CHICAGO – Pemetrexed maintenance therapy following pemetrexed plus cisplatin induction reduced the risk of progression by 38% in patients with advanced nonsquamous non–small cell lung cancer in the phase III PARAMOUNT trial.

The study’s primary end point of investigator-assessed progression-free survival was 4.1 months for pemetrexed (Alimta) plus best supportive care and 2.8 months for placebo plus best supportive care (log rank P = .00006; unadjusted hazard ratio, 0.62).

Independent review, completed in 88% of patients, confirmed the robustness of the primary end point, revealing a progression-free survival of 3.9 months for pemetrexed vs. 2.6 months for placebo (log rank P = .0002; HR, 0.64), lead author Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.

Overall survival data were not mature enough at the time of the analysis, with just 16 deaths.

"The magnitude of the benefit shown on progression-free survival, a 38% decrease in the risk of progression, is in favor of saying this is an effective treatment for patients with advanced nonsquamous non–small cell lung cancer," he said.

A previous trial (Lancet 2009;374:1432-40) showed that switching patients to pemetrexed maintenance improved the time free of cancer, but until now, it was unclear whether patients initially treated with pemetrexed would benefit from maintenance.

"This trial answers that," Dr. Mark Kris, chief of thoracic oncology at Memorial Sloan-Kettering Cancer Center in New York, told reporters in a press briefing at the meeting. "I think it’s very important in that it’s an example of how we can achieve an incremental benefit in our patients by the optimal use of drugs that are already available."

Pemetrexed (Eli Lilly) is approved in combination with cisplatin as first-line therapy for advanced nonsquamous non–small cell lung cancer (NSCLC) and in the second line as maintenance therapy in patients initially treated with chemotherapy.

Standard treatment for nonsquamous NSCLC is to continue bevacizumab until disease progression, but on the basis of these results, clinicians will likely give bevacizumab with pemetrexed, Dr. Kris said in an interview.

"The guidelines don’t say that because they didn’t have any data, but this will be the data that I’m pretty confident will change the guidelines," said Dr. Kris, who also is the William and Joy Ruane Chair in Thoracic Oncology at Sloan-Kettering.

During the formal presentation of the data, invited discussant Dr. Martin Edelman, director of solid tumor oncology at the University of Maryland Greenebaum Cancer Center in Baltimore, described the use of maintenance therapy as a contentious issue. He noted that many questions remain regarding maintenance trials, including the value of progression-free survival as an end point, how and when control patients are crossed over to active treatment, and whether the RECIST criteria should be used to determine progression.

Dr. Edelman described progression-free survival as an arbitrary end point subject to testing interval and considerable bias. To the credit of the PARAMOUNT investigators, he pointed out that there was use of independent review for this end point, but he said it still does not answer the question of overall survival.

"If one is supposed to change practice based on progression-free survival, we really need to know if particularly small differences are really beneficial," Dr. Edelman said. "That is where quality of life analysis can help us."

The PARAMOUNT investigators assessed health-related quality of life using the EuroQol-5D at baseline, day 1 of each cycle of induction or maintenance therapy, and at the 30-day postdiscontinuation visit. Compliance at all time points during the maintenance phase was more than 80%, but no statistical differences in the EQ-5D index score or its visual analog scale were observed between treatment arms, said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocío, Seville, Spain.

A total of 939 patients were enrolled in the trial. They received pemetrexed 500 mg/m² on day 1 of a 21-day cycle plus cisplatin 75 mg/m² induction. In all, 539 patients whose disease had not progressed and had a performance status of 0-2 were then randomized to pemetrexed maintenance 500 mg/m² on day 1 of a 21-day cycle plus best supportive care or placebo plus best supportive care until disease progression.

Dr. Paz-Ares said pemetrexed had a well-tolerated safety profile, similar to that seen in the previous pemetrexed switch maintenance trial. The pemetrexed and placebo groups had similar drug-related deaths (0.6% for both), drug-related serious adverse events (9% vs. 3%, respectively), and discontinuations due to adverse events (5.3% vs. 3.3%). Patients in the pemetrexed arm had significantly more grade 3/4 adverse fatigue (4.2% vs. 0.6%), anemia (4.5% vs. 0.6%), and neutropenia (3.6% vs. 0%). There was one on-study death with pemetrexed (pneumonia) and placebo (not otherwise specified), and one death within 30 days with pemetrexed (endocarditis), Dr. Paz-Ares reported.

"While overall very reasonable, this still comes at a cost in terms of significant toxicity, not to mention the cost of additional treatment," Dr. Edelman observed. "We really need a cost-effectiveness analysis in this era to follow strategies of frequent visits and scanning with early institution of second-line therapy versus the maintenance approach."

Eli Lilly funded the study. Dr. Paz-Ares disclosed no relevant relationships. Several coauthors reported relationships with industry, including employment, stock ownership, honoraria, and consultancy with Lilly, which markets pemetrexed.

CHICAGO – Pemetrexed maintenance therapy following pemetrexed plus cisplatin induction reduced the risk of progression by 38% in patients with advanced nonsquamous non–small cell lung cancer in the phase III PARAMOUNT trial.

The study’s primary end point of investigator-assessed progression-free survival was 4.1 months for pemetrexed (Alimta) plus best supportive care and 2.8 months for placebo plus best supportive care (log rank P = .00006; unadjusted hazard ratio, 0.62).

Independent review, completed in 88% of patients, confirmed the robustness of the primary end point, revealing a progression-free survival of 3.9 months for pemetrexed vs. 2.6 months for placebo (log rank P = .0002; HR, 0.64), lead author Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.

Overall survival data were not mature enough at the time of the analysis, with just 16 deaths.

"The magnitude of the benefit shown on progression-free survival, a 38% decrease in the risk of progression, is in favor of saying this is an effective treatment for patients with advanced nonsquamous non–small cell lung cancer," he said.

A previous trial (Lancet 2009;374:1432-40) showed that switching patients to pemetrexed maintenance improved the time free of cancer, but until now, it was unclear whether patients initially treated with pemetrexed would benefit from maintenance.

"This trial answers that," Dr. Mark Kris, chief of thoracic oncology at Memorial Sloan-Kettering Cancer Center in New York, told reporters in a press briefing at the meeting. "I think it’s very important in that it’s an example of how we can achieve an incremental benefit in our patients by the optimal use of drugs that are already available."

Pemetrexed (Eli Lilly) is approved in combination with cisplatin as first-line therapy for advanced nonsquamous non–small cell lung cancer (NSCLC) and in the second line as maintenance therapy in patients initially treated with chemotherapy.

Standard treatment for nonsquamous NSCLC is to continue bevacizumab until disease progression, but on the basis of these results, clinicians will likely give bevacizumab with pemetrexed, Dr. Kris said in an interview.

"The guidelines don’t say that because they didn’t have any data, but this will be the data that I’m pretty confident will change the guidelines," said Dr. Kris, who also is the William and Joy Ruane Chair in Thoracic Oncology at Sloan-Kettering.

During the formal presentation of the data, invited discussant Dr. Martin Edelman, director of solid tumor oncology at the University of Maryland Greenebaum Cancer Center in Baltimore, described the use of maintenance therapy as a contentious issue. He noted that many questions remain regarding maintenance trials, including the value of progression-free survival as an end point, how and when control patients are crossed over to active treatment, and whether the RECIST criteria should be used to determine progression.

Dr. Edelman described progression-free survival as an arbitrary end point subject to testing interval and considerable bias. To the credit of the PARAMOUNT investigators, he pointed out that there was use of independent review for this end point, but he said it still does not answer the question of overall survival.

"If one is supposed to change practice based on progression-free survival, we really need to know if particularly small differences are really beneficial," Dr. Edelman said. "That is where quality of life analysis can help us."

The PARAMOUNT investigators assessed health-related quality of life using the EuroQol-5D at baseline, day 1 of each cycle of induction or maintenance therapy, and at the 30-day postdiscontinuation visit. Compliance at all time points during the maintenance phase was more than 80%, but no statistical differences in the EQ-5D index score or its visual analog scale were observed between treatment arms, said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocío, Seville, Spain.

A total of 939 patients were enrolled in the trial. They received pemetrexed 500 mg/m² on day 1 of a 21-day cycle plus cisplatin 75 mg/m² induction. In all, 539 patients whose disease had not progressed and had a performance status of 0-2 were then randomized to pemetrexed maintenance 500 mg/m² on day 1 of a 21-day cycle plus best supportive care or placebo plus best supportive care until disease progression.

Dr. Paz-Ares said pemetrexed had a well-tolerated safety profile, similar to that seen in the previous pemetrexed switch maintenance trial. The pemetrexed and placebo groups had similar drug-related deaths (0.6% for both), drug-related serious adverse events (9% vs. 3%, respectively), and discontinuations due to adverse events (5.3% vs. 3.3%). Patients in the pemetrexed arm had significantly more grade 3/4 adverse fatigue (4.2% vs. 0.6%), anemia (4.5% vs. 0.6%), and neutropenia (3.6% vs. 0%). There was one on-study death with pemetrexed (pneumonia) and placebo (not otherwise specified), and one death within 30 days with pemetrexed (endocarditis), Dr. Paz-Ares reported.

"While overall very reasonable, this still comes at a cost in terms of significant toxicity, not to mention the cost of additional treatment," Dr. Edelman observed. "We really need a cost-effectiveness analysis in this era to follow strategies of frequent visits and scanning with early institution of second-line therapy versus the maintenance approach."

Eli Lilly funded the study. Dr. Paz-Ares disclosed no relevant relationships. Several coauthors reported relationships with industry, including employment, stock ownership, honoraria, and consultancy with Lilly, which markets pemetrexed.

CHICAGO – Pemetrexed maintenance therapy following pemetrexed plus cisplatin induction reduced the risk of progression by 38% in patients with advanced nonsquamous non–small cell lung cancer in the phase III PARAMOUNT trial.

The study’s primary end point of investigator-assessed progression-free survival was 4.1 months for pemetrexed (Alimta) plus best supportive care and 2.8 months for placebo plus best supportive care (log rank P = .00006; unadjusted hazard ratio, 0.62).

Independent review, completed in 88% of patients, confirmed the robustness of the primary end point, revealing a progression-free survival of 3.9 months for pemetrexed vs. 2.6 months for placebo (log rank P = .0002; HR, 0.64), lead author Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.

Overall survival data were not mature enough at the time of the analysis, with just 16 deaths.

"The magnitude of the benefit shown on progression-free survival, a 38% decrease in the risk of progression, is in favor of saying this is an effective treatment for patients with advanced nonsquamous non–small cell lung cancer," he said.

A previous trial (Lancet 2009;374:1432-40) showed that switching patients to pemetrexed maintenance improved the time free of cancer, but until now, it was unclear whether patients initially treated with pemetrexed would benefit from maintenance.

"This trial answers that," Dr. Mark Kris, chief of thoracic oncology at Memorial Sloan-Kettering Cancer Center in New York, told reporters in a press briefing at the meeting. "I think it’s very important in that it’s an example of how we can achieve an incremental benefit in our patients by the optimal use of drugs that are already available."

Pemetrexed (Eli Lilly) is approved in combination with cisplatin as first-line therapy for advanced nonsquamous non–small cell lung cancer (NSCLC) and in the second line as maintenance therapy in patients initially treated with chemotherapy.

Standard treatment for nonsquamous NSCLC is to continue bevacizumab until disease progression, but on the basis of these results, clinicians will likely give bevacizumab with pemetrexed, Dr. Kris said in an interview.

"The guidelines don’t say that because they didn’t have any data, but this will be the data that I’m pretty confident will change the guidelines," said Dr. Kris, who also is the William and Joy Ruane Chair in Thoracic Oncology at Sloan-Kettering.

During the formal presentation of the data, invited discussant Dr. Martin Edelman, director of solid tumor oncology at the University of Maryland Greenebaum Cancer Center in Baltimore, described the use of maintenance therapy as a contentious issue. He noted that many questions remain regarding maintenance trials, including the value of progression-free survival as an end point, how and when control patients are crossed over to active treatment, and whether the RECIST criteria should be used to determine progression.

Dr. Edelman described progression-free survival as an arbitrary end point subject to testing interval and considerable bias. To the credit of the PARAMOUNT investigators, he pointed out that there was use of independent review for this end point, but he said it still does not answer the question of overall survival.

"If one is supposed to change practice based on progression-free survival, we really need to know if particularly small differences are really beneficial," Dr. Edelman said. "That is where quality of life analysis can help us."

The PARAMOUNT investigators assessed health-related quality of life using the EuroQol-5D at baseline, day 1 of each cycle of induction or maintenance therapy, and at the 30-day postdiscontinuation visit. Compliance at all time points during the maintenance phase was more than 80%, but no statistical differences in the EQ-5D index score or its visual analog scale were observed between treatment arms, said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocío, Seville, Spain.

A total of 939 patients were enrolled in the trial. They received pemetrexed 500 mg/m² on day 1 of a 21-day cycle plus cisplatin 75 mg/m² induction. In all, 539 patients whose disease had not progressed and had a performance status of 0-2 were then randomized to pemetrexed maintenance 500 mg/m² on day 1 of a 21-day cycle plus best supportive care or placebo plus best supportive care until disease progression.

Dr. Paz-Ares said pemetrexed had a well-tolerated safety profile, similar to that seen in the previous pemetrexed switch maintenance trial. The pemetrexed and placebo groups had similar drug-related deaths (0.6% for both), drug-related serious adverse events (9% vs. 3%, respectively), and discontinuations due to adverse events (5.3% vs. 3.3%). Patients in the pemetrexed arm had significantly more grade 3/4 adverse fatigue (4.2% vs. 0.6%), anemia (4.5% vs. 0.6%), and neutropenia (3.6% vs. 0%). There was one on-study death with pemetrexed (pneumonia) and placebo (not otherwise specified), and one death within 30 days with pemetrexed (endocarditis), Dr. Paz-Ares reported.

"While overall very reasonable, this still comes at a cost in terms of significant toxicity, not to mention the cost of additional treatment," Dr. Edelman observed. "We really need a cost-effectiveness analysis in this era to follow strategies of frequent visits and scanning with early institution of second-line therapy versus the maintenance approach."

Eli Lilly funded the study. Dr. Paz-Ares disclosed no relevant relationships. Several coauthors reported relationships with industry, including employment, stock ownership, honoraria, and consultancy with Lilly, which markets pemetrexed.

CHICAGO – Pemetrexed maintenance therapy following pemetrexed plus cisplatin induction reduced the risk of progression by 38% in patients with advanced nonsquamous non–small cell lung cancer in the phase III PARAMOUNT trial.

The study’s primary end point of investigator-assessed progression-free survival was 4.1 months for pemetrexed (Alimta) plus best supportive care and 2.8 months for placebo plus best supportive care (log rank P = .00006; unadjusted hazard ratio, 0.62).

Independent review, completed in 88% of patients, confirmed the robustness of the primary end point, revealing a progression-free survival of 3.9 months for pemetrexed vs. 2.6 months for placebo (log rank P = .0002; HR, 0.64), lead author Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.

Overall survival data were not mature enough at the time of the analysis, with just 16 deaths.

"The magnitude of the benefit shown on progression-free survival, a 38% decrease in the risk of progression, is in favor of saying this is an effective treatment for patients with advanced nonsquamous non–small cell lung cancer," he said.

A previous trial (Lancet 2009;374:1432-40) showed that switching patients to pemetrexed maintenance improved the time free of cancer, but until now, it was unclear whether patients initially treated with pemetrexed would benefit from maintenance.

"This trial answers that," Dr. Mark Kris, chief of thoracic oncology at Memorial Sloan-Kettering Cancer Center in New York, told reporters in a press briefing at the meeting. "I think it’s very important in that it’s an example of how we can achieve an incremental benefit in our patients by the optimal use of drugs that are already available."

Pemetrexed (Eli Lilly) is approved in combination with cisplatin as first-line therapy for advanced nonsquamous non–small cell lung cancer (NSCLC) and in the second line as maintenance therapy in patients initially treated with chemotherapy.

Standard treatment for nonsquamous NSCLC is to continue bevacizumab until disease progression, but on the basis of these results, clinicians will likely give bevacizumab with pemetrexed, Dr. Kris said in an interview.

"The guidelines don’t say that because they didn’t have any data, but this will be the data that I’m pretty confident will change the guidelines," said Dr. Kris, who also is the William and Joy Ruane Chair in Thoracic Oncology at Sloan-Kettering.

During the formal presentation of the data, invited discussant Dr. Martin Edelman, director of solid tumor oncology at the University of Maryland Greenebaum Cancer Center in Baltimore, described the use of maintenance therapy as a contentious issue. He noted that many questions remain regarding maintenance trials, including the value of progression-free survival as an end point, how and when control patients are crossed over to active treatment, and whether the RECIST criteria should be used to determine progression.

Dr. Edelman described progression-free survival as an arbitrary end point subject to testing interval and considerable bias. To the credit of the PARAMOUNT investigators, he pointed out that there was use of independent review for this end point, but he said it still does not answer the question of overall survival.

"If one is supposed to change practice based on progression-free survival, we really need to know if particularly small differences are really beneficial," Dr. Edelman said. "That is where quality of life analysis can help us."

The PARAMOUNT investigators assessed health-related quality of life using the EuroQol-5D at baseline, day 1 of each cycle of induction or maintenance therapy, and at the 30-day postdiscontinuation visit. Compliance at all time points during the maintenance phase was more than 80%, but no statistical differences in the EQ-5D index score or its visual analog scale were observed between treatment arms, said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocío, Seville, Spain.

A total of 939 patients were enrolled in the trial. They received pemetrexed 500 mg/m² on day 1 of a 21-day cycle plus cisplatin 75 mg/m² induction. In all, 539 patients whose disease had not progressed and had a performance status of 0-2 were then randomized to pemetrexed maintenance 500 mg/m² on day 1 of a 21-day cycle plus best supportive care or placebo plus best supportive care until disease progression.

Dr. Paz-Ares said pemetrexed had a well-tolerated safety profile, similar to that seen in the previous pemetrexed switch maintenance trial. The pemetrexed and placebo groups had similar drug-related deaths (0.6% for both), drug-related serious adverse events (9% vs. 3%, respectively), and discontinuations due to adverse events (5.3% vs. 3.3%). Patients in the pemetrexed arm had significantly more grade 3/4 adverse fatigue (4.2% vs. 0.6%), anemia (4.5% vs. 0.6%), and neutropenia (3.6% vs. 0%). There was one on-study death with pemetrexed (pneumonia) and placebo (not otherwise specified), and one death within 30 days with pemetrexed (endocarditis), Dr. Paz-Ares reported.

"While overall very reasonable, this still comes at a cost in terms of significant toxicity, not to mention the cost of additional treatment," Dr. Edelman observed. "We really need a cost-effectiveness analysis in this era to follow strategies of frequent visits and scanning with early institution of second-line therapy versus the maintenance approach."

Eli Lilly funded the study. Dr. Paz-Ares disclosed no relevant relationships. Several coauthors reported relationships with industry, including employment, stock ownership, honoraria, and consultancy with Lilly, which markets pemetrexed.

CHICAGO – Pemetrexed maintenance therapy following pemetrexed plus cisplatin induction reduced the risk of progression by 38% in patients with advanced nonsquamous non–small cell lung cancer in the phase III PARAMOUNT trial.

The study’s primary end point of investigator-assessed progression-free survival was 4.1 months for pemetrexed (Alimta) plus best supportive care and 2.8 months for placebo plus best supportive care (log rank P = .00006; unadjusted hazard ratio, 0.62).

Independent review, completed in 88% of patients, confirmed the robustness of the primary end point, revealing a progression-free survival of 3.9 months for pemetrexed vs. 2.6 months for placebo (log rank P = .0002; HR, 0.64), lead author Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.

Overall survival data were not mature enough at the time of the analysis, with just 16 deaths.

"The magnitude of the benefit shown on progression-free survival, a 38% decrease in the risk of progression, is in favor of saying this is an effective treatment for patients with advanced nonsquamous non–small cell lung cancer," he said.

A previous trial (Lancet 2009;374:1432-40) showed that switching patients to pemetrexed maintenance improved the time free of cancer, but until now, it was unclear whether patients initially treated with pemetrexed would benefit from maintenance.

"This trial answers that," Dr. Mark Kris, chief of thoracic oncology at Memorial Sloan-Kettering Cancer Center in New York, told reporters in a press briefing at the meeting. "I think it’s very important in that it’s an example of how we can achieve an incremental benefit in our patients by the optimal use of drugs that are already available."

Pemetrexed (Eli Lilly) is approved in combination with cisplatin as first-line therapy for advanced nonsquamous non–small cell lung cancer (NSCLC) and in the second line as maintenance therapy in patients initially treated with chemotherapy.

Standard treatment for nonsquamous NSCLC is to continue bevacizumab until disease progression, but on the basis of these results, clinicians will likely give bevacizumab with pemetrexed, Dr. Kris said in an interview.

"The guidelines don’t say that because they didn’t have any data, but this will be the data that I’m pretty confident will change the guidelines," said Dr. Kris, who also is the William and Joy Ruane Chair in Thoracic Oncology at Sloan-Kettering.

During the formal presentation of the data, invited discussant Dr. Martin Edelman, director of solid tumor oncology at the University of Maryland Greenebaum Cancer Center in Baltimore, described the use of maintenance therapy as a contentious issue. He noted that many questions remain regarding maintenance trials, including the value of progression-free survival as an end point, how and when control patients are crossed over to active treatment, and whether the RECIST criteria should be used to determine progression.

Dr. Edelman described progression-free survival as an arbitrary end point subject to testing interval and considerable bias. To the credit of the PARAMOUNT investigators, he pointed out that there was use of independent review for this end point, but he said it still does not answer the question of overall survival.

"If one is supposed to change practice based on progression-free survival, we really need to know if particularly small differences are really beneficial," Dr. Edelman said. "That is where quality of life analysis can help us."

The PARAMOUNT investigators assessed health-related quality of life using the EuroQol-5D at baseline, day 1 of each cycle of induction or maintenance therapy, and at the 30-day postdiscontinuation visit. Compliance at all time points during the maintenance phase was more than 80%, but no statistical differences in the EQ-5D index score or its visual analog scale were observed between treatment arms, said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocío, Seville, Spain.

A total of 939 patients were enrolled in the trial. They received pemetrexed 500 mg/m² on day 1 of a 21-day cycle plus cisplatin 75 mg/m² induction. In all, 539 patients whose disease had not progressed and had a performance status of 0-2 were then randomized to pemetrexed maintenance 500 mg/m² on day 1 of a 21-day cycle plus best supportive care or placebo plus best supportive care until disease progression.

Dr. Paz-Ares said pemetrexed had a well-tolerated safety profile, similar to that seen in the previous pemetrexed switch maintenance trial. The pemetrexed and placebo groups had similar drug-related deaths (0.6% for both), drug-related serious adverse events (9% vs. 3%, respectively), and discontinuations due to adverse events (5.3% vs. 3.3%). Patients in the pemetrexed arm had significantly more grade 3/4 adverse fatigue (4.2% vs. 0.6%), anemia (4.5% vs. 0.6%), and neutropenia (3.6% vs. 0%). There was one on-study death with pemetrexed (pneumonia) and placebo (not otherwise specified), and one death within 30 days with pemetrexed (endocarditis), Dr. Paz-Ares reported.

"While overall very reasonable, this still comes at a cost in terms of significant toxicity, not to mention the cost of additional treatment," Dr. Edelman observed. "We really need a cost-effectiveness analysis in this era to follow strategies of frequent visits and scanning with early institution of second-line therapy versus the maintenance approach."

Eli Lilly funded the study. Dr. Paz-Ares disclosed no relevant relationships. Several coauthors reported relationships with industry, including employment, stock ownership, honoraria, and consultancy with Lilly, which markets pemetrexed.

CHICAGO – Pemetrexed maintenance therapy following pemetrexed plus cisplatin induction reduced the risk of progression by 38% in patients with advanced nonsquamous non–small cell lung cancer in the phase III PARAMOUNT trial.

The study’s primary end point of investigator-assessed progression-free survival was 4.1 months for pemetrexed (Alimta) plus best supportive care and 2.8 months for placebo plus best supportive care (log rank P = .00006; unadjusted hazard ratio, 0.62).

Independent review, completed in 88% of patients, confirmed the robustness of the primary end point, revealing a progression-free survival of 3.9 months for pemetrexed vs. 2.6 months for placebo (log rank P = .0002; HR, 0.64), lead author Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.

Overall survival data were not mature enough at the time of the analysis, with just 16 deaths.

"The magnitude of the benefit shown on progression-free survival, a 38% decrease in the risk of progression, is in favor of saying this is an effective treatment for patients with advanced nonsquamous non–small cell lung cancer," he said.

A previous trial (Lancet 2009;374:1432-40) showed that switching patients to pemetrexed maintenance improved the time free of cancer, but until now, it was unclear whether patients initially treated with pemetrexed would benefit from maintenance.

"This trial answers that," Dr. Mark Kris, chief of thoracic oncology at Memorial Sloan-Kettering Cancer Center in New York, told reporters in a press briefing at the meeting. "I think it’s very important in that it’s an example of how we can achieve an incremental benefit in our patients by the optimal use of drugs that are already available."

Pemetrexed (Eli Lilly) is approved in combination with cisplatin as first-line therapy for advanced nonsquamous non–small cell lung cancer (NSCLC) and in the second line as maintenance therapy in patients initially treated with chemotherapy.

Standard treatment for nonsquamous NSCLC is to continue bevacizumab until disease progression, but on the basis of these results, clinicians will likely give bevacizumab with pemetrexed, Dr. Kris said in an interview.

"The guidelines don’t say that because they didn’t have any data, but this will be the data that I’m pretty confident will change the guidelines," said Dr. Kris, who also is the William and Joy Ruane Chair in Thoracic Oncology at Sloan-Kettering.

During the formal presentation of the data, invited discussant Dr. Martin Edelman, director of solid tumor oncology at the University of Maryland Greenebaum Cancer Center in Baltimore, described the use of maintenance therapy as a contentious issue. He noted that many questions remain regarding maintenance trials, including the value of progression-free survival as an end point, how and when control patients are crossed over to active treatment, and whether the RECIST criteria should be used to determine progression.

Dr. Edelman described progression-free survival as an arbitrary end point subject to testing interval and considerable bias. To the credit of the PARAMOUNT investigators, he pointed out that there was use of independent review for this end point, but he said it still does not answer the question of overall survival.

"If one is supposed to change practice based on progression-free survival, we really need to know if particularly small differences are really beneficial," Dr. Edelman said. "That is where quality of life analysis can help us."

The PARAMOUNT investigators assessed health-related quality of life using the EuroQol-5D at baseline, day 1 of each cycle of induction or maintenance therapy, and at the 30-day postdiscontinuation visit. Compliance at all time points during the maintenance phase was more than 80%, but no statistical differences in the EQ-5D index score or its visual analog scale were observed between treatment arms, said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocío, Seville, Spain.

A total of 939 patients were enrolled in the trial. They received pemetrexed 500 mg/m² on day 1 of a 21-day cycle plus cisplatin 75 mg/m² induction. In all, 539 patients whose disease had not progressed and had a performance status of 0-2 were then randomized to pemetrexed maintenance 500 mg/m² on day 1 of a 21-day cycle plus best supportive care or placebo plus best supportive care until disease progression.

Dr. Paz-Ares said pemetrexed had a well-tolerated safety profile, similar to that seen in the previous pemetrexed switch maintenance trial. The pemetrexed and placebo groups had similar drug-related deaths (0.6% for both), drug-related serious adverse events (9% vs. 3%, respectively), and discontinuations due to adverse events (5.3% vs. 3.3%). Patients in the pemetrexed arm had significantly more grade 3/4 adverse fatigue (4.2% vs. 0.6%), anemia (4.5% vs. 0.6%), and neutropenia (3.6% vs. 0%). There was one on-study death with pemetrexed (pneumonia) and placebo (not otherwise specified), and one death within 30 days with pemetrexed (endocarditis), Dr. Paz-Ares reported.

"While overall very reasonable, this still comes at a cost in terms of significant toxicity, not to mention the cost of additional treatment," Dr. Edelman observed. "We really need a cost-effectiveness analysis in this era to follow strategies of frequent visits and scanning with early institution of second-line therapy versus the maintenance approach."

Eli Lilly funded the study. Dr. Paz-Ares disclosed no relevant relationships. Several coauthors reported relationships with industry, including employment, stock ownership, honoraria, and consultancy with Lilly, which markets pemetrexed.

CHICAGO – Nearly two-thirds of patients with non–small cell lung cancer who were positive for the anaplastic lymphoma kinase responded to the experimental agent crizotinib. The responses were "rapid, dramatic, and durable," investigators reported at the annual meeting of the American Society of Clinical Oncology.

In an ongoing phase I trial, the overall response to crizotinub was 61%, and the median duration of response was 48 weeks. Median progression-free survival was 10 months, reported Dr. D. Ross Camidge, associate clinical director of the thoracic oncology program, University of Colorado, Aurora.

The study and its results are "truly brilliant," commented Dr. Nasser H. Hanna, associate professor of medicine at Indiana University in Indianapolis. Dr. Hanna was the invited discussant.

He added, however, that "most lung cancer is not driven by one or two gene mutations, so ultimately our future success depends upon combining targeted agents in these more complex tumors."

Activation of the anaplastic lymphoma kinase (ALK), primarily through gene rearrangements, is thought to be a primary oncogenic trigger in several different human cancers, including about 3-5% of non-small cell lung cancers (NSCLC).

Crizotinib is a potent and selective oral inhibitor of ALK. Interim results of the agent in ALK-positive NSCLC in a study of 82 patients treated for an average of 6.4 months were reported at the 2010 ASCO annual meeting and in the New England Journal of Medicine (N. Engl. J. Med. 2010; 363:1693-1703). Those data showed an overall response rate of 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response). Additionally, 27 patients (33%) had stable disease.

In the current report, a continuation of the same study with 119 patients, Dr. Camidge reported data on 116 evaluable patients with a median duration of follow-up of 11 months. The median age was 51 years (range 21-79), and the sample was split evenly between men and women. In all, 72% of patients had never smoked. Nearly all of the cancers (97%) were adenocarcinomas.

The median time to response was 8 weeks, although some patients displayed measurable responses in as little as 2 weeks. The disease control rate was 79% at 8 weeks, and 67% at 16 weeks.

Patients 65 and older did slightly better, with a 69% objective response rate (ORR), compared with 60% for those under 65. Patients with no prior systemic therapies fared best, with an 80% ORR, compared with 60% for patients with metastatic disease who had received one prior systemic therapy, and 58% for those who had received at least two lines of therapy. Patients of Asian origin had an 82% ORR, compared with 52% of non-Asians; the difference could be due to pharmacogenomic differences in drug exposure, but the numbers are small and this effect needs to be explored further, Dr. Camidge said.

Median overall survival has not yet been reached. There have been 23 deaths (19%) and 2 patients lost to follow-up, leaving 94 patients (79%) for the overall survival analysis. No treatment-related study deaths have been reported.

Patients with documented disease progression could continue to receive crizotinib if, in the opinion of the investigators, they would derive a clinical benefit. A total of 40 patients (34%) experienced disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) at the time of the data cutoff (Oct. 29, 2010). Sixteen of these patients continued to receive crizotinib for more than 2 weeks.

Nearly all patients (96%) reported a treatment-related adverse event. Most of the events were grade 1 or 2, although 19 patients (16%) had grade 3 or 4 events. The most common adverse events were visual effects, nausea, diarrhea, vomiting, edema (both localized and peripheral), and constipation.

The results of the trial and another study (PROFILE 1005) have prompted investigators to seek accelerated approval for the drug in patients with ALK-positive NSCLC.

"Preclinical evidence suggests that ALK inhibitors are more effective than chemotherapy in ALK-positive disease, and retrospective clinical data supports this hypothesis. But ultimately, we have to wait for a definitive answer in a phase III trial which has just been completed comparing an ALK inhibitor vs. chemotherapy in this group of patients," Dr. Hanna noted.

The study was funded by Pfizer. Dr. Camidge and several of his coauthors have served in an advisory role and received research funding and honoraria from the company. Dr. Hanna had no relevant disclosures.

CHICAGO – Nearly two-thirds of patients with non–small cell lung cancer who were positive for the anaplastic lymphoma kinase responded to the experimental agent crizotinib. The responses were "rapid, dramatic, and durable," investigators reported at the annual meeting of the American Society of Clinical Oncology.

In an ongoing phase I trial, the overall response to crizotinub was 61%, and the median duration of response was 48 weeks. Median progression-free survival was 10 months, reported Dr. D. Ross Camidge, associate clinical director of the thoracic oncology program, University of Colorado, Aurora.

The study and its results are "truly brilliant," commented Dr. Nasser H. Hanna, associate professor of medicine at Indiana University in Indianapolis. Dr. Hanna was the invited discussant.

He added, however, that "most lung cancer is not driven by one or two gene mutations, so ultimately our future success depends upon combining targeted agents in these more complex tumors."

Activation of the anaplastic lymphoma kinase (ALK), primarily through gene rearrangements, is thought to be a primary oncogenic trigger in several different human cancers, including about 3-5% of non-small cell lung cancers (NSCLC).

Crizotinib is a potent and selective oral inhibitor of ALK. Interim results of the agent in ALK-positive NSCLC in a study of 82 patients treated for an average of 6.4 months were reported at the 2010 ASCO annual meeting and in the New England Journal of Medicine (N. Engl. J. Med. 2010; 363:1693-1703). Those data showed an overall response rate of 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response). Additionally, 27 patients (33%) had stable disease.

In the current report, a continuation of the same study with 119 patients, Dr. Camidge reported data on 116 evaluable patients with a median duration of follow-up of 11 months. The median age was 51 years (range 21-79), and the sample was split evenly between men and women. In all, 72% of patients had never smoked. Nearly all of the cancers (97%) were adenocarcinomas.

The median time to response was 8 weeks, although some patients displayed measurable responses in as little as 2 weeks. The disease control rate was 79% at 8 weeks, and 67% at 16 weeks.

Patients 65 and older did slightly better, with a 69% objective response rate (ORR), compared with 60% for those under 65. Patients with no prior systemic therapies fared best, with an 80% ORR, compared with 60% for patients with metastatic disease who had received one prior systemic therapy, and 58% for those who had received at least two lines of therapy. Patients of Asian origin had an 82% ORR, compared with 52% of non-Asians; the difference could be due to pharmacogenomic differences in drug exposure, but the numbers are small and this effect needs to be explored further, Dr. Camidge said.

Median overall survival has not yet been reached. There have been 23 deaths (19%) and 2 patients lost to follow-up, leaving 94 patients (79%) for the overall survival analysis. No treatment-related study deaths have been reported.

Patients with documented disease progression could continue to receive crizotinib if, in the opinion of the investigators, they would derive a clinical benefit. A total of 40 patients (34%) experienced disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) at the time of the data cutoff (Oct. 29, 2010). Sixteen of these patients continued to receive crizotinib for more than 2 weeks.

Nearly all patients (96%) reported a treatment-related adverse event. Most of the events were grade 1 or 2, although 19 patients (16%) had grade 3 or 4 events. The most common adverse events were visual effects, nausea, diarrhea, vomiting, edema (both localized and peripheral), and constipation.

The results of the trial and another study (PROFILE 1005) have prompted investigators to seek accelerated approval for the drug in patients with ALK-positive NSCLC.

"Preclinical evidence suggests that ALK inhibitors are more effective than chemotherapy in ALK-positive disease, and retrospective clinical data supports this hypothesis. But ultimately, we have to wait for a definitive answer in a phase III trial which has just been completed comparing an ALK inhibitor vs. chemotherapy in this group of patients," Dr. Hanna noted.

The study was funded by Pfizer. Dr. Camidge and several of his coauthors have served in an advisory role and received research funding and honoraria from the company. Dr. Hanna had no relevant disclosures.

CHICAGO – Nearly two-thirds of patients with non–small cell lung cancer who were positive for the anaplastic lymphoma kinase responded to the experimental agent crizotinib. The responses were "rapid, dramatic, and durable," investigators reported at the annual meeting of the American Society of Clinical Oncology.

In an ongoing phase I trial, the overall response to crizotinub was 61%, and the median duration of response was 48 weeks. Median progression-free survival was 10 months, reported Dr. D. Ross Camidge, associate clinical director of the thoracic oncology program, University of Colorado, Aurora.

The study and its results are "truly brilliant," commented Dr. Nasser H. Hanna, associate professor of medicine at Indiana University in Indianapolis. Dr. Hanna was the invited discussant.

He added, however, that "most lung cancer is not driven by one or two gene mutations, so ultimately our future success depends upon combining targeted agents in these more complex tumors."

Activation of the anaplastic lymphoma kinase (ALK), primarily through gene rearrangements, is thought to be a primary oncogenic trigger in several different human cancers, including about 3-5% of non-small cell lung cancers (NSCLC).

Crizotinib is a potent and selective oral inhibitor of ALK. Interim results of the agent in ALK-positive NSCLC in a study of 82 patients treated for an average of 6.4 months were reported at the 2010 ASCO annual meeting and in the New England Journal of Medicine (N. Engl. J. Med. 2010; 363:1693-1703). Those data showed an overall response rate of 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response). Additionally, 27 patients (33%) had stable disease.

In the current report, a continuation of the same study with 119 patients, Dr. Camidge reported data on 116 evaluable patients with a median duration of follow-up of 11 months. The median age was 51 years (range 21-79), and the sample was split evenly between men and women. In all, 72% of patients had never smoked. Nearly all of the cancers (97%) were adenocarcinomas.

The median time to response was 8 weeks, although some patients displayed measurable responses in as little as 2 weeks. The disease control rate was 79% at 8 weeks, and 67% at 16 weeks.

Patients 65 and older did slightly better, with a 69% objective response rate (ORR), compared with 60% for those under 65. Patients with no prior systemic therapies fared best, with an 80% ORR, compared with 60% for patients with metastatic disease who had received one prior systemic therapy, and 58% for those who had received at least two lines of therapy. Patients of Asian origin had an 82% ORR, compared with 52% of non-Asians; the difference could be due to pharmacogenomic differences in drug exposure, but the numbers are small and this effect needs to be explored further, Dr. Camidge said.

Median overall survival has not yet been reached. There have been 23 deaths (19%) and 2 patients lost to follow-up, leaving 94 patients (79%) for the overall survival analysis. No treatment-related study deaths have been reported.

Patients with documented disease progression could continue to receive crizotinib if, in the opinion of the investigators, they would derive a clinical benefit. A total of 40 patients (34%) experienced disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) at the time of the data cutoff (Oct. 29, 2010). Sixteen of these patients continued to receive crizotinib for more than 2 weeks.

Nearly all patients (96%) reported a treatment-related adverse event. Most of the events were grade 1 or 2, although 19 patients (16%) had grade 3 or 4 events. The most common adverse events were visual effects, nausea, diarrhea, vomiting, edema (both localized and peripheral), and constipation.

The results of the trial and another study (PROFILE 1005) have prompted investigators to seek accelerated approval for the drug in patients with ALK-positive NSCLC.

"Preclinical evidence suggests that ALK inhibitors are more effective than chemotherapy in ALK-positive disease, and retrospective clinical data supports this hypothesis. But ultimately, we have to wait for a definitive answer in a phase III trial which has just been completed comparing an ALK inhibitor vs. chemotherapy in this group of patients," Dr. Hanna noted.

The study was funded by Pfizer. Dr. Camidge and several of his coauthors have served in an advisory role and received research funding and honoraria from the company. Dr. Hanna had no relevant disclosures.

CHICAGO – Nearly two-thirds of patients with non–small cell lung cancer who were positive for the anaplastic lymphoma kinase responded to the experimental agent crizotinib. The responses were "rapid, dramatic, and durable," investigators reported at the annual meeting of the American Society of Clinical Oncology.

In an ongoing phase I trial, the overall response to crizotinub was 61%, and the median duration of response was 48 weeks. Median progression-free survival was 10 months, reported Dr. D. Ross Camidge, associate clinical director of the thoracic oncology program, University of Colorado, Aurora.

The study and its results are "truly brilliant," commented Dr. Nasser H. Hanna, associate professor of medicine at Indiana University in Indianapolis. Dr. Hanna was the invited discussant.

He added, however, that "most lung cancer is not driven by one or two gene mutations, so ultimately our future success depends upon combining targeted agents in these more complex tumors."

Activation of the anaplastic lymphoma kinase (ALK), primarily through gene rearrangements, is thought to be a primary oncogenic trigger in several different human cancers, including about 3-5% of non-small cell lung cancers (NSCLC).

Crizotinib is a potent and selective oral inhibitor of ALK. Interim results of the agent in ALK-positive NSCLC in a study of 82 patients treated for an average of 6.4 months were reported at the 2010 ASCO annual meeting and in the New England Journal of Medicine (N. Engl. J. Med. 2010; 363:1693-1703). Those data showed an overall response rate of 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response). Additionally, 27 patients (33%) had stable disease.

In the current report, a continuation of the same study with 119 patients, Dr. Camidge reported data on 116 evaluable patients with a median duration of follow-up of 11 months. The median age was 51 years (range 21-79), and the sample was split evenly between men and women. In all, 72% of patients had never smoked. Nearly all of the cancers (97%) were adenocarcinomas.

The median time to response was 8 weeks, although some patients displayed measurable responses in as little as 2 weeks. The disease control rate was 79% at 8 weeks, and 67% at 16 weeks.

Patients 65 and older did slightly better, with a 69% objective response rate (ORR), compared with 60% for those under 65. Patients with no prior systemic therapies fared best, with an 80% ORR, compared with 60% for patients with metastatic disease who had received one prior systemic therapy, and 58% for those who had received at least two lines of therapy. Patients of Asian origin had an 82% ORR, compared with 52% of non-Asians; the difference could be due to pharmacogenomic differences in drug exposure, but the numbers are small and this effect needs to be explored further, Dr. Camidge said.

Median overall survival has not yet been reached. There have been 23 deaths (19%) and 2 patients lost to follow-up, leaving 94 patients (79%) for the overall survival analysis. No treatment-related study deaths have been reported.

Patients with documented disease progression could continue to receive crizotinib if, in the opinion of the investigators, they would derive a clinical benefit. A total of 40 patients (34%) experienced disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) at the time of the data cutoff (Oct. 29, 2010). Sixteen of these patients continued to receive crizotinib for more than 2 weeks.

Nearly all patients (96%) reported a treatment-related adverse event. Most of the events were grade 1 or 2, although 19 patients (16%) had grade 3 or 4 events. The most common adverse events were visual effects, nausea, diarrhea, vomiting, edema (both localized and peripheral), and constipation.

The results of the trial and another study (PROFILE 1005) have prompted investigators to seek accelerated approval for the drug in patients with ALK-positive NSCLC.

"Preclinical evidence suggests that ALK inhibitors are more effective than chemotherapy in ALK-positive disease, and retrospective clinical data supports this hypothesis. But ultimately, we have to wait for a definitive answer in a phase III trial which has just been completed comparing an ALK inhibitor vs. chemotherapy in this group of patients," Dr. Hanna noted.

The study was funded by Pfizer. Dr. Camidge and several of his coauthors have served in an advisory role and received research funding and honoraria from the company. Dr. Hanna had no relevant disclosures.

CHICAGO – Nearly two-thirds of patients with non–small cell lung cancer who were positive for the anaplastic lymphoma kinase responded to the experimental agent crizotinib. The responses were "rapid, dramatic, and durable," investigators reported at the annual meeting of the American Society of Clinical Oncology.

In an ongoing phase I trial, the overall response to crizotinub was 61%, and the median duration of response was 48 weeks. Median progression-free survival was 10 months, reported Dr. D. Ross Camidge, associate clinical director of the thoracic oncology program, University of Colorado, Aurora.

The study and its results are "truly brilliant," commented Dr. Nasser H. Hanna, associate professor of medicine at Indiana University in Indianapolis. Dr. Hanna was the invited discussant.

He added, however, that "most lung cancer is not driven by one or two gene mutations, so ultimately our future success depends upon combining targeted agents in these more complex tumors."

Activation of the anaplastic lymphoma kinase (ALK), primarily through gene rearrangements, is thought to be a primary oncogenic trigger in several different human cancers, including about 3-5% of non-small cell lung cancers (NSCLC).

Crizotinib is a potent and selective oral inhibitor of ALK. Interim results of the agent in ALK-positive NSCLC in a study of 82 patients treated for an average of 6.4 months were reported at the 2010 ASCO annual meeting and in the New England Journal of Medicine (N. Engl. J. Med. 2010; 363:1693-1703). Those data showed an overall response rate of 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response). Additionally, 27 patients (33%) had stable disease.

In the current report, a continuation of the same study with 119 patients, Dr. Camidge reported data on 116 evaluable patients with a median duration of follow-up of 11 months. The median age was 51 years (range 21-79), and the sample was split evenly between men and women. In all, 72% of patients had never smoked. Nearly all of the cancers (97%) were adenocarcinomas.

The median time to response was 8 weeks, although some patients displayed measurable responses in as little as 2 weeks. The disease control rate was 79% at 8 weeks, and 67% at 16 weeks.

Patients 65 and older did slightly better, with a 69% objective response rate (ORR), compared with 60% for those under 65. Patients with no prior systemic therapies fared best, with an 80% ORR, compared with 60% for patients with metastatic disease who had received one prior systemic therapy, and 58% for those who had received at least two lines of therapy. Patients of Asian origin had an 82% ORR, compared with 52% of non-Asians; the difference could be due to pharmacogenomic differences in drug exposure, but the numbers are small and this effect needs to be explored further, Dr. Camidge said.

Median overall survival has not yet been reached. There have been 23 deaths (19%) and 2 patients lost to follow-up, leaving 94 patients (79%) for the overall survival analysis. No treatment-related study deaths have been reported.

Patients with documented disease progression could continue to receive crizotinib if, in the opinion of the investigators, they would derive a clinical benefit. A total of 40 patients (34%) experienced disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) at the time of the data cutoff (Oct. 29, 2010). Sixteen of these patients continued to receive crizotinib for more than 2 weeks.

Nearly all patients (96%) reported a treatment-related adverse event. Most of the events were grade 1 or 2, although 19 patients (16%) had grade 3 or 4 events. The most common adverse events were visual effects, nausea, diarrhea, vomiting, edema (both localized and peripheral), and constipation.

The results of the trial and another study (PROFILE 1005) have prompted investigators to seek accelerated approval for the drug in patients with ALK-positive NSCLC.

"Preclinical evidence suggests that ALK inhibitors are more effective than chemotherapy in ALK-positive disease, and retrospective clinical data supports this hypothesis. But ultimately, we have to wait for a definitive answer in a phase III trial which has just been completed comparing an ALK inhibitor vs. chemotherapy in this group of patients," Dr. Hanna noted.

The study was funded by Pfizer. Dr. Camidge and several of his coauthors have served in an advisory role and received research funding and honoraria from the company. Dr. Hanna had no relevant disclosures.

CHICAGO – Nearly two-thirds of patients with non–small cell lung cancer who were positive for the anaplastic lymphoma kinase responded to the experimental agent crizotinib. The responses were "rapid, dramatic, and durable," investigators reported at the annual meeting of the American Society of Clinical Oncology.

In an ongoing phase I trial, the overall response to crizotinub was 61%, and the median duration of response was 48 weeks. Median progression-free survival was 10 months, reported Dr. D. Ross Camidge, associate clinical director of the thoracic oncology program, University of Colorado, Aurora.

The study and its results are "truly brilliant," commented Dr. Nasser H. Hanna, associate professor of medicine at Indiana University in Indianapolis. Dr. Hanna was the invited discussant.

He added, however, that "most lung cancer is not driven by one or two gene mutations, so ultimately our future success depends upon combining targeted agents in these more complex tumors."

Activation of the anaplastic lymphoma kinase (ALK), primarily through gene rearrangements, is thought to be a primary oncogenic trigger in several different human cancers, including about 3-5% of non-small cell lung cancers (NSCLC).

Crizotinib is a potent and selective oral inhibitor of ALK. Interim results of the agent in ALK-positive NSCLC in a study of 82 patients treated for an average of 6.4 months were reported at the 2010 ASCO annual meeting and in the New England Journal of Medicine (N. Engl. J. Med. 2010; 363:1693-1703). Those data showed an overall response rate of 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response). Additionally, 27 patients (33%) had stable disease.

In the current report, a continuation of the same study with 119 patients, Dr. Camidge reported data on 116 evaluable patients with a median duration of follow-up of 11 months. The median age was 51 years (range 21-79), and the sample was split evenly between men and women. In all, 72% of patients had never smoked. Nearly all of the cancers (97%) were adenocarcinomas.

The median time to response was 8 weeks, although some patients displayed measurable responses in as little as 2 weeks. The disease control rate was 79% at 8 weeks, and 67% at 16 weeks.

Patients 65 and older did slightly better, with a 69% objective response rate (ORR), compared with 60% for those under 65. Patients with no prior systemic therapies fared best, with an 80% ORR, compared with 60% for patients with metastatic disease who had received one prior systemic therapy, and 58% for those who had received at least two lines of therapy. Patients of Asian origin had an 82% ORR, compared with 52% of non-Asians; the difference could be due to pharmacogenomic differences in drug exposure, but the numbers are small and this effect needs to be explored further, Dr. Camidge said.

Median overall survival has not yet been reached. There have been 23 deaths (19%) and 2 patients lost to follow-up, leaving 94 patients (79%) for the overall survival analysis. No treatment-related study deaths have been reported.

Patients with documented disease progression could continue to receive crizotinib if, in the opinion of the investigators, they would derive a clinical benefit. A total of 40 patients (34%) experienced disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) at the time of the data cutoff (Oct. 29, 2010). Sixteen of these patients continued to receive crizotinib for more than 2 weeks.

Nearly all patients (96%) reported a treatment-related adverse event. Most of the events were grade 1 or 2, although 19 patients (16%) had grade 3 or 4 events. The most common adverse events were visual effects, nausea, diarrhea, vomiting, edema (both localized and peripheral), and constipation.

The results of the trial and another study (PROFILE 1005) have prompted investigators to seek accelerated approval for the drug in patients with ALK-positive NSCLC.

"Preclinical evidence suggests that ALK inhibitors are more effective than chemotherapy in ALK-positive disease, and retrospective clinical data supports this hypothesis. But ultimately, we have to wait for a definitive answer in a phase III trial which has just been completed comparing an ALK inhibitor vs. chemotherapy in this group of patients," Dr. Hanna noted.

The study was funded by Pfizer. Dr. Camidge and several of his coauthors have served in an advisory role and received research funding and honoraria from the company. Dr. Hanna had no relevant disclosures.

CHICAGO — A new chemotherapy regimen that starts children and young adults on 50 times the standard dose of methotrexate for high-risk B-precursor acute lymphoblastic leukemia leads to significantly fewer recurrences five years after treatment without an increase in toxicity.

A randomized phase III trial comparing the high-dose regimen to standard therapy was halted in January 2011 after an interim analysis found the 5-year event-free survival rate reached 82% with the new regimen vs. 75% with the old (P = .0006).

Pediatric oncologists began using the new high-dose regimen as standard practice "as soon as we stopped the protocol," Dr. Eric C. Larsen, principal investigator of the study, said at a press briefing June 3, on the opening day of the annual meeting of the American Society of Clinical Oncology. He will present the results June 5 in a plenary session featuring the most important research at the meeting.

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children. Children with high-risk ALL have a high white blood count at diagnosis and/or are 10 years or more of age.

Although pediatric ALL has a high cure rate and the standard regimen had reduced relapses in the bone marrow over time, investigators were concerned that relapses in the central nervous system had not declined as much. Therefore, they sought a regimen with the potential for greater penetration of tumor cells in the central nervous system.

When the study was conceived 10 years ago, the investigators did not have a new drug or targeted therapy, however, said Dr. Larsen, director of the Maine Children’s Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children’s Hospital at Maine Medical Center in Portland. Therefore, "rather than trying something brand new," they decided to try to optimize treatment with a drug that "had been around for awhile."

One of the earliest chemotherapy drugs, methotrexate promotes cancer cell death by preventing leukemia cells from using folate, an essential vitamin. Its use dates to 1947 when Dr. Sidney Farber induced the first remissions in children with ALL by giving them an early form of methotrexate called aminopterin. It is an essential component of treatment for pediatric ALL, but the optimal regimen was not resolved.

Dr. Richard Schilsky, a professor of medicine and chief of the section of hematology-oncology at the University of Chicago Pritzker School of Medicine, suggested oncologists treating adults have much to learn from how the investigators focused on an existing therapy. "The pediatric oncologists have recognized that to get optimal results in treating cancer you have to optimize the way cancer treatment is given," said Dr. Schilsky, a former ASCO president and moderator of the press briefing.

The Children’s Oncology Group AALL0232 trial started in 2004 and enrolled 3,154 newly diagnosed patients ages 1 to 30. Most pediatric ALL trials do not enroll patients older than 21 years of age, Dr. Larsen said in an interview, but current thinking suggests that young adult patients may do better on pediatric protocols.

At the time of the interim analysis, 2,426 patients had been randomized. About half the population in the interim analysis, 1,217 patients, was treated with a standard Capizzi regimen in which intravenous methotrexate is delivered at a starting dose of 100 mg/m² and escalated by 50 mg/m² every 10 days up to a maximum of 5 doses depending on the child’s ability to tolerate the medication. In this regimen methotrexate is followed by a second chemotherapy drug called asparaginase.

The other 1,209 patients were assigned to the high-dose arm, and received 5 g/m² – that is, 5,000 mg/m² of methotrexate biweekly in four doses.

Despite concerns that the high-dose regimen would lead to more toxicity, febrile neutropenia occurred less in the experimental arm of the trial: 5.2% vs. 8.2% in the standard arm (P = .005). Leucovorin rescue was available for patients on high-dose methotrexate, which may partially explain the lower incidence of neutropenia in this group. Acute neurotoxicity, osteonecrosis, and other clinically relevant side effects were not significantly different.

Investigators are not sure why the high-dose regimen is less toxic, but side effects with standard therapy may be more the result of the combination of drugs in the Capizzi regimen than of methotrexate itself, Dr. Larsen said.

A substudy is looking at the comparative costs of the two regimens, he added. Methotrexate is inexpensive, but the high-dose regimen requires hospitalization. This needs to be balanced against the cost of hospitalizing and treating with antibiotics the greater proportion of children developing febrile neutropenia, a serious toxicity, on the Capizzi regimen.

A new wrinkle, Dr. Larsen noted, is that the Children’s Oncology Group and the adult Cancer and Leukemia Group B are planning a joint trial comparing adult and children’s regimens for teens and young adults with ALL. It was scheduled to use the Capizzi regimen but needs to be reconsidered.

The National Institutes of Health provided funds for the trial. Two co-authors said they received research funding from Becton-Dickinson.

CHICAGO — A new chemotherapy regimen that starts children and young adults on 50 times the standard dose of methotrexate for high-risk B-precursor acute lymphoblastic leukemia leads to significantly fewer recurrences five years after treatment without an increase in toxicity.

A randomized phase III trial comparing the high-dose regimen to standard therapy was halted in January 2011 after an interim analysis found the 5-year event-free survival rate reached 82% with the new regimen vs. 75% with the old (P = .0006).

Pediatric oncologists began using the new high-dose regimen as standard practice "as soon as we stopped the protocol," Dr. Eric C. Larsen, principal investigator of the study, said at a press briefing June 3, on the opening day of the annual meeting of the American Society of Clinical Oncology. He will present the results June 5 in a plenary session featuring the most important research at the meeting.

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children. Children with high-risk ALL have a high white blood count at diagnosis and/or are 10 years or more of age.

Although pediatric ALL has a high cure rate and the standard regimen had reduced relapses in the bone marrow over time, investigators were concerned that relapses in the central nervous system had not declined as much. Therefore, they sought a regimen with the potential for greater penetration of tumor cells in the central nervous system.

When the study was conceived 10 years ago, the investigators did not have a new drug or targeted therapy, however, said Dr. Larsen, director of the Maine Children’s Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children’s Hospital at Maine Medical Center in Portland. Therefore, "rather than trying something brand new," they decided to try to optimize treatment with a drug that "had been around for awhile."

One of the earliest chemotherapy drugs, methotrexate promotes cancer cell death by preventing leukemia cells from using folate, an essential vitamin. Its use dates to 1947 when Dr. Sidney Farber induced the first remissions in children with ALL by giving them an early form of methotrexate called aminopterin. It is an essential component of treatment for pediatric ALL, but the optimal regimen was not resolved.

Dr. Richard Schilsky, a professor of medicine and chief of the section of hematology-oncology at the University of Chicago Pritzker School of Medicine, suggested oncologists treating adults have much to learn from how the investigators focused on an existing therapy. "The pediatric oncologists have recognized that to get optimal results in treating cancer you have to optimize the way cancer treatment is given," said Dr. Schilsky, a former ASCO president and moderator of the press briefing.

The Children’s Oncology Group AALL0232 trial started in 2004 and enrolled 3,154 newly diagnosed patients ages 1 to 30. Most pediatric ALL trials do not enroll patients older than 21 years of age, Dr. Larsen said in an interview, but current thinking suggests that young adult patients may do better on pediatric protocols.

At the time of the interim analysis, 2,426 patients had been randomized. About half the population in the interim analysis, 1,217 patients, was treated with a standard Capizzi regimen in which intravenous methotrexate is delivered at a starting dose of 100 mg/m² and escalated by 50 mg/m² every 10 days up to a maximum of 5 doses depending on the child’s ability to tolerate the medication. In this regimen methotrexate is followed by a second chemotherapy drug called asparaginase.

The other 1,209 patients were assigned to the high-dose arm, and received 5 g/m² – that is, 5,000 mg/m² of methotrexate biweekly in four doses.

Despite concerns that the high-dose regimen would lead to more toxicity, febrile neutropenia occurred less in the experimental arm of the trial: 5.2% vs. 8.2% in the standard arm (P = .005). Leucovorin rescue was available for patients on high-dose methotrexate, which may partially explain the lower incidence of neutropenia in this group. Acute neurotoxicity, osteonecrosis, and other clinically relevant side effects were not significantly different.

Investigators are not sure why the high-dose regimen is less toxic, but side effects with standard therapy may be more the result of the combination of drugs in the Capizzi regimen than of methotrexate itself, Dr. Larsen said.

A substudy is looking at the comparative costs of the two regimens, he added. Methotrexate is inexpensive, but the high-dose regimen requires hospitalization. This needs to be balanced against the cost of hospitalizing and treating with antibiotics the greater proportion of children developing febrile neutropenia, a serious toxicity, on the Capizzi regimen.

A new wrinkle, Dr. Larsen noted, is that the Children’s Oncology Group and the adult Cancer and Leukemia Group B are planning a joint trial comparing adult and children’s regimens for teens and young adults with ALL. It was scheduled to use the Capizzi regimen but needs to be reconsidered.

The National Institutes of Health provided funds for the trial. Two co-authors said they received research funding from Becton-Dickinson.

CHICAGO — A new chemotherapy regimen that starts children and young adults on 50 times the standard dose of methotrexate for high-risk B-precursor acute lymphoblastic leukemia leads to significantly fewer recurrences five years after treatment without an increase in toxicity.

A randomized phase III trial comparing the high-dose regimen to standard therapy was halted in January 2011 after an interim analysis found the 5-year event-free survival rate reached 82% with the new regimen vs. 75% with the old (P = .0006).

Pediatric oncologists began using the new high-dose regimen as standard practice "as soon as we stopped the protocol," Dr. Eric C. Larsen, principal investigator of the study, said at a press briefing June 3, on the opening day of the annual meeting of the American Society of Clinical Oncology. He will present the results June 5 in a plenary session featuring the most important research at the meeting.

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children. Children with high-risk ALL have a high white blood count at diagnosis and/or are 10 years or more of age.

Although pediatric ALL has a high cure rate and the standard regimen had reduced relapses in the bone marrow over time, investigators were concerned that relapses in the central nervous system had not declined as much. Therefore, they sought a regimen with the potential for greater penetration of tumor cells in the central nervous system.

When the study was conceived 10 years ago, the investigators did not have a new drug or targeted therapy, however, said Dr. Larsen, director of the Maine Children’s Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children’s Hospital at Maine Medical Center in Portland. Therefore, "rather than trying something brand new," they decided to try to optimize treatment with a drug that "had been around for awhile."

One of the earliest chemotherapy drugs, methotrexate promotes cancer cell death by preventing leukemia cells from using folate, an essential vitamin. Its use dates to 1947 when Dr. Sidney Farber induced the first remissions in children with ALL by giving them an early form of methotrexate called aminopterin. It is an essential component of treatment for pediatric ALL, but the optimal regimen was not resolved.

Dr. Richard Schilsky, a professor of medicine and chief of the section of hematology-oncology at the University of Chicago Pritzker School of Medicine, suggested oncologists treating adults have much to learn from how the investigators focused on an existing therapy. "The pediatric oncologists have recognized that to get optimal results in treating cancer you have to optimize the way cancer treatment is given," said Dr. Schilsky, a former ASCO president and moderator of the press briefing.

The Children’s Oncology Group AALL0232 trial started in 2004 and enrolled 3,154 newly diagnosed patients ages 1 to 30. Most pediatric ALL trials do not enroll patients older than 21 years of age, Dr. Larsen said in an interview, but current thinking suggests that young adult patients may do better on pediatric protocols.

At the time of the interim analysis, 2,426 patients had been randomized. About half the population in the interim analysis, 1,217 patients, was treated with a standard Capizzi regimen in which intravenous methotrexate is delivered at a starting dose of 100 mg/m² and escalated by 50 mg/m² every 10 days up to a maximum of 5 doses depending on the child’s ability to tolerate the medication. In this regimen methotrexate is followed by a second chemotherapy drug called asparaginase.

The other 1,209 patients were assigned to the high-dose arm, and received 5 g/m² – that is, 5,000 mg/m² of methotrexate biweekly in four doses.

Despite concerns that the high-dose regimen would lead to more toxicity, febrile neutropenia occurred less in the experimental arm of the trial: 5.2% vs. 8.2% in the standard arm (P = .005). Leucovorin rescue was available for patients on high-dose methotrexate, which may partially explain the lower incidence of neutropenia in this group. Acute neurotoxicity, osteonecrosis, and other clinically relevant side effects were not significantly different.

Investigators are not sure why the high-dose regimen is less toxic, but side effects with standard therapy may be more the result of the combination of drugs in the Capizzi regimen than of methotrexate itself, Dr. Larsen said.

A substudy is looking at the comparative costs of the two regimens, he added. Methotrexate is inexpensive, but the high-dose regimen requires hospitalization. This needs to be balanced against the cost of hospitalizing and treating with antibiotics the greater proportion of children developing febrile neutropenia, a serious toxicity, on the Capizzi regimen.

A new wrinkle, Dr. Larsen noted, is that the Children’s Oncology Group and the adult Cancer and Leukemia Group B are planning a joint trial comparing adult and children’s regimens for teens and young adults with ALL. It was scheduled to use the Capizzi regimen but needs to be reconsidered.

The National Institutes of Health provided funds for the trial. Two co-authors said they received research funding from Becton-Dickinson.

Click here to listen to Dr. Conway

Click here to listen to Dr. Conway

Click here to listen to Dr. Conway

A new survey of patients showing that less than one-third reported receiving DVT prophylaxis, even though 2 out of every 5 had a family member who previously had an embolism clot in their leg or lung, is a sign physicians need to improve their communication skills, one hospitalist says.

The survey, conducted online by the National Blood Clot Alliance (NCBA) and presented at HM11, queried 500 patients with a length of stay of three days or higher. According to the survey, only 28% of patients had heard of DVT when the term was used, and just 15% knew pulmonary embolism when the term was used. In comparison, 83% knew what a blood clot was and 99% knew it could be life-threatening. Still, 46% said their doctor did not provide info about blood-clot-related risks.

Greg Maynard, MD, MSc, SFHM, chief of the Division of Hospital Medicine at the University of California at San Diego, says the results should serve as a wake-up call to hospitalists and other physicians. "They don't speak the language," says Dr. Maynard, a member of the NCBA's Medical and Scientific Advisory Board. "If we use that terminology with them, we fail. ... The first part of this puzzle is how we educate our patients."

Dr. Maynard says increased use of prophylaxis would help reduce care delivery costs and increase efficiency by eliminating preventable DVT or VTE incidences. Hospitalists are "well positioned" to lead the effort, but a few steps must happen first, he says. These changes require institutional commitment to do everything from adding prophylaxis checks to order sets to adopting new safety checklists to patient brochures explaining symptoms of blood clots. In addition, according to Dr. Maynard, baseline measurements must be set to determine what factors will classify patients as low-risk versus high-risk. Everyone above the low-risk line should receive prophylaxis, be it ambulation, compression stockings, or anticoagulant therapies, he says.

"It's all part of a bundle," Dr. Maynard says. "Any one of these things by themselves would not work as well."

A new survey of patients showing that less than one-third reported receiving DVT prophylaxis, even though 2 out of every 5 had a family member who previously had an embolism clot in their leg or lung, is a sign physicians need to improve their communication skills, one hospitalist says.

The survey, conducted online by the National Blood Clot Alliance (NCBA) and presented at HM11, queried 500 patients with a length of stay of three days or higher. According to the survey, only 28% of patients had heard of DVT when the term was used, and just 15% knew pulmonary embolism when the term was used. In comparison, 83% knew what a blood clot was and 99% knew it could be life-threatening. Still, 46% said their doctor did not provide info about blood-clot-related risks.

Greg Maynard, MD, MSc, SFHM, chief of the Division of Hospital Medicine at the University of California at San Diego, says the results should serve as a wake-up call to hospitalists and other physicians. "They don't speak the language," says Dr. Maynard, a member of the NCBA's Medical and Scientific Advisory Board. "If we use that terminology with them, we fail. ... The first part of this puzzle is how we educate our patients."

Dr. Maynard says increased use of prophylaxis would help reduce care delivery costs and increase efficiency by eliminating preventable DVT or VTE incidences. Hospitalists are "well positioned" to lead the effort, but a few steps must happen first, he says. These changes require institutional commitment to do everything from adding prophylaxis checks to order sets to adopting new safety checklists to patient brochures explaining symptoms of blood clots. In addition, according to Dr. Maynard, baseline measurements must be set to determine what factors will classify patients as low-risk versus high-risk. Everyone above the low-risk line should receive prophylaxis, be it ambulation, compression stockings, or anticoagulant therapies, he says.

"It's all part of a bundle," Dr. Maynard says. "Any one of these things by themselves would not work as well."

A new survey of patients showing that less than one-third reported receiving DVT prophylaxis, even though 2 out of every 5 had a family member who previously had an embolism clot in their leg or lung, is a sign physicians need to improve their communication skills, one hospitalist says.

The survey, conducted online by the National Blood Clot Alliance (NCBA) and presented at HM11, queried 500 patients with a length of stay of three days or higher. According to the survey, only 28% of patients had heard of DVT when the term was used, and just 15% knew pulmonary embolism when the term was used. In comparison, 83% knew what a blood clot was and 99% knew it could be life-threatening. Still, 46% said their doctor did not provide info about blood-clot-related risks.

Greg Maynard, MD, MSc, SFHM, chief of the Division of Hospital Medicine at the University of California at San Diego, says the results should serve as a wake-up call to hospitalists and other physicians. "They don't speak the language," says Dr. Maynard, a member of the NCBA's Medical and Scientific Advisory Board. "If we use that terminology with them, we fail. ... The first part of this puzzle is how we educate our patients."

Dr. Maynard says increased use of prophylaxis would help reduce care delivery costs and increase efficiency by eliminating preventable DVT or VTE incidences. Hospitalists are "well positioned" to lead the effort, but a few steps must happen first, he says. These changes require institutional commitment to do everything from adding prophylaxis checks to order sets to adopting new safety checklists to patient brochures explaining symptoms of blood clots. In addition, according to Dr. Maynard, baseline measurements must be set to determine what factors will classify patients as low-risk versus high-risk. Everyone above the low-risk line should receive prophylaxis, be it ambulation, compression stockings, or anticoagulant therapies, he says.

"It's all part of a bundle," Dr. Maynard says. "Any one of these things by themselves would not work as well."

Telemedicine links increasingly extend scarce neurologic services to underserved areas. Given the urgency of administering the FDA-approved clot-busting drug intravenous recombinant tissue plasminogen activator (t-PA) to reduce long-term, disabling effects of acute ischemic strokes, for hospitalists working in settings without timely inpatient access to stroke specialists, these arrangements can be lifesavers.

A telestroke system implemented by Dallas-based hospitalist company Eagle Hospital Physicians at South Fulton Medical Center in East Point, Ga., has enabled that hospital to achieve certification as a primary stroke center using coverage from remotely based "teleneurologists." But onsite presence of hospitalists and their integration into the stroke service are keys to its success, says Karim Godamunne, MD, MBA, FHM, FPHM, director of the hospitalist service at South Fulton and founder of the stroke program.

"My responsibility is for overall quality of the program, use of guidelines, tracking quality measures, and the like," Dr. Godamunne explains.

Around-the-clock coverage is provided by four board-certified vascular neurologists who work at other Atlanta-area hospitals and can "beam in" electronically upon request within 15 minutes of admission to consult on a stroke case. Typically, the teleneurologists are accessed by physicians in the ED or by hospitalists. South Fulton has one part-time neurologist on staff and a neurologic nurse practitioner who coordinates the stroke service. "All of the stroke patients get oversight and daily visits from the hospitalists to maintain quality," he says.

Eagle manages hospitalist programs in 25 hospitals in 10 primarily southeastern states. Dr. Godamunne also serves as hosting faculty for a remotely broadcast medical workshop on leveraging remote presence to meet inpatient needs, offered by Eagle's Remote Presence University.

Telemedicine links increasingly extend scarce neurologic services to underserved areas. Given the urgency of administering the FDA-approved clot-busting drug intravenous recombinant tissue plasminogen activator (t-PA) to reduce long-term, disabling effects of acute ischemic strokes, for hospitalists working in settings without timely inpatient access to stroke specialists, these arrangements can be lifesavers.

A telestroke system implemented by Dallas-based hospitalist company Eagle Hospital Physicians at South Fulton Medical Center in East Point, Ga., has enabled that hospital to achieve certification as a primary stroke center using coverage from remotely based "teleneurologists." But onsite presence of hospitalists and their integration into the stroke service are keys to its success, says Karim Godamunne, MD, MBA, FHM, FPHM, director of the hospitalist service at South Fulton and founder of the stroke program.

"My responsibility is for overall quality of the program, use of guidelines, tracking quality measures, and the like," Dr. Godamunne explains.

Around-the-clock coverage is provided by four board-certified vascular neurologists who work at other Atlanta-area hospitals and can "beam in" electronically upon request within 15 minutes of admission to consult on a stroke case. Typically, the teleneurologists are accessed by physicians in the ED or by hospitalists. South Fulton has one part-time neurologist on staff and a neurologic nurse practitioner who coordinates the stroke service. "All of the stroke patients get oversight and daily visits from the hospitalists to maintain quality," he says.

Eagle manages hospitalist programs in 25 hospitals in 10 primarily southeastern states. Dr. Godamunne also serves as hosting faculty for a remotely broadcast medical workshop on leveraging remote presence to meet inpatient needs, offered by Eagle's Remote Presence University.

Telemedicine links increasingly extend scarce neurologic services to underserved areas. Given the urgency of administering the FDA-approved clot-busting drug intravenous recombinant tissue plasminogen activator (t-PA) to reduce long-term, disabling effects of acute ischemic strokes, for hospitalists working in settings without timely inpatient access to stroke specialists, these arrangements can be lifesavers.

A telestroke system implemented by Dallas-based hospitalist company Eagle Hospital Physicians at South Fulton Medical Center in East Point, Ga., has enabled that hospital to achieve certification as a primary stroke center using coverage from remotely based "teleneurologists." But onsite presence of hospitalists and their integration into the stroke service are keys to its success, says Karim Godamunne, MD, MBA, FHM, FPHM, director of the hospitalist service at South Fulton and founder of the stroke program.

"My responsibility is for overall quality of the program, use of guidelines, tracking quality measures, and the like," Dr. Godamunne explains.

Around-the-clock coverage is provided by four board-certified vascular neurologists who work at other Atlanta-area hospitals and can "beam in" electronically upon request within 15 minutes of admission to consult on a stroke case. Typically, the teleneurologists are accessed by physicians in the ED or by hospitalists. South Fulton has one part-time neurologist on staff and a neurologic nurse practitioner who coordinates the stroke service. "All of the stroke patients get oversight and daily visits from the hospitalists to maintain quality," he says.

Eagle manages hospitalist programs in 25 hospitals in 10 primarily southeastern states. Dr. Godamunne also serves as hosting faculty for a remotely broadcast medical workshop on leveraging remote presence to meet inpatient needs, offered by Eagle's Remote Presence University.

As director of the hospitalist program at University of Utah Healthcare and the medical director of the University of Utah Health Care Thrombosis Service, Robert Pendleton, MD, closely monitored the progress of the anticoagulant dabigatran as it marched toward regulatory approval in the U.S. Developed by Boehringer Ingelheim and marketed as Pradaxa, the drug is a big deal.

“We were sort of primed and poised and anticipating that dabigatran would be approved,” Dr. Pendleton says. The FDA approved dabigatran in October for stroke prevention in nonvalvular atrial fibrillation patients. It is the first new oral anticoagulant approved in 50 years and the first of three drugs expected to mount a challenge to the longtime standard of care, warfarin (Coumadin).

When Dr. Pendleton’s hospital got ready to add the drug to its formulary, though, the process had to slow down. The hospital wasn’t quite ready for dabigatran.

“The first thing we did is sent out an institution-wide survey to get some understanding of baseline knowledge of practitioners who might be prescribing dabigatran … and found an enormous educational need,” Dr. Pendleton explains, but “most people who we anticipated would have been prescribing dabigatran, such as our cardiologists, had a very poor understanding of the clinical data and the drug itself.”

So University of Utah Healthcare developed an education plan for providers, made resources available so that providers could easily get information about the drug, and developed institutional guidelines on appropriate use, how they would handle off-label uses, and managing urgent situations. The drug was added to the formulary in February, and the change has been working out well, with “an exponential increase in prescribing,” Dr. Pendleton says.

The challenges at University of Utah Healthcare are being experienced—or probably soon will be—by hospitalists around the country as new oral anticoagulants become available for use. Experts say hospitalists need to take a keen interest in the new drugs, given the large number of CVT, VTE, atrial fibrillation, and other patients who are at an increased risk of clotting.

Most hospitalists see anticoagulated patients on a daily or weekly basis, experts say. Dr. Pendleton estimates that if you include patients who are on a preventive dose (e.g. to prevent DVT), as many as 80% or more of HM patients use anticoagulants.

“The first thing we did is sent out an institution-wide survey to get some understanding of baseline knowledge of practitioners who might be prescribing dabigatran … and found an enormous educational need.”–Robert Pendleton, MD, University of Utah Health Care Thrombosis Service

“Anticoagulants are dangerous and they are often a bit tricky to use,” says Gregory Maynard, MD, MSc, SFHM, chief of the Division of Hospital Medicine at the University of California at San Diego, where he has won awards for their DVT prevention program. “If you look at the top three or four adverse drug events that occur, usually warfarin is one of those. … It’s common, it’s a safety issue, it’s tricky to use—all of those things add up to something that hospitalists need to pay attention to.”

New Options, New Challenges, New Costs

Dabigatran, which inhibits thrombin, is part of a new anticoagulant parade, along with rivaroxaban (Xarelto) and apixaban, both of which inhibit Factor Xa. They offer patients attractive anticoagulant options that, unlike warfarin, don’t require blood draws for monitoring every few weeks. The new options also omit the lengthy list of drug and food contraindications of warfarin.

But questions about the ability to reverse bleeds while patients are on the new drugs, as well as concerns about their costs, are forcing hospitalists to evaluate carefully. So far, dabigatran is the only one approved in the U.S., and only for one indication.

The intention in development was to create “drugs that don’t require monitoring, drugs that have very little drug-drug interaction, and drugs that have no food interaction; a drug where you give a fixed dose and the patients get the same effect anticoagulation-wise,” says Geno Merli, MD, FHM, director of the Jefferson Center for Vascular Disease and CMO at Thomas Jefferson University Hospital in Philadelphia. “When you look at the studies, actually they do reasonably well. It’s a pretty big step.” (For a list of major anticoagulant studies, see Figure 1, below.)

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Rivaroxaban, being developed jointly by Bayer Healthcare and Johnson & Johnson, has been submitted to the FDA for approval for stroke prevention in nonvalvular atrial fibrillation patients, which would put it in direct competition with dabigatran. And apixaban, being co-developed by the global alliance of Bristol-Myers Squibb and Pfizer, expects to submit for the same indication approval this year, Bristol-Myers Squibb spokeswoman Christina Trank says. (updated June 16)

All three are under study for other indications, including VTE prevention after hip and knee replacement surgeries, and clot prevention in the acutely ill.

The stakes are high for the companies: Manufacturers and analysts estimate that the market for anticoagulants will top $10 billion by 2015, with some estimates even higher. Dabigatran has been in development by Boehringer for about 15 years and studied in more than 19,000 patients, spokeswoman Anna Moses says.

Bayer Healthcare says rivaroxaban’s development costs amount to more than $1.5 billion.

“I think all of them are promising,” says Shaun Mickus, a Johnson & Johnson spokesman. “We’re looking at meeting unmet medical needs. We have patients who, for one reason or another, are having blood clots in these indicated areas, and some of them are doing fine and getting the help they need, and others may not be.”

Boehringer spokeswoman Anna Moses said dabigatran is on formulary with 70% of the top 1,600 hospitals in the U.S.

“Our current focus is on efforts to educate physicians and payors about the product, including its efficacy, safety, and appropriate use,” Moses said in an email.

“[These are] drugs that don’t require monitoring, drugs that have very little drug-drug interaction, and drugs that have no food interaction; a drug where you give a fixed dose and the patients get the same effect anticoagulation-wise.”–Geno Merli, MD, FHM, director of the Jefferson Center for Vascular Disease and CMO at Thomas Jefferson University Hospital in Philadelphia

Warfarin’s Way Out?

Data on Pradaxa for stroke prevention in nonvalvular atrial fibrillation might be encouraging, but to some experts, it’s not automatically going to prove to be a superior alternative to warfarin, says Ian Jenkins, MD, assistant professor in the Division of Hospital Medicine and part of the VTE prevention team at UC San Diego.

“It is, statistically, significantly better than warfarin for nonvalvular atrial fibrillation when you look at the stroke rate, but the number needed to treat is not small—it’s 172 patients a year,” Dr. Jenkins says. “So, as far as looking at an individual patient and saying, ‘Am I going to prevent a stroke in this person by switching them to dabigatran?’ it’s actually unlikely that you would. And depending on the type of institution you’re at and how good they are at managing warfarin, you might be able to get a similar improvement in their stroke risk by, say, improving the quality practices for warfarin use at your hospital.”

“I think a lot of people are reluctant to start it on people who are doing well on warfarin,” Dr. Maynard adds. “There’s a lot of people who have been fine for many years on warfarin, even though it’s a tricky drug.”

At Thomas Jefferson, Pradaxa’s use is restricted to cardiologists, hematologists, and the hospital’s vascular anticoagulation service, and a doctor outside those categories has to get a consult first, Dr. Merli says. At University of Utah Healthcare, off-label uses have to be funneled through the thrombosis service, Dr. Pendleton says.

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Warfarin’s Many Medical Contributions Have Strange Origins

The standard in anticoagulation therapy for 50 years, warfarin might not have been discovered if a farmer hadn’t sought help for his dying cattle.

In February 1933, farmer Ed Carlson drove through a blizzard to Madison, Wis., stopped biochemist Karl Paul Link on the campus of the University of Wisconsin, and told him that sweet clover hay disease was causing his cattle to bleed to death. Link’s advice was perfunctory: have the cattle avoid eating spoiled hay.

But after the farmer’s visit, Link’s “senior student” persuaded him to try to find the agent within spoiled sweet clover hay that was causing the hemorrhaging effects. Link’s work eventually led to warfarin, a derivative of Coumadin, the substance that gives sweet clover its sweet smell. The name is a combination of WARF, which stands for Wisconsin Alumni Research Foundation, and coumarin. It was first used as a rodenticide.

Faith grew that the compound would not be fatal to people when, in 1951, an army inductee tried to commit suicide using the rat-killing compound. But he was unsuccessful, and his bleeding was reversed with doses of vitamin K.

By then, Link had perfected warfarin sodium and it was first made available for widespread clinical use under the trade name Coumadin sodium.

Howard Bremer, a retired patent attorney for WARF who still does consulting work for the foundation, says warfarin made $4 million for the foundation during the patent period from 1952 to 1972 (about $20 million in today’s dollars).

Money isn’t the main point, though, he says. “All the inventors are dead, the royalties long since ceased to flow to WARF with the expiration of the patents that were licensed,” Bremer says. “And here it still is the number-one anticoagulant utilized in cardiovascular programs worldwide.”

Thrombosis experts say that warfarin will still play a big role in anticoagulation treatment even as new drugs hit the market, in part because of familiarity and because some indications will not be studied right away.

“For all of its limitations and complexities, it has absolutely and markedly improved healthcare for patients with those disorders,” Dr. Pendleton says. “It took a long period of time to understand how to use warfarin appropriately and in what patients and at what dose. I think there will be—although different—similar challenges with the new drugs.”—TC

“Our concern was that our clinicians may use the drug for off-label indications and not for atrial fibrillation, as approved by the FDA,” says Dr. Merli, whose job as chief medical officer includes overseeing patient safety. “We felt that Pradaxa’s a good drug, has a good track record, but our fear was, how do we control the doctors who may want to use Pradaxa for other indications that have never been studied?”

Pradaxa also is considered for use in especially complicated cases that might be unsuitable for warfarin, he says.

A major consideration for the new drugs is that, unlike warfarin, they have no proven antidote should a patient have a bleeding episode while taking them. Warfarin patients are given vitamin K to ease the bleeding, but it’s not so simple with the new medications.

Dr. Merli expects those concerns will have a “big impact on physician utilization of these new agents.”

Experts say the main option in the event of a bleed on the new agents, at least for now, is to simply wait it out while giving the patient fresh frozen plasma.

“What if you fall down and hit your head and you bleed into your brain?” Dr. Merli asks. “I’m waiting for our first patient to come in, you know, with a massive brain bleed on Pradaxa.” The hospital, he notes, probably would treat with fresh frozen plasma, but then resort to Factor VII, which costs $10,000 to $12,000 per treatment.

Dr. Merli also says that the test recommended by Boehringer for assessing the degree of anticoagulation (the ecarin test) is not widely available. “That test is not available even at our hospital in Philadelphia,” he says. “The companies that make them tell us that in the case of Pradaxa, you can use the [activated] partial thromboplastin time as a measure of the degree of anticoagulation, but in the studies, there was no correlation.”

“If you look at the top three or four adverse drug events that occur, usually warfarin is one of those. … It’s common, it’s a safety issue, it’s tricky to use—all of those things add up to something that hospitalists need to pay attention to.”–Gregory Maynard, MD, MSc, SFHM, chief of the Division of Hospital Medicine at the University of California at San Diego

Then there is the cost hurdle. Warfarin, even with one or two blood tests a month to monitor international normalized ratio (INR) and assess its effectiveness, costs patients a total of $15 to $50 a month out of pocket. Paying cash for dabigatran is about $200 a month.

“Some sites haven’t added it to their formulary because they were concerned that it could get started in the hospital and then the patient might not be able to obtain it outside of the hospital, and then they would end up on no anticoagulation for a period of time,” Dr. Jenkins says.

On the flipside, dabigatran use could shorten hospital stays, saving costs. Patients on warfarin typically have to be weaned off faster-acting IV heparin first, then weaned onto warfarin. It also can take time to make sure anticoagulation is at the proper level, also extending the stay.

Boehringer Ingelheim spokeswoman Moses notes that the company is taking steps to address the cost. “Pradaxa is now included at the lowest branded copay level on formularies that insure about 35 percent of NVAF patients [Irregular heartbeat in a patient without a diseased, repaired, or replaced mitral heart valve] in the U.S.,” she wrote in an email. “For those patients who may not otherwise be able to afford treatment, BIPI [Boehring Ingelheim] offers patients assistance programs to help provide coverage for the cost of their medications.”

Dr. Merli expects the majority of physicians will take a wait-and-see approach to the new anticoagulants.

“I think 20 percent will adopt the drug early,” he says. “Then there’s that big group in the middle, 60 percent, that will wait and see and they’ll start using it. And then there’s that end group of 20 percent that will never use the drug.” TH

Thomas R. Collins is a freelance writer based in Florida.

As director of the hospitalist program at University of Utah Healthcare and the medical director of the University of Utah Health Care Thrombosis Service, Robert Pendleton, MD, closely monitored the progress of the anticoagulant dabigatran as it marched toward regulatory approval in the U.S. Developed by Boehringer Ingelheim and marketed as Pradaxa, the drug is a big deal.

“We were sort of primed and poised and anticipating that dabigatran would be approved,” Dr. Pendleton says. The FDA approved dabigatran in October for stroke prevention in nonvalvular atrial fibrillation patients. It is the first new oral anticoagulant approved in 50 years and the first of three drugs expected to mount a challenge to the longtime standard of care, warfarin (Coumadin).

When Dr. Pendleton’s hospital got ready to add the drug to its formulary, though, the process had to slow down. The hospital wasn’t quite ready for dabigatran.

“The first thing we did is sent out an institution-wide survey to get some understanding of baseline knowledge of practitioners who might be prescribing dabigatran … and found an enormous educational need,” Dr. Pendleton explains, but “most people who we anticipated would have been prescribing dabigatran, such as our cardiologists, had a very poor understanding of the clinical data and the drug itself.”

So University of Utah Healthcare developed an education plan for providers, made resources available so that providers could easily get information about the drug, and developed institutional guidelines on appropriate use, how they would handle off-label uses, and managing urgent situations. The drug was added to the formulary in February, and the change has been working out well, with “an exponential increase in prescribing,” Dr. Pendleton says.

The challenges at University of Utah Healthcare are being experienced—or probably soon will be—by hospitalists around the country as new oral anticoagulants become available for use. Experts say hospitalists need to take a keen interest in the new drugs, given the large number of CVT, VTE, atrial fibrillation, and other patients who are at an increased risk of clotting.

Most hospitalists see anticoagulated patients on a daily or weekly basis, experts say. Dr. Pendleton estimates that if you include patients who are on a preventive dose (e.g. to prevent DVT), as many as 80% or more of HM patients use anticoagulants.

“The first thing we did is sent out an institution-wide survey to get some understanding of baseline knowledge of practitioners who might be prescribing dabigatran … and found an enormous educational need.”–Robert Pendleton, MD, University of Utah Health Care Thrombosis Service

“Anticoagulants are dangerous and they are often a bit tricky to use,” says Gregory Maynard, MD, MSc, SFHM, chief of the Division of Hospital Medicine at the University of California at San Diego, where he has won awards for their DVT prevention program. “If you look at the top three or four adverse drug events that occur, usually warfarin is one of those. … It’s common, it’s a safety issue, it’s tricky to use—all of those things add up to something that hospitalists need to pay attention to.”

New Options, New Challenges, New Costs

Dabigatran, which inhibits thrombin, is part of a new anticoagulant parade, along with rivaroxaban (Xarelto) and apixaban, both of which inhibit Factor Xa. They offer patients attractive anticoagulant options that, unlike warfarin, don’t require blood draws for monitoring every few weeks. The new options also omit the lengthy list of drug and food contraindications of warfarin.

But questions about the ability to reverse bleeds while patients are on the new drugs, as well as concerns about their costs, are forcing hospitalists to evaluate carefully. So far, dabigatran is the only one approved in the U.S., and only for one indication.

The intention in development was to create “drugs that don’t require monitoring, drugs that have very little drug-drug interaction, and drugs that have no food interaction; a drug where you give a fixed dose and the patients get the same effect anticoagulation-wise,” says Geno Merli, MD, FHM, director of the Jefferson Center for Vascular Disease and CMO at Thomas Jefferson University Hospital in Philadelphia. “When you look at the studies, actually they do reasonably well. It’s a pretty big step.” (For a list of major anticoagulant studies, see Figure 1, below.)

Story continues below...

Rivaroxaban, being developed jointly by Bayer Healthcare and Johnson & Johnson, has been submitted to the FDA for approval for stroke prevention in nonvalvular atrial fibrillation patients, which would put it in direct competition with dabigatran. And apixaban, being co-developed by the global alliance of Bristol-Myers Squibb and Pfizer, expects to submit for the same indication approval this year, Bristol-Myers Squibb spokeswoman Christina Trank says. (updated June 16)

All three are under study for other indications, including VTE prevention after hip and knee replacement surgeries, and clot prevention in the acutely ill.

The stakes are high for the companies: Manufacturers and analysts estimate that the market for anticoagulants will top $10 billion by 2015, with some estimates even higher. Dabigatran has been in development by Boehringer for about 15 years and studied in more than 19,000 patients, spokeswoman Anna Moses says.

Bayer Healthcare says rivaroxaban’s development costs amount to more than $1.5 billion.

“I think all of them are promising,” says Shaun Mickus, a Johnson & Johnson spokesman. “We’re looking at meeting unmet medical needs. We have patients who, for one reason or another, are having blood clots in these indicated areas, and some of them are doing fine and getting the help they need, and others may not be.”

Boehringer spokeswoman Anna Moses said dabigatran is on formulary with 70% of the top 1,600 hospitals in the U.S.

“Our current focus is on efforts to educate physicians and payors about the product, including its efficacy, safety, and appropriate use,” Moses said in an email.

“[These are] drugs that don’t require monitoring, drugs that have very little drug-drug interaction, and drugs that have no food interaction; a drug where you give a fixed dose and the patients get the same effect anticoagulation-wise.”–Geno Merli, MD, FHM, director of the Jefferson Center for Vascular Disease and CMO at Thomas Jefferson University Hospital in Philadelphia

Warfarin’s Way Out?

Data on Pradaxa for stroke prevention in nonvalvular atrial fibrillation might be encouraging, but to some experts, it’s not automatically going to prove to be a superior alternative to warfarin, says Ian Jenkins, MD, assistant professor in the Division of Hospital Medicine and part of the VTE prevention team at UC San Diego.

“It is, statistically, significantly better than warfarin for nonvalvular atrial fibrillation when you look at the stroke rate, but the number needed to treat is not small—it’s 172 patients a year,” Dr. Jenkins says. “So, as far as looking at an individual patient and saying, ‘Am I going to prevent a stroke in this person by switching them to dabigatran?’ it’s actually unlikely that you would. And depending on the type of institution you’re at and how good they are at managing warfarin, you might be able to get a similar improvement in their stroke risk by, say, improving the quality practices for warfarin use at your hospital.”

“I think a lot of people are reluctant to start it on people who are doing well on warfarin,” Dr. Maynard adds. “There’s a lot of people who have been fine for many years on warfarin, even though it’s a tricky drug.”

At Thomas Jefferson, Pradaxa’s use is restricted to cardiologists, hematologists, and the hospital’s vascular anticoagulation service, and a doctor outside those categories has to get a consult first, Dr. Merli says. At University of Utah Healthcare, off-label uses have to be funneled through the thrombosis service, Dr. Pendleton says.

Story continues below...

Warfarin’s Many Medical Contributions Have Strange Origins

The standard in anticoagulation therapy for 50 years, warfarin might not have been discovered if a farmer hadn’t sought help for his dying cattle.

In February 1933, farmer Ed Carlson drove through a blizzard to Madison, Wis., stopped biochemist Karl Paul Link on the campus of the University of Wisconsin, and told him that sweet clover hay disease was causing his cattle to bleed to death. Link’s advice was perfunctory: have the cattle avoid eating spoiled hay.

But after the farmer’s visit, Link’s “senior student” persuaded him to try to find the agent within spoiled sweet clover hay that was causing the hemorrhaging effects. Link’s work eventually led to warfarin, a derivative of Coumadin, the substance that gives sweet clover its sweet smell. The name is a combination of WARF, which stands for Wisconsin Alumni Research Foundation, and coumarin. It was first used as a rodenticide.

Faith grew that the compound would not be fatal to people when, in 1951, an army inductee tried to commit suicide using the rat-killing compound. But he was unsuccessful, and his bleeding was reversed with doses of vitamin K.

By then, Link had perfected warfarin sodium and it was first made available for widespread clinical use under the trade name Coumadin sodium.

Howard Bremer, a retired patent attorney for WARF who still does consulting work for the foundation, says warfarin made $4 million for the foundation during the patent period from 1952 to 1972 (about $20 million in today’s dollars).

Money isn’t the main point, though, he says. “All the inventors are dead, the royalties long since ceased to flow to WARF with the expiration of the patents that were licensed,” Bremer says. “And here it still is the number-one anticoagulant utilized in cardiovascular programs worldwide.”

Thrombosis experts say that warfarin will still play a big role in anticoagulation treatment even as new drugs hit the market, in part because of familiarity and because some indications will not be studied right away.

“For all of its limitations and complexities, it has absolutely and markedly improved healthcare for patients with those disorders,” Dr. Pendleton says. “It took a long period of time to understand how to use warfarin appropriately and in what patients and at what dose. I think there will be—although different—similar challenges with the new drugs.”—TC

“Our concern was that our clinicians may use the drug for off-label indications and not for atrial fibrillation, as approved by the FDA,” says Dr. Merli, whose job as chief medical officer includes overseeing patient safety. “We felt that Pradaxa’s a good drug, has a good track record, but our fear was, how do we control the doctors who may want to use Pradaxa for other indications that have never been studied?”

Pradaxa also is considered for use in especially complicated cases that might be unsuitable for warfarin, he says.

A major consideration for the new drugs is that, unlike warfarin, they have no proven antidote should a patient have a bleeding episode while taking them. Warfarin patients are given vitamin K to ease the bleeding, but it’s not so simple with the new medications.

Dr. Merli expects those concerns will have a “big impact on physician utilization of these new agents.”

Experts say the main option in the event of a bleed on the new agents, at least for now, is to simply wait it out while giving the patient fresh frozen plasma.

“What if you fall down and hit your head and you bleed into your brain?” Dr. Merli asks. “I’m waiting for our first patient to come in, you know, with a massive brain bleed on Pradaxa.” The hospital, he notes, probably would treat with fresh frozen plasma, but then resort to Factor VII, which costs $10,000 to $12,000 per treatment.

Dr. Merli also says that the test recommended by Boehringer for assessing the degree of anticoagulation (the ecarin test) is not widely available. “That test is not available even at our hospital in Philadelphia,” he says. “The companies that make them tell us that in the case of Pradaxa, you can use the [activated] partial thromboplastin time as a measure of the degree of anticoagulation, but in the studies, there was no correlation.”

“If you look at the top three or four adverse drug events that occur, usually warfarin is one of those. … It’s common, it’s a safety issue, it’s tricky to use—all of those things add up to something that hospitalists need to pay attention to.”–Gregory Maynard, MD, MSc, SFHM, chief of the Division of Hospital Medicine at the University of California at San Diego

Then there is the cost hurdle. Warfarin, even with one or two blood tests a month to monitor international normalized ratio (INR) and assess its effectiveness, costs patients a total of $15 to $50 a month out of pocket. Paying cash for dabigatran is about $200 a month.

“Some sites haven’t added it to their formulary because they were concerned that it could get started in the hospital and then the patient might not be able to obtain it outside of the hospital, and then they would end up on no anticoagulation for a period of time,” Dr. Jenkins says.

On the flipside, dabigatran use could shorten hospital stays, saving costs. Patients on warfarin typically have to be weaned off faster-acting IV heparin first, then weaned onto warfarin. It also can take time to make sure anticoagulation is at the proper level, also extending the stay.

Boehringer Ingelheim spokeswoman Moses notes that the company is taking steps to address the cost. “Pradaxa is now included at the lowest branded copay level on formularies that insure about 35 percent of NVAF patients [Irregular heartbeat in a patient without a diseased, repaired, or replaced mitral heart valve] in the U.S.,” she wrote in an email. “For those patients who may not otherwise be able to afford treatment, BIPI [Boehring Ingelheim] offers patients assistance programs to help provide coverage for the cost of their medications.”

Dr. Merli expects the majority of physicians will take a wait-and-see approach to the new anticoagulants.

“I think 20 percent will adopt the drug early,” he says. “Then there’s that big group in the middle, 60 percent, that will wait and see and they’ll start using it. And then there’s that end group of 20 percent that will never use the drug.” TH

Thomas R. Collins is a freelance writer based in Florida.

As director of the hospitalist program at University of Utah Healthcare and the medical director of the University of Utah Health Care Thrombosis Service, Robert Pendleton, MD, closely monitored the progress of the anticoagulant dabigatran as it marched toward regulatory approval in the U.S. Developed by Boehringer Ingelheim and marketed as Pradaxa, the drug is a big deal.

“We were sort of primed and poised and anticipating that dabigatran would be approved,” Dr. Pendleton says. The FDA approved dabigatran in October for stroke prevention in nonvalvular atrial fibrillation patients. It is the first new oral anticoagulant approved in 50 years and the first of three drugs expected to mount a challenge to the longtime standard of care, warfarin (Coumadin).

When Dr. Pendleton’s hospital got ready to add the drug to its formulary, though, the process had to slow down. The hospital wasn’t quite ready for dabigatran.

“The first thing we did is sent out an institution-wide survey to get some understanding of baseline knowledge of practitioners who might be prescribing dabigatran … and found an enormous educational need,” Dr. Pendleton explains, but “most people who we anticipated would have been prescribing dabigatran, such as our cardiologists, had a very poor understanding of the clinical data and the drug itself.”

So University of Utah Healthcare developed an education plan for providers, made resources available so that providers could easily get information about the drug, and developed institutional guidelines on appropriate use, how they would handle off-label uses, and managing urgent situations. The drug was added to the formulary in February, and the change has been working out well, with “an exponential increase in prescribing,” Dr. Pendleton says.

The challenges at University of Utah Healthcare are being experienced—or probably soon will be—by hospitalists around the country as new oral anticoagulants become available for use. Experts say hospitalists need to take a keen interest in the new drugs, given the large number of CVT, VTE, atrial fibrillation, and other patients who are at an increased risk of clotting.

Most hospitalists see anticoagulated patients on a daily or weekly basis, experts say. Dr. Pendleton estimates that if you include patients who are on a preventive dose (e.g. to prevent DVT), as many as 80% or more of HM patients use anticoagulants.

“The first thing we did is sent out an institution-wide survey to get some understanding of baseline knowledge of practitioners who might be prescribing dabigatran … and found an enormous educational need.”–Robert Pendleton, MD, University of Utah Health Care Thrombosis Service

“Anticoagulants are dangerous and they are often a bit tricky to use,” says Gregory Maynard, MD, MSc, SFHM, chief of the Division of Hospital Medicine at the University of California at San Diego, where he has won awards for their DVT prevention program. “If you look at the top three or four adverse drug events that occur, usually warfarin is one of those. … It’s common, it’s a safety issue, it’s tricky to use—all of those things add up to something that hospitalists need to pay attention to.”

New Options, New Challenges, New Costs

Dabigatran, which inhibits thrombin, is part of a new anticoagulant parade, along with rivaroxaban (Xarelto) and apixaban, both of which inhibit Factor Xa. They offer patients attractive anticoagulant options that, unlike warfarin, don’t require blood draws for monitoring every few weeks. The new options also omit the lengthy list of drug and food contraindications of warfarin.

But questions about the ability to reverse bleeds while patients are on the new drugs, as well as concerns about their costs, are forcing hospitalists to evaluate carefully. So far, dabigatran is the only one approved in the U.S., and only for one indication.

The intention in development was to create “drugs that don’t require monitoring, drugs that have very little drug-drug interaction, and drugs that have no food interaction; a drug where you give a fixed dose and the patients get the same effect anticoagulation-wise,” says Geno Merli, MD, FHM, director of the Jefferson Center for Vascular Disease and CMO at Thomas Jefferson University Hospital in Philadelphia. “When you look at the studies, actually they do reasonably well. It’s a pretty big step.” (For a list of major anticoagulant studies, see Figure 1, below.)

Story continues below...

Rivaroxaban, being developed jointly by Bayer Healthcare and Johnson & Johnson, has been submitted to the FDA for approval for stroke prevention in nonvalvular atrial fibrillation patients, which would put it in direct competition with dabigatran. And apixaban, being co-developed by the global alliance of Bristol-Myers Squibb and Pfizer, expects to submit for the same indication approval this year, Bristol-Myers Squibb spokeswoman Christina Trank says. (updated June 16)

All three are under study for other indications, including VTE prevention after hip and knee replacement surgeries, and clot prevention in the acutely ill.

The stakes are high for the companies: Manufacturers and analysts estimate that the market for anticoagulants will top $10 billion by 2015, with some estimates even higher. Dabigatran has been in development by Boehringer for about 15 years and studied in more than 19,000 patients, spokeswoman Anna Moses says.

Bayer Healthcare says rivaroxaban’s development costs amount to more than $1.5 billion.

“I think all of them are promising,” says Shaun Mickus, a Johnson & Johnson spokesman. “We’re looking at meeting unmet medical needs. We have patients who, for one reason or another, are having blood clots in these indicated areas, and some of them are doing fine and getting the help they need, and others may not be.”

Boehringer spokeswoman Anna Moses said dabigatran is on formulary with 70% of the top 1,600 hospitals in the U.S.

“Our current focus is on efforts to educate physicians and payors about the product, including its efficacy, safety, and appropriate use,” Moses said in an email.

“[These are] drugs that don’t require monitoring, drugs that have very little drug-drug interaction, and drugs that have no food interaction; a drug where you give a fixed dose and the patients get the same effect anticoagulation-wise.”–Geno Merli, MD, FHM, director of the Jefferson Center for Vascular Disease and CMO at Thomas Jefferson University Hospital in Philadelphia

Warfarin’s Way Out?

Data on Pradaxa for stroke prevention in nonvalvular atrial fibrillation might be encouraging, but to some experts, it’s not automatically going to prove to be a superior alternative to warfarin, says Ian Jenkins, MD, assistant professor in the Division of Hospital Medicine and part of the VTE prevention team at UC San Diego.

“It is, statistically, significantly better than warfarin for nonvalvular atrial fibrillation when you look at the stroke rate, but the number needed to treat is not small—it’s 172 patients a year,” Dr. Jenkins says. “So, as far as looking at an individual patient and saying, ‘Am I going to prevent a stroke in this person by switching them to dabigatran?’ it’s actually unlikely that you would. And depending on the type of institution you’re at and how good they are at managing warfarin, you might be able to get a similar improvement in their stroke risk by, say, improving the quality practices for warfarin use at your hospital.”

“I think a lot of people are reluctant to start it on people who are doing well on warfarin,” Dr. Maynard adds. “There’s a lot of people who have been fine for many years on warfarin, even though it’s a tricky drug.”

At Thomas Jefferson, Pradaxa’s use is restricted to cardiologists, hematologists, and the hospital’s vascular anticoagulation service, and a doctor outside those categories has to get a consult first, Dr. Merli says. At University of Utah Healthcare, off-label uses have to be funneled through the thrombosis service, Dr. Pendleton says.

Story continues below...

Warfarin’s Many Medical Contributions Have Strange Origins

The standard in anticoagulation therapy for 50 years, warfarin might not have been discovered if a farmer hadn’t sought help for his dying cattle.

In February 1933, farmer Ed Carlson drove through a blizzard to Madison, Wis., stopped biochemist Karl Paul Link on the campus of the University of Wisconsin, and told him that sweet clover hay disease was causing his cattle to bleed to death. Link’s advice was perfunctory: have the cattle avoid eating spoiled hay.

But after the farmer’s visit, Link’s “senior student” persuaded him to try to find the agent within spoiled sweet clover hay that was causing the hemorrhaging effects. Link’s work eventually led to warfarin, a derivative of Coumadin, the substance that gives sweet clover its sweet smell. The name is a combination of WARF, which stands for Wisconsin Alumni Research Foundation, and coumarin. It was first used as a rodenticide.

Faith grew that the compound would not be fatal to people when, in 1951, an army inductee tried to commit suicide using the rat-killing compound. But he was unsuccessful, and his bleeding was reversed with doses of vitamin K.

By then, Link had perfected warfarin sodium and it was first made available for widespread clinical use under the trade name Coumadin sodium.

Howard Bremer, a retired patent attorney for WARF who still does consulting work for the foundation, says warfarin made $4 million for the foundation during the patent period from 1952 to 1972 (about $20 million in today’s dollars).

Money isn’t the main point, though, he says. “All the inventors are dead, the royalties long since ceased to flow to WARF with the expiration of the patents that were licensed,” Bremer says. “And here it still is the number-one anticoagulant utilized in cardiovascular programs worldwide.”

Thrombosis experts say that warfarin will still play a big role in anticoagulation treatment even as new drugs hit the market, in part because of familiarity and because some indications will not be studied right away.

“For all of its limitations and complexities, it has absolutely and markedly improved healthcare for patients with those disorders,” Dr. Pendleton says. “It took a long period of time to understand how to use warfarin appropriately and in what patients and at what dose. I think there will be—although different—similar challenges with the new drugs.”—TC

“Our concern was that our clinicians may use the drug for off-label indications and not for atrial fibrillation, as approved by the FDA,” says Dr. Merli, whose job as chief medical officer includes overseeing patient safety. “We felt that Pradaxa’s a good drug, has a good track record, but our fear was, how do we control the doctors who may want to use Pradaxa for other indications that have never been studied?”

Pradaxa also is considered for use in especially complicated cases that might be unsuitable for warfarin, he says.

A major consideration for the new drugs is that, unlike warfarin, they have no proven antidote should a patient have a bleeding episode while taking them. Warfarin patients are given vitamin K to ease the bleeding, but it’s not so simple with the new medications.

Dr. Merli expects those concerns will have a “big impact on physician utilization of these new agents.”

Experts say the main option in the event of a bleed on the new agents, at least for now, is to simply wait it out while giving the patient fresh frozen plasma.

“What if you fall down and hit your head and you bleed into your brain?” Dr. Merli asks. “I’m waiting for our first patient to come in, you know, with a massive brain bleed on Pradaxa.” The hospital, he notes, probably would treat with fresh frozen plasma, but then resort to Factor VII, which costs $10,000 to $12,000 per treatment.

Dr. Merli also says that the test recommended by Boehringer for assessing the degree of anticoagulation (the ecarin test) is not widely available. “That test is not available even at our hospital in Philadelphia,” he says. “The companies that make them tell us that in the case of Pradaxa, you can use the [activated] partial thromboplastin time as a measure of the degree of anticoagulation, but in the studies, there was no correlation.”

“If you look at the top three or four adverse drug events that occur, usually warfarin is one of those. … It’s common, it’s a safety issue, it’s tricky to use—all of those things add up to something that hospitalists need to pay attention to.”–Gregory Maynard, MD, MSc, SFHM, chief of the Division of Hospital Medicine at the University of California at San Diego

Then there is the cost hurdle. Warfarin, even with one or two blood tests a month to monitor international normalized ratio (INR) and assess its effectiveness, costs patients a total of $15 to $50 a month out of pocket. Paying cash for dabigatran is about $200 a month.

“Some sites haven’t added it to their formulary because they were concerned that it could get started in the hospital and then the patient might not be able to obtain it outside of the hospital, and then they would end up on no anticoagulation for a period of time,” Dr. Jenkins says.

On the flipside, dabigatran use could shorten hospital stays, saving costs. Patients on warfarin typically have to be weaned off faster-acting IV heparin first, then weaned onto warfarin. It also can take time to make sure anticoagulation is at the proper level, also extending the stay.

Boehringer Ingelheim spokeswoman Moses notes that the company is taking steps to address the cost. “Pradaxa is now included at the lowest branded copay level on formularies that insure about 35 percent of NVAF patients [Irregular heartbeat in a patient without a diseased, repaired, or replaced mitral heart valve] in the U.S.,” she wrote in an email. “For those patients who may not otherwise be able to afford treatment, BIPI [Boehring Ingelheim] offers patients assistance programs to help provide coverage for the cost of their medications.”

Dr. Merli expects the majority of physicians will take a wait-and-see approach to the new anticoagulants.

“I think 20 percent will adopt the drug early,” he says. “Then there’s that big group in the middle, 60 percent, that will wait and see and they’ll start using it. And then there’s that end group of 20 percent that will never use the drug.” TH

Thomas R. Collins is a freelance writer based in Florida.

SHM’s annual meeting was a Texas-sized birthday party for a teenager. Fifteen years after the term “hospitalist” was coined, more than 2,500 hospitalists, residents, nonphysician providers, and at least one pharmacist attended HM11 May 10-13 at the Gaylord Texan Resort and Convention Center in Grapevine, Texas.

The four-day celebration of all things HM drew arguably its most impressive batch of speakers, including AMA President Cecil Wilson, MD, and Robert

Kocher, MD, a former special assistant to President Obama. Robert Wachter, MD, MHM, who coauthored the term “hospitalist,” gave the penultimate address.

But attendees say the value of the meeting wasn’t the speeches, the more than 100 breakout sessions, or the endless networking opportunities. It was all of it.

“People talking about how excited they are about hospitalized medicine, you’re like, ‘Yeah, let’s do this,’ ” said first-time attendee Randa Perkins, MD, chief resident at Tallahassee Memorial’s Family Medicine Residency Program in Florida. “You feel like it is ‘Braveheart’!”

SHM’s annual meeting was a Texas-sized birthday party for a teenager. Fifteen years after the term “hospitalist” was coined, more than 2,500 hospitalists, residents, nonphysician providers, and at least one pharmacist attended HM11 May 10-13 at the Gaylord Texan Resort and Convention Center in Grapevine, Texas.

The four-day celebration of all things HM drew arguably its most impressive batch of speakers, including AMA President Cecil Wilson, MD, and Robert

Kocher, MD, a former special assistant to President Obama. Robert Wachter, MD, MHM, who coauthored the term “hospitalist,” gave the penultimate address.

But attendees say the value of the meeting wasn’t the speeches, the more than 100 breakout sessions, or the endless networking opportunities. It was all of it.

“People talking about how excited they are about hospitalized medicine, you’re like, ‘Yeah, let’s do this,’ ” said first-time attendee Randa Perkins, MD, chief resident at Tallahassee Memorial’s Family Medicine Residency Program in Florida. “You feel like it is ‘Braveheart’!”

SHM’s annual meeting was a Texas-sized birthday party for a teenager. Fifteen years after the term “hospitalist” was coined, more than 2,500 hospitalists, residents, nonphysician providers, and at least one pharmacist attended HM11 May 10-13 at the Gaylord Texan Resort and Convention Center in Grapevine, Texas.

The four-day celebration of all things HM drew arguably its most impressive batch of speakers, including AMA President Cecil Wilson, MD, and Robert

Kocher, MD, a former special assistant to President Obama. Robert Wachter, MD, MHM, who coauthored the term “hospitalist,” gave the penultimate address.

But attendees say the value of the meeting wasn’t the speeches, the more than 100 breakout sessions, or the endless networking opportunities. It was all of it.

“People talking about how excited they are about hospitalized medicine, you’re like, ‘Yeah, let’s do this,’ ” said first-time attendee Randa Perkins, MD, chief resident at Tallahassee Memorial’s Family Medicine Residency Program in Florida. “You feel like it is ‘Braveheart’!”