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’!”

Dr. Conway

Patrick Conway, MD, MSc, SFHM, a pediatric hospitalist and director of hospital medicine at Cincinnati Children’s Hospital Medical Center, has been appointed chief medical officer of the Centers for Medicare & Medicaid Services (CMS). Dr. Conway’s key responsibilities will be administering federal healthcare quality initiatives and setting the government’s quality agenda in an era of massive changes resulting from the Patient Protection and Accountable Care Act of 2010 (ACA).

Dr. Conway, who previously served as CMO of the Policy Division of the Office of Secretary of Health and Human Services and was a 2007-2008 White House fellow assigned to the Agency for Healthcare Research and Quality (AHRQ), is a leader in safety, quality, and outcomes initiatives at Cincinnati Children’s, and is the immediate past chair of SHM’s Public Policy Committee. He also served on the Federal Coordinating Council for Comparative Effectiveness Research. In his new job, which he started May 9, he is directing CMS’ Office of Clinical Standards and Quality, which coordinates development and implementation of a CMS-wide approach to promoting health quality.

“Patrick Conway’s appointment represents a major milestone for hospitalists and patients alike,” says Larry Wellikson, MD, SFHM, CEO of SHM. “As hospitalists approach the 15th anniversary of the specialty, it is fitting that one of our own takes on the considerable responsibility of caring for millions of Americans through Medicare and Medicaid. Dr. Conway and thousands of other hospitalists have been on the front lines of systematically improving patient care for more than a decade; his sound judgment and compassion as a clinician are now a major national asset.”

Dr. Conway maintains his associate professorship at the University of Cincinnati and will work some weekends seeing patients at Children’s National Medical Center in Washington, D.C. “I love patient care, so I don’t want to stop doing that. Plus, it helps me connect to the front lines of providing medical care,” he says.

“Dr. Conway’s passion for improving healthcare delivery systems, his day-to-day experience as a hospitalist physician, and his accomplishments in quality-improvement research, such as implementing evidence-based healthcare for all children, provide a strong background for his critical role at CMS as chief medical officer,” says Arnold W. Strauss, MD, chair of pediatrics at the University of Cincinnati, where many of the pediatric physicians at Children’s Hospital hold academic appointments. “Dr. Conway and our colleagues at Cincinnati Children’s have demonstrated that improving patient outcomes at lower cost—the goal of healthcare reform—is feasible.”

Dr. Conway’s role at CMS will include major components of surveys, certification, and accreditation issues for hospitals and other Medicare providers; healthcare information technology; and hospital value-based purchasing initiatives (see “Value-Based Purchasing Raises the Stakes,” The Hospitalist, May 2011, p. 1).

But his initial priorities will focus on quality-measures development, illustrated by CMS’ Hospital Compare website (www.hospitalcompare.hhs.gov), and quality improvement. Another major issue involves care transitions and readmissions, “which I try to frame positively—how can we have the most effective care transitions possible?” he says. “SHM and its publications have done a good job of stressing how hospitals and hospitalists can add value.”

Emphasizing his own experience directing an HM department for a health system that admits 7,000 pediatric patients per year, Dr. Conway says other hospitalists can take a similar lead in embracing quality measurement in their hospitals. “I may be working on quality measures for fiscal years 2013 and 2014, but you already know what will be measured in 2012. Don’t wait until September 2012 to get started,” he explains. “Hospitalists can help their institution pose the question: ‘What do we want to get better at in the next year?’ Then you test. Understand your current performance, set a goal, compare benchmarks with other hospitals, and keep working on improvement.”

Over the course of a year, he adds, quality will improve, and then your HM group will have “something to talk about with hospital administrators.”

Married with two children, says his experience at both the macro and micro levels of healthcare will benefit the overall system. “I actually think if we realign incentives, the system can perform better,” he says. “So I see it as an opportunity to perform a public service. But we also need front-line clinicians, including hospitalists, working to improve our healthcare system. … We need frontline providers that are measuring the quality of their care and improving it.” TH

Larry Beresford is a freelance writer based in California.

Dr. Conway

Patrick Conway, MD, MSc, SFHM, a pediatric hospitalist and director of hospital medicine at Cincinnati Children’s Hospital Medical Center, has been appointed chief medical officer of the Centers for Medicare & Medicaid Services (CMS). Dr. Conway’s key responsibilities will be administering federal healthcare quality initiatives and setting the government’s quality agenda in an era of massive changes resulting from the Patient Protection and Accountable Care Act of 2010 (ACA).

Dr. Conway, who previously served as CMO of the Policy Division of the Office of Secretary of Health and Human Services and was a 2007-2008 White House fellow assigned to the Agency for Healthcare Research and Quality (AHRQ), is a leader in safety, quality, and outcomes initiatives at Cincinnati Children’s, and is the immediate past chair of SHM’s Public Policy Committee. He also served on the Federal Coordinating Council for Comparative Effectiveness Research. In his new job, which he started May 9, he is directing CMS’ Office of Clinical Standards and Quality, which coordinates development and implementation of a CMS-wide approach to promoting health quality.

“Patrick Conway’s appointment represents a major milestone for hospitalists and patients alike,” says Larry Wellikson, MD, SFHM, CEO of SHM. “As hospitalists approach the 15th anniversary of the specialty, it is fitting that one of our own takes on the considerable responsibility of caring for millions of Americans through Medicare and Medicaid. Dr. Conway and thousands of other hospitalists have been on the front lines of systematically improving patient care for more than a decade; his sound judgment and compassion as a clinician are now a major national asset.”

Dr. Conway maintains his associate professorship at the University of Cincinnati and will work some weekends seeing patients at Children’s National Medical Center in Washington, D.C. “I love patient care, so I don’t want to stop doing that. Plus, it helps me connect to the front lines of providing medical care,” he says.

“Dr. Conway’s passion for improving healthcare delivery systems, his day-to-day experience as a hospitalist physician, and his accomplishments in quality-improvement research, such as implementing evidence-based healthcare for all children, provide a strong background for his critical role at CMS as chief medical officer,” says Arnold W. Strauss, MD, chair of pediatrics at the University of Cincinnati, where many of the pediatric physicians at Children’s Hospital hold academic appointments. “Dr. Conway and our colleagues at Cincinnati Children’s have demonstrated that improving patient outcomes at lower cost—the goal of healthcare reform—is feasible.”

Dr. Conway’s role at CMS will include major components of surveys, certification, and accreditation issues for hospitals and other Medicare providers; healthcare information technology; and hospital value-based purchasing initiatives (see “Value-Based Purchasing Raises the Stakes,” The Hospitalist, May 2011, p. 1).

But his initial priorities will focus on quality-measures development, illustrated by CMS’ Hospital Compare website (www.hospitalcompare.hhs.gov), and quality improvement. Another major issue involves care transitions and readmissions, “which I try to frame positively—how can we have the most effective care transitions possible?” he says. “SHM and its publications have done a good job of stressing how hospitals and hospitalists can add value.”

Emphasizing his own experience directing an HM department for a health system that admits 7,000 pediatric patients per year, Dr. Conway says other hospitalists can take a similar lead in embracing quality measurement in their hospitals. “I may be working on quality measures for fiscal years 2013 and 2014, but you already know what will be measured in 2012. Don’t wait until September 2012 to get started,” he explains. “Hospitalists can help their institution pose the question: ‘What do we want to get better at in the next year?’ Then you test. Understand your current performance, set a goal, compare benchmarks with other hospitals, and keep working on improvement.”

Over the course of a year, he adds, quality will improve, and then your HM group will have “something to talk about with hospital administrators.”

Married with two children, says his experience at both the macro and micro levels of healthcare will benefit the overall system. “I actually think if we realign incentives, the system can perform better,” he says. “So I see it as an opportunity to perform a public service. But we also need front-line clinicians, including hospitalists, working to improve our healthcare system. … We need frontline providers that are measuring the quality of their care and improving it.” TH

Larry Beresford is a freelance writer based in California.

Dr. Conway

Patrick Conway, MD, MSc, SFHM, a pediatric hospitalist and director of hospital medicine at Cincinnati Children’s Hospital Medical Center, has been appointed chief medical officer of the Centers for Medicare & Medicaid Services (CMS). Dr. Conway’s key responsibilities will be administering federal healthcare quality initiatives and setting the government’s quality agenda in an era of massive changes resulting from the Patient Protection and Accountable Care Act of 2010 (ACA).

Dr. Conway, who previously served as CMO of the Policy Division of the Office of Secretary of Health and Human Services and was a 2007-2008 White House fellow assigned to the Agency for Healthcare Research and Quality (AHRQ), is a leader in safety, quality, and outcomes initiatives at Cincinnati Children’s, and is the immediate past chair of SHM’s Public Policy Committee. He also served on the Federal Coordinating Council for Comparative Effectiveness Research. In his new job, which he started May 9, he is directing CMS’ Office of Clinical Standards and Quality, which coordinates development and implementation of a CMS-wide approach to promoting health quality.

“Patrick Conway’s appointment represents a major milestone for hospitalists and patients alike,” says Larry Wellikson, MD, SFHM, CEO of SHM. “As hospitalists approach the 15th anniversary of the specialty, it is fitting that one of our own takes on the considerable responsibility of caring for millions of Americans through Medicare and Medicaid. Dr. Conway and thousands of other hospitalists have been on the front lines of systematically improving patient care for more than a decade; his sound judgment and compassion as a clinician are now a major national asset.”

Dr. Conway maintains his associate professorship at the University of Cincinnati and will work some weekends seeing patients at Children’s National Medical Center in Washington, D.C. “I love patient care, so I don’t want to stop doing that. Plus, it helps me connect to the front lines of providing medical care,” he says.

“Dr. Conway’s passion for improving healthcare delivery systems, his day-to-day experience as a hospitalist physician, and his accomplishments in quality-improvement research, such as implementing evidence-based healthcare for all children, provide a strong background for his critical role at CMS as chief medical officer,” says Arnold W. Strauss, MD, chair of pediatrics at the University of Cincinnati, where many of the pediatric physicians at Children’s Hospital hold academic appointments. “Dr. Conway and our colleagues at Cincinnati Children’s have demonstrated that improving patient outcomes at lower cost—the goal of healthcare reform—is feasible.”

Dr. Conway’s role at CMS will include major components of surveys, certification, and accreditation issues for hospitals and other Medicare providers; healthcare information technology; and hospital value-based purchasing initiatives (see “Value-Based Purchasing Raises the Stakes,” The Hospitalist, May 2011, p. 1).

But his initial priorities will focus on quality-measures development, illustrated by CMS’ Hospital Compare website (www.hospitalcompare.hhs.gov), and quality improvement. Another major issue involves care transitions and readmissions, “which I try to frame positively—how can we have the most effective care transitions possible?” he says. “SHM and its publications have done a good job of stressing how hospitals and hospitalists can add value.”

Emphasizing his own experience directing an HM department for a health system that admits 7,000 pediatric patients per year, Dr. Conway says other hospitalists can take a similar lead in embracing quality measurement in their hospitals. “I may be working on quality measures for fiscal years 2013 and 2014, but you already know what will be measured in 2012. Don’t wait until September 2012 to get started,” he explains. “Hospitalists can help their institution pose the question: ‘What do we want to get better at in the next year?’ Then you test. Understand your current performance, set a goal, compare benchmarks with other hospitals, and keep working on improvement.”

Over the course of a year, he adds, quality will improve, and then your HM group will have “something to talk about with hospital administrators.”

Married with two children, says his experience at both the macro and micro levels of healthcare will benefit the overall system. “I actually think if we realign incentives, the system can perform better,” he says. “So I see it as an opportunity to perform a public service. But we also need front-line clinicians, including hospitalists, working to improve our healthcare system. … We need frontline providers that are measuring the quality of their care and improving it.” TH

Larry Beresford is a freelance writer based in California.

In This Edition

Literature at a Glance

A guide to this month’s studies

1. Eplerenone and heart failure mortality
2. Fidaxomicin for C. difficile diarrhea
3. Guidelines for intensive insulin therapy
4. Benefits of hospitalist comanagement
5. Peritoneal dialysis versus hemodialysis
6. Pneumococcal urinary antigen to guide CAP treatment
7. Race and readmission rate
8. Factors associated with readmission
9. Unplanned transfers to the ICU

Eplerenone Improves Mortality in Patients with Systolic Heart Failure and Mild Symptoms

Clinical question: Does the selective mineralocorticoid antagonist eplerenone improve outcomes in patients with chronic heart failure and mild symptoms?

Background: In prior studies of miner alocorticoid antagonists in systolic heart failure, spironolactone reduced mortality in patients with moderate to severe heart failure symptoms, and eplerenone reduced mortality in patients with acute myocardial infarction complicated by left ventricular dysfunction. The use of eplerenone in patients with systolic heart failure and mild symptoms has not previously been examined.

Study design: Randomized, double-blind, multicenter, placebo-controlled trial.

Setting: Two hundred seventy-eight centers in 29 countries.

Synopsis: The study authors randomized 2,737 patients with New York Heart Association Class II heart failure and an ejection fraction of no more than 35% to either eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. Patients with baseline potassium levels >5 mmol/L or estimated GFR <30 were excluded. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.

The trial was stopped early, after a median follow-up period of 21 months, when an interim analysis showed significant benefit with eplerenone. The primary outcome occurred in 18.3% of patients in the eplerenone group and 25.9% in the placebo group (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.74; P<0.001). All-cause mortality was 12.5% in the eplerenone group and 15.5% in the placebo group (HR 0.76; 95% CI, 0.62 to 0.93; P=0.008). A serum potassium level exceeding 5.5 mmol/L occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).

Bottom line: Eplerenone reduces both the risk of death and the risk of hospitalization in patients with systolic heart failure and mild symptoms.

Citation: Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21.

Fidaxomicin Noninferior to Vancomycin for C. Difficile Treatment

Clinical question: What is the safety and efficacy of fidaxomicin compared to vancomycin in the treatment of patients with C. difficile infection?

Background: Fidaxomicin, a new macrocyclic antibiotic, has shown high efficacy in vitro against C. diff, minimal systemic absorption, and a narrow-spectrum profile. In previously published Phase 2 trials of fidaxomicin for the treatment of C. diff, it has been associated with good clinical response and low recurrence rates.

Study design: Prospective, multicenter, double-blind, randomized trial.

Setting: Fifty-two sites in the United States and 15 in Canada.

Synopsis: The study included 629 adults with acute symptoms of C. diff and a positive stool toxin test. The patients were randomly assigned to 200-mg twice-daily fidaxomicin or 125-mg four-times-daily vancomycin for a course of 10 days. The primary endpoint was rate of clinical cure (resolution of diarrhea), and secondary endpoints were recurrence of C. diff and global cure (clinical cure and lack of relapse within four weeks of cessation of therapy).

The rate of clinical cure associated with fidaxomicin was noninferior to that associated with vancomycin (88.2% vs. 85.8%, respectively). Patients receiving fidaxomicin had a lower rate of relapse than those receiving vancomycin (15.4% vs. 25.3%, respectively, P=0.005) and a higher global cure rate (74.6 vs. 61.1%, P=0.006). In subgroup analysis, the lower rate of recurrence was seen in patients with non-North American pulsed-field Type 1 strain (NAP1/BI/027 strain), while in patients with the NAP1/BI/027 strain, the recurrence rate was similar for both drugs. There was no difference in adverse event rates.

Bottom line: Clinical cure rates of C. diff with fidaxomicin are noninferior to those with vancomycin; however, fidaxomicin is associated with a significantly lower rate of recurrence among those infected with the non-NAP1/BI/027 strain.

Citation: Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.

ACP Guideline Discourages Use of Intensive Insulin Therapy in Hospitalized Patients

Clinical question: Does the use of intensive insulin therapy (IIT) to achieve tight glycemic control in hospitalized patients (whether in the SICU, MICU, or on the general medicine floor) improve important health outcomes?

Background: Hyperglycemia is a common finding in hospitalized patients and is associated with prolonged length of stay (LOS), death, and worsening health outcomes. Despite this, prospective studies have yet to provide consistent evidence that using IIT to achieve strict glycemic control (80 mg/dL-110 mg/dL) improves outcomes in hospitalized patients.

Study design: Systematic review of MEDLINE and the Cochrane Database of Systematic Reviews from 1950 to January 2010.

Setting: Trials included subjects with myocardial infarction, stroke, and brain injury, as well as those in perioperative settings and ICUs.

Synopsis: The review informing this guideline meta-analyzed 21 trials and found that IIT did not improve short-term mortality, long-term mortality, infection rates, LOS, or the need for renal replacement therapy. Furthermore, IIT was associated with a sixfold increase in risk for severe hypoglycemia in all hospital settings.

Based on these findings, the American College of Physicians (ACP) issued three recommendations:

• To not use IIT to strictly control blood glucose in non-SICU/non-MICU patients with or without diabetes (strong recommendation, moderate-quality evidence);
• To not use IIT to normalize blood glucose in SICU or MICU patients with or without diabetes (strong recommendation, high-quality evidence); and
• To consider a target blood glucose level of 140 mg to 200 mg if insulin therapy is used in SICU or MICU patients (weak recommendation, moderate-quality evidence).

Bottom line: The ACP recommends against using IIT to strictly control blood glucose (80 mg/dL-180 mg/dL) in hospitalized patients, whether in the SICU, MICU, or on the general medicine floor.

Citation: Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154(4):260-267.

Limited Benefits Seen with Hospitalist-Neurosurgeon Comanagement

Clinical question: Does hospitalist-neurosurgeon comanagement improve patient outcomes?

Background: The shared management of surgical patients between surgeons and hospitalists is increasingly common despite limited data supporting its effectiveness in reducing costs or improving patient outcomes.

Study design: Single-center, retrospective study.

Setting: Tertiary-care academic medical center.

Synopsis: Data were collected on the 7,596 patients who were admitted to the neurosurgical service of the University of California San Francisco Medical Center from June 1, 2005, to December 31, 2008. The study looked at 4,203 patients (55.3%) admitted before July 1, 2007, when hospitalist comanagement was implemented, and 3,393 patients (44.7%) after comanagement began. Of those admitted during the post-implementation period, 988 (29.1%) were comanaged.

After adjusting for patient characteristics and background trends, and accounting for clustering at the physician level, no differences were found in patient mortality rate, readmissions, or LOS after implementation of comanagement. No consistent improvements were seen in patient satisfaction.

However, physician and staff perceptions of safety and quality of care were significantly better after comanagement. There was a moderate decrease in adjusted hospital costs after implementation (adjusted cost ratio 0.94, range 0.88-1.00) equivalent to a cost savings of about $1,439 per hospitalization.

Bottom line: The implementation of a hospitalist-neurosurgery comanagement service did not improve patient outcomes or satisfaction, but it did appear to improve providers’ perception of care quality and reduce hospital costs.

Citation: Auerbach AD, Wachter RM, Cheng HQ, et al. Comanagement of surgical patients between neurosurgeons and hospitalists. Arch Intern Med. 2010;170(22):2004-2010.

Comparable Mortality Between Hemodialysis and Peritoneal Dialysis

Clinical question: What effect does the initial dialysis modality used have on mortality for patients with end-stage renal disease (ESRD)?

Background: Despite the substantially lower annual per-person costs of peritoneal dialysis (PD) as compared with hemodialysis (HD), only 7% of dialysis patients were treated with PD in 2008. It is unknown whether there are differences in mortality between those using PD and HD when examined in contemporary cohorts.

Study design: Retrospective cohort study.

Setting: National cohort.

Synopsis: Data for patients with incident ESRD over a nine-year period were obtained from the U.S. Renal Data Systems (USRDS), a national registry of all patients with ESRD. Initial dialysis modality was defined as the dialysis modality used 90 days after initiation of dialysis. Patients were divided into three three-year cohorts (1996-1998, 1999-2001, and 2002-2004) based on the date dialysis was initiated and followed for up to five years.

A substantial and consistent reduction in mortality was seen for PD patients across the three time periods. No such improvements were observed across the time periods for the HD patients. PD patients were, on average, younger, healthier, and more likely to be white. In an analysis of the most recent cohort adjusting for these factors, there was no significant difference in the risk of death between HD and PD patients. The median life expectancy of HD and PD patients was 38.4 and 36.6 months, respectively.

Limitations of the study include a lack of randomization and failure to consider switches from one dialysis modality to the other.

Bottom line: Patients beginning their renal replacement therapy with PD had similar mortality after five years compared to patients using in-center HD.

Citation: Mehrotra R, Chiu YW, Kalantar-Zadeh K, Bargman J, Vonesh E. Similar outcomes with hemodialysis and peritoneal dialysis in patients with end-stage renal disease. Arch Intern Med. 2011;171(2):110-118.

Pneumococcal Urinary Antigen Test Might Guide Community-Acquired Pneumonia Treatment

Clinical question: What is the diagnostic accuracy and clinical utility of pneumococcal urinary antigen testing in adult patients hospitalized with community-acquired pneumonia (CAP)?

Background: Although CAP is common, our ability to determine its etiology is limited, and empirical broad-spectrum antibiotic therapy is the norm. Pneumococcal urinary antigen testing could allow for the more frequent use of narrow-spectrum pathogen-focused antibiotic therapy.

Study design: Prospective cohort study.

Setting: University-affiliated hospital in Spain.

Synopsis: This study included consecutive adult patients hospitalized with CAP from February 2007 though January 2008. A total of 464 patients with 474 episodes of CAP were included. Pneumococcal urinary antigen testing was performed in 383 (80.8%) episodes of CAP. Streptococcus pneumoniae was felt to be the causative pathogen in 171 cases (36.1%). It was detected exclusively by urinary antigen test in 75 of those cases (43.8%).

For the urine antigen test, specificity was 96% (95% CI, 86.5 to 99.5), and the positive predictive value was 96.5% (95% CI, 87.9 to 99.5). The results of the test led clinicians to reduce the spectrum of antibiotics in 41 patients, and pneumonia was cured in all 41 of these patients. Treatment was not modified despite positive antigen test results in 89 patients.

Limitations of this study include a lack of complete microbiological data for all patients. The study also highlighted the difficulty in changing clinicians’ prescribing patterns, even when test results indicate the need for treatment modification.

Bottom line: A positive pneumococcal urinary antigen test result in adult patients hospitalized with CAP can help clinicians narrow antimicrobial therapy with good clinical outcomes.

Citation: Sordé R, Falcó V, Lowak M, et al. Current and potential usefulness of pneumococcal urinary antigen detection in hospitalized patients with community-acquired pneumonia to guide antimicrobial therapy. Arch Intern Med. 2011;171(2):166-172.

Racial Disparities Detected in Hospital Readmission Rates

Clinical question: Do black patients have higher odds of readmission than white patients, and, if so, are these disparities related to where black patients receive care?

Background: Racial disparities in healthcare are well documented. Understanding and eliminating those disparities remains a national priority. Reducing hospital readmissions also is a policy focus, as it represents an opportunity to improve quality while reducing costs. Whether there are racial disparities in hospital readmissions at the national level is unknown.

Study design: Retrospective cohort study.

Setting: Medicare fee-for-service beneficiaries from 2006 to 2008.

Synopsis: Medicare discharge data for more than 3 million Medicare fee-for-service beneficiaries aged 65 years or older discharged from January 1, 2006, to November 30, 2008, with the primary discharge diagnosis of acute myocardial infarction (MI), congestive heart failure, or pneumonia were used to calculate risk-adjusted odds of readmission within 30 days of discharge. Hospitals in the highest decile of proportion of black patients were categorized as minority-serving.

Overall, black patients had 13% higher odds of all-cause 30-day readmission than white patients (24.8% vs. 22.6%, OR 1.13, 95% CI, 1.11-1.14), and patients discharged from minority-serving hospitals had 23% higher odds of readmission than patients from non-minority-serving hospitals (25.5% vs. 22.0%, OR 1.23, 95% CI, 1.20-1.27). Among those with acute MI, black patients had 13% higher odds of readmission (OR 1.13, 95% CI, 1.10-1.16), irrespective of the site of care, while patients from minority-serving hospitals had 22% higher odds of readmissions (OR 1.22, 95% CI, 1.17-1.27), even after adjusting for patient race. Similar disparities were seen for CHF and pneumonia. Results were unchanged after adjusting for hospital characteristics, including markers of caring for poor patients.

Bottom line: Compared with white patients, elderly black Medicare patients have a higher 30-day hospital readmission rate for MI, CHF, and pneumonia that is not fully explained by the higher readmission rates seen among hospitals that disproportionately care for black patients.

Citation: Joynt KE, Orav EJ, Jha AK. Thirty-day readmission rates for Medicare beneficiaries by race and site of care. JAMA. 2011;305(7):675-681.

Easily Identifiable Clinical and Demographic Factors Associated with Hospital Readmission

Clinical question: Which clinical, operational, or demographic factors are associated with 30-day readmission for general medicine patients?

Background: While a few clinical risk factors for hospital readmission have been well defined in subgroups of inpatients, there are still limited data regarding readmission risk that might be associated with a broad range of operational, demographic, and clinical factors in a heterogeneous population of general medicine patients.

Study design: Retrospective observational study.

Setting: Single academic medical center.

Synopsis: The study examined more than 10,300 consecutive admissions (6,805 patients) discharged over a two-year period from 2006 to 2008 from the general medicine service of an urban academic medical center. The 30-day readmission rate was 17.0%.

In multivariate analysis, factors associated with readmission included black race (OR 1.43, 95% CI, 1.24-1.65), inpatient use of narcotics (OR 1.33, 95% CI, 1.16-1.53) and corticosteroids (OR 1.24, 95% CI, 1.09-1.42), and the disease states of cancer (with metastasis 1.61, 95% CI, 1.33-1.95; without metastasis 1.95, 95% CI 1.54-2.47), renal failure (OR 1.19, 95% CI 1.05-1.36), congestive heart failure (OR 1.30, 95% CI, 1.09-1.56), and weight loss (OR 1.26, 95% CI, 1.09-1.47). Medicaid payor status (OR 1.15, 95% CI, 0.97-1.36) had a trend toward readmission. None of the operational factors were significantly associated with readmission, including discharge to skilled nursing facility or weekend discharge.

A major limitation of the study was its inability to capture readmissions to hospitals other than the study hospital, which, based on prior studies, could have accounted for nearly a quarter of readmissions.

Bottom line: Readmission of general medicine patients within 30 days is common and associated with several easily identifiable clinical and nonclinical factors.

Citation: Allaudeen N, Vidyarthi A, Maselli J, Auerbach A. Redefining readmission risk factors for general medicine patients. J Hosp Med. 2011;6(2):54-60.

Unplanned Medical ICU Transfers Tied to Preventable Errors

Clinical question: What fraction of unplanned medical ICU (MICU) transfers result from errors in care and why do they occur?

Background: Prior studies have suggested that 14% to 28% of patients admitted to the MICU are unplanned transfers. It is not known what fraction of these transfers result from errors in care, and whether these transfers could be prevented.

Study design: Retrospective cohort study.

Setting: University-affiliated academic medical center.

Synopsis: All unplanned transfers to the MICU from June 1, 2005, to May 30, 2006, were included in the study. Three independent observers, all hospitalists for more than three years, reviewed patient records to determine the cause of unplanned transfers according to a taxonomy the researchers developed for classifying the transfers. They also determined whether the transfer could have been prevented.

Of the 4,468 general medicine admissions during the study period, 152 met inclusion criteria for an unplanned MICU transfer. Errors in care were judged to account for 19% (n=29) of unplanned transfers, 15 of which were due to incorrect triage at admission and 14 to iatrogenic errors, such as opiate overdose during pain treatment or delayed treatment. All 15 triage errors were considered preventable. Of the iatrogenic errors, eight were considered preventable through an earlier intervention. Overall, 23 errors (15%) were thought to be preventable. Observer agreement was moderate to almost perfect (κ0.55-0.90).

Bottom line: Nearly 1 in 7 unplanned transfers to the medical ICU are associated with preventable errors in care, with the most common error being inappropriate admission triage.

Citation: Bapoje SR, Gaudiani JL, Narayanan V, Albert RK. Unplanned transfers to a medical intensive care unit: causes and relationship to preventable errors in care. J Hosp Med. 2011;6(2):68-72. TH

Pediatric HM Literature

Well Visits Prevent Ambulatory-Care-Sensitive Hospitalizations

Reviewed by Pediatric Editor Mark Shen, MD, FHM, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Clinical question: Is routine well-child care visit adherence associated with a decreased risk of ambulatory-care-sensitive hospitalizations?

Background: Ambulatory-care-sensitive hospitalizations (ACSHs) represent admissions that might have been prevented by quality outpatient care. They are an improvement opportunity for healthcare systems; thus, it is important to characterize factors associated with increased ACSH. Although continuity of care (COC) with the same provider has been associated with reduced hospitalizations, the relationship between regularly scheduled well-child care (WCC) and ACSH is less clear.

Study design: Population-based, retrospective cohort study.

Setting: Hawaii’s largest health insurer.

Synopsis: Young children with the highest likelihood of ACSH (two months to 3.5 years old) who were continuously enrolled in coverage by Hawaii’s largest health insurer (representing 70% of the civilian population) were included. Ultimately, administrative data on 36,944 children were analyzed for WCC adherence rate and a nonlinear COC index, both of which were modeled as time-varying categorical variables.

ACSH were defined by conditions, and notably included acute respiratory-tract infections. Both high WCC visit adherence and COC index were independently associated with decreased risk of ACSH and were modified significantly by chronic-disease status.

This study examines a somewhat unique population: insured children in Hawaii with a relatively high degree of consistency in care. Thus, it is not applicable to the most vulnerable Medicaid and uninsured groups of children. In addition, the relationship between WCC visit adherence and ACSH seemed to disappear in healthy children, further limiting generalizability. Nevertheless, it appears that WCC visits without provider continuity might still be protective for ACSH. It will be important to replicate these findings in a population served by safety-net clinics: children who most often have WCC without continuity.

Bottom line: WCC visit adherence in insured patients with chronic disease reduces the risk of ACSH.

Citation: Tom JO, Tseng CW, Davis J, Solomon C, Zhou C, Mangione-Smith R. Missed well-child care visits, low continuity of care, and risk of ambulatory care-sensitive hospitalizations in young children. Arch Pediatr Adolesc Med. 2010;164(11):1052-1058.

In This Edition

Literature at a Glance

A guide to this month’s studies

1. Eplerenone and heart failure mortality
2. Fidaxomicin for C. difficile diarrhea
3. Guidelines for intensive insulin therapy
4. Benefits of hospitalist comanagement
5. Peritoneal dialysis versus hemodialysis
6. Pneumococcal urinary antigen to guide CAP treatment
7. Race and readmission rate
8. Factors associated with readmission
9. Unplanned transfers to the ICU

Eplerenone Improves Mortality in Patients with Systolic Heart Failure and Mild Symptoms

Clinical question: Does the selective mineralocorticoid antagonist eplerenone improve outcomes in patients with chronic heart failure and mild symptoms?

Background: In prior studies of miner alocorticoid antagonists in systolic heart failure, spironolactone reduced mortality in patients with moderate to severe heart failure symptoms, and eplerenone reduced mortality in patients with acute myocardial infarction complicated by left ventricular dysfunction. The use of eplerenone in patients with systolic heart failure and mild symptoms has not previously been examined.

Study design: Randomized, double-blind, multicenter, placebo-controlled trial.

Setting: Two hundred seventy-eight centers in 29 countries.

Synopsis: The study authors randomized 2,737 patients with New York Heart Association Class II heart failure and an ejection fraction of no more than 35% to either eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. Patients with baseline potassium levels >5 mmol/L or estimated GFR <30 were excluded. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.

The trial was stopped early, after a median follow-up period of 21 months, when an interim analysis showed significant benefit with eplerenone. The primary outcome occurred in 18.3% of patients in the eplerenone group and 25.9% in the placebo group (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.74; P<0.001). All-cause mortality was 12.5% in the eplerenone group and 15.5% in the placebo group (HR 0.76; 95% CI, 0.62 to 0.93; P=0.008). A serum potassium level exceeding 5.5 mmol/L occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).

Bottom line: Eplerenone reduces both the risk of death and the risk of hospitalization in patients with systolic heart failure and mild symptoms.

Citation: Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21.

Fidaxomicin Noninferior to Vancomycin for C. Difficile Treatment

Clinical question: What is the safety and efficacy of fidaxomicin compared to vancomycin in the treatment of patients with C. difficile infection?

Background: Fidaxomicin, a new macrocyclic antibiotic, has shown high efficacy in vitro against C. diff, minimal systemic absorption, and a narrow-spectrum profile. In previously published Phase 2 trials of fidaxomicin for the treatment of C. diff, it has been associated with good clinical response and low recurrence rates.

Study design: Prospective, multicenter, double-blind, randomized trial.

Setting: Fifty-two sites in the United States and 15 in Canada.

Synopsis: The study included 629 adults with acute symptoms of C. diff and a positive stool toxin test. The patients were randomly assigned to 200-mg twice-daily fidaxomicin or 125-mg four-times-daily vancomycin for a course of 10 days. The primary endpoint was rate of clinical cure (resolution of diarrhea), and secondary endpoints were recurrence of C. diff and global cure (clinical cure and lack of relapse within four weeks of cessation of therapy).

The rate of clinical cure associated with fidaxomicin was noninferior to that associated with vancomycin (88.2% vs. 85.8%, respectively). Patients receiving fidaxomicin had a lower rate of relapse than those receiving vancomycin (15.4% vs. 25.3%, respectively, P=0.005) and a higher global cure rate (74.6 vs. 61.1%, P=0.006). In subgroup analysis, the lower rate of recurrence was seen in patients with non-North American pulsed-field Type 1 strain (NAP1/BI/027 strain), while in patients with the NAP1/BI/027 strain, the recurrence rate was similar for both drugs. There was no difference in adverse event rates.

Bottom line: Clinical cure rates of C. diff with fidaxomicin are noninferior to those with vancomycin; however, fidaxomicin is associated with a significantly lower rate of recurrence among those infected with the non-NAP1/BI/027 strain.

Citation: Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.

ACP Guideline Discourages Use of Intensive Insulin Therapy in Hospitalized Patients

Clinical question: Does the use of intensive insulin therapy (IIT) to achieve tight glycemic control in hospitalized patients (whether in the SICU, MICU, or on the general medicine floor) improve important health outcomes?

Background: Hyperglycemia is a common finding in hospitalized patients and is associated with prolonged length of stay (LOS), death, and worsening health outcomes. Despite this, prospective studies have yet to provide consistent evidence that using IIT to achieve strict glycemic control (80 mg/dL-110 mg/dL) improves outcomes in hospitalized patients.

Study design: Systematic review of MEDLINE and the Cochrane Database of Systematic Reviews from 1950 to January 2010.

Setting: Trials included subjects with myocardial infarction, stroke, and brain injury, as well as those in perioperative settings and ICUs.

Synopsis: The review informing this guideline meta-analyzed 21 trials and found that IIT did not improve short-term mortality, long-term mortality, infection rates, LOS, or the need for renal replacement therapy. Furthermore, IIT was associated with a sixfold increase in risk for severe hypoglycemia in all hospital settings.

Based on these findings, the American College of Physicians (ACP) issued three recommendations:

• To not use IIT to strictly control blood glucose in non-SICU/non-MICU patients with or without diabetes (strong recommendation, moderate-quality evidence);
• To not use IIT to normalize blood glucose in SICU or MICU patients with or without diabetes (strong recommendation, high-quality evidence); and
• To consider a target blood glucose level of 140 mg to 200 mg if insulin therapy is used in SICU or MICU patients (weak recommendation, moderate-quality evidence).

Bottom line: The ACP recommends against using IIT to strictly control blood glucose (80 mg/dL-180 mg/dL) in hospitalized patients, whether in the SICU, MICU, or on the general medicine floor.

Citation: Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154(4):260-267.

Limited Benefits Seen with Hospitalist-Neurosurgeon Comanagement

Clinical question: Does hospitalist-neurosurgeon comanagement improve patient outcomes?

Background: The shared management of surgical patients between surgeons and hospitalists is increasingly common despite limited data supporting its effectiveness in reducing costs or improving patient outcomes.

Study design: Single-center, retrospective study.

Setting: Tertiary-care academic medical center.

Synopsis: Data were collected on the 7,596 patients who were admitted to the neurosurgical service of the University of California San Francisco Medical Center from June 1, 2005, to December 31, 2008. The study looked at 4,203 patients (55.3%) admitted before July 1, 2007, when hospitalist comanagement was implemented, and 3,393 patients (44.7%) after comanagement began. Of those admitted during the post-implementation period, 988 (29.1%) were comanaged.

After adjusting for patient characteristics and background trends, and accounting for clustering at the physician level, no differences were found in patient mortality rate, readmissions, or LOS after implementation of comanagement. No consistent improvements were seen in patient satisfaction.

However, physician and staff perceptions of safety and quality of care were significantly better after comanagement. There was a moderate decrease in adjusted hospital costs after implementation (adjusted cost ratio 0.94, range 0.88-1.00) equivalent to a cost savings of about $1,439 per hospitalization.

Bottom line: The implementation of a hospitalist-neurosurgery comanagement service did not improve patient outcomes or satisfaction, but it did appear to improve providers’ perception of care quality and reduce hospital costs.

Citation: Auerbach AD, Wachter RM, Cheng HQ, et al. Comanagement of surgical patients between neurosurgeons and hospitalists. Arch Intern Med. 2010;170(22):2004-2010.

Comparable Mortality Between Hemodialysis and Peritoneal Dialysis

Clinical question: What effect does the initial dialysis modality used have on mortality for patients with end-stage renal disease (ESRD)?

Background: Despite the substantially lower annual per-person costs of peritoneal dialysis (PD) as compared with hemodialysis (HD), only 7% of dialysis patients were treated with PD in 2008. It is unknown whether there are differences in mortality between those using PD and HD when examined in contemporary cohorts.

Study design: Retrospective cohort study.

Setting: National cohort.

Synopsis: Data for patients with incident ESRD over a nine-year period were obtained from the U.S. Renal Data Systems (USRDS), a national registry of all patients with ESRD. Initial dialysis modality was defined as the dialysis modality used 90 days after initiation of dialysis. Patients were divided into three three-year cohorts (1996-1998, 1999-2001, and 2002-2004) based on the date dialysis was initiated and followed for up to five years.

A substantial and consistent reduction in mortality was seen for PD patients across the three time periods. No such improvements were observed across the time periods for the HD patients. PD patients were, on average, younger, healthier, and more likely to be white. In an analysis of the most recent cohort adjusting for these factors, there was no significant difference in the risk of death between HD and PD patients. The median life expectancy of HD and PD patients was 38.4 and 36.6 months, respectively.

Limitations of the study include a lack of randomization and failure to consider switches from one dialysis modality to the other.

Bottom line: Patients beginning their renal replacement therapy with PD had similar mortality after five years compared to patients using in-center HD.

Citation: Mehrotra R, Chiu YW, Kalantar-Zadeh K, Bargman J, Vonesh E. Similar outcomes with hemodialysis and peritoneal dialysis in patients with end-stage renal disease. Arch Intern Med. 2011;171(2):110-118.

Pneumococcal Urinary Antigen Test Might Guide Community-Acquired Pneumonia Treatment

Clinical question: What is the diagnostic accuracy and clinical utility of pneumococcal urinary antigen testing in adult patients hospitalized with community-acquired pneumonia (CAP)?

Background: Although CAP is common, our ability to determine its etiology is limited, and empirical broad-spectrum antibiotic therapy is the norm. Pneumococcal urinary antigen testing could allow for the more frequent use of narrow-spectrum pathogen-focused antibiotic therapy.

Study design: Prospective cohort study.

Setting: University-affiliated hospital in Spain.

Synopsis: This study included consecutive adult patients hospitalized with CAP from February 2007 though January 2008. A total of 464 patients with 474 episodes of CAP were included. Pneumococcal urinary antigen testing was performed in 383 (80.8%) episodes of CAP. Streptococcus pneumoniae was felt to be the causative pathogen in 171 cases (36.1%). It was detected exclusively by urinary antigen test in 75 of those cases (43.8%).

For the urine antigen test, specificity was 96% (95% CI, 86.5 to 99.5), and the positive predictive value was 96.5% (95% CI, 87.9 to 99.5). The results of the test led clinicians to reduce the spectrum of antibiotics in 41 patients, and pneumonia was cured in all 41 of these patients. Treatment was not modified despite positive antigen test results in 89 patients.

Limitations of this study include a lack of complete microbiological data for all patients. The study also highlighted the difficulty in changing clinicians’ prescribing patterns, even when test results indicate the need for treatment modification.

Bottom line: A positive pneumococcal urinary antigen test result in adult patients hospitalized with CAP can help clinicians narrow antimicrobial therapy with good clinical outcomes.

Citation: Sordé R, Falcó V, Lowak M, et al. Current and potential usefulness of pneumococcal urinary antigen detection in hospitalized patients with community-acquired pneumonia to guide antimicrobial therapy. Arch Intern Med. 2011;171(2):166-172.

Racial Disparities Detected in Hospital Readmission Rates

Clinical question: Do black patients have higher odds of readmission than white patients, and, if so, are these disparities related to where black patients receive care?

Background: Racial disparities in healthcare are well documented. Understanding and eliminating those disparities remains a national priority. Reducing hospital readmissions also is a policy focus, as it represents an opportunity to improve quality while reducing costs. Whether there are racial disparities in hospital readmissions at the national level is unknown.

Study design: Retrospective cohort study.

Setting: Medicare fee-for-service beneficiaries from 2006 to 2008.

Synopsis: Medicare discharge data for more than 3 million Medicare fee-for-service beneficiaries aged 65 years or older discharged from January 1, 2006, to November 30, 2008, with the primary discharge diagnosis of acute myocardial infarction (MI), congestive heart failure, or pneumonia were used to calculate risk-adjusted odds of readmission within 30 days of discharge. Hospitals in the highest decile of proportion of black patients were categorized as minority-serving.

Overall, black patients had 13% higher odds of all-cause 30-day readmission than white patients (24.8% vs. 22.6%, OR 1.13, 95% CI, 1.11-1.14), and patients discharged from minority-serving hospitals had 23% higher odds of readmission than patients from non-minority-serving hospitals (25.5% vs. 22.0%, OR 1.23, 95% CI, 1.20-1.27). Among those with acute MI, black patients had 13% higher odds of readmission (OR 1.13, 95% CI, 1.10-1.16), irrespective of the site of care, while patients from minority-serving hospitals had 22% higher odds of readmissions (OR 1.22, 95% CI, 1.17-1.27), even after adjusting for patient race. Similar disparities were seen for CHF and pneumonia. Results were unchanged after adjusting for hospital characteristics, including markers of caring for poor patients.

Bottom line: Compared with white patients, elderly black Medicare patients have a higher 30-day hospital readmission rate for MI, CHF, and pneumonia that is not fully explained by the higher readmission rates seen among hospitals that disproportionately care for black patients.

Citation: Joynt KE, Orav EJ, Jha AK. Thirty-day readmission rates for Medicare beneficiaries by race and site of care. JAMA. 2011;305(7):675-681.

Easily Identifiable Clinical and Demographic Factors Associated with Hospital Readmission

Clinical question: Which clinical, operational, or demographic factors are associated with 30-day readmission for general medicine patients?

Background: While a few clinical risk factors for hospital readmission have been well defined in subgroups of inpatients, there are still limited data regarding readmission risk that might be associated with a broad range of operational, demographic, and clinical factors in a heterogeneous population of general medicine patients.

Study design: Retrospective observational study.

Setting: Single academic medical center.

Synopsis: The study examined more than 10,300 consecutive admissions (6,805 patients) discharged over a two-year period from 2006 to 2008 from the general medicine service of an urban academic medical center. The 30-day readmission rate was 17.0%.

In multivariate analysis, factors associated with readmission included black race (OR 1.43, 95% CI, 1.24-1.65), inpatient use of narcotics (OR 1.33, 95% CI, 1.16-1.53) and corticosteroids (OR 1.24, 95% CI, 1.09-1.42), and the disease states of cancer (with metastasis 1.61, 95% CI, 1.33-1.95; without metastasis 1.95, 95% CI 1.54-2.47), renal failure (OR 1.19, 95% CI 1.05-1.36), congestive heart failure (OR 1.30, 95% CI, 1.09-1.56), and weight loss (OR 1.26, 95% CI, 1.09-1.47). Medicaid payor status (OR 1.15, 95% CI, 0.97-1.36) had a trend toward readmission. None of the operational factors were significantly associated with readmission, including discharge to skilled nursing facility or weekend discharge.

A major limitation of the study was its inability to capture readmissions to hospitals other than the study hospital, which, based on prior studies, could have accounted for nearly a quarter of readmissions.

Bottom line: Readmission of general medicine patients within 30 days is common and associated with several easily identifiable clinical and nonclinical factors.

Citation: Allaudeen N, Vidyarthi A, Maselli J, Auerbach A. Redefining readmission risk factors for general medicine patients. J Hosp Med. 2011;6(2):54-60.

Unplanned Medical ICU Transfers Tied to Preventable Errors

Clinical question: What fraction of unplanned medical ICU (MICU) transfers result from errors in care and why do they occur?

Background: Prior studies have suggested that 14% to 28% of patients admitted to the MICU are unplanned transfers. It is not known what fraction of these transfers result from errors in care, and whether these transfers could be prevented.

Study design: Retrospective cohort study.

Setting: University-affiliated academic medical center.

Synopsis: All unplanned transfers to the MICU from June 1, 2005, to May 30, 2006, were included in the study. Three independent observers, all hospitalists for more than three years, reviewed patient records to determine the cause of unplanned transfers according to a taxonomy the researchers developed for classifying the transfers. They also determined whether the transfer could have been prevented.

Of the 4,468 general medicine admissions during the study period, 152 met inclusion criteria for an unplanned MICU transfer. Errors in care were judged to account for 19% (n=29) of unplanned transfers, 15 of which were due to incorrect triage at admission and 14 to iatrogenic errors, such as opiate overdose during pain treatment or delayed treatment. All 15 triage errors were considered preventable. Of the iatrogenic errors, eight were considered preventable through an earlier intervention. Overall, 23 errors (15%) were thought to be preventable. Observer agreement was moderate to almost perfect (κ0.55-0.90).

Bottom line: Nearly 1 in 7 unplanned transfers to the medical ICU are associated with preventable errors in care, with the most common error being inappropriate admission triage.

Citation: Bapoje SR, Gaudiani JL, Narayanan V, Albert RK. Unplanned transfers to a medical intensive care unit: causes and relationship to preventable errors in care. J Hosp Med. 2011;6(2):68-72. TH

Pediatric HM Literature

Well Visits Prevent Ambulatory-Care-Sensitive Hospitalizations

Reviewed by Pediatric Editor Mark Shen, MD, FHM, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Clinical question: Is routine well-child care visit adherence associated with a decreased risk of ambulatory-care-sensitive hospitalizations?

Background: Ambulatory-care-sensitive hospitalizations (ACSHs) represent admissions that might have been prevented by quality outpatient care. They are an improvement opportunity for healthcare systems; thus, it is important to characterize factors associated with increased ACSH. Although continuity of care (COC) with the same provider has been associated with reduced hospitalizations, the relationship between regularly scheduled well-child care (WCC) and ACSH is less clear.

Study design: Population-based, retrospective cohort study.

Setting: Hawaii’s largest health insurer.

Synopsis: Young children with the highest likelihood of ACSH (two months to 3.5 years old) who were continuously enrolled in coverage by Hawaii’s largest health insurer (representing 70% of the civilian population) were included. Ultimately, administrative data on 36,944 children were analyzed for WCC adherence rate and a nonlinear COC index, both of which were modeled as time-varying categorical variables.

ACSH were defined by conditions, and notably included acute respiratory-tract infections. Both high WCC visit adherence and COC index were independently associated with decreased risk of ACSH and were modified significantly by chronic-disease status.

This study examines a somewhat unique population: insured children in Hawaii with a relatively high degree of consistency in care. Thus, it is not applicable to the most vulnerable Medicaid and uninsured groups of children. In addition, the relationship between WCC visit adherence and ACSH seemed to disappear in healthy children, further limiting generalizability. Nevertheless, it appears that WCC visits without provider continuity might still be protective for ACSH. It will be important to replicate these findings in a population served by safety-net clinics: children who most often have WCC without continuity.

Bottom line: WCC visit adherence in insured patients with chronic disease reduces the risk of ACSH.

Citation: Tom JO, Tseng CW, Davis J, Solomon C, Zhou C, Mangione-Smith R. Missed well-child care visits, low continuity of care, and risk of ambulatory care-sensitive hospitalizations in young children. Arch Pediatr Adolesc Med. 2010;164(11):1052-1058.

In This Edition

Literature at a Glance

A guide to this month’s studies

1. Eplerenone and heart failure mortality
2. Fidaxomicin for C. difficile diarrhea
3. Guidelines for intensive insulin therapy
4. Benefits of hospitalist comanagement
5. Peritoneal dialysis versus hemodialysis
6. Pneumococcal urinary antigen to guide CAP treatment
7. Race and readmission rate
8. Factors associated with readmission
9. Unplanned transfers to the ICU

Eplerenone Improves Mortality in Patients with Systolic Heart Failure and Mild Symptoms

Clinical question: Does the selective mineralocorticoid antagonist eplerenone improve outcomes in patients with chronic heart failure and mild symptoms?

Background: In prior studies of miner alocorticoid antagonists in systolic heart failure, spironolactone reduced mortality in patients with moderate to severe heart failure symptoms, and eplerenone reduced mortality in patients with acute myocardial infarction complicated by left ventricular dysfunction. The use of eplerenone in patients with systolic heart failure and mild symptoms has not previously been examined.

Study design: Randomized, double-blind, multicenter, placebo-controlled trial.

Setting: Two hundred seventy-eight centers in 29 countries.

Synopsis: The study authors randomized 2,737 patients with New York Heart Association Class II heart failure and an ejection fraction of no more than 35% to either eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. Patients with baseline potassium levels >5 mmol/L or estimated GFR <30 were excluded. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.

The trial was stopped early, after a median follow-up period of 21 months, when an interim analysis showed significant benefit with eplerenone. The primary outcome occurred in 18.3% of patients in the eplerenone group and 25.9% in the placebo group (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.74; P<0.001). All-cause mortality was 12.5% in the eplerenone group and 15.5% in the placebo group (HR 0.76; 95% CI, 0.62 to 0.93; P=0.008). A serum potassium level exceeding 5.5 mmol/L occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).

Bottom line: Eplerenone reduces both the risk of death and the risk of hospitalization in patients with systolic heart failure and mild symptoms.

Citation: Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21.

Fidaxomicin Noninferior to Vancomycin for C. Difficile Treatment

Clinical question: What is the safety and efficacy of fidaxomicin compared to vancomycin in the treatment of patients with C. difficile infection?

Background: Fidaxomicin, a new macrocyclic antibiotic, has shown high efficacy in vitro against C. diff, minimal systemic absorption, and a narrow-spectrum profile. In previously published Phase 2 trials of fidaxomicin for the treatment of C. diff, it has been associated with good clinical response and low recurrence rates.

Study design: Prospective, multicenter, double-blind, randomized trial.

Setting: Fifty-two sites in the United States and 15 in Canada.

Synopsis: The study included 629 adults with acute symptoms of C. diff and a positive stool toxin test. The patients were randomly assigned to 200-mg twice-daily fidaxomicin or 125-mg four-times-daily vancomycin for a course of 10 days. The primary endpoint was rate of clinical cure (resolution of diarrhea), and secondary endpoints were recurrence of C. diff and global cure (clinical cure and lack of relapse within four weeks of cessation of therapy).

The rate of clinical cure associated with fidaxomicin was noninferior to that associated with vancomycin (88.2% vs. 85.8%, respectively). Patients receiving fidaxomicin had a lower rate of relapse than those receiving vancomycin (15.4% vs. 25.3%, respectively, P=0.005) and a higher global cure rate (74.6 vs. 61.1%, P=0.006). In subgroup analysis, the lower rate of recurrence was seen in patients with non-North American pulsed-field Type 1 strain (NAP1/BI/027 strain), while in patients with the NAP1/BI/027 strain, the recurrence rate was similar for both drugs. There was no difference in adverse event rates.

Bottom line: Clinical cure rates of C. diff with fidaxomicin are noninferior to those with vancomycin; however, fidaxomicin is associated with a significantly lower rate of recurrence among those infected with the non-NAP1/BI/027 strain.

Citation: Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.

ACP Guideline Discourages Use of Intensive Insulin Therapy in Hospitalized Patients

Clinical question: Does the use of intensive insulin therapy (IIT) to achieve tight glycemic control in hospitalized patients (whether in the SICU, MICU, or on the general medicine floor) improve important health outcomes?

Background: Hyperglycemia is a common finding in hospitalized patients and is associated with prolonged length of stay (LOS), death, and worsening health outcomes. Despite this, prospective studies have yet to provide consistent evidence that using IIT to achieve strict glycemic control (80 mg/dL-110 mg/dL) improves outcomes in hospitalized patients.

Study design: Systematic review of MEDLINE and the Cochrane Database of Systematic Reviews from 1950 to January 2010.

Setting: Trials included subjects with myocardial infarction, stroke, and brain injury, as well as those in perioperative settings and ICUs.

Synopsis: The review informing this guideline meta-analyzed 21 trials and found that IIT did not improve short-term mortality, long-term mortality, infection rates, LOS, or the need for renal replacement therapy. Furthermore, IIT was associated with a sixfold increase in risk for severe hypoglycemia in all hospital settings.

Based on these findings, the American College of Physicians (ACP) issued three recommendations:

• To not use IIT to strictly control blood glucose in non-SICU/non-MICU patients with or without diabetes (strong recommendation, moderate-quality evidence);
• To not use IIT to normalize blood glucose in SICU or MICU patients with or without diabetes (strong recommendation, high-quality evidence); and
• To consider a target blood glucose level of 140 mg to 200 mg if insulin therapy is used in SICU or MICU patients (weak recommendation, moderate-quality evidence).

Bottom line: The ACP recommends against using IIT to strictly control blood glucose (80 mg/dL-180 mg/dL) in hospitalized patients, whether in the SICU, MICU, or on the general medicine floor.

Citation: Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154(4):260-267.

Limited Benefits Seen with Hospitalist-Neurosurgeon Comanagement

Clinical question: Does hospitalist-neurosurgeon comanagement improve patient outcomes?

Background: The shared management of surgical patients between surgeons and hospitalists is increasingly common despite limited data supporting its effectiveness in reducing costs or improving patient outcomes.

Study design: Single-center, retrospective study.

Setting: Tertiary-care academic medical center.

Synopsis: Data were collected on the 7,596 patients who were admitted to the neurosurgical service of the University of California San Francisco Medical Center from June 1, 2005, to December 31, 2008. The study looked at 4,203 patients (55.3%) admitted before July 1, 2007, when hospitalist comanagement was implemented, and 3,393 patients (44.7%) after comanagement began. Of those admitted during the post-implementation period, 988 (29.1%) were comanaged.

After adjusting for patient characteristics and background trends, and accounting for clustering at the physician level, no differences were found in patient mortality rate, readmissions, or LOS after implementation of comanagement. No consistent improvements were seen in patient satisfaction.

However, physician and staff perceptions of safety and quality of care were significantly better after comanagement. There was a moderate decrease in adjusted hospital costs after implementation (adjusted cost ratio 0.94, range 0.88-1.00) equivalent to a cost savings of about $1,439 per hospitalization.

Bottom line: The implementation of a hospitalist-neurosurgery comanagement service did not improve patient outcomes or satisfaction, but it did appear to improve providers’ perception of care quality and reduce hospital costs.

Citation: Auerbach AD, Wachter RM, Cheng HQ, et al. Comanagement of surgical patients between neurosurgeons and hospitalists. Arch Intern Med. 2010;170(22):2004-2010.

Comparable Mortality Between Hemodialysis and Peritoneal Dialysis

Clinical question: What effect does the initial dialysis modality used have on mortality for patients with end-stage renal disease (ESRD)?

Background: Despite the substantially lower annual per-person costs of peritoneal dialysis (PD) as compared with hemodialysis (HD), only 7% of dialysis patients were treated with PD in 2008. It is unknown whether there are differences in mortality between those using PD and HD when examined in contemporary cohorts.

Study design: Retrospective cohort study.

Setting: National cohort.

Synopsis: Data for patients with incident ESRD over a nine-year period were obtained from the U.S. Renal Data Systems (USRDS), a national registry of all patients with ESRD. Initial dialysis modality was defined as the dialysis modality used 90 days after initiation of dialysis. Patients were divided into three three-year cohorts (1996-1998, 1999-2001, and 2002-2004) based on the date dialysis was initiated and followed for up to five years.

A substantial and consistent reduction in mortality was seen for PD patients across the three time periods. No such improvements were observed across the time periods for the HD patients. PD patients were, on average, younger, healthier, and more likely to be white. In an analysis of the most recent cohort adjusting for these factors, there was no significant difference in the risk of death between HD and PD patients. The median life expectancy of HD and PD patients was 38.4 and 36.6 months, respectively.

Limitations of the study include a lack of randomization and failure to consider switches from one dialysis modality to the other.

Bottom line: Patients beginning their renal replacement therapy with PD had similar mortality after five years compared to patients using in-center HD.

Citation: Mehrotra R, Chiu YW, Kalantar-Zadeh K, Bargman J, Vonesh E. Similar outcomes with hemodialysis and peritoneal dialysis in patients with end-stage renal disease. Arch Intern Med. 2011;171(2):110-118.

Pneumococcal Urinary Antigen Test Might Guide Community-Acquired Pneumonia Treatment

Clinical question: What is the diagnostic accuracy and clinical utility of pneumococcal urinary antigen testing in adult patients hospitalized with community-acquired pneumonia (CAP)?

Background: Although CAP is common, our ability to determine its etiology is limited, and empirical broad-spectrum antibiotic therapy is the norm. Pneumococcal urinary antigen testing could allow for the more frequent use of narrow-spectrum pathogen-focused antibiotic therapy.

Study design: Prospective cohort study.

Setting: University-affiliated hospital in Spain.

Synopsis: This study included consecutive adult patients hospitalized with CAP from February 2007 though January 2008. A total of 464 patients with 474 episodes of CAP were included. Pneumococcal urinary antigen testing was performed in 383 (80.8%) episodes of CAP. Streptococcus pneumoniae was felt to be the causative pathogen in 171 cases (36.1%). It was detected exclusively by urinary antigen test in 75 of those cases (43.8%).

For the urine antigen test, specificity was 96% (95% CI, 86.5 to 99.5), and the positive predictive value was 96.5% (95% CI, 87.9 to 99.5). The results of the test led clinicians to reduce the spectrum of antibiotics in 41 patients, and pneumonia was cured in all 41 of these patients. Treatment was not modified despite positive antigen test results in 89 patients.

Limitations of this study include a lack of complete microbiological data for all patients. The study also highlighted the difficulty in changing clinicians’ prescribing patterns, even when test results indicate the need for treatment modification.

Bottom line: A positive pneumococcal urinary antigen test result in adult patients hospitalized with CAP can help clinicians narrow antimicrobial therapy with good clinical outcomes.

Citation: Sordé R, Falcó V, Lowak M, et al. Current and potential usefulness of pneumococcal urinary antigen detection in hospitalized patients with community-acquired pneumonia to guide antimicrobial therapy. Arch Intern Med. 2011;171(2):166-172.

Racial Disparities Detected in Hospital Readmission Rates

Clinical question: Do black patients have higher odds of readmission than white patients, and, if so, are these disparities related to where black patients receive care?

Background: Racial disparities in healthcare are well documented. Understanding and eliminating those disparities remains a national priority. Reducing hospital readmissions also is a policy focus, as it represents an opportunity to improve quality while reducing costs. Whether there are racial disparities in hospital readmissions at the national level is unknown.

Study design: Retrospective cohort study.

Setting: Medicare fee-for-service beneficiaries from 2006 to 2008.

Synopsis: Medicare discharge data for more than 3 million Medicare fee-for-service beneficiaries aged 65 years or older discharged from January 1, 2006, to November 30, 2008, with the primary discharge diagnosis of acute myocardial infarction (MI), congestive heart failure, or pneumonia were used to calculate risk-adjusted odds of readmission within 30 days of discharge. Hospitals in the highest decile of proportion of black patients were categorized as minority-serving.

Overall, black patients had 13% higher odds of all-cause 30-day readmission than white patients (24.8% vs. 22.6%, OR 1.13, 95% CI, 1.11-1.14), and patients discharged from minority-serving hospitals had 23% higher odds of readmission than patients from non-minority-serving hospitals (25.5% vs. 22.0%, OR 1.23, 95% CI, 1.20-1.27). Among those with acute MI, black patients had 13% higher odds of readmission (OR 1.13, 95% CI, 1.10-1.16), irrespective of the site of care, while patients from minority-serving hospitals had 22% higher odds of readmissions (OR 1.22, 95% CI, 1.17-1.27), even after adjusting for patient race. Similar disparities were seen for CHF and pneumonia. Results were unchanged after adjusting for hospital characteristics, including markers of caring for poor patients.

Bottom line: Compared with white patients, elderly black Medicare patients have a higher 30-day hospital readmission rate for MI, CHF, and pneumonia that is not fully explained by the higher readmission rates seen among hospitals that disproportionately care for black patients.

Citation: Joynt KE, Orav EJ, Jha AK. Thirty-day readmission rates for Medicare beneficiaries by race and site of care. JAMA. 2011;305(7):675-681.

Easily Identifiable Clinical and Demographic Factors Associated with Hospital Readmission

Clinical question: Which clinical, operational, or demographic factors are associated with 30-day readmission for general medicine patients?

Background: While a few clinical risk factors for hospital readmission have been well defined in subgroups of inpatients, there are still limited data regarding readmission risk that might be associated with a broad range of operational, demographic, and clinical factors in a heterogeneous population of general medicine patients.

Study design: Retrospective observational study.

Setting: Single academic medical center.

Synopsis: The study examined more than 10,300 consecutive admissions (6,805 patients) discharged over a two-year period from 2006 to 2008 from the general medicine service of an urban academic medical center. The 30-day readmission rate was 17.0%.

In multivariate analysis, factors associated with readmission included black race (OR 1.43, 95% CI, 1.24-1.65), inpatient use of narcotics (OR 1.33, 95% CI, 1.16-1.53) and corticosteroids (OR 1.24, 95% CI, 1.09-1.42), and the disease states of cancer (with metastasis 1.61, 95% CI, 1.33-1.95; without metastasis 1.95, 95% CI 1.54-2.47), renal failure (OR 1.19, 95% CI 1.05-1.36), congestive heart failure (OR 1.30, 95% CI, 1.09-1.56), and weight loss (OR 1.26, 95% CI, 1.09-1.47). Medicaid payor status (OR 1.15, 95% CI, 0.97-1.36) had a trend toward readmission. None of the operational factors were significantly associated with readmission, including discharge to skilled nursing facility or weekend discharge.

A major limitation of the study was its inability to capture readmissions to hospitals other than the study hospital, which, based on prior studies, could have accounted for nearly a quarter of readmissions.

Bottom line: Readmission of general medicine patients within 30 days is common and associated with several easily identifiable clinical and nonclinical factors.

Citation: Allaudeen N, Vidyarthi A, Maselli J, Auerbach A. Redefining readmission risk factors for general medicine patients. J Hosp Med. 2011;6(2):54-60.

Unplanned Medical ICU Transfers Tied to Preventable Errors

Clinical question: What fraction of unplanned medical ICU (MICU) transfers result from errors in care and why do they occur?

Background: Prior studies have suggested that 14% to 28% of patients admitted to the MICU are unplanned transfers. It is not known what fraction of these transfers result from errors in care, and whether these transfers could be prevented.

Study design: Retrospective cohort study.

Setting: University-affiliated academic medical center.

Synopsis: All unplanned transfers to the MICU from June 1, 2005, to May 30, 2006, were included in the study. Three independent observers, all hospitalists for more than three years, reviewed patient records to determine the cause of unplanned transfers according to a taxonomy the researchers developed for classifying the transfers. They also determined whether the transfer could have been prevented.

Of the 4,468 general medicine admissions during the study period, 152 met inclusion criteria for an unplanned MICU transfer. Errors in care were judged to account for 19% (n=29) of unplanned transfers, 15 of which were due to incorrect triage at admission and 14 to iatrogenic errors, such as opiate overdose during pain treatment or delayed treatment. All 15 triage errors were considered preventable. Of the iatrogenic errors, eight were considered preventable through an earlier intervention. Overall, 23 errors (15%) were thought to be preventable. Observer agreement was moderate to almost perfect (κ0.55-0.90).

Bottom line: Nearly 1 in 7 unplanned transfers to the medical ICU are associated with preventable errors in care, with the most common error being inappropriate admission triage.

Citation: Bapoje SR, Gaudiani JL, Narayanan V, Albert RK. Unplanned transfers to a medical intensive care unit: causes and relationship to preventable errors in care. J Hosp Med. 2011;6(2):68-72. TH

Pediatric HM Literature

Well Visits Prevent Ambulatory-Care-Sensitive Hospitalizations

Reviewed by Pediatric Editor Mark Shen, MD, FHM, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Clinical question: Is routine well-child care visit adherence associated with a decreased risk of ambulatory-care-sensitive hospitalizations?

Background: Ambulatory-care-sensitive hospitalizations (ACSHs) represent admissions that might have been prevented by quality outpatient care. They are an improvement opportunity for healthcare systems; thus, it is important to characterize factors associated with increased ACSH. Although continuity of care (COC) with the same provider has been associated with reduced hospitalizations, the relationship between regularly scheduled well-child care (WCC) and ACSH is less clear.

Study design: Population-based, retrospective cohort study.

Setting: Hawaii’s largest health insurer.

Synopsis: Young children with the highest likelihood of ACSH (two months to 3.5 years old) who were continuously enrolled in coverage by Hawaii’s largest health insurer (representing 70% of the civilian population) were included. Ultimately, administrative data on 36,944 children were analyzed for WCC adherence rate and a nonlinear COC index, both of which were modeled as time-varying categorical variables.

ACSH were defined by conditions, and notably included acute respiratory-tract infections. Both high WCC visit adherence and COC index were independently associated with decreased risk of ACSH and were modified significantly by chronic-disease status.

This study examines a somewhat unique population: insured children in Hawaii with a relatively high degree of consistency in care. Thus, it is not applicable to the most vulnerable Medicaid and uninsured groups of children. In addition, the relationship between WCC visit adherence and ACSH seemed to disappear in healthy children, further limiting generalizability. Nevertheless, it appears that WCC visits without provider continuity might still be protective for ACSH. It will be important to replicate these findings in a population served by safety-net clinics: children who most often have WCC without continuity.

Bottom line: WCC visit adherence in insured patients with chronic disease reduces the risk of ACSH.

Citation: Tom JO, Tseng CW, Davis J, Solomon C, Zhou C, Mangione-Smith R. Missed well-child care visits, low continuity of care, and risk of ambulatory care-sensitive hospitalizations in young children. Arch Pediatr Adolesc Med. 2010;164(11):1052-1058.