Doug Brunk

The addition of pertuzumab to a standard chemotherapy combination of trastuzumab and docetaxel led to an additional 6 months of progression-free survival in patients with HER2-positive metastatic breast cancer, CLEOPATRA trial investigators reported in the New England Journal of Medicine.

Adding pertuzumab drove median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in the pertuzumab group, they wrote. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival.

The results support dual blockade of the HER2 growth factor, which is targeted in different locations by pertuzumab and trastuzumab (Herceptin). In a prepared statement, lead investigator Dr. José Baselga, chief of hematology/oncology at Massachusetts General Hospital in Boston, characterized the improvement as "huge."

"Most metastatic patients with HER2-positive breast cancer eventually stop responding to trastuzumab, so the fact that we now have an agent that can be added to current treatment to delay progression is very exciting," he said of the research, which was published online Dec. 7 and is being presented at the San Antonio Breast Cancer Symposium.

"With the advent of trastuzumab and now pertuzumab, we have come a very long way in treating a type of breast cancer that once had a very poor prognosis."

For the double-blind phase III trial, known as CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized from February 2008 through July 2010 either to a control group that received placebo plus trastuzumab and docetaxel (Taxotere) or the pertuzumab group, which received pertuzumab plus trastuzumab* and docetaxel.

To be eligible for the trial, patients had to have a baseline left ventricular ejection fraction of 50% or greater and no history of declines to less than 50% during or after prior trastuzumab therapy (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1113216]). Patients could have received one prior hormonal treatment for metastatic breast cancer and/or prior systemic neoadjuvant or adjuvant therapy, including prior trastuzumab and docetaxel. The median age of patients was 54 years, and 59% were white.

Study medication consisted of an 840-mg loading dose of pertuzumab followed by 420-mg three times weekly; an 8-mg/kg loading dose of trastuzumab followed by 6 mg/kg three times weekly, and a 75 mg/m² dose of docetaxel every three weeks with subsequent dose escalation to 100 mg/m² if 75 mg/m² was well tolerated. At least six cycles of docetaxel were recommended. The primary study end point was progression-free survival as determined by independent review.

The researchers noted that the survival data are not complete, "since the interim analysis of overall survival was performed after 165 events had occurred (43% of the prespecified total number of events for the final analysis). Although there is a strong trend toward prolonged survival with pertuzumab plus trastuzumab plus docetaxel, the result is exploratory ... The final analysis of overall survival is event-driven and is estimated to be performed in 2013," they wrote.

The objective response rate was 69.3% in the control group vs. 80.2% in the pertuzumab group. While the difference favored the pertuzumab group statistically, the researchers consider the finding exploratory until the final analysis is conducted.

No increased rates of symptomatic or asymptomatic cardiac dysfunction were observed in the pertuzumab group, compared with the control group. However, diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin were reported more frequently in the pertuzumab group, compared with the control group.

"The events were mostly grade 1 or 2 and occurred during the period of concomitant docetaxel administration," the researchers wrote. "Grade 3 or higher febrile neutropenia and diarrhea were also increased in the pertuzumab group."

Dr. Baselga and his associates went on to state that the study findings "suggest that targeting HER2-positive tumors with two anti-HER2 monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of HER2 and highlights the clinical importance of preventing the ligand-dependent formation of HER2 dimers in order to silence HER2 signaling to the greatest extent possible."

The study was funded by F. Hoffmann-LaRoche and Genentech. Dr. Baselga disclosed that he is a member of the scientific advisory board for F. Hoffmann-LaRoche and for numerous other pharmaceutical companies. He is also a paid consultant for F. Hoffmann-LaRoche, Genentech, and for numerous other pharmaceutical companies.

* Correction 12/8/11: An earlier version of this story incorrectly described the regimen in the pertuzumab group. The error has been corrected.

The addition of pertuzumab to a standard chemotherapy combination of trastuzumab and docetaxel led to an additional 6 months of progression-free survival in patients with HER2-positive metastatic breast cancer, CLEOPATRA trial investigators reported in the New England Journal of Medicine.

Adding pertuzumab drove median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in the pertuzumab group, they wrote. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival.

The results support dual blockade of the HER2 growth factor, which is targeted in different locations by pertuzumab and trastuzumab (Herceptin). In a prepared statement, lead investigator Dr. José Baselga, chief of hematology/oncology at Massachusetts General Hospital in Boston, characterized the improvement as "huge."

"Most metastatic patients with HER2-positive breast cancer eventually stop responding to trastuzumab, so the fact that we now have an agent that can be added to current treatment to delay progression is very exciting," he said of the research, which was published online Dec. 7 and is being presented at the San Antonio Breast Cancer Symposium.

"With the advent of trastuzumab and now pertuzumab, we have come a very long way in treating a type of breast cancer that once had a very poor prognosis."

For the double-blind phase III trial, known as CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized from February 2008 through July 2010 either to a control group that received placebo plus trastuzumab and docetaxel (Taxotere) or the pertuzumab group, which received pertuzumab plus trastuzumab* and docetaxel.

To be eligible for the trial, patients had to have a baseline left ventricular ejection fraction of 50% or greater and no history of declines to less than 50% during or after prior trastuzumab therapy (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1113216]). Patients could have received one prior hormonal treatment for metastatic breast cancer and/or prior systemic neoadjuvant or adjuvant therapy, including prior trastuzumab and docetaxel. The median age of patients was 54 years, and 59% were white.

Study medication consisted of an 840-mg loading dose of pertuzumab followed by 420-mg three times weekly; an 8-mg/kg loading dose of trastuzumab followed by 6 mg/kg three times weekly, and a 75 mg/m² dose of docetaxel every three weeks with subsequent dose escalation to 100 mg/m² if 75 mg/m² was well tolerated. At least six cycles of docetaxel were recommended. The primary study end point was progression-free survival as determined by independent review.

The researchers noted that the survival data are not complete, "since the interim analysis of overall survival was performed after 165 events had occurred (43% of the prespecified total number of events for the final analysis). Although there is a strong trend toward prolonged survival with pertuzumab plus trastuzumab plus docetaxel, the result is exploratory ... The final analysis of overall survival is event-driven and is estimated to be performed in 2013," they wrote.

The objective response rate was 69.3% in the control group vs. 80.2% in the pertuzumab group. While the difference favored the pertuzumab group statistically, the researchers consider the finding exploratory until the final analysis is conducted.

No increased rates of symptomatic or asymptomatic cardiac dysfunction were observed in the pertuzumab group, compared with the control group. However, diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin were reported more frequently in the pertuzumab group, compared with the control group.

"The events were mostly grade 1 or 2 and occurred during the period of concomitant docetaxel administration," the researchers wrote. "Grade 3 or higher febrile neutropenia and diarrhea were also increased in the pertuzumab group."

Dr. Baselga and his associates went on to state that the study findings "suggest that targeting HER2-positive tumors with two anti-HER2 monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of HER2 and highlights the clinical importance of preventing the ligand-dependent formation of HER2 dimers in order to silence HER2 signaling to the greatest extent possible."

The study was funded by F. Hoffmann-LaRoche and Genentech. Dr. Baselga disclosed that he is a member of the scientific advisory board for F. Hoffmann-LaRoche and for numerous other pharmaceutical companies. He is also a paid consultant for F. Hoffmann-LaRoche, Genentech, and for numerous other pharmaceutical companies.

* Correction 12/8/11: An earlier version of this story incorrectly described the regimen in the pertuzumab group. The error has been corrected.

The addition of pertuzumab to a standard chemotherapy combination of trastuzumab and docetaxel led to an additional 6 months of progression-free survival in patients with HER2-positive metastatic breast cancer, CLEOPATRA trial investigators reported in the New England Journal of Medicine.

Adding pertuzumab drove median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in the pertuzumab group, they wrote. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival.

The results support dual blockade of the HER2 growth factor, which is targeted in different locations by pertuzumab and trastuzumab (Herceptin). In a prepared statement, lead investigator Dr. José Baselga, chief of hematology/oncology at Massachusetts General Hospital in Boston, characterized the improvement as "huge."

"Most metastatic patients with HER2-positive breast cancer eventually stop responding to trastuzumab, so the fact that we now have an agent that can be added to current treatment to delay progression is very exciting," he said of the research, which was published online Dec. 7 and is being presented at the San Antonio Breast Cancer Symposium.

"With the advent of trastuzumab and now pertuzumab, we have come a very long way in treating a type of breast cancer that once had a very poor prognosis."

For the double-blind phase III trial, known as CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized from February 2008 through July 2010 either to a control group that received placebo plus trastuzumab and docetaxel (Taxotere) or the pertuzumab group, which received pertuzumab plus trastuzumab* and docetaxel.

To be eligible for the trial, patients had to have a baseline left ventricular ejection fraction of 50% or greater and no history of declines to less than 50% during or after prior trastuzumab therapy (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1113216]). Patients could have received one prior hormonal treatment for metastatic breast cancer and/or prior systemic neoadjuvant or adjuvant therapy, including prior trastuzumab and docetaxel. The median age of patients was 54 years, and 59% were white.

Study medication consisted of an 840-mg loading dose of pertuzumab followed by 420-mg three times weekly; an 8-mg/kg loading dose of trastuzumab followed by 6 mg/kg three times weekly, and a 75 mg/m² dose of docetaxel every three weeks with subsequent dose escalation to 100 mg/m² if 75 mg/m² was well tolerated. At least six cycles of docetaxel were recommended. The primary study end point was progression-free survival as determined by independent review.

The researchers noted that the survival data are not complete, "since the interim analysis of overall survival was performed after 165 events had occurred (43% of the prespecified total number of events for the final analysis). Although there is a strong trend toward prolonged survival with pertuzumab plus trastuzumab plus docetaxel, the result is exploratory ... The final analysis of overall survival is event-driven and is estimated to be performed in 2013," they wrote.

The objective response rate was 69.3% in the control group vs. 80.2% in the pertuzumab group. While the difference favored the pertuzumab group statistically, the researchers consider the finding exploratory until the final analysis is conducted.

No increased rates of symptomatic or asymptomatic cardiac dysfunction were observed in the pertuzumab group, compared with the control group. However, diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin were reported more frequently in the pertuzumab group, compared with the control group.

"The events were mostly grade 1 or 2 and occurred during the period of concomitant docetaxel administration," the researchers wrote. "Grade 3 or higher febrile neutropenia and diarrhea were also increased in the pertuzumab group."

Dr. Baselga and his associates went on to state that the study findings "suggest that targeting HER2-positive tumors with two anti-HER2 monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of HER2 and highlights the clinical importance of preventing the ligand-dependent formation of HER2 dimers in order to silence HER2 signaling to the greatest extent possible."

The study was funded by F. Hoffmann-LaRoche and Genentech. Dr. Baselga disclosed that he is a member of the scientific advisory board for F. Hoffmann-LaRoche and for numerous other pharmaceutical companies. He is also a paid consultant for F. Hoffmann-LaRoche, Genentech, and for numerous other pharmaceutical companies.

* Correction 12/8/11: An earlier version of this story incorrectly described the regimen in the pertuzumab group. The error has been corrected.

Combined treatment with everolimus and exemestane more than doubled median progression-free survival in postmenopausal women with hormone receptor–positive breast cancer that had advanced previously after hormone therapy.

Compared with exemestane (Aromasin) and placebo, the everolimus (Afinitor) and exemestane combination increased the median progression-free interval from 3.2 months to 7.4 months, according to Dr. Gabriel N. Hortobagyi, who will present new data from the phase III BOLERO-2 trial at the San Antonio Breast Cancer Symposium.

Moreover, the clinical benefit rate doubled from 25.5% to 50.5%, as twice as many women had either a complete or partial response or stable disease exceeding 6 months, Dr. Hortobagyi, professor and chair of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center, will report.

The BOLERO-2 findings could shift standard treatment of therapy-resistant patients from sequential use of aromatase inhibitors to simultaneous inhibition of the estrogen-signaling pathway with an aromatase inhibitor such as exemestane and of the PI3-kinase/AKT/mTOR pathway with everolimus.

"For the first time in a large phase III trial, we have demonstrated that this dual-attack is more effective than a single endocrine treatment for patients who have received prior endocrine therapy," Dr. Hortobagyi said in a press statement.

The gain from addition of an mTOR inhibitor comes with a higher incidence of adverse events such as stomatitis, anemia, and dyspnea in patients taking the combination. "In the current study, a high percentage of patients discontinued everolimus because of lack of tolerability," the BOLERO-2 researchers wrote in a report published online Dec. 7 in the New England Journal of Medicine.

"The longer treatment duration in the combination therapy group might have contributed to the high discontinuation rate. Careful monitoring of patients and increased physician awareness of the safety profile of everolimus are warranted," wrote lead author José Baselga, MD, PhD, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, and his co-authors.

Between June 2009 and January 2011, Dr. Baselga and his associates at 189 centers in 24 countries randomized 485 women with HR-positive breast cancer refractory to nonsteroidal aromatase inhibitors to receive a combination of everolimus and exemestane (combination therapy group), and 239 women to receive exemestane plus placebo (exemestane-alone group) in the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2). The mean age of patients was 62 years, 56% had visceral involvement, and 76% had bone metastasis. The primary end point was progression-free survival (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1109653]).

Dr. Baselga and his associates reported that previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse event was stomatitis (8% in the combination therapy group vs. 1% in the exemestane-alone group), followed by anemia (6% vs. less than 1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. less than 1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).

"Our positive results are consistent with the outcomes of two other studies of everolimus and antiestrogen therapy in patients with HR-positive breast cancer ... [and] the magnitude of the observed benefit compares favorably with that of the limited options available to this group of patients," the researchers wrote.

Nearly twice as many adverse events were reported among patients in the combination therapy group compared with the exemestane-alone group (23% vs. 12%). Dr. Baselga and his associates observed that "a higher percentage of patients discontinued everolimus in the combination therapy group than discontinued placebo in the control group because of adverse events (19% vs. 4%), and withdrawal of consent (5% vs. 2%). For exemestane discontinuation, the corresponding numbers were 7% versus 3% and 7% versus 2%."

The researchers went on to note that the adverse events seen in the combination therapy group "are consistent with those reported with everolimus and other rapamycin analogues and include stomatitis, fatigue and asthenia, diarrhea, cough, pyrexia, and hyperglycemia."

The study was sponsored by Novartis. Dr. Baselga disclosed that he is a member of the scientific advisory board for Novartis and numerous other companies including Merck and Bayer. He also has accepted consulting fees from numerous pharmaceutical companies. Dr. Hortobagyi reported receiving research funds from and serving as a consultant for Novartis. Some of the other researchers have ties to a variety of pharmaceutical companies.

Combined treatment with everolimus and exemestane more than doubled median progression-free survival in postmenopausal women with hormone receptor–positive breast cancer that had advanced previously after hormone therapy.

Compared with exemestane (Aromasin) and placebo, the everolimus (Afinitor) and exemestane combination increased the median progression-free interval from 3.2 months to 7.4 months, according to Dr. Gabriel N. Hortobagyi, who will present new data from the phase III BOLERO-2 trial at the San Antonio Breast Cancer Symposium.

Moreover, the clinical benefit rate doubled from 25.5% to 50.5%, as twice as many women had either a complete or partial response or stable disease exceeding 6 months, Dr. Hortobagyi, professor and chair of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center, will report.

The BOLERO-2 findings could shift standard treatment of therapy-resistant patients from sequential use of aromatase inhibitors to simultaneous inhibition of the estrogen-signaling pathway with an aromatase inhibitor such as exemestane and of the PI3-kinase/AKT/mTOR pathway with everolimus.

"For the first time in a large phase III trial, we have demonstrated that this dual-attack is more effective than a single endocrine treatment for patients who have received prior endocrine therapy," Dr. Hortobagyi said in a press statement.

The gain from addition of an mTOR inhibitor comes with a higher incidence of adverse events such as stomatitis, anemia, and dyspnea in patients taking the combination. "In the current study, a high percentage of patients discontinued everolimus because of lack of tolerability," the BOLERO-2 researchers wrote in a report published online Dec. 7 in the New England Journal of Medicine.

"The longer treatment duration in the combination therapy group might have contributed to the high discontinuation rate. Careful monitoring of patients and increased physician awareness of the safety profile of everolimus are warranted," wrote lead author José Baselga, MD, PhD, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, and his co-authors.

Between June 2009 and January 2011, Dr. Baselga and his associates at 189 centers in 24 countries randomized 485 women with HR-positive breast cancer refractory to nonsteroidal aromatase inhibitors to receive a combination of everolimus and exemestane (combination therapy group), and 239 women to receive exemestane plus placebo (exemestane-alone group) in the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2). The mean age of patients was 62 years, 56% had visceral involvement, and 76% had bone metastasis. The primary end point was progression-free survival (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1109653]).

Dr. Baselga and his associates reported that previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse event was stomatitis (8% in the combination therapy group vs. 1% in the exemestane-alone group), followed by anemia (6% vs. less than 1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. less than 1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).

"Our positive results are consistent with the outcomes of two other studies of everolimus and antiestrogen therapy in patients with HR-positive breast cancer ... [and] the magnitude of the observed benefit compares favorably with that of the limited options available to this group of patients," the researchers wrote.

Nearly twice as many adverse events were reported among patients in the combination therapy group compared with the exemestane-alone group (23% vs. 12%). Dr. Baselga and his associates observed that "a higher percentage of patients discontinued everolimus in the combination therapy group than discontinued placebo in the control group because of adverse events (19% vs. 4%), and withdrawal of consent (5% vs. 2%). For exemestane discontinuation, the corresponding numbers were 7% versus 3% and 7% versus 2%."

The researchers went on to note that the adverse events seen in the combination therapy group "are consistent with those reported with everolimus and other rapamycin analogues and include stomatitis, fatigue and asthenia, diarrhea, cough, pyrexia, and hyperglycemia."

The study was sponsored by Novartis. Dr. Baselga disclosed that he is a member of the scientific advisory board for Novartis and numerous other companies including Merck and Bayer. He also has accepted consulting fees from numerous pharmaceutical companies. Dr. Hortobagyi reported receiving research funds from and serving as a consultant for Novartis. Some of the other researchers have ties to a variety of pharmaceutical companies.

Combined treatment with everolimus and exemestane more than doubled median progression-free survival in postmenopausal women with hormone receptor–positive breast cancer that had advanced previously after hormone therapy.

Compared with exemestane (Aromasin) and placebo, the everolimus (Afinitor) and exemestane combination increased the median progression-free interval from 3.2 months to 7.4 months, according to Dr. Gabriel N. Hortobagyi, who will present new data from the phase III BOLERO-2 trial at the San Antonio Breast Cancer Symposium.

Moreover, the clinical benefit rate doubled from 25.5% to 50.5%, as twice as many women had either a complete or partial response or stable disease exceeding 6 months, Dr. Hortobagyi, professor and chair of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center, will report.

The BOLERO-2 findings could shift standard treatment of therapy-resistant patients from sequential use of aromatase inhibitors to simultaneous inhibition of the estrogen-signaling pathway with an aromatase inhibitor such as exemestane and of the PI3-kinase/AKT/mTOR pathway with everolimus.

"For the first time in a large phase III trial, we have demonstrated that this dual-attack is more effective than a single endocrine treatment for patients who have received prior endocrine therapy," Dr. Hortobagyi said in a press statement.

The gain from addition of an mTOR inhibitor comes with a higher incidence of adverse events such as stomatitis, anemia, and dyspnea in patients taking the combination. "In the current study, a high percentage of patients discontinued everolimus because of lack of tolerability," the BOLERO-2 researchers wrote in a report published online Dec. 7 in the New England Journal of Medicine.

"The longer treatment duration in the combination therapy group might have contributed to the high discontinuation rate. Careful monitoring of patients and increased physician awareness of the safety profile of everolimus are warranted," wrote lead author José Baselga, MD, PhD, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, and his co-authors.

Between June 2009 and January 2011, Dr. Baselga and his associates at 189 centers in 24 countries randomized 485 women with HR-positive breast cancer refractory to nonsteroidal aromatase inhibitors to receive a combination of everolimus and exemestane (combination therapy group), and 239 women to receive exemestane plus placebo (exemestane-alone group) in the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2). The mean age of patients was 62 years, 56% had visceral involvement, and 76% had bone metastasis. The primary end point was progression-free survival (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1109653]).

Dr. Baselga and his associates reported that previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse event was stomatitis (8% in the combination therapy group vs. 1% in the exemestane-alone group), followed by anemia (6% vs. less than 1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. less than 1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).

"Our positive results are consistent with the outcomes of two other studies of everolimus and antiestrogen therapy in patients with HR-positive breast cancer ... [and] the magnitude of the observed benefit compares favorably with that of the limited options available to this group of patients," the researchers wrote.

Nearly twice as many adverse events were reported among patients in the combination therapy group compared with the exemestane-alone group (23% vs. 12%). Dr. Baselga and his associates observed that "a higher percentage of patients discontinued everolimus in the combination therapy group than discontinued placebo in the control group because of adverse events (19% vs. 4%), and withdrawal of consent (5% vs. 2%). For exemestane discontinuation, the corresponding numbers were 7% versus 3% and 7% versus 2%."

The researchers went on to note that the adverse events seen in the combination therapy group "are consistent with those reported with everolimus and other rapamycin analogues and include stomatitis, fatigue and asthenia, diarrhea, cough, pyrexia, and hyperglycemia."

The study was sponsored by Novartis. Dr. Baselga disclosed that he is a member of the scientific advisory board for Novartis and numerous other companies including Merck and Bayer. He also has accepted consulting fees from numerous pharmaceutical companies. Dr. Hortobagyi reported receiving research funds from and serving as a consultant for Novartis. Some of the other researchers have ties to a variety of pharmaceutical companies.

HONOLULU – Current interventions for chronic obstructive pulmonary disease leave many patients with unmet needs, according to Dr. Nicola A. Hanania.

"We know from large clinical trials that current pharmacotherapies do not change the natural history of COPD, and many patients remain symptomatic with current therapies," Dr. Hanania, director of the asthma clinical research center at Baylor College of Medicine, Houston, said at the annual meeting of the American College of Chest Physicians.

Inadequate adherence to therapy "is a major cause of poor clinical outcomes in the treatment of COPD," he said. The cost, compliance, and safety of certain agents are issues "that we cannot ignore."

When considering a therapy for COPD, clinicians should factor in components of COPD beyond bronchoconstriction, he advised, including mucociliary dysfunction, structural changes in the airway and the lung, systemic components, and airway inflammation. "We also have to look at outcomes other than lung function including exacerbations, activity limitation, and symptoms of dyspnea," he said. "We are no more satisfied with just a drug that improves lung function but does nothing for the patient-reported outcomes."

Dr. Hanania’s "wish list" for an ideal COPD therapeutic option in the future is one that addresses the multiple components and phenotypes of COPD. He said he would like to see drugs that blunt proinflammatory cells and molecules known to be involved in COPD. "We’d also like to see drugs that could modify the disease progression and comorbid conditions," he said. Such drugs, he continued, should be well tolerated and compatible with other therapies for COPD and comorbid conditions, be simple to administer, and have the potential to improve patient adherence, he added.

Treatment approaches being studied include novel formulations of existing medications, such as the combination of ultralong-acting beta-2 agonists and long-acting antimuscarinics. Among the agents that are the most promising on this front, he said, are indacaterol plus glycopyrronium (QVA-149) and vilanterol plus GSK-573719.

Other agents in development include bifunctional muscarinic antagonist–beta-2 agonists such as GSK-961081 and THRX-200495 as well as combinations of once-daily long-acting beta-2 agonists and inhaled corticosteroids, including formoterol and mometasone (MFF258) and vilanterol and fluticasone (Relovair).

However, perhaps the most promising pharmacotherapies will be novel agents aimed at reducing local and systemic inflammation. "We know that COPD is an inflammatory disease, so we need drugs that can target inflammation right from the very beginning," Dr. Hanania explained. "Inhaled steroids are important, but they’re not as effective in COPD as they are in asthma."

Phosphodiesterase type 4 inhibitors are currently being studied in COPD. These agents reduce the activity of neutrophils, macrophages, and CD8-positive T-lymphocytes, as well as the expression of cytokines and other inflammatory mediators. Currently, the only phosphodiesterase type 4 inhibitor approved in the United States for use in patients with COPD is roflumilast (Daliresp). Several others are in development.

"We know from large clinical trials that current pharmaco-therapies do not change the natural history of COPD."

Because they target airway inflammation, p38 mitogen-activated protein kinase inhibitors are also being studied in COPD patients. However, so far clinical trials have found potential problems related to systemic side effects and toxicity, "indicating that it is probably necessary to deliver these drugs by inhalation to reduce systemic exposure," Dr. Hanania said.

He concluded his presentation by noting that certain medications used to treat comorbidities in COPD may have beneficial effects on COPD outcomes. These include statins, ACE inhibitors, beta-blockers, peroxisome proliferator–activated receptor agonists, and macrolides. The National Heart, Lung, and Blood Institute COPD Clinical Research Network is currently conducting a prospective randomized controlled trial in 1,126 patients with severe COPD randomized to daily simvastatin (40 mg) vs. placebo for at least 1 year. The primary outcome is exacerbation of COPD. The secondary outcomes include change in forced expiratory volume in 1 second (FEV₁), St. George’s Respiratory Questionnaire responses, 6-minute walk test results, BODE Index score, a combined cardiovascular end point, and serum inflammatory biomarker levels. Furthermore, a recent study showed that daily azithromycin significantly reduced exacerbations in high-risk patients.

Dr. Hanania disclosed that he has received grant support from the National Institutes of Health, the American Lung Association, GlaxoSmithKline (GSK), Boehringer Ingelheim (BI), Sunovion, Novartis, Pfizer, and Forest Pharmaceuticals. He also serves as a consultant for GSK, Dey Pharmaceuticals, Sunovion, Pfizer, and Forest, and is a member of the speakers bureau for GSK, BI, AstraZeneca, and Forest.

HONOLULU – Current interventions for chronic obstructive pulmonary disease leave many patients with unmet needs, according to Dr. Nicola A. Hanania.

"We know from large clinical trials that current pharmacotherapies do not change the natural history of COPD, and many patients remain symptomatic with current therapies," Dr. Hanania, director of the asthma clinical research center at Baylor College of Medicine, Houston, said at the annual meeting of the American College of Chest Physicians.

Inadequate adherence to therapy "is a major cause of poor clinical outcomes in the treatment of COPD," he said. The cost, compliance, and safety of certain agents are issues "that we cannot ignore."

When considering a therapy for COPD, clinicians should factor in components of COPD beyond bronchoconstriction, he advised, including mucociliary dysfunction, structural changes in the airway and the lung, systemic components, and airway inflammation. "We also have to look at outcomes other than lung function including exacerbations, activity limitation, and symptoms of dyspnea," he said. "We are no more satisfied with just a drug that improves lung function but does nothing for the patient-reported outcomes."

Dr. Hanania’s "wish list" for an ideal COPD therapeutic option in the future is one that addresses the multiple components and phenotypes of COPD. He said he would like to see drugs that blunt proinflammatory cells and molecules known to be involved in COPD. "We’d also like to see drugs that could modify the disease progression and comorbid conditions," he said. Such drugs, he continued, should be well tolerated and compatible with other therapies for COPD and comorbid conditions, be simple to administer, and have the potential to improve patient adherence, he added.

Treatment approaches being studied include novel formulations of existing medications, such as the combination of ultralong-acting beta-2 agonists and long-acting antimuscarinics. Among the agents that are the most promising on this front, he said, are indacaterol plus glycopyrronium (QVA-149) and vilanterol plus GSK-573719.

Other agents in development include bifunctional muscarinic antagonist–beta-2 agonists such as GSK-961081 and THRX-200495 as well as combinations of once-daily long-acting beta-2 agonists and inhaled corticosteroids, including formoterol and mometasone (MFF258) and vilanterol and fluticasone (Relovair).

However, perhaps the most promising pharmacotherapies will be novel agents aimed at reducing local and systemic inflammation. "We know that COPD is an inflammatory disease, so we need drugs that can target inflammation right from the very beginning," Dr. Hanania explained. "Inhaled steroids are important, but they’re not as effective in COPD as they are in asthma."

Phosphodiesterase type 4 inhibitors are currently being studied in COPD. These agents reduce the activity of neutrophils, macrophages, and CD8-positive T-lymphocytes, as well as the expression of cytokines and other inflammatory mediators. Currently, the only phosphodiesterase type 4 inhibitor approved in the United States for use in patients with COPD is roflumilast (Daliresp). Several others are in development.

"We know from large clinical trials that current pharmaco-therapies do not change the natural history of COPD."

Because they target airway inflammation, p38 mitogen-activated protein kinase inhibitors are also being studied in COPD patients. However, so far clinical trials have found potential problems related to systemic side effects and toxicity, "indicating that it is probably necessary to deliver these drugs by inhalation to reduce systemic exposure," Dr. Hanania said.

He concluded his presentation by noting that certain medications used to treat comorbidities in COPD may have beneficial effects on COPD outcomes. These include statins, ACE inhibitors, beta-blockers, peroxisome proliferator–activated receptor agonists, and macrolides. The National Heart, Lung, and Blood Institute COPD Clinical Research Network is currently conducting a prospective randomized controlled trial in 1,126 patients with severe COPD randomized to daily simvastatin (40 mg) vs. placebo for at least 1 year. The primary outcome is exacerbation of COPD. The secondary outcomes include change in forced expiratory volume in 1 second (FEV₁), St. George’s Respiratory Questionnaire responses, 6-minute walk test results, BODE Index score, a combined cardiovascular end point, and serum inflammatory biomarker levels. Furthermore, a recent study showed that daily azithromycin significantly reduced exacerbations in high-risk patients.

Dr. Hanania disclosed that he has received grant support from the National Institutes of Health, the American Lung Association, GlaxoSmithKline (GSK), Boehringer Ingelheim (BI), Sunovion, Novartis, Pfizer, and Forest Pharmaceuticals. He also serves as a consultant for GSK, Dey Pharmaceuticals, Sunovion, Pfizer, and Forest, and is a member of the speakers bureau for GSK, BI, AstraZeneca, and Forest.

HONOLULU – Current interventions for chronic obstructive pulmonary disease leave many patients with unmet needs, according to Dr. Nicola A. Hanania.

"We know from large clinical trials that current pharmacotherapies do not change the natural history of COPD, and many patients remain symptomatic with current therapies," Dr. Hanania, director of the asthma clinical research center at Baylor College of Medicine, Houston, said at the annual meeting of the American College of Chest Physicians.

Inadequate adherence to therapy "is a major cause of poor clinical outcomes in the treatment of COPD," he said. The cost, compliance, and safety of certain agents are issues "that we cannot ignore."

When considering a therapy for COPD, clinicians should factor in components of COPD beyond bronchoconstriction, he advised, including mucociliary dysfunction, structural changes in the airway and the lung, systemic components, and airway inflammation. "We also have to look at outcomes other than lung function including exacerbations, activity limitation, and symptoms of dyspnea," he said. "We are no more satisfied with just a drug that improves lung function but does nothing for the patient-reported outcomes."

Dr. Hanania’s "wish list" for an ideal COPD therapeutic option in the future is one that addresses the multiple components and phenotypes of COPD. He said he would like to see drugs that blunt proinflammatory cells and molecules known to be involved in COPD. "We’d also like to see drugs that could modify the disease progression and comorbid conditions," he said. Such drugs, he continued, should be well tolerated and compatible with other therapies for COPD and comorbid conditions, be simple to administer, and have the potential to improve patient adherence, he added.

Treatment approaches being studied include novel formulations of existing medications, such as the combination of ultralong-acting beta-2 agonists and long-acting antimuscarinics. Among the agents that are the most promising on this front, he said, are indacaterol plus glycopyrronium (QVA-149) and vilanterol plus GSK-573719.

Other agents in development include bifunctional muscarinic antagonist–beta-2 agonists such as GSK-961081 and THRX-200495 as well as combinations of once-daily long-acting beta-2 agonists and inhaled corticosteroids, including formoterol and mometasone (MFF258) and vilanterol and fluticasone (Relovair).

However, perhaps the most promising pharmacotherapies will be novel agents aimed at reducing local and systemic inflammation. "We know that COPD is an inflammatory disease, so we need drugs that can target inflammation right from the very beginning," Dr. Hanania explained. "Inhaled steroids are important, but they’re not as effective in COPD as they are in asthma."

Phosphodiesterase type 4 inhibitors are currently being studied in COPD. These agents reduce the activity of neutrophils, macrophages, and CD8-positive T-lymphocytes, as well as the expression of cytokines and other inflammatory mediators. Currently, the only phosphodiesterase type 4 inhibitor approved in the United States for use in patients with COPD is roflumilast (Daliresp). Several others are in development.

"We know from large clinical trials that current pharmaco-therapies do not change the natural history of COPD."

Because they target airway inflammation, p38 mitogen-activated protein kinase inhibitors are also being studied in COPD patients. However, so far clinical trials have found potential problems related to systemic side effects and toxicity, "indicating that it is probably necessary to deliver these drugs by inhalation to reduce systemic exposure," Dr. Hanania said.

He concluded his presentation by noting that certain medications used to treat comorbidities in COPD may have beneficial effects on COPD outcomes. These include statins, ACE inhibitors, beta-blockers, peroxisome proliferator–activated receptor agonists, and macrolides. The National Heart, Lung, and Blood Institute COPD Clinical Research Network is currently conducting a prospective randomized controlled trial in 1,126 patients with severe COPD randomized to daily simvastatin (40 mg) vs. placebo for at least 1 year. The primary outcome is exacerbation of COPD. The secondary outcomes include change in forced expiratory volume in 1 second (FEV₁), St. George’s Respiratory Questionnaire responses, 6-minute walk test results, BODE Index score, a combined cardiovascular end point, and serum inflammatory biomarker levels. Furthermore, a recent study showed that daily azithromycin significantly reduced exacerbations in high-risk patients.

Dr. Hanania disclosed that he has received grant support from the National Institutes of Health, the American Lung Association, GlaxoSmithKline (GSK), Boehringer Ingelheim (BI), Sunovion, Novartis, Pfizer, and Forest Pharmaceuticals. He also serves as a consultant for GSK, Dey Pharmaceuticals, Sunovion, Pfizer, and Forest, and is a member of the speakers bureau for GSK, BI, AstraZeneca, and Forest.

HONOLULU – Acute worsening is an important part of the natural history of many interstitial lung diseases, especially idiopathic pulmonary fibrosis.

But the roots of acute worsening in interstitial lung disease (ILD) are not fully understood, Dr. Harold R. Collard said at the annual meeting of the American College of Chest Physicians.

"A lot of what’s known in the medical literature comes from patients with idiopathic pulmonary fibrosis [IPF]," said Dr. Collard, who directs the interstitial lung disease program at the University of California, San Francisco. "I think it’s an open question whether that can be extrapolated to patients with other forms of ILD or not. The course of many ILDs – certainly IPF – is unpredictable; it’s not always a linear decline," he continued. "This is an important shift in how we think about the disease – to recognize that this is the case for many patients."

According to a survey of academic pulmonologists, 88% of respondents reported that acute exacerbations in ILD patients occur "sometimes" or "frequently," while 92% of respondents reported that exacerbations were "sometimes" or "frequently" fatal (Respir. Med. 2007;101:2011-6).

If these are not fatal, they often leave patients significantly worse than they were before, unlike exacerbations in other forms of lung disease, said Dr. Collard, who was the survey’s lead investigator.

Potential causes of acute worsening include infection, aspiration, myocardial infarction, pulmonary embolism, pneumothorax, and heart failure, as well as idiopathic causes. Acute worsening has not been studied in all ILDs, but it has been most closely studied in IPF. In Dr. Collard’s opinion, the best data on acute worsening in IPF come from a Korean cohort study of 461 patients with IPF who were followed longitudinally (Eur. Resp. J. 2011;37:356-63). The researchers divided patients into two groups: those with respiratory deterioration (defined as acute worsening with radiographic abnormalities) and those with acute exacerbation (defined as acute worsening in the absence of an identifiable etiology).

The researchers found that the 1-year incidence of respiratory deterioration was 23%, "which is higher than a lot of us have taken from clinical trials," Dr. Collard said. Of these cases, 55% were idiopathic, while the remainder had known causes that included infection and heart failure.

"These idiopathic acute worsenings, as defined in this study, are what we call acute exacerbation," Dr. Collard noted. "In IPF, acute exacerbation has a specific connotation compared with asthma or [chronic obstructive pulmonary disease]. It’s an idiopathic acute worsening."

The median survival among patients with acute exacerbation of IPF was 2.2 months from the onset of exacerbation. "This is a highly morbid and fatal condition," he said.

Dr. Collard led a panel of experts that established criteria for acute exacerbations of IPF (Am. J. Respir. Crit. Care Med. 2007;176:636-43). The criteria include previous or concurrent diagnosis of IPF, unexplained worsening or development of dyspnea over a period of 30 days or less, new bilateral ground glass and/or consolidation superimposed on a usual interstitial pneumonitis pattern on high-resolution CT, no microbiologic evidence of respiratory infection by endotracheal aspirate or bronchoalveolar lavage, and exclusion of other known causes of acute worsening.

According to the Korean IPF cohort study, significant risk factors for acute exacerbation include never having smoked tobacco and having a low forced vital capacity (FVC). "The higher your FVC, the lower your risk of acute exacerbation," Dr. Collard said. "That makes sense, [but] the protective effect of smoking is hard to explain."

He acknowledged that certain aspects of acute exacerbation remain elusive. "Does exacerbation actually represent an abrupt acceleration of the underlying disease process, or is it a manifestation of an occult secondary complication such as an infection that we’re missing because of the limitations of our clinical assessment?" he asked.

Researchers who conducted a test of gene expression profiling in this patient population found no differences in the global expression pattern between patients with stable IPF and those with acute exacerbation (Am. J. Respir. Crit. Care Med. 2009;180:167-75). "They did find evidence of enhanced alveolar epithelial cell activity," Dr. Collard said. "That was the main predominant pattern."

A study of biomarkers conducted by Dr. Collard and his associates yielded similar findings (Am. J. Physiol. Lung Cell Mol. Physiol. 2010;299:L3-7).

Dr. Collard hypothesized that acute exacerbation of IPF represents a primary acceleration of IPF in the setting of acute lung stress. "This stress may be minor, at a level that would not cause clinical disease in a normal lung," he said. Potential sources of stress include infection, occult aspiration, interventions, and drugs.

Dr. Collard disclosed that he receives research funding from the National Institutes of Health, the University of California, Boehringer Ingelheim, and Genentech. He also receives consulting fees from Fibrogen, Gilead, InterMune, and Onyx.

HONOLULU – Acute worsening is an important part of the natural history of many interstitial lung diseases, especially idiopathic pulmonary fibrosis.

But the roots of acute worsening in interstitial lung disease (ILD) are not fully understood, Dr. Harold R. Collard said at the annual meeting of the American College of Chest Physicians.

"A lot of what’s known in the medical literature comes from patients with idiopathic pulmonary fibrosis [IPF]," said Dr. Collard, who directs the interstitial lung disease program at the University of California, San Francisco. "I think it’s an open question whether that can be extrapolated to patients with other forms of ILD or not. The course of many ILDs – certainly IPF – is unpredictable; it’s not always a linear decline," he continued. "This is an important shift in how we think about the disease – to recognize that this is the case for many patients."

According to a survey of academic pulmonologists, 88% of respondents reported that acute exacerbations in ILD patients occur "sometimes" or "frequently," while 92% of respondents reported that exacerbations were "sometimes" or "frequently" fatal (Respir. Med. 2007;101:2011-6).

If these are not fatal, they often leave patients significantly worse than they were before, unlike exacerbations in other forms of lung disease, said Dr. Collard, who was the survey’s lead investigator.

Potential causes of acute worsening include infection, aspiration, myocardial infarction, pulmonary embolism, pneumothorax, and heart failure, as well as idiopathic causes. Acute worsening has not been studied in all ILDs, but it has been most closely studied in IPF. In Dr. Collard’s opinion, the best data on acute worsening in IPF come from a Korean cohort study of 461 patients with IPF who were followed longitudinally (Eur. Resp. J. 2011;37:356-63). The researchers divided patients into two groups: those with respiratory deterioration (defined as acute worsening with radiographic abnormalities) and those with acute exacerbation (defined as acute worsening in the absence of an identifiable etiology).

The researchers found that the 1-year incidence of respiratory deterioration was 23%, "which is higher than a lot of us have taken from clinical trials," Dr. Collard said. Of these cases, 55% were idiopathic, while the remainder had known causes that included infection and heart failure.

"These idiopathic acute worsenings, as defined in this study, are what we call acute exacerbation," Dr. Collard noted. "In IPF, acute exacerbation has a specific connotation compared with asthma or [chronic obstructive pulmonary disease]. It’s an idiopathic acute worsening."

The median survival among patients with acute exacerbation of IPF was 2.2 months from the onset of exacerbation. "This is a highly morbid and fatal condition," he said.

Dr. Collard led a panel of experts that established criteria for acute exacerbations of IPF (Am. J. Respir. Crit. Care Med. 2007;176:636-43). The criteria include previous or concurrent diagnosis of IPF, unexplained worsening or development of dyspnea over a period of 30 days or less, new bilateral ground glass and/or consolidation superimposed on a usual interstitial pneumonitis pattern on high-resolution CT, no microbiologic evidence of respiratory infection by endotracheal aspirate or bronchoalveolar lavage, and exclusion of other known causes of acute worsening.

According to the Korean IPF cohort study, significant risk factors for acute exacerbation include never having smoked tobacco and having a low forced vital capacity (FVC). "The higher your FVC, the lower your risk of acute exacerbation," Dr. Collard said. "That makes sense, [but] the protective effect of smoking is hard to explain."

He acknowledged that certain aspects of acute exacerbation remain elusive. "Does exacerbation actually represent an abrupt acceleration of the underlying disease process, or is it a manifestation of an occult secondary complication such as an infection that we’re missing because of the limitations of our clinical assessment?" he asked.

Researchers who conducted a test of gene expression profiling in this patient population found no differences in the global expression pattern between patients with stable IPF and those with acute exacerbation (Am. J. Respir. Crit. Care Med. 2009;180:167-75). "They did find evidence of enhanced alveolar epithelial cell activity," Dr. Collard said. "That was the main predominant pattern."

A study of biomarkers conducted by Dr. Collard and his associates yielded similar findings (Am. J. Physiol. Lung Cell Mol. Physiol. 2010;299:L3-7).

Dr. Collard hypothesized that acute exacerbation of IPF represents a primary acceleration of IPF in the setting of acute lung stress. "This stress may be minor, at a level that would not cause clinical disease in a normal lung," he said. Potential sources of stress include infection, occult aspiration, interventions, and drugs.

Dr. Collard disclosed that he receives research funding from the National Institutes of Health, the University of California, Boehringer Ingelheim, and Genentech. He also receives consulting fees from Fibrogen, Gilead, InterMune, and Onyx.

HONOLULU – Acute worsening is an important part of the natural history of many interstitial lung diseases, especially idiopathic pulmonary fibrosis.

But the roots of acute worsening in interstitial lung disease (ILD) are not fully understood, Dr. Harold R. Collard said at the annual meeting of the American College of Chest Physicians.

"A lot of what’s known in the medical literature comes from patients with idiopathic pulmonary fibrosis [IPF]," said Dr. Collard, who directs the interstitial lung disease program at the University of California, San Francisco. "I think it’s an open question whether that can be extrapolated to patients with other forms of ILD or not. The course of many ILDs – certainly IPF – is unpredictable; it’s not always a linear decline," he continued. "This is an important shift in how we think about the disease – to recognize that this is the case for many patients."

According to a survey of academic pulmonologists, 88% of respondents reported that acute exacerbations in ILD patients occur "sometimes" or "frequently," while 92% of respondents reported that exacerbations were "sometimes" or "frequently" fatal (Respir. Med. 2007;101:2011-6).

If these are not fatal, they often leave patients significantly worse than they were before, unlike exacerbations in other forms of lung disease, said Dr. Collard, who was the survey’s lead investigator.

Potential causes of acute worsening include infection, aspiration, myocardial infarction, pulmonary embolism, pneumothorax, and heart failure, as well as idiopathic causes. Acute worsening has not been studied in all ILDs, but it has been most closely studied in IPF. In Dr. Collard’s opinion, the best data on acute worsening in IPF come from a Korean cohort study of 461 patients with IPF who were followed longitudinally (Eur. Resp. J. 2011;37:356-63). The researchers divided patients into two groups: those with respiratory deterioration (defined as acute worsening with radiographic abnormalities) and those with acute exacerbation (defined as acute worsening in the absence of an identifiable etiology).

The researchers found that the 1-year incidence of respiratory deterioration was 23%, "which is higher than a lot of us have taken from clinical trials," Dr. Collard said. Of these cases, 55% were idiopathic, while the remainder had known causes that included infection and heart failure.

"These idiopathic acute worsenings, as defined in this study, are what we call acute exacerbation," Dr. Collard noted. "In IPF, acute exacerbation has a specific connotation compared with asthma or [chronic obstructive pulmonary disease]. It’s an idiopathic acute worsening."

The median survival among patients with acute exacerbation of IPF was 2.2 months from the onset of exacerbation. "This is a highly morbid and fatal condition," he said.

Dr. Collard led a panel of experts that established criteria for acute exacerbations of IPF (Am. J. Respir. Crit. Care Med. 2007;176:636-43). The criteria include previous or concurrent diagnosis of IPF, unexplained worsening or development of dyspnea over a period of 30 days or less, new bilateral ground glass and/or consolidation superimposed on a usual interstitial pneumonitis pattern on high-resolution CT, no microbiologic evidence of respiratory infection by endotracheal aspirate or bronchoalveolar lavage, and exclusion of other known causes of acute worsening.

According to the Korean IPF cohort study, significant risk factors for acute exacerbation include never having smoked tobacco and having a low forced vital capacity (FVC). "The higher your FVC, the lower your risk of acute exacerbation," Dr. Collard said. "That makes sense, [but] the protective effect of smoking is hard to explain."

He acknowledged that certain aspects of acute exacerbation remain elusive. "Does exacerbation actually represent an abrupt acceleration of the underlying disease process, or is it a manifestation of an occult secondary complication such as an infection that we’re missing because of the limitations of our clinical assessment?" he asked.

Researchers who conducted a test of gene expression profiling in this patient population found no differences in the global expression pattern between patients with stable IPF and those with acute exacerbation (Am. J. Respir. Crit. Care Med. 2009;180:167-75). "They did find evidence of enhanced alveolar epithelial cell activity," Dr. Collard said. "That was the main predominant pattern."

A study of biomarkers conducted by Dr. Collard and his associates yielded similar findings (Am. J. Physiol. Lung Cell Mol. Physiol. 2010;299:L3-7).

Dr. Collard hypothesized that acute exacerbation of IPF represents a primary acceleration of IPF in the setting of acute lung stress. "This stress may be minor, at a level that would not cause clinical disease in a normal lung," he said. Potential sources of stress include infection, occult aspiration, interventions, and drugs.

Dr. Collard disclosed that he receives research funding from the National Institutes of Health, the University of California, Boehringer Ingelheim, and Genentech. He also receives consulting fees from Fibrogen, Gilead, InterMune, and Onyx.

HONOLULU – Although large numbers of patients are surviving acute lung injury/adult respiratory distress syndrome, long-term impairments are common and "striking for their relationship to neuropsychiatric dysfunction," Dr. Jesse Hall said at the annual meeting of the American College of Chest Physicians.

"The pace of recovery is protracted and likely incomplete in the current paradigm of care," said Dr. Hall, professor of medicine, anesthesia, and critical care at the University of Chicago. "Interventions including those begun at the onset of critical illness will hopefully improve these outcomes."

According to the best epidemiologic study on the topic, an estimated 191,000 cases of acute lung injury (ALI) and 141,500 cases of adult respiratory distress syndrome (ARDS) occur each year in the United States, causing a combined 133,500 deaths annually (N. Engl. J. Med 2005;353:1685-93). Implementation of low-tidal-volume ventilation over the past decade has led to an improvement in survival among this patient population, Dr. Hall said, but "we are just beginning to understand through descriptive studies what the path is for these patients down the road. We really lack many prospective trials in that arena."

One study of 109 ARDS patients who were followed for 1 year found that most developed a restrictive lung lesion that improved in the first 6-12 months (N. Engl. J. Med 2003;348:683-93). "The most consistent pulmonary function test abnormality tends to be low diffusion capacity that often resolves over time," Dr. Hall said. Some of their general functional limitation correlates to their pulmonary dysfunction, "but much of it does not," he said. "In fact, it’s not what the patients report. They start to have a very low functional status 6, 12, and more months out, and they don’t ascribe it primarily to their lung dysfunction."

Residual areas of fibrosis are not unusual on follow-up CT scans of ALI/ARDS patients, and many of these patients develop airway abnormalities such as bronchiectasis associated with their lung injury, said Dr. Hall, who is also section chief of pulmonary and critical care medicine at the University of Chicago.

The 2003 study of 109 ARDS patients found that all subjects reported poor function due to loss of muscle bulk, proximal weakness, and fatigue. Some (12%) reported persistent pain at the chest tube site, 7% reported entrapment neuropathies, 7% had tracheotomy site problems, 5% had large joint enlargement/immobility from heterotopic ossification, and 4% had immobility in the form of contracted fingers or frozen shoulders. "It can be up to a year before patients regain their body weight after this episode," Dr. Hall said.

Neuromuscular sequelae may include myopathy, peripheral neuropathy, or deconditioning. "Any given patient can have any combination of those," he said. "Some of these disorders are reasonably strongly associated with some of our therapies. Most of our patients have a combination of peripheral neuropathies and myopathies that may by themselves be modest but are attended by extreme deconditioning. The neuromuscular sequelae of critical illness are variable in terms of recovery over months and years, and some patients seem to never fully recover."

The impact of neuropsychiatric sequelae can be significant. One study of 55 ARDS patients found that 100% had cognitive and affective impairments at hospital discharge, and 30% had generalized cognitive decline 1 year later (Am. J. Respir. Crit. Care Med. 1999;160:50-6). In the 2003 study, only 49% of the ARDS patients who had been employed were back to work at 1 year. "This is an astounding economic and financial consequence for the patient and the family," Dr. Hall commented. "Scores on the Short Form-36 were below normal in all eight domains at 3-, 6-, and 12-month follow-up from ICU discharge. There were improvements in most SF-36 categories, but almost none were back to normal."

Dr. Hall said that changes in the current health care system are needed to improve outcomes for ALI/ARDS patients. Currently, "it’s difficult for those in our discipline to figure out how to become a change agent, or help our patients acquire what they need to optimize their recovery," he explained. "It’s not likely, in fact, to be done by critical care doctors down the road."

One study from the United Kingdom sought to determine if giving patients a self-help rehabilitation manual would affect their general functional status "and therefore their psychiatric axes as well, and maybe even make them more functional," Dr. Hall said. For the study, patients in the control group received ward visits, three telephone calls at home, and clinic appointments at 8 weeks and 6 months, whereas patients in the intervention group received the same plus a 6-week self-help rehabilitation manual. At the end of 6 weeks, patients in the intervention group had significantly better physical function scores, compared with controls (Crit. Care Med. 2003;31:2456-61). Unfortunately, such benefits were not seen in another recent prospective trial.

In a recent trial conducted by a group of researchers that included Dr. Hall, 104 critical care patients who required ventilation were randomized to either early physical and occupational therapy during periods of daily interruption of sedation, or to daily interruption of sedation with therapy as ordered by the primary care team (Lancet 2009;373:1874-82). Compared with controls, patients who received early physical and occupational therapy had better return to independent functional status at hospital discharge (59% vs. 35%, respectively) and less ICU delirium (2 days vs. 4 days).

Dr. Hall concluded by noting that the brain and the neurologic and musculoskeletal systems "are likely the last to recover after ALI/ARDS, and may not recover fully to the status patients had before. We don’t know what matters most for long-term recovery. It’s reasonable to think that shortening ICU and mechanical ventilation time would be beneficial."

Dr. Hall disclosed that he receives honoraria from the American College of Chest Physicians and the American Thoracic Society.

HONOLULU – Although large numbers of patients are surviving acute lung injury/adult respiratory distress syndrome, long-term impairments are common and "striking for their relationship to neuropsychiatric dysfunction," Dr. Jesse Hall said at the annual meeting of the American College of Chest Physicians.

"The pace of recovery is protracted and likely incomplete in the current paradigm of care," said Dr. Hall, professor of medicine, anesthesia, and critical care at the University of Chicago. "Interventions including those begun at the onset of critical illness will hopefully improve these outcomes."

According to the best epidemiologic study on the topic, an estimated 191,000 cases of acute lung injury (ALI) and 141,500 cases of adult respiratory distress syndrome (ARDS) occur each year in the United States, causing a combined 133,500 deaths annually (N. Engl. J. Med 2005;353:1685-93). Implementation of low-tidal-volume ventilation over the past decade has led to an improvement in survival among this patient population, Dr. Hall said, but "we are just beginning to understand through descriptive studies what the path is for these patients down the road. We really lack many prospective trials in that arena."

One study of 109 ARDS patients who were followed for 1 year found that most developed a restrictive lung lesion that improved in the first 6-12 months (N. Engl. J. Med 2003;348:683-93). "The most consistent pulmonary function test abnormality tends to be low diffusion capacity that often resolves over time," Dr. Hall said. Some of their general functional limitation correlates to their pulmonary dysfunction, "but much of it does not," he said. "In fact, it’s not what the patients report. They start to have a very low functional status 6, 12, and more months out, and they don’t ascribe it primarily to their lung dysfunction."

Residual areas of fibrosis are not unusual on follow-up CT scans of ALI/ARDS patients, and many of these patients develop airway abnormalities such as bronchiectasis associated with their lung injury, said Dr. Hall, who is also section chief of pulmonary and critical care medicine at the University of Chicago.

The 2003 study of 109 ARDS patients found that all subjects reported poor function due to loss of muscle bulk, proximal weakness, and fatigue. Some (12%) reported persistent pain at the chest tube site, 7% reported entrapment neuropathies, 7% had tracheotomy site problems, 5% had large joint enlargement/immobility from heterotopic ossification, and 4% had immobility in the form of contracted fingers or frozen shoulders. "It can be up to a year before patients regain their body weight after this episode," Dr. Hall said.

Neuromuscular sequelae may include myopathy, peripheral neuropathy, or deconditioning. "Any given patient can have any combination of those," he said. "Some of these disorders are reasonably strongly associated with some of our therapies. Most of our patients have a combination of peripheral neuropathies and myopathies that may by themselves be modest but are attended by extreme deconditioning. The neuromuscular sequelae of critical illness are variable in terms of recovery over months and years, and some patients seem to never fully recover."

The impact of neuropsychiatric sequelae can be significant. One study of 55 ARDS patients found that 100% had cognitive and affective impairments at hospital discharge, and 30% had generalized cognitive decline 1 year later (Am. J. Respir. Crit. Care Med. 1999;160:50-6). In the 2003 study, only 49% of the ARDS patients who had been employed were back to work at 1 year. "This is an astounding economic and financial consequence for the patient and the family," Dr. Hall commented. "Scores on the Short Form-36 were below normal in all eight domains at 3-, 6-, and 12-month follow-up from ICU discharge. There were improvements in most SF-36 categories, but almost none were back to normal."

Dr. Hall said that changes in the current health care system are needed to improve outcomes for ALI/ARDS patients. Currently, "it’s difficult for those in our discipline to figure out how to become a change agent, or help our patients acquire what they need to optimize their recovery," he explained. "It’s not likely, in fact, to be done by critical care doctors down the road."

One study from the United Kingdom sought to determine if giving patients a self-help rehabilitation manual would affect their general functional status "and therefore their psychiatric axes as well, and maybe even make them more functional," Dr. Hall said. For the study, patients in the control group received ward visits, three telephone calls at home, and clinic appointments at 8 weeks and 6 months, whereas patients in the intervention group received the same plus a 6-week self-help rehabilitation manual. At the end of 6 weeks, patients in the intervention group had significantly better physical function scores, compared with controls (Crit. Care Med. 2003;31:2456-61). Unfortunately, such benefits were not seen in another recent prospective trial.

In a recent trial conducted by a group of researchers that included Dr. Hall, 104 critical care patients who required ventilation were randomized to either early physical and occupational therapy during periods of daily interruption of sedation, or to daily interruption of sedation with therapy as ordered by the primary care team (Lancet 2009;373:1874-82). Compared with controls, patients who received early physical and occupational therapy had better return to independent functional status at hospital discharge (59% vs. 35%, respectively) and less ICU delirium (2 days vs. 4 days).

Dr. Hall concluded by noting that the brain and the neurologic and musculoskeletal systems "are likely the last to recover after ALI/ARDS, and may not recover fully to the status patients had before. We don’t know what matters most for long-term recovery. It’s reasonable to think that shortening ICU and mechanical ventilation time would be beneficial."

Dr. Hall disclosed that he receives honoraria from the American College of Chest Physicians and the American Thoracic Society.

HONOLULU – Although large numbers of patients are surviving acute lung injury/adult respiratory distress syndrome, long-term impairments are common and "striking for their relationship to neuropsychiatric dysfunction," Dr. Jesse Hall said at the annual meeting of the American College of Chest Physicians.

"The pace of recovery is protracted and likely incomplete in the current paradigm of care," said Dr. Hall, professor of medicine, anesthesia, and critical care at the University of Chicago. "Interventions including those begun at the onset of critical illness will hopefully improve these outcomes."

According to the best epidemiologic study on the topic, an estimated 191,000 cases of acute lung injury (ALI) and 141,500 cases of adult respiratory distress syndrome (ARDS) occur each year in the United States, causing a combined 133,500 deaths annually (N. Engl. J. Med 2005;353:1685-93). Implementation of low-tidal-volume ventilation over the past decade has led to an improvement in survival among this patient population, Dr. Hall said, but "we are just beginning to understand through descriptive studies what the path is for these patients down the road. We really lack many prospective trials in that arena."

One study of 109 ARDS patients who were followed for 1 year found that most developed a restrictive lung lesion that improved in the first 6-12 months (N. Engl. J. Med 2003;348:683-93). "The most consistent pulmonary function test abnormality tends to be low diffusion capacity that often resolves over time," Dr. Hall said. Some of their general functional limitation correlates to their pulmonary dysfunction, "but much of it does not," he said. "In fact, it’s not what the patients report. They start to have a very low functional status 6, 12, and more months out, and they don’t ascribe it primarily to their lung dysfunction."

Residual areas of fibrosis are not unusual on follow-up CT scans of ALI/ARDS patients, and many of these patients develop airway abnormalities such as bronchiectasis associated with their lung injury, said Dr. Hall, who is also section chief of pulmonary and critical care medicine at the University of Chicago.

The 2003 study of 109 ARDS patients found that all subjects reported poor function due to loss of muscle bulk, proximal weakness, and fatigue. Some (12%) reported persistent pain at the chest tube site, 7% reported entrapment neuropathies, 7% had tracheotomy site problems, 5% had large joint enlargement/immobility from heterotopic ossification, and 4% had immobility in the form of contracted fingers or frozen shoulders. "It can be up to a year before patients regain their body weight after this episode," Dr. Hall said.

Neuromuscular sequelae may include myopathy, peripheral neuropathy, or deconditioning. "Any given patient can have any combination of those," he said. "Some of these disorders are reasonably strongly associated with some of our therapies. Most of our patients have a combination of peripheral neuropathies and myopathies that may by themselves be modest but are attended by extreme deconditioning. The neuromuscular sequelae of critical illness are variable in terms of recovery over months and years, and some patients seem to never fully recover."

The impact of neuropsychiatric sequelae can be significant. One study of 55 ARDS patients found that 100% had cognitive and affective impairments at hospital discharge, and 30% had generalized cognitive decline 1 year later (Am. J. Respir. Crit. Care Med. 1999;160:50-6). In the 2003 study, only 49% of the ARDS patients who had been employed were back to work at 1 year. "This is an astounding economic and financial consequence for the patient and the family," Dr. Hall commented. "Scores on the Short Form-36 were below normal in all eight domains at 3-, 6-, and 12-month follow-up from ICU discharge. There were improvements in most SF-36 categories, but almost none were back to normal."

Dr. Hall said that changes in the current health care system are needed to improve outcomes for ALI/ARDS patients. Currently, "it’s difficult for those in our discipline to figure out how to become a change agent, or help our patients acquire what they need to optimize their recovery," he explained. "It’s not likely, in fact, to be done by critical care doctors down the road."

One study from the United Kingdom sought to determine if giving patients a self-help rehabilitation manual would affect their general functional status "and therefore their psychiatric axes as well, and maybe even make them more functional," Dr. Hall said. For the study, patients in the control group received ward visits, three telephone calls at home, and clinic appointments at 8 weeks and 6 months, whereas patients in the intervention group received the same plus a 6-week self-help rehabilitation manual. At the end of 6 weeks, patients in the intervention group had significantly better physical function scores, compared with controls (Crit. Care Med. 2003;31:2456-61). Unfortunately, such benefits were not seen in another recent prospective trial.

In a recent trial conducted by a group of researchers that included Dr. Hall, 104 critical care patients who required ventilation were randomized to either early physical and occupational therapy during periods of daily interruption of sedation, or to daily interruption of sedation with therapy as ordered by the primary care team (Lancet 2009;373:1874-82). Compared with controls, patients who received early physical and occupational therapy had better return to independent functional status at hospital discharge (59% vs. 35%, respectively) and less ICU delirium (2 days vs. 4 days).

Dr. Hall concluded by noting that the brain and the neurologic and musculoskeletal systems "are likely the last to recover after ALI/ARDS, and may not recover fully to the status patients had before. We don’t know what matters most for long-term recovery. It’s reasonable to think that shortening ICU and mechanical ventilation time would be beneficial."

Dr. Hall disclosed that he receives honoraria from the American College of Chest Physicians and the American Thoracic Society.

HONOLULU – Having a higher body mass index is not significantly associated with hospital mortality among patients admitted to the surgical ICU.

While similar findings have been reported in medical ICUs, this is believed to be the largest study to investigate the relationship between BMI and mortality exclusively in a surgical ICU, Dr. Adam Khader said in an interview during a poster session at the annual meeting of the American College of Chest Physicians.

Dr. Khader, a resident in the department of surgery at Hofstra North Shore–Long Island Jewish Medical Center, Manhasset, N.Y., and his associates evaluated the records of 1,860 patients admitted to the medical center’s surgical ICU. Patients younger than age 18 years and those who did not undergo surgery were excluded from the analysis. The researchers used area under the receiver operating characteristic curves to assess the effect of BMI on mortality and categorized patients as underweight (BMI less than 20 kg/m²), normal weight (20-25 kg/m²), overweight (25-30 kg/m²), obese (30-35 kg/m²), severely obese (35-50 kg/m²), and super obese (greater than 50 kg/m²).

Overall 30-day hospital mortality was 10%. Hospital mortality was 15% for underweight patients, 11% for normal weight patients, 8% for overweight patients, 9% for obese patients, 13% for severely obese patients, and 22% for super obese patients. Area under the receiver operating characteristic curve analysis yielded no significant association between BMI and mortality, even after stratification of patients by elective vs. emergent surgery, and patients younger vs. older than age 75 years.

Dr. Khader and his associates observed a trend toward increased mortality for patients in the underweight, obese, and severely obese categories of BMI, "but nothing statistically significant," he said. "Still, there was a large number of patients [in this study]. You can’t really ignore the numbers."

Dr. Khader said that he had no relevant financial conflicts to disclose.

HONOLULU – Having a higher body mass index is not significantly associated with hospital mortality among patients admitted to the surgical ICU.

While similar findings have been reported in medical ICUs, this is believed to be the largest study to investigate the relationship between BMI and mortality exclusively in a surgical ICU, Dr. Adam Khader said in an interview during a poster session at the annual meeting of the American College of Chest Physicians.

Dr. Khader, a resident in the department of surgery at Hofstra North Shore–Long Island Jewish Medical Center, Manhasset, N.Y., and his associates evaluated the records of 1,860 patients admitted to the medical center’s surgical ICU. Patients younger than age 18 years and those who did not undergo surgery were excluded from the analysis. The researchers used area under the receiver operating characteristic curves to assess the effect of BMI on mortality and categorized patients as underweight (BMI less than 20 kg/m²), normal weight (20-25 kg/m²), overweight (25-30 kg/m²), obese (30-35 kg/m²), severely obese (35-50 kg/m²), and super obese (greater than 50 kg/m²).

Overall 30-day hospital mortality was 10%. Hospital mortality was 15% for underweight patients, 11% for normal weight patients, 8% for overweight patients, 9% for obese patients, 13% for severely obese patients, and 22% for super obese patients. Area under the receiver operating characteristic curve analysis yielded no significant association between BMI and mortality, even after stratification of patients by elective vs. emergent surgery, and patients younger vs. older than age 75 years.

Dr. Khader and his associates observed a trend toward increased mortality for patients in the underweight, obese, and severely obese categories of BMI, "but nothing statistically significant," he said. "Still, there was a large number of patients [in this study]. You can’t really ignore the numbers."

Dr. Khader said that he had no relevant financial conflicts to disclose.

HONOLULU – Having a higher body mass index is not significantly associated with hospital mortality among patients admitted to the surgical ICU.

While similar findings have been reported in medical ICUs, this is believed to be the largest study to investigate the relationship between BMI and mortality exclusively in a surgical ICU, Dr. Adam Khader said in an interview during a poster session at the annual meeting of the American College of Chest Physicians.

Dr. Khader, a resident in the department of surgery at Hofstra North Shore–Long Island Jewish Medical Center, Manhasset, N.Y., and his associates evaluated the records of 1,860 patients admitted to the medical center’s surgical ICU. Patients younger than age 18 years and those who did not undergo surgery were excluded from the analysis. The researchers used area under the receiver operating characteristic curves to assess the effect of BMI on mortality and categorized patients as underweight (BMI less than 20 kg/m²), normal weight (20-25 kg/m²), overweight (25-30 kg/m²), obese (30-35 kg/m²), severely obese (35-50 kg/m²), and super obese (greater than 50 kg/m²).

Overall 30-day hospital mortality was 10%. Hospital mortality was 15% for underweight patients, 11% for normal weight patients, 8% for overweight patients, 9% for obese patients, 13% for severely obese patients, and 22% for super obese patients. Area under the receiver operating characteristic curve analysis yielded no significant association between BMI and mortality, even after stratification of patients by elective vs. emergent surgery, and patients younger vs. older than age 75 years.

Dr. Khader and his associates observed a trend toward increased mortality for patients in the underweight, obese, and severely obese categories of BMI, "but nothing statistically significant," he said. "Still, there was a large number of patients [in this study]. You can’t really ignore the numbers."

Dr. Khader said that he had no relevant financial conflicts to disclose.

HONOLULU – Not long ago, patients older than 65 years were rarely considered candidates for lung transplantation. But that’s not quite true anymore.

Being elderly is still a relative contraindication, but according to data from the International Society for Heart and Lung Transplantation, an increasing proportion of people older than age 65 are receiving lung transplants, from about 2% in 1995-1999 to about 6% between 2000 and June of 2010.

Instead of age and the length of time spent on the list waiting for a transplant, candidacy for the procedure is now based on whether patients’ advanced respiratory disease has progressed despite medical therapy, and whether they have a 50% or less chance of survival in the next 2-3 years, Dr. Luis F. Angel explained at the annual meeting of the American College of Chest Physicians.

"Potential candidates must be capable of comprehending the procedure, undergoing the selection process, and waiting the time necessary on the waiting list," said Dr. Angel, director of lung transplantation for the University of Texas Health Science Center at San Antonio.

In a review of the latest criteria, he explained that patients "must also be free of significant medical comorbidities and be sufficiently fit to handle this major surgical procedure and multiple medications post procedure."

The list of absolute contraindications for lung transplantation is lengthy, and includes recent malignancy (other than nonmelanoma skin cancer); infection with HIV; infection with hepatitis B or C with histologic evidence of cirrhosis; active cigarette smoking or substance abuse; severe and untreated psychiatric illness; documented noncompliance with medical care; and absence of a reliable social network.

Relative contraindications, Dr. Angel said, include the clinical state at the moment of notification or referral, such as the presence of hemodynamic instability, excessive physical deterioration, or severe muscle atrophy that impedes performing outpatient rehabilitation. Also taken into account is the need for invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) support.

"Colonization by multiresistant or panresistant bacteria, fungus, or mycobacteria is another contraindication," Dr. Angel said, "as are other medical conditions such as coronary artery disease, liver and renal disease, gastroesophageal reflux, or symptomatic osteoporosis, and having a body mass index higher than 30 kg/m²."

Regarding the following specific indication for transplantation, the success rates vary according to the condition:

• COPD/emphysema. In a select group of patients with COPD/emphysema, transplantation provides both survival and quality of life benefits.

Referral criteria include a BODE index of 7-10 points, or at least one of the following: a history of hospitalization for exacerbation associated with acute hypercapnia; pulmonary hypertension or cor pulmonale, or both, despite oxygen therapy; and an FEV₁ (forced expiratory volume in 1 second) of less than 20% and either a DLCO (diffusing capacity of the lungs for carbon monoxide) finding of less than 20% or homogenous distribution of emphysema.

• Pulmonary fibrosis. "The natural history of the disease is more predictable, and there are major limitations in effective therapy for this diagnosis," said Dr. Angel of the department of pulmonary and critical care medicine at the university.

Referral criteria, he said, include histologic or radiographic evidence of interstitial pneumonia, and any of the following: a DLCO of less than 39% predicted; a 10% or greater decrement in forced vital capacity during 6 months of follow-up; a decrease in pulse oximetry less than 88% during a 6-minute walk test; honeycombing on high-resolution CT; or development of secondary pulmonary hypertension.

• Cystic fibrosis. Patients with this condition "can get the most significant benefit and prolonged survival with lung transplantation," Dr. Angel said. "Referrals are often delayed, as there is [a] high emotional aspect in the management of these patients and their families."

Referral criteria, he said, include a FEV₁ of less than 30% of predicted, or rapidly declining lung function if FEV₁ is greater than 30% of predicted, and/or any of the following: increasing oxygen requirements, hypercapnia, and pulmonary hypertension.

• Idiopathic PAH (pulmonary arterial hypertension). "This is one of the most difficult conditions [in which] to determine the right time for transplantation," Dr. Angel said. "Significant improvements with medical therapy and increased awareness of the disease have decreased the number of lung transplants for this indication."

Referral criteria, he said, include persistent New York Heart Association class III or IV on maximal medical therapy; low or declining 6-minute walk test findings; failing therapy with intravenous epoprostenol or equivalent; a cardiac index of less than 2 L/min per square meter, or a right atrial pressure exceeding 15 mm Hg.

Dr. Angel said that he had no relevant financial conflicts to disclose.

HONOLULU – Not long ago, patients older than 65 years were rarely considered candidates for lung transplantation. But that’s not quite true anymore.

Being elderly is still a relative contraindication, but according to data from the International Society for Heart and Lung Transplantation, an increasing proportion of people older than age 65 are receiving lung transplants, from about 2% in 1995-1999 to about 6% between 2000 and June of 2010.

Instead of age and the length of time spent on the list waiting for a transplant, candidacy for the procedure is now based on whether patients’ advanced respiratory disease has progressed despite medical therapy, and whether they have a 50% or less chance of survival in the next 2-3 years, Dr. Luis F. Angel explained at the annual meeting of the American College of Chest Physicians.

"Potential candidates must be capable of comprehending the procedure, undergoing the selection process, and waiting the time necessary on the waiting list," said Dr. Angel, director of lung transplantation for the University of Texas Health Science Center at San Antonio.

In a review of the latest criteria, he explained that patients "must also be free of significant medical comorbidities and be sufficiently fit to handle this major surgical procedure and multiple medications post procedure."

The list of absolute contraindications for lung transplantation is lengthy, and includes recent malignancy (other than nonmelanoma skin cancer); infection with HIV; infection with hepatitis B or C with histologic evidence of cirrhosis; active cigarette smoking or substance abuse; severe and untreated psychiatric illness; documented noncompliance with medical care; and absence of a reliable social network.

Relative contraindications, Dr. Angel said, include the clinical state at the moment of notification or referral, such as the presence of hemodynamic instability, excessive physical deterioration, or severe muscle atrophy that impedes performing outpatient rehabilitation. Also taken into account is the need for invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) support.

"Colonization by multiresistant or panresistant bacteria, fungus, or mycobacteria is another contraindication," Dr. Angel said, "as are other medical conditions such as coronary artery disease, liver and renal disease, gastroesophageal reflux, or symptomatic osteoporosis, and having a body mass index higher than 30 kg/m²."

Regarding the following specific indication for transplantation, the success rates vary according to the condition:

• COPD/emphysema. In a select group of patients with COPD/emphysema, transplantation provides both survival and quality of life benefits.

Referral criteria include a BODE index of 7-10 points, or at least one of the following: a history of hospitalization for exacerbation associated with acute hypercapnia; pulmonary hypertension or cor pulmonale, or both, despite oxygen therapy; and an FEV₁ (forced expiratory volume in 1 second) of less than 20% and either a DLCO (diffusing capacity of the lungs for carbon monoxide) finding of less than 20% or homogenous distribution of emphysema.

• Pulmonary fibrosis. "The natural history of the disease is more predictable, and there are major limitations in effective therapy for this diagnosis," said Dr. Angel of the department of pulmonary and critical care medicine at the university.

Referral criteria, he said, include histologic or radiographic evidence of interstitial pneumonia, and any of the following: a DLCO of less than 39% predicted; a 10% or greater decrement in forced vital capacity during 6 months of follow-up; a decrease in pulse oximetry less than 88% during a 6-minute walk test; honeycombing on high-resolution CT; or development of secondary pulmonary hypertension.

• Cystic fibrosis. Patients with this condition "can get the most significant benefit and prolonged survival with lung transplantation," Dr. Angel said. "Referrals are often delayed, as there is [a] high emotional aspect in the management of these patients and their families."

Referral criteria, he said, include a FEV₁ of less than 30% of predicted, or rapidly declining lung function if FEV₁ is greater than 30% of predicted, and/or any of the following: increasing oxygen requirements, hypercapnia, and pulmonary hypertension.

• Idiopathic PAH (pulmonary arterial hypertension). "This is one of the most difficult conditions [in which] to determine the right time for transplantation," Dr. Angel said. "Significant improvements with medical therapy and increased awareness of the disease have decreased the number of lung transplants for this indication."

Referral criteria, he said, include persistent New York Heart Association class III or IV on maximal medical therapy; low or declining 6-minute walk test findings; failing therapy with intravenous epoprostenol or equivalent; a cardiac index of less than 2 L/min per square meter, or a right atrial pressure exceeding 15 mm Hg.

Dr. Angel said that he had no relevant financial conflicts to disclose.

HONOLULU – Not long ago, patients older than 65 years were rarely considered candidates for lung transplantation. But that’s not quite true anymore.

Being elderly is still a relative contraindication, but according to data from the International Society for Heart and Lung Transplantation, an increasing proportion of people older than age 65 are receiving lung transplants, from about 2% in 1995-1999 to about 6% between 2000 and June of 2010.

Instead of age and the length of time spent on the list waiting for a transplant, candidacy for the procedure is now based on whether patients’ advanced respiratory disease has progressed despite medical therapy, and whether they have a 50% or less chance of survival in the next 2-3 years, Dr. Luis F. Angel explained at the annual meeting of the American College of Chest Physicians.

"Potential candidates must be capable of comprehending the procedure, undergoing the selection process, and waiting the time necessary on the waiting list," said Dr. Angel, director of lung transplantation for the University of Texas Health Science Center at San Antonio.

In a review of the latest criteria, he explained that patients "must also be free of significant medical comorbidities and be sufficiently fit to handle this major surgical procedure and multiple medications post procedure."

The list of absolute contraindications for lung transplantation is lengthy, and includes recent malignancy (other than nonmelanoma skin cancer); infection with HIV; infection with hepatitis B or C with histologic evidence of cirrhosis; active cigarette smoking or substance abuse; severe and untreated psychiatric illness; documented noncompliance with medical care; and absence of a reliable social network.

Relative contraindications, Dr. Angel said, include the clinical state at the moment of notification or referral, such as the presence of hemodynamic instability, excessive physical deterioration, or severe muscle atrophy that impedes performing outpatient rehabilitation. Also taken into account is the need for invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) support.

"Colonization by multiresistant or panresistant bacteria, fungus, or mycobacteria is another contraindication," Dr. Angel said, "as are other medical conditions such as coronary artery disease, liver and renal disease, gastroesophageal reflux, or symptomatic osteoporosis, and having a body mass index higher than 30 kg/m²."

Regarding the following specific indication for transplantation, the success rates vary according to the condition:

• COPD/emphysema. In a select group of patients with COPD/emphysema, transplantation provides both survival and quality of life benefits.

Referral criteria include a BODE index of 7-10 points, or at least one of the following: a history of hospitalization for exacerbation associated with acute hypercapnia; pulmonary hypertension or cor pulmonale, or both, despite oxygen therapy; and an FEV₁ (forced expiratory volume in 1 second) of less than 20% and either a DLCO (diffusing capacity of the lungs for carbon monoxide) finding of less than 20% or homogenous distribution of emphysema.

• Pulmonary fibrosis. "The natural history of the disease is more predictable, and there are major limitations in effective therapy for this diagnosis," said Dr. Angel of the department of pulmonary and critical care medicine at the university.

Referral criteria, he said, include histologic or radiographic evidence of interstitial pneumonia, and any of the following: a DLCO of less than 39% predicted; a 10% or greater decrement in forced vital capacity during 6 months of follow-up; a decrease in pulse oximetry less than 88% during a 6-minute walk test; honeycombing on high-resolution CT; or development of secondary pulmonary hypertension.

• Cystic fibrosis. Patients with this condition "can get the most significant benefit and prolonged survival with lung transplantation," Dr. Angel said. "Referrals are often delayed, as there is [a] high emotional aspect in the management of these patients and their families."

Referral criteria, he said, include a FEV₁ of less than 30% of predicted, or rapidly declining lung function if FEV₁ is greater than 30% of predicted, and/or any of the following: increasing oxygen requirements, hypercapnia, and pulmonary hypertension.

• Idiopathic PAH (pulmonary arterial hypertension). "This is one of the most difficult conditions [in which] to determine the right time for transplantation," Dr. Angel said. "Significant improvements with medical therapy and increased awareness of the disease have decreased the number of lung transplants for this indication."

Referral criteria, he said, include persistent New York Heart Association class III or IV on maximal medical therapy; low or declining 6-minute walk test findings; failing therapy with intravenous epoprostenol or equivalent; a cardiac index of less than 2 L/min per square meter, or a right atrial pressure exceeding 15 mm Hg.

Dr. Angel said that he had no relevant financial conflicts to disclose.

HONOLULU – What do patients in the ICU want at the end of life?

Research has shown that pain control typically ranks at the top of the list, "but they also want to avoid inappropriate prolongation of dying," Dr. Richard Mularski said at the annual meeting of the American College of Chest Physicians.

Patients "want to achieve a sense of control at the end of life," continued Dr. Mularski, a pulmonologist who is a clinical investigator with the Center for Health Research at Kaiser Permanente Northwest, Portland, Ore. "They don’t want to be a burden on their family. We have to offer professional help, which primarily comes from talking with our patients and providing opportunities to strengthen relationships with loved ones. This might mean backing off on sedatives and pain medications so that patients and loved ones can interact before withdrawal of life support."

Dr. Mularski highlighted four key points from a 2009 consensus statement he helped to create on pain management during the palliative and end-of-life experience in the ICU (Chest 2009;135:1360-9). The first point reads that all ICU patients "experience opportunities for discomfort and suffering regardless of prognosis or goals, thus palliative therapy is a requisite approach for every patient, of which pain management is a principal component."

According to the second, third, and fourth key points, "for those dying in the ICU, an explicit shift in management to comfort-oriented care is often warranted and may be the most beneficial treatment the health-care team can offer; communication and cultural sensitivity with the patient-family unit is a principal approach for optimizing palliative and pain management as part of comprehensive ICU care, [and] ethical and legal misconceptions about the escalation of opiates and other palliative therapies should not be barriers to appropriate care, provided the intention of treatment is alleviation of pain and suffering."

Communicating effectively with the patient and family about prognosis in the critical care setting can be difficult "because we’re often limited by what treatments or interventions we can make," Dr. Mularski said. "This creates a certain tension: Patients have a widespread and deeply held desire not to be dead. We have to try to focus on that desire and acknowledge our limitations. Data show we don’t really prognosticate when death will occur very well."

"For those dying in the ICU, an explicit shift in management to comfort-oriented care ... may be the most beneficial treatment the health-care team can offer."

The potential for limited treatment options is only part of the problem. A trial conducted in a university-affiliated ICU found that 54% of families fail to comprehend a diagnosis, a prognosis, or treatment options (Crit. Care Med. 2000;28:3044-9). "We also know that family members experience a fair amount of moderate to severe posttraumatic stress," Dr. Mularski added. "This stress is increased when we provide inadequate information. We have to be careful not to use phrases that suggest abandonment or a failure of medicine to care, such as ‘there’s nothing more we can do,’ or ‘we have nothing to offer.’ We have plenty to offer. Palliative care may be the most important thing we have to offer at the end of life."

Key factors in shared decision making between clinicians and families about end-of-life care include prognosis, level of certainty "which may not be there," and family preferences. "The role of the patient and family is to help us understand patient values and preferences, and for us as clinicians to indicate which treatments might be concurrent with those values and preferences," Dr. Mularski said.

In a 2008 article, "Practical Guidance for Evidence-Based ICU Family Conferences," Dr. J. Randall Curtis and Dr. Douglas B. White offered a five-step approach to improving communication in the ICU with families (Chest 2008;134:835-43). It centers on the mnemonic "VALUE," which stands for value family statements, acknowledge family emotions, listen to the family, understand the patient as a person, and elicit family questions.

At Kaiser Permanente Northwest, Dr. Mularski and his colleagues created pocket cards for critical care staff that contain the VALUE mnemonic to remind them of how to best interact with families of patients in the ICU. He also recommends the book by Dr. Anthony L. Back and colleagues, "Mastering Communication with Seriously Ill Patients: Balancing Honesty with Empathy and Hope" (New York: Cambridge University Press, 2009).

Dr. Mularski disclosed that he has received research funding from several agencies including the Agency for Healthcare Research and Quality, National Cancer Institute, National Quality Forum, and Robert Wood Johnson Foundation. He also has received research support from Novartis and Spiration for unrelated work in chronic obstructive pulmonary disorder.

HONOLULU – What do patients in the ICU want at the end of life?

Research has shown that pain control typically ranks at the top of the list, "but they also want to avoid inappropriate prolongation of dying," Dr. Richard Mularski said at the annual meeting of the American College of Chest Physicians.

Patients "want to achieve a sense of control at the end of life," continued Dr. Mularski, a pulmonologist who is a clinical investigator with the Center for Health Research at Kaiser Permanente Northwest, Portland, Ore. "They don’t want to be a burden on their family. We have to offer professional help, which primarily comes from talking with our patients and providing opportunities to strengthen relationships with loved ones. This might mean backing off on sedatives and pain medications so that patients and loved ones can interact before withdrawal of life support."

Dr. Mularski highlighted four key points from a 2009 consensus statement he helped to create on pain management during the palliative and end-of-life experience in the ICU (Chest 2009;135:1360-9). The first point reads that all ICU patients "experience opportunities for discomfort and suffering regardless of prognosis or goals, thus palliative therapy is a requisite approach for every patient, of which pain management is a principal component."

According to the second, third, and fourth key points, "for those dying in the ICU, an explicit shift in management to comfort-oriented care is often warranted and may be the most beneficial treatment the health-care team can offer; communication and cultural sensitivity with the patient-family unit is a principal approach for optimizing palliative and pain management as part of comprehensive ICU care, [and] ethical and legal misconceptions about the escalation of opiates and other palliative therapies should not be barriers to appropriate care, provided the intention of treatment is alleviation of pain and suffering."

Communicating effectively with the patient and family about prognosis in the critical care setting can be difficult "because we’re often limited by what treatments or interventions we can make," Dr. Mularski said. "This creates a certain tension: Patients have a widespread and deeply held desire not to be dead. We have to try to focus on that desire and acknowledge our limitations. Data show we don’t really prognosticate when death will occur very well."

"For those dying in the ICU, an explicit shift in management to comfort-oriented care ... may be the most beneficial treatment the health-care team can offer."

The potential for limited treatment options is only part of the problem. A trial conducted in a university-affiliated ICU found that 54% of families fail to comprehend a diagnosis, a prognosis, or treatment options (Crit. Care Med. 2000;28:3044-9). "We also know that family members experience a fair amount of moderate to severe posttraumatic stress," Dr. Mularski added. "This stress is increased when we provide inadequate information. We have to be careful not to use phrases that suggest abandonment or a failure of medicine to care, such as ‘there’s nothing more we can do,’ or ‘we have nothing to offer.’ We have plenty to offer. Palliative care may be the most important thing we have to offer at the end of life."

Key factors in shared decision making between clinicians and families about end-of-life care include prognosis, level of certainty "which may not be there," and family preferences. "The role of the patient and family is to help us understand patient values and preferences, and for us as clinicians to indicate which treatments might be concurrent with those values and preferences," Dr. Mularski said.

In a 2008 article, "Practical Guidance for Evidence-Based ICU Family Conferences," Dr. J. Randall Curtis and Dr. Douglas B. White offered a five-step approach to improving communication in the ICU with families (Chest 2008;134:835-43). It centers on the mnemonic "VALUE," which stands for value family statements, acknowledge family emotions, listen to the family, understand the patient as a person, and elicit family questions.

At Kaiser Permanente Northwest, Dr. Mularski and his colleagues created pocket cards for critical care staff that contain the VALUE mnemonic to remind them of how to best interact with families of patients in the ICU. He also recommends the book by Dr. Anthony L. Back and colleagues, "Mastering Communication with Seriously Ill Patients: Balancing Honesty with Empathy and Hope" (New York: Cambridge University Press, 2009).

Dr. Mularski disclosed that he has received research funding from several agencies including the Agency for Healthcare Research and Quality, National Cancer Institute, National Quality Forum, and Robert Wood Johnson Foundation. He also has received research support from Novartis and Spiration for unrelated work in chronic obstructive pulmonary disorder.

HONOLULU – What do patients in the ICU want at the end of life?

Research has shown that pain control typically ranks at the top of the list, "but they also want to avoid inappropriate prolongation of dying," Dr. Richard Mularski said at the annual meeting of the American College of Chest Physicians.

Patients "want to achieve a sense of control at the end of life," continued Dr. Mularski, a pulmonologist who is a clinical investigator with the Center for Health Research at Kaiser Permanente Northwest, Portland, Ore. "They don’t want to be a burden on their family. We have to offer professional help, which primarily comes from talking with our patients and providing opportunities to strengthen relationships with loved ones. This might mean backing off on sedatives and pain medications so that patients and loved ones can interact before withdrawal of life support."

Dr. Mularski highlighted four key points from a 2009 consensus statement he helped to create on pain management during the palliative and end-of-life experience in the ICU (Chest 2009;135:1360-9). The first point reads that all ICU patients "experience opportunities for discomfort and suffering regardless of prognosis or goals, thus palliative therapy is a requisite approach for every patient, of which pain management is a principal component."

According to the second, third, and fourth key points, "for those dying in the ICU, an explicit shift in management to comfort-oriented care is often warranted and may be the most beneficial treatment the health-care team can offer; communication and cultural sensitivity with the patient-family unit is a principal approach for optimizing palliative and pain management as part of comprehensive ICU care, [and] ethical and legal misconceptions about the escalation of opiates and other palliative therapies should not be barriers to appropriate care, provided the intention of treatment is alleviation of pain and suffering."

Communicating effectively with the patient and family about prognosis in the critical care setting can be difficult "because we’re often limited by what treatments or interventions we can make," Dr. Mularski said. "This creates a certain tension: Patients have a widespread and deeply held desire not to be dead. We have to try to focus on that desire and acknowledge our limitations. Data show we don’t really prognosticate when death will occur very well."

"For those dying in the ICU, an explicit shift in management to comfort-oriented care ... may be the most beneficial treatment the health-care team can offer."

The potential for limited treatment options is only part of the problem. A trial conducted in a university-affiliated ICU found that 54% of families fail to comprehend a diagnosis, a prognosis, or treatment options (Crit. Care Med. 2000;28:3044-9). "We also know that family members experience a fair amount of moderate to severe posttraumatic stress," Dr. Mularski added. "This stress is increased when we provide inadequate information. We have to be careful not to use phrases that suggest abandonment or a failure of medicine to care, such as ‘there’s nothing more we can do,’ or ‘we have nothing to offer.’ We have plenty to offer. Palliative care may be the most important thing we have to offer at the end of life."

Key factors in shared decision making between clinicians and families about end-of-life care include prognosis, level of certainty "which may not be there," and family preferences. "The role of the patient and family is to help us understand patient values and preferences, and for us as clinicians to indicate which treatments might be concurrent with those values and preferences," Dr. Mularski said.

In a 2008 article, "Practical Guidance for Evidence-Based ICU Family Conferences," Dr. J. Randall Curtis and Dr. Douglas B. White offered a five-step approach to improving communication in the ICU with families (Chest 2008;134:835-43). It centers on the mnemonic "VALUE," which stands for value family statements, acknowledge family emotions, listen to the family, understand the patient as a person, and elicit family questions.

At Kaiser Permanente Northwest, Dr. Mularski and his colleagues created pocket cards for critical care staff that contain the VALUE mnemonic to remind them of how to best interact with families of patients in the ICU. He also recommends the book by Dr. Anthony L. Back and colleagues, "Mastering Communication with Seriously Ill Patients: Balancing Honesty with Empathy and Hope" (New York: Cambridge University Press, 2009).

Dr. Mularski disclosed that he has received research funding from several agencies including the Agency for Healthcare Research and Quality, National Cancer Institute, National Quality Forum, and Robert Wood Johnson Foundation. He also has received research support from Novartis and Spiration for unrelated work in chronic obstructive pulmonary disorder.

HONOLULU – The use of oral sildenafil helped improve oxygen delivery and exercise capacity in children with pulmonary arterial hypertension, results from a randomized, multicenter trial showed.

The study, which employed cardiopulmonary exercise testing – including assessment of ventilation to carbon dioxide (VE/VCO₂) slope – "confirmed our suspicion that ventilatory efficiency, as measured by VE/VCO₂, appears to be a sensitive measurement to assess exercise ability in pediatric pulmonary arterial hypertension as long as the children are old enough and developmentally able to exercise reliably," lead investigator Dr. Robyn J. Barst said in an interview in advance of the annual meeting of the American College of Chest Physicians, where the study was presented. Using such measures may allow future trials to determine drug effectiveness and safety with fewer study participants, thus shortening time to approval for new drugs, she said.

The STARTS-1 study included 234 treatment-naive children with pulmonary arterial hypertension (PAH), who were aged 1-17 years and weighed 8 kg or more. Participants were randomized to receive placebo or low, medium, or high doses of oral sildenafil three times a day at 1 of 32 centers in 16 countries, including the United States. Doses were based on weight groups – 8-20 kg, 20-45 kg, and more than 45 kg – with the doses ranging from 10 to 80 mg t.i.d. Sildenafil is approved in the European Union for the treatment of PAH in children at a dose of 10 mg t.i.d. for children who weigh less than 20 kg and a dose of 20 mg t.i.d. for children who weigh more than 20 kg, but is not currently approved in the United States for this population.

The researchers measured peak oxygen consumption (VO₂) and VE/VCO₂ levels at the beginning of the study and again at 16 weeks in 106 children who could reliably exercise on a bicycle. The primary outcome was percent change in peak VO₂. Cardiopulmonary exercise testing, rather than the more frequently used 6-minute walk test, was used to assess exercise capacity, because cardiopulmonary exercise testing is "considered a more sensitive exercise test than the 6-minute walk test; many patients have a fairly good 6-minute walk test despite significant pulmonary arterial hypertension," explained Dr. Barst, professor emeritus of pediatrics at Columbia University, New York.

Although the primary end point of percent change in peak VO₂ comparing the combined three sildenafil dose groups with placebo did not meet predefined criteria (P = .056), children in the medium- and high-dose sildenafil groups did have significantly greater improvements in peak VO₂ and VE/VCO₂ slope, compared with those on placebo, whether the pulmonary arterial hypertension was idiopathic/heritable or associated with congenital heart disease. Upper respiratory tract infections, pyrexia, and vomiting occurred more often with sildenafil than placebo. The majority of adverse events were mild or moderate.

The study demonstrated that cardiopulmonary exercise testing "is a relatively simple exercise test that can be carried out safely in an exercise lab experienced in caring for children and adults with PAH," Dr. Barst said. "Further, measurement of ventilatory efficiency does not require the patient to exercise to maximal exertion. And there now is a more simplified gas analysis system available than what was used in this study to assess these same parameters. It is a miniaturized, simplified, and portable system that has been designed for submaximal exercise testing. Utilizing the [Shape-HF Cardiopulmonary Testing System, Shape Medical Systems] should be useful to clinicians for long-term follow-up assessments to determine if their patients are responding adequately to their current treatments."

Dr. Barst acknowledged certain limitations of the study, including the fact that not all children were old enough or able to perform cardiopulmonary exercise testing. "However, all enrolled patients did have safety assessments, functional capacity evaluations, and pulmonary hemodynamic parameters obtained by invasive right heart catheterization at both baseline and at the end of the 16-week study, to obtain objective parameters of disease severity known to be prognostic for long-term outcomes," she said.

An additional limitation of most controlled studies performed in PAH, she added, is the relatively short study duration – 16 weeks in this case. "When the data from STARTS-1 [were] combined with interim data – more than 2 years – from the ongoing extension STARTS-2 study, in which all patients received active drug, the overall profile [favored] the medium dose," she said. "Further investigation is warranted to determine optimal dosing based on age and body weight."

Pfizer funded the study. Dr. Barst served as a consultant for the company during the July 2010 Food and Drug Administration advisory committee meeting on sildenafil treatment for pediatric pulmonary arterial hypertension. Dr. Barst also has received honoraria from Actelion, Eli Lilly, Gilead, GlaxoSmithKline, Ikaria, Merck, and Novartis for consulting work.

HONOLULU – The use of oral sildenafil helped improve oxygen delivery and exercise capacity in children with pulmonary arterial hypertension, results from a randomized, multicenter trial showed.

The study, which employed cardiopulmonary exercise testing – including assessment of ventilation to carbon dioxide (VE/VCO₂) slope – "confirmed our suspicion that ventilatory efficiency, as measured by VE/VCO₂, appears to be a sensitive measurement to assess exercise ability in pediatric pulmonary arterial hypertension as long as the children are old enough and developmentally able to exercise reliably," lead investigator Dr. Robyn J. Barst said in an interview in advance of the annual meeting of the American College of Chest Physicians, where the study was presented. Using such measures may allow future trials to determine drug effectiveness and safety with fewer study participants, thus shortening time to approval for new drugs, she said.

The STARTS-1 study included 234 treatment-naive children with pulmonary arterial hypertension (PAH), who were aged 1-17 years and weighed 8 kg or more. Participants were randomized to receive placebo or low, medium, or high doses of oral sildenafil three times a day at 1 of 32 centers in 16 countries, including the United States. Doses were based on weight groups – 8-20 kg, 20-45 kg, and more than 45 kg – with the doses ranging from 10 to 80 mg t.i.d. Sildenafil is approved in the European Union for the treatment of PAH in children at a dose of 10 mg t.i.d. for children who weigh less than 20 kg and a dose of 20 mg t.i.d. for children who weigh more than 20 kg, but is not currently approved in the United States for this population.

The researchers measured peak oxygen consumption (VO₂) and VE/VCO₂ levels at the beginning of the study and again at 16 weeks in 106 children who could reliably exercise on a bicycle. The primary outcome was percent change in peak VO₂. Cardiopulmonary exercise testing, rather than the more frequently used 6-minute walk test, was used to assess exercise capacity, because cardiopulmonary exercise testing is "considered a more sensitive exercise test than the 6-minute walk test; many patients have a fairly good 6-minute walk test despite significant pulmonary arterial hypertension," explained Dr. Barst, professor emeritus of pediatrics at Columbia University, New York.

Although the primary end point of percent change in peak VO₂ comparing the combined three sildenafil dose groups with placebo did not meet predefined criteria (P = .056), children in the medium- and high-dose sildenafil groups did have significantly greater improvements in peak VO₂ and VE/VCO₂ slope, compared with those on placebo, whether the pulmonary arterial hypertension was idiopathic/heritable or associated with congenital heart disease. Upper respiratory tract infections, pyrexia, and vomiting occurred more often with sildenafil than placebo. The majority of adverse events were mild or moderate.

The study demonstrated that cardiopulmonary exercise testing "is a relatively simple exercise test that can be carried out safely in an exercise lab experienced in caring for children and adults with PAH," Dr. Barst said. "Further, measurement of ventilatory efficiency does not require the patient to exercise to maximal exertion. And there now is a more simplified gas analysis system available than what was used in this study to assess these same parameters. It is a miniaturized, simplified, and portable system that has been designed for submaximal exercise testing. Utilizing the [Shape-HF Cardiopulmonary Testing System, Shape Medical Systems] should be useful to clinicians for long-term follow-up assessments to determine if their patients are responding adequately to their current treatments."

Dr. Barst acknowledged certain limitations of the study, including the fact that not all children were old enough or able to perform cardiopulmonary exercise testing. "However, all enrolled patients did have safety assessments, functional capacity evaluations, and pulmonary hemodynamic parameters obtained by invasive right heart catheterization at both baseline and at the end of the 16-week study, to obtain objective parameters of disease severity known to be prognostic for long-term outcomes," she said.

An additional limitation of most controlled studies performed in PAH, she added, is the relatively short study duration – 16 weeks in this case. "When the data from STARTS-1 [were] combined with interim data – more than 2 years – from the ongoing extension STARTS-2 study, in which all patients received active drug, the overall profile [favored] the medium dose," she said. "Further investigation is warranted to determine optimal dosing based on age and body weight."

Pfizer funded the study. Dr. Barst served as a consultant for the company during the July 2010 Food and Drug Administration advisory committee meeting on sildenafil treatment for pediatric pulmonary arterial hypertension. Dr. Barst also has received honoraria from Actelion, Eli Lilly, Gilead, GlaxoSmithKline, Ikaria, Merck, and Novartis for consulting work.

HONOLULU – The use of oral sildenafil helped improve oxygen delivery and exercise capacity in children with pulmonary arterial hypertension, results from a randomized, multicenter trial showed.

The study, which employed cardiopulmonary exercise testing – including assessment of ventilation to carbon dioxide (VE/VCO₂) slope – "confirmed our suspicion that ventilatory efficiency, as measured by VE/VCO₂, appears to be a sensitive measurement to assess exercise ability in pediatric pulmonary arterial hypertension as long as the children are old enough and developmentally able to exercise reliably," lead investigator Dr. Robyn J. Barst said in an interview in advance of the annual meeting of the American College of Chest Physicians, where the study was presented. Using such measures may allow future trials to determine drug effectiveness and safety with fewer study participants, thus shortening time to approval for new drugs, she said.

The STARTS-1 study included 234 treatment-naive children with pulmonary arterial hypertension (PAH), who were aged 1-17 years and weighed 8 kg or more. Participants were randomized to receive placebo or low, medium, or high doses of oral sildenafil three times a day at 1 of 32 centers in 16 countries, including the United States. Doses were based on weight groups – 8-20 kg, 20-45 kg, and more than 45 kg – with the doses ranging from 10 to 80 mg t.i.d. Sildenafil is approved in the European Union for the treatment of PAH in children at a dose of 10 mg t.i.d. for children who weigh less than 20 kg and a dose of 20 mg t.i.d. for children who weigh more than 20 kg, but is not currently approved in the United States for this population.

The researchers measured peak oxygen consumption (VO₂) and VE/VCO₂ levels at the beginning of the study and again at 16 weeks in 106 children who could reliably exercise on a bicycle. The primary outcome was percent change in peak VO₂. Cardiopulmonary exercise testing, rather than the more frequently used 6-minute walk test, was used to assess exercise capacity, because cardiopulmonary exercise testing is "considered a more sensitive exercise test than the 6-minute walk test; many patients have a fairly good 6-minute walk test despite significant pulmonary arterial hypertension," explained Dr. Barst, professor emeritus of pediatrics at Columbia University, New York.

Although the primary end point of percent change in peak VO₂ comparing the combined three sildenafil dose groups with placebo did not meet predefined criteria (P = .056), children in the medium- and high-dose sildenafil groups did have significantly greater improvements in peak VO₂ and VE/VCO₂ slope, compared with those on placebo, whether the pulmonary arterial hypertension was idiopathic/heritable or associated with congenital heart disease. Upper respiratory tract infections, pyrexia, and vomiting occurred more often with sildenafil than placebo. The majority of adverse events were mild or moderate.

The study demonstrated that cardiopulmonary exercise testing "is a relatively simple exercise test that can be carried out safely in an exercise lab experienced in caring for children and adults with PAH," Dr. Barst said. "Further, measurement of ventilatory efficiency does not require the patient to exercise to maximal exertion. And there now is a more simplified gas analysis system available than what was used in this study to assess these same parameters. It is a miniaturized, simplified, and portable system that has been designed for submaximal exercise testing. Utilizing the [Shape-HF Cardiopulmonary Testing System, Shape Medical Systems] should be useful to clinicians for long-term follow-up assessments to determine if their patients are responding adequately to their current treatments."

Dr. Barst acknowledged certain limitations of the study, including the fact that not all children were old enough or able to perform cardiopulmonary exercise testing. "However, all enrolled patients did have safety assessments, functional capacity evaluations, and pulmonary hemodynamic parameters obtained by invasive right heart catheterization at both baseline and at the end of the 16-week study, to obtain objective parameters of disease severity known to be prognostic for long-term outcomes," she said.

An additional limitation of most controlled studies performed in PAH, she added, is the relatively short study duration – 16 weeks in this case. "When the data from STARTS-1 [were] combined with interim data – more than 2 years – from the ongoing extension STARTS-2 study, in which all patients received active drug, the overall profile [favored] the medium dose," she said. "Further investigation is warranted to determine optimal dosing based on age and body weight."

Pfizer funded the study. Dr. Barst served as a consultant for the company during the July 2010 Food and Drug Administration advisory committee meeting on sildenafil treatment for pediatric pulmonary arterial hypertension. Dr. Barst also has received honoraria from Actelion, Eli Lilly, Gilead, GlaxoSmithKline, Ikaria, Merck, and Novartis for consulting work.