, Dr. Farber said.

"Seven of the subjects have actually continued ranolazine for a year or greater and the 6-minute-walk and functional class improvements have actually been maintained to this point," he said.

No significant changes were seen in cardiac index, pulmonary vascular resistance, echocardiogram parameters, brain natriuretic peptide, N-terminal pro-BNP, or troponin.

There was, however, a significant reduction in LV mass at 6 months on blinded MRI evaluation, and a trend for improved right ventricular ejection fraction and decrease in RV mass, he said.

Session comoderator Dr. Namita Sood with Ohio State University in Columbus congratulated the authors on "a courageous study" in an understudied population and asked whether the drop in PAP and PCWP was a consequence of improved LV and diastolic dysfunction or whether ranolazine may have a direct effect on pulmonary vasculature.

Dr. Farber responded, "To be honest, the answer is I don’t know, but since the two were sort of in concert, my guess would be – although it was a small study and I can’t tell you for sure – it was more of an effect on the left ventricle and a concomitant drop in the pulmonary pressures."

Some audience members questioned whether the investigators targeted the right population since patients did not appear to be sufficiently diuresed at entry. Dr. Farber said the exploratory analysis was done to determine if a signal was present and that tighter controls would be needed if they go forward. Diuretics were not controlled in the 10 patients, although no dramatic changes in doses occurred. No patients were on nitrates.

One patient discontinued treatment because of the worsening of an existing symptomatic bradyarrhythmia. Otherwise, the drug was well tolerated, with the only other side effect being headache that went away in the first week of treatment, he said.

Dr. Farber and his coauthors reported grant support from Gilead Sciences, which makes ranolazine.

[email protected]

This article was updated 11/7/13.