American College of Chest Physicians (ACCP): Annual International Scientific Assembly (CHEST 2012)

ATLANTA – The investigational drug riociguat significantly improved 6-minute walk distance in patients with symptomatic pulmonary arterial hypertension in the phase III PATENT-1 trial.

Of 443 patients who participated in the randomized, double-blind trial, those who received active treatment with the novel oral soluble guanylate cyclase (sCG) stimulator experienced a 36-m improvement in 6-minute walk distance, compared with those who received placebo, after 12 weeks. This "clinically meaningful as well as highly statistically significant" improvement was evident in both treatment-naive patients and pretreated patients, who each comprised about 50% of the study population, Dr. Hossein Ghofrani reported at the annual meeting of the American College of Chest Physicians.

Treatment also resulted in "significant and robust" improvements on several secondary endpoints, including pulmonary vascular resistance, N-terminal prohormone brain natriuretic peptide, World Health Organization functional class, time to clinical worsening, and Borg dyspnea score, said Dr. Ghofrani of University Hospital Giessen and Marburg in Giessen, Germany.

For pulmonary vascular resistance, for example, a 29% reduction was noted in the treatment group, compared with the placebo group. This translated into a 226-dyne reduction, with more than a half liter increase in cardiac output and a highly statistically significant reduction of 432 ng/L in the serum biomarker, he said.

The findings suggest that riociguat – the first of the new sGC-stimulator class of drugs – represents a new treatment option for patients with PAH.

Riociguat has a dual mode of action, as it synergizes with endogenous nitric oxide and directly stimulates sGC independent of nitric oxide availability. Therefore, it may restore the NO-sGC-cGMP pathway, Dr. Ghofrani explained.

"I think it is well appreciated that, despite the major achievement over the past two decades in the field of the treatment of PAH, there is still a high mortality in this devastating progressive disease, which welcomes this representative of a new class of drug to the therapeutic armamentarium of this very special disease form," he said, noting that study of riociguat is ongoing.

Patients who participated in the multicenter, multinational PATENT-1 trial (Pulmonary Arterial Hypertension sGC-Stimulator Trial) were adults aged 18-80 years (with an average of about 50 years), including both treatment naive patients and patients pretreated with endothelin receptor antagonists or prostanoids. They were randomized to receive placebo or treatment with riociguat at a starting dose of 1 mg three times daily titrated over 8 weeks in 0.5-mg increments up to 2.5 mg three times daily.

The completion rate among participants was high, at about 93% for the treatment group and 88% for the placebo group, with 90% in the treatment group achieving the maximum dose, which reflected the tolerability of the drug, Dr. Ghofrani said.

The drug was also safe, with only 1.2% of patients experiencing an adverse event, although it is important to note that the observation period was relatively short, he added.

The 10 most frequently reported treatment-emergent adverse events occurring more often in the treatment group were headache, dyspepsia, peripheral edema, nausea, dizziness, diarrhea, nasopharyngitis, dyspnea, cough, and vomiting, he said.

When combined with phase II study data, PATENT-1 now has 5 years of follow-up, and it appears that the treatment effect is preserved for up to 12 months. Those who completed phase III had the option of continuing in an open-label phase, and results from that study are expected to be reported next year.

Additionally, riociguat was found in the phase III CHEST-1 trial to improve 6-minute walk distance in patients with inoperable chronic thromboembolic pulmonary hypertension. Thus, riociguat appears to be the first-ever drug to demonstrate robust efficacy in two distinct pulmonary hypertension groups, Dr. Ghofrani said.

The PATENT and CHEST trials are supported by Bayer, the maker of riocigualt. Dr. Ghofrani disclosed that he has received sponsored grants over the past 3 years from the German Research Foundation, Excellence Cluster Cardiopulmonary Research, and the Germany Ministry for Education and Research. He has also received industry-sponsored grants over the last 3 years from Bayer HealthCare AG, Aires, Encysive/Pfizer, and Novartis, and has received payment for consulting and serving on speaker bureaus and/or advisory committees for Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Novartis, and GlaxoSmithKline.

ATLANTA – The investigational drug riociguat significantly improved 6-minute walk distance in patients with symptomatic pulmonary arterial hypertension in the phase III PATENT-1 trial.

Of 443 patients who participated in the randomized, double-blind trial, those who received active treatment with the novel oral soluble guanylate cyclase (sCG) stimulator experienced a 36-m improvement in 6-minute walk distance, compared with those who received placebo, after 12 weeks. This "clinically meaningful as well as highly statistically significant" improvement was evident in both treatment-naive patients and pretreated patients, who each comprised about 50% of the study population, Dr. Hossein Ghofrani reported at the annual meeting of the American College of Chest Physicians.

Treatment also resulted in "significant and robust" improvements on several secondary endpoints, including pulmonary vascular resistance, N-terminal prohormone brain natriuretic peptide, World Health Organization functional class, time to clinical worsening, and Borg dyspnea score, said Dr. Ghofrani of University Hospital Giessen and Marburg in Giessen, Germany.

For pulmonary vascular resistance, for example, a 29% reduction was noted in the treatment group, compared with the placebo group. This translated into a 226-dyne reduction, with more than a half liter increase in cardiac output and a highly statistically significant reduction of 432 ng/L in the serum biomarker, he said.

The findings suggest that riociguat – the first of the new sGC-stimulator class of drugs – represents a new treatment option for patients with PAH.

Riociguat has a dual mode of action, as it synergizes with endogenous nitric oxide and directly stimulates sGC independent of nitric oxide availability. Therefore, it may restore the NO-sGC-cGMP pathway, Dr. Ghofrani explained.

"I think it is well appreciated that, despite the major achievement over the past two decades in the field of the treatment of PAH, there is still a high mortality in this devastating progressive disease, which welcomes this representative of a new class of drug to the therapeutic armamentarium of this very special disease form," he said, noting that study of riociguat is ongoing.

Patients who participated in the multicenter, multinational PATENT-1 trial (Pulmonary Arterial Hypertension sGC-Stimulator Trial) were adults aged 18-80 years (with an average of about 50 years), including both treatment naive patients and patients pretreated with endothelin receptor antagonists or prostanoids. They were randomized to receive placebo or treatment with riociguat at a starting dose of 1 mg three times daily titrated over 8 weeks in 0.5-mg increments up to 2.5 mg three times daily.

The completion rate among participants was high, at about 93% for the treatment group and 88% for the placebo group, with 90% in the treatment group achieving the maximum dose, which reflected the tolerability of the drug, Dr. Ghofrani said.

The drug was also safe, with only 1.2% of patients experiencing an adverse event, although it is important to note that the observation period was relatively short, he added.

The 10 most frequently reported treatment-emergent adverse events occurring more often in the treatment group were headache, dyspepsia, peripheral edema, nausea, dizziness, diarrhea, nasopharyngitis, dyspnea, cough, and vomiting, he said.

When combined with phase II study data, PATENT-1 now has 5 years of follow-up, and it appears that the treatment effect is preserved for up to 12 months. Those who completed phase III had the option of continuing in an open-label phase, and results from that study are expected to be reported next year.

Additionally, riociguat was found in the phase III CHEST-1 trial to improve 6-minute walk distance in patients with inoperable chronic thromboembolic pulmonary hypertension. Thus, riociguat appears to be the first-ever drug to demonstrate robust efficacy in two distinct pulmonary hypertension groups, Dr. Ghofrani said.

The PATENT and CHEST trials are supported by Bayer, the maker of riocigualt. Dr. Ghofrani disclosed that he has received sponsored grants over the past 3 years from the German Research Foundation, Excellence Cluster Cardiopulmonary Research, and the Germany Ministry for Education and Research. He has also received industry-sponsored grants over the last 3 years from Bayer HealthCare AG, Aires, Encysive/Pfizer, and Novartis, and has received payment for consulting and serving on speaker bureaus and/or advisory committees for Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Novartis, and GlaxoSmithKline.

ATLANTA – The investigational drug riociguat significantly improved 6-minute walk distance in patients with symptomatic pulmonary arterial hypertension in the phase III PATENT-1 trial.

Of 443 patients who participated in the randomized, double-blind trial, those who received active treatment with the novel oral soluble guanylate cyclase (sCG) stimulator experienced a 36-m improvement in 6-minute walk distance, compared with those who received placebo, after 12 weeks. This "clinically meaningful as well as highly statistically significant" improvement was evident in both treatment-naive patients and pretreated patients, who each comprised about 50% of the study population, Dr. Hossein Ghofrani reported at the annual meeting of the American College of Chest Physicians.

Treatment also resulted in "significant and robust" improvements on several secondary endpoints, including pulmonary vascular resistance, N-terminal prohormone brain natriuretic peptide, World Health Organization functional class, time to clinical worsening, and Borg dyspnea score, said Dr. Ghofrani of University Hospital Giessen and Marburg in Giessen, Germany.

For pulmonary vascular resistance, for example, a 29% reduction was noted in the treatment group, compared with the placebo group. This translated into a 226-dyne reduction, with more than a half liter increase in cardiac output and a highly statistically significant reduction of 432 ng/L in the serum biomarker, he said.

The findings suggest that riociguat – the first of the new sGC-stimulator class of drugs – represents a new treatment option for patients with PAH.

Riociguat has a dual mode of action, as it synergizes with endogenous nitric oxide and directly stimulates sGC independent of nitric oxide availability. Therefore, it may restore the NO-sGC-cGMP pathway, Dr. Ghofrani explained.

"I think it is well appreciated that, despite the major achievement over the past two decades in the field of the treatment of PAH, there is still a high mortality in this devastating progressive disease, which welcomes this representative of a new class of drug to the therapeutic armamentarium of this very special disease form," he said, noting that study of riociguat is ongoing.

Patients who participated in the multicenter, multinational PATENT-1 trial (Pulmonary Arterial Hypertension sGC-Stimulator Trial) were adults aged 18-80 years (with an average of about 50 years), including both treatment naive patients and patients pretreated with endothelin receptor antagonists or prostanoids. They were randomized to receive placebo or treatment with riociguat at a starting dose of 1 mg three times daily titrated over 8 weeks in 0.5-mg increments up to 2.5 mg three times daily.

The completion rate among participants was high, at about 93% for the treatment group and 88% for the placebo group, with 90% in the treatment group achieving the maximum dose, which reflected the tolerability of the drug, Dr. Ghofrani said.

The drug was also safe, with only 1.2% of patients experiencing an adverse event, although it is important to note that the observation period was relatively short, he added.

The 10 most frequently reported treatment-emergent adverse events occurring more often in the treatment group were headache, dyspepsia, peripheral edema, nausea, dizziness, diarrhea, nasopharyngitis, dyspnea, cough, and vomiting, he said.

When combined with phase II study data, PATENT-1 now has 5 years of follow-up, and it appears that the treatment effect is preserved for up to 12 months. Those who completed phase III had the option of continuing in an open-label phase, and results from that study are expected to be reported next year.

Additionally, riociguat was found in the phase III CHEST-1 trial to improve 6-minute walk distance in patients with inoperable chronic thromboembolic pulmonary hypertension. Thus, riociguat appears to be the first-ever drug to demonstrate robust efficacy in two distinct pulmonary hypertension groups, Dr. Ghofrani said.

The PATENT and CHEST trials are supported by Bayer, the maker of riocigualt. Dr. Ghofrani disclosed that he has received sponsored grants over the past 3 years from the German Research Foundation, Excellence Cluster Cardiopulmonary Research, and the Germany Ministry for Education and Research. He has also received industry-sponsored grants over the last 3 years from Bayer HealthCare AG, Aires, Encysive/Pfizer, and Novartis, and has received payment for consulting and serving on speaker bureaus and/or advisory committees for Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Novartis, and GlaxoSmithKline.

ATLANTA – The perception of dyspnea among patients with chronic obstructive pulmonary disorder plays a bigger role in quality of life, functional status, and depression than do objective measures of disease severity, according to findings from cross-sectional study involving 158 patients.

The findings suggest that assessing and addressing dyspnea in COPD patients could play an important role in improving quality of life outcomes, Dr. Sandra Adams reported at the annual meeting of the American College of Chest Physicians.

The patients included in this analysis are part of the CASCADE study, a 2-year longitudinal observational study of genes and depression in COPD. They completed spirometry, the modified Medical Research Council (mMRC) dyspnea scale, questions related to exacerbation risk within the last year, the Chronic Respiratory Questionnaire (CRQ), a nine-item depression interview, the Personal Health Questionnaire (PHQ-9), and a 6-minute walk test at baseline.

Study participants had a mean age of about 67 years, about 25% were women, 40% were on supplemental oxygen, and the mean forced expiratory volume in 1 second (FEV₁) percent predicted was 43%. Exacerbations were self-reported.

More than 60% had a self-reported physician diagnosis of depression.

About 20% of the patients were found to be grade A patients, based on the revised Global Initiative for Chronic Obstructive Lung Disease (GOLD) released in December 2011, about 10% were grade B patients, about 20% were grade C patients, and about 50% were grade D patients, said Dr. Adams of the University of Texas Health Science Center, San Antonio.

Patients with grade A disease have mild disease severity, airflow limitation, and few exacerbations; those with grade B disease are similar to those with grade A, except they have more symptoms (in this study, the grade B patients had no exacerbations). Those with grade C disease have minimal symptoms, severe airflow limitation, and/or two or more exacerbations each year; those with grade D disease are similar to those with grade C disease, except they have more symptoms.

"One thing we were actually really surprised to find is that the group of A and C with minimal symptoms may be a lot more similar than we think, whereas D and B with the severe symptoms – even though they have significant differences in exacerbations and/or airflow limitation, may be very similar," she said.

Indeed, no differences on the various measures used in this study were seen between the A and C patients, and between the B and D patients. But when the A and C patients were combined and compared with the combined group of B and D patients, significant differences emerged for every measure.

"Again, the big difference is symptoms; A and C have minimal symptoms and B and D have severe symptoms," Dr. Adams said.

As it turned out, grades A and C patients had significantly higher CRQ scores (higher scores are better) than did grades B and D patients (mean of 105 and 98 for A and C vs. 80 and 84 for B and D, respectively). Grades A and C also had statistically and clinically significantly greater 6-minute walk test distances, Dr. Adams noted.

On a physical function measure of steps walked in a day, the A and C patients averaged 7,900, and the B and D patients averaged only 4,800, she added.

That’s 3,900 fewer steps despite inclusion of B-group patient (10% of the total study population) in the B/D combined group, Dr. Adams noted.

"Again ... grade B had relatively normal lung function and no exacerbations, but yet they’re severely dyspneic," she noted.

As for depression, the history was similar across all grades, although more grade B and D patients than A and C patients had PHQ-9 scores of 10 or greater, which indicates significant depression. On linear regression, an mMRC dyspnea scale score of 2 or higher was associated with a significant increase in depression (odds ratio, 2.8).

"So the bottom line to this is grades A and C have similar levels of depression, quality of life, physical function, and physical activity despite significant differences in FEV₁ percent predicted and and/or the number of exacerbations," she said, explaining that it appears that the perception of dyspnea is the main factor associated with these outcomes.

"And, in fact, those who report severe dyspnea may be even more limited than those with frequent exacerbations," she said.

What are the clinical implications of the findings?

"We ask our patients, ‘How are you doing? How is your shortness of breath?’ but actually getting an assessment and also trying to really address the dyspnea in addition to the exacerbations is going to be really key in this population," Dr. Adams concluded.

Dr. Adams disclosed that she has received grant money for research from the Chest Foundation, the NIH, the Veterans Affairs Cooperative Studies Program, Bayer, Boehringer Ingelheim, Centocor, GlaxoSmithKline, Novartis, Pfizer, and Schering-Plough. She also has received honoraria for speaking from ABCam, Altana, AstraZeneca, Aventis, Bayer, Boehringer Ingelheim, GSK, Novartis, AG, Mycomed, Pfizer, and Schering-Plough.

ATLANTA – The perception of dyspnea among patients with chronic obstructive pulmonary disorder plays a bigger role in quality of life, functional status, and depression than do objective measures of disease severity, according to findings from cross-sectional study involving 158 patients.

The findings suggest that assessing and addressing dyspnea in COPD patients could play an important role in improving quality of life outcomes, Dr. Sandra Adams reported at the annual meeting of the American College of Chest Physicians.

The patients included in this analysis are part of the CASCADE study, a 2-year longitudinal observational study of genes and depression in COPD. They completed spirometry, the modified Medical Research Council (mMRC) dyspnea scale, questions related to exacerbation risk within the last year, the Chronic Respiratory Questionnaire (CRQ), a nine-item depression interview, the Personal Health Questionnaire (PHQ-9), and a 6-minute walk test at baseline.

Study participants had a mean age of about 67 years, about 25% were women, 40% were on supplemental oxygen, and the mean forced expiratory volume in 1 second (FEV₁) percent predicted was 43%. Exacerbations were self-reported.

More than 60% had a self-reported physician diagnosis of depression.

About 20% of the patients were found to be grade A patients, based on the revised Global Initiative for Chronic Obstructive Lung Disease (GOLD) released in December 2011, about 10% were grade B patients, about 20% were grade C patients, and about 50% were grade D patients, said Dr. Adams of the University of Texas Health Science Center, San Antonio.

Patients with grade A disease have mild disease severity, airflow limitation, and few exacerbations; those with grade B disease are similar to those with grade A, except they have more symptoms (in this study, the grade B patients had no exacerbations). Those with grade C disease have minimal symptoms, severe airflow limitation, and/or two or more exacerbations each year; those with grade D disease are similar to those with grade C disease, except they have more symptoms.

"One thing we were actually really surprised to find is that the group of A and C with minimal symptoms may be a lot more similar than we think, whereas D and B with the severe symptoms – even though they have significant differences in exacerbations and/or airflow limitation, may be very similar," she said.

Indeed, no differences on the various measures used in this study were seen between the A and C patients, and between the B and D patients. But when the A and C patients were combined and compared with the combined group of B and D patients, significant differences emerged for every measure.

"Again, the big difference is symptoms; A and C have minimal symptoms and B and D have severe symptoms," Dr. Adams said.

As it turned out, grades A and C patients had significantly higher CRQ scores (higher scores are better) than did grades B and D patients (mean of 105 and 98 for A and C vs. 80 and 84 for B and D, respectively). Grades A and C also had statistically and clinically significantly greater 6-minute walk test distances, Dr. Adams noted.

On a physical function measure of steps walked in a day, the A and C patients averaged 7,900, and the B and D patients averaged only 4,800, she added.

That’s 3,900 fewer steps despite inclusion of B-group patient (10% of the total study population) in the B/D combined group, Dr. Adams noted.

"Again ... grade B had relatively normal lung function and no exacerbations, but yet they’re severely dyspneic," she noted.

As for depression, the history was similar across all grades, although more grade B and D patients than A and C patients had PHQ-9 scores of 10 or greater, which indicates significant depression. On linear regression, an mMRC dyspnea scale score of 2 or higher was associated with a significant increase in depression (odds ratio, 2.8).

"So the bottom line to this is grades A and C have similar levels of depression, quality of life, physical function, and physical activity despite significant differences in FEV₁ percent predicted and and/or the number of exacerbations," she said, explaining that it appears that the perception of dyspnea is the main factor associated with these outcomes.

"And, in fact, those who report severe dyspnea may be even more limited than those with frequent exacerbations," she said.

What are the clinical implications of the findings?

"We ask our patients, ‘How are you doing? How is your shortness of breath?’ but actually getting an assessment and also trying to really address the dyspnea in addition to the exacerbations is going to be really key in this population," Dr. Adams concluded.

Dr. Adams disclosed that she has received grant money for research from the Chest Foundation, the NIH, the Veterans Affairs Cooperative Studies Program, Bayer, Boehringer Ingelheim, Centocor, GlaxoSmithKline, Novartis, Pfizer, and Schering-Plough. She also has received honoraria for speaking from ABCam, Altana, AstraZeneca, Aventis, Bayer, Boehringer Ingelheim, GSK, Novartis, AG, Mycomed, Pfizer, and Schering-Plough.

ATLANTA – The perception of dyspnea among patients with chronic obstructive pulmonary disorder plays a bigger role in quality of life, functional status, and depression than do objective measures of disease severity, according to findings from cross-sectional study involving 158 patients.

The findings suggest that assessing and addressing dyspnea in COPD patients could play an important role in improving quality of life outcomes, Dr. Sandra Adams reported at the annual meeting of the American College of Chest Physicians.

The patients included in this analysis are part of the CASCADE study, a 2-year longitudinal observational study of genes and depression in COPD. They completed spirometry, the modified Medical Research Council (mMRC) dyspnea scale, questions related to exacerbation risk within the last year, the Chronic Respiratory Questionnaire (CRQ), a nine-item depression interview, the Personal Health Questionnaire (PHQ-9), and a 6-minute walk test at baseline.

Study participants had a mean age of about 67 years, about 25% were women, 40% were on supplemental oxygen, and the mean forced expiratory volume in 1 second (FEV₁) percent predicted was 43%. Exacerbations were self-reported.

More than 60% had a self-reported physician diagnosis of depression.

About 20% of the patients were found to be grade A patients, based on the revised Global Initiative for Chronic Obstructive Lung Disease (GOLD) released in December 2011, about 10% were grade B patients, about 20% were grade C patients, and about 50% were grade D patients, said Dr. Adams of the University of Texas Health Science Center, San Antonio.

Patients with grade A disease have mild disease severity, airflow limitation, and few exacerbations; those with grade B disease are similar to those with grade A, except they have more symptoms (in this study, the grade B patients had no exacerbations). Those with grade C disease have minimal symptoms, severe airflow limitation, and/or two or more exacerbations each year; those with grade D disease are similar to those with grade C disease, except they have more symptoms.

"One thing we were actually really surprised to find is that the group of A and C with minimal symptoms may be a lot more similar than we think, whereas D and B with the severe symptoms – even though they have significant differences in exacerbations and/or airflow limitation, may be very similar," she said.

Indeed, no differences on the various measures used in this study were seen between the A and C patients, and between the B and D patients. But when the A and C patients were combined and compared with the combined group of B and D patients, significant differences emerged for every measure.

"Again, the big difference is symptoms; A and C have minimal symptoms and B and D have severe symptoms," Dr. Adams said.

As it turned out, grades A and C patients had significantly higher CRQ scores (higher scores are better) than did grades B and D patients (mean of 105 and 98 for A and C vs. 80 and 84 for B and D, respectively). Grades A and C also had statistically and clinically significantly greater 6-minute walk test distances, Dr. Adams noted.

On a physical function measure of steps walked in a day, the A and C patients averaged 7,900, and the B and D patients averaged only 4,800, she added.

That’s 3,900 fewer steps despite inclusion of B-group patient (10% of the total study population) in the B/D combined group, Dr. Adams noted.

"Again ... grade B had relatively normal lung function and no exacerbations, but yet they’re severely dyspneic," she noted.

As for depression, the history was similar across all grades, although more grade B and D patients than A and C patients had PHQ-9 scores of 10 or greater, which indicates significant depression. On linear regression, an mMRC dyspnea scale score of 2 or higher was associated with a significant increase in depression (odds ratio, 2.8).

"So the bottom line to this is grades A and C have similar levels of depression, quality of life, physical function, and physical activity despite significant differences in FEV₁ percent predicted and and/or the number of exacerbations," she said, explaining that it appears that the perception of dyspnea is the main factor associated with these outcomes.

"And, in fact, those who report severe dyspnea may be even more limited than those with frequent exacerbations," she said.

What are the clinical implications of the findings?

"We ask our patients, ‘How are you doing? How is your shortness of breath?’ but actually getting an assessment and also trying to really address the dyspnea in addition to the exacerbations is going to be really key in this population," Dr. Adams concluded.

Dr. Adams disclosed that she has received grant money for research from the Chest Foundation, the NIH, the Veterans Affairs Cooperative Studies Program, Bayer, Boehringer Ingelheim, Centocor, GlaxoSmithKline, Novartis, Pfizer, and Schering-Plough. She also has received honoraria for speaking from ABCam, Altana, AstraZeneca, Aventis, Bayer, Boehringer Ingelheim, GSK, Novartis, AG, Mycomed, Pfizer, and Schering-Plough.