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Suboptimal Outcomes Using IVC Filters for VTE Prophylaxis, Treatment
Clinical question: In patients who undergo inferior vena cava (IVC) filter placement for venous thromboembolism (VTE) prophylaxis or treatment, what are the associated patient characteristics, indications for placement, complications, retrieval date, and use of concomitant anticoagulant therapy?
Background: Retrievable IVC filters were designed to provide short-term protection from pulmonary embolism but are often left in place indefinitely. Retrievable IVC filters that are not removed can carry significant long-term risks. Further, the use of filters for VTE prophylaxis is controversial, and there are multiple sets of conflicting guidelines for filter insertion provided by various professional groups.
Study design: Retrospective review of IVC filter use over an eight-year period.
Setting: Boston Medical Center.
Synopsis: Medical records from all patients at Boston Medical Center who had a billing code for placement of an IVC filter between August 2003 and February 2011 were manually reviewed. Nine hundred fifty-two medical records were evaluated, of which 679 (71.3%) patients had retrievable IVC filters placed. The most common indications for filter placement were trauma (50.2%), malignancy (15.9%), and bleeding during anticoagulation (11.8%).
In total, 448 patients (47.1%) had filters placed for prophylactic purposes in the absence of documented VTE. Seventy-four patients developed VTE after filter placement; 48.2% of post-filter insertion VTEs occurred in patients who had no VTE prior to the filter; and 89.4% occurred in patients not receiving anticoagulants. An attempt was made to remove 71 of 679 (10.5%) retrievable filters, and 58 (8.5%) attempts were successful. There were 10 serious complications related to mechanical filter failure, including migration or fracture of the filter.
In this study, there was a high volume of filter use by the trauma service; thus, the patient population might be different from the hospital medicine patient population. The study also lacked systematic imaging and follow-up data. Further studies are needed to analyze the risks associated with IVC filter placement.
Bottom line: Use of IVC filters for VTE treatment and prophylaxis, in the context of low filter retrieval rates and lack of appropriate anticoagulant therapy, results in suboptimal outcomes.
Citation: Sarosiek S, Crowther M, Sloan M. Indications, complications, and management of inferior vena cava filters: the experience in 952 patients at an academic hospital with a level I trauma center. JAMA Intern Med. 2013;173:513-517.
Clinical question: In patients who undergo inferior vena cava (IVC) filter placement for venous thromboembolism (VTE) prophylaxis or treatment, what are the associated patient characteristics, indications for placement, complications, retrieval date, and use of concomitant anticoagulant therapy?
Background: Retrievable IVC filters were designed to provide short-term protection from pulmonary embolism but are often left in place indefinitely. Retrievable IVC filters that are not removed can carry significant long-term risks. Further, the use of filters for VTE prophylaxis is controversial, and there are multiple sets of conflicting guidelines for filter insertion provided by various professional groups.
Study design: Retrospective review of IVC filter use over an eight-year period.
Setting: Boston Medical Center.
Synopsis: Medical records from all patients at Boston Medical Center who had a billing code for placement of an IVC filter between August 2003 and February 2011 were manually reviewed. Nine hundred fifty-two medical records were evaluated, of which 679 (71.3%) patients had retrievable IVC filters placed. The most common indications for filter placement were trauma (50.2%), malignancy (15.9%), and bleeding during anticoagulation (11.8%).
In total, 448 patients (47.1%) had filters placed for prophylactic purposes in the absence of documented VTE. Seventy-four patients developed VTE after filter placement; 48.2% of post-filter insertion VTEs occurred in patients who had no VTE prior to the filter; and 89.4% occurred in patients not receiving anticoagulants. An attempt was made to remove 71 of 679 (10.5%) retrievable filters, and 58 (8.5%) attempts were successful. There were 10 serious complications related to mechanical filter failure, including migration or fracture of the filter.
In this study, there was a high volume of filter use by the trauma service; thus, the patient population might be different from the hospital medicine patient population. The study also lacked systematic imaging and follow-up data. Further studies are needed to analyze the risks associated with IVC filter placement.
Bottom line: Use of IVC filters for VTE treatment and prophylaxis, in the context of low filter retrieval rates and lack of appropriate anticoagulant therapy, results in suboptimal outcomes.
Citation: Sarosiek S, Crowther M, Sloan M. Indications, complications, and management of inferior vena cava filters: the experience in 952 patients at an academic hospital with a level I trauma center. JAMA Intern Med. 2013;173:513-517.
Clinical question: In patients who undergo inferior vena cava (IVC) filter placement for venous thromboembolism (VTE) prophylaxis or treatment, what are the associated patient characteristics, indications for placement, complications, retrieval date, and use of concomitant anticoagulant therapy?
Background: Retrievable IVC filters were designed to provide short-term protection from pulmonary embolism but are often left in place indefinitely. Retrievable IVC filters that are not removed can carry significant long-term risks. Further, the use of filters for VTE prophylaxis is controversial, and there are multiple sets of conflicting guidelines for filter insertion provided by various professional groups.
Study design: Retrospective review of IVC filter use over an eight-year period.
Setting: Boston Medical Center.
Synopsis: Medical records from all patients at Boston Medical Center who had a billing code for placement of an IVC filter between August 2003 and February 2011 were manually reviewed. Nine hundred fifty-two medical records were evaluated, of which 679 (71.3%) patients had retrievable IVC filters placed. The most common indications for filter placement were trauma (50.2%), malignancy (15.9%), and bleeding during anticoagulation (11.8%).
In total, 448 patients (47.1%) had filters placed for prophylactic purposes in the absence of documented VTE. Seventy-four patients developed VTE after filter placement; 48.2% of post-filter insertion VTEs occurred in patients who had no VTE prior to the filter; and 89.4% occurred in patients not receiving anticoagulants. An attempt was made to remove 71 of 679 (10.5%) retrievable filters, and 58 (8.5%) attempts were successful. There were 10 serious complications related to mechanical filter failure, including migration or fracture of the filter.
In this study, there was a high volume of filter use by the trauma service; thus, the patient population might be different from the hospital medicine patient population. The study also lacked systematic imaging and follow-up data. Further studies are needed to analyze the risks associated with IVC filter placement.
Bottom line: Use of IVC filters for VTE treatment and prophylaxis, in the context of low filter retrieval rates and lack of appropriate anticoagulant therapy, results in suboptimal outcomes.
Citation: Sarosiek S, Crowther M, Sloan M. Indications, complications, and management of inferior vena cava filters: the experience in 952 patients at an academic hospital with a level I trauma center. JAMA Intern Med. 2013;173:513-517.
Prediction Model Identifies Potentially Avoidable 30-Day Readmissions
Clinical question: Can a prediction model based on administrative and clinical data identify potentially avoidable 30-day readmissions in medical patients prior to discharge?
Background: An estimated 18% of Medicare beneficiaries are readmitted to the hospital within 30 days of discharge, costing nearly $17 billion per year. Interventions to reduce readmission rates are costly and should be focused on high-risk patients. To date, using models to predict 30-day readmission has been problematic and unreliable.
Study design: Retrospective cohort.
Setting: Academic medical center in Boston.
Synopsis: Using consecutive discharges from all medical services of Brigham and Women’s Hospital occurring over one year, this study derived and internally validated a prediction model for potentially avoidable 30-day readmissions. Of 10,731 discharges, there were 2,399 (22%) 30-day readmissions, and 879 (8.5%) were deemed potentially avoidable. Seven independent predictors for readmission were identified and used to create a predictor score referred to as the HOSPITAL score. Predictors included hemoglobin and sodium levels at discharge, number of hospitalizations in the past year, and four features of the index hospitalization, including type, discharge from an oncology service, presence of procedures, and length of stay. The score was internally validated and found to predict potentially avoidable 30-day readmission in medical patients with fair discriminatory power and good calibration.
This study is unique in that none of the classic comorbidities (e.g. congestive heart failure) were associated with a higher risk of 30-day readmission. Previously unrecognized predictors, including hemoglobin, sodium, and number of procedures performed, were incorporated. This suggests that comorbidities are not as important as illness severity or clinical instability. Hospitalists should await studies that externally validate the HOSPITAL score before incorporating it into practice.
Bottom line: A unique and simple seven-item prediction model identifies potentially avoidable 30-day readmissions but needs to be externally validated before being widely utilized.
Citation: Donze J, Drahomir A, Williams D, Schnipper JL. Potentially avoidable 30-day hospital readmissions in medical patients. JAMA Intern Med. 2013;137(8):632-638.
Clinical question: Can a prediction model based on administrative and clinical data identify potentially avoidable 30-day readmissions in medical patients prior to discharge?
Background: An estimated 18% of Medicare beneficiaries are readmitted to the hospital within 30 days of discharge, costing nearly $17 billion per year. Interventions to reduce readmission rates are costly and should be focused on high-risk patients. To date, using models to predict 30-day readmission has been problematic and unreliable.
Study design: Retrospective cohort.
Setting: Academic medical center in Boston.
Synopsis: Using consecutive discharges from all medical services of Brigham and Women’s Hospital occurring over one year, this study derived and internally validated a prediction model for potentially avoidable 30-day readmissions. Of 10,731 discharges, there were 2,399 (22%) 30-day readmissions, and 879 (8.5%) were deemed potentially avoidable. Seven independent predictors for readmission were identified and used to create a predictor score referred to as the HOSPITAL score. Predictors included hemoglobin and sodium levels at discharge, number of hospitalizations in the past year, and four features of the index hospitalization, including type, discharge from an oncology service, presence of procedures, and length of stay. The score was internally validated and found to predict potentially avoidable 30-day readmission in medical patients with fair discriminatory power and good calibration.
This study is unique in that none of the classic comorbidities (e.g. congestive heart failure) were associated with a higher risk of 30-day readmission. Previously unrecognized predictors, including hemoglobin, sodium, and number of procedures performed, were incorporated. This suggests that comorbidities are not as important as illness severity or clinical instability. Hospitalists should await studies that externally validate the HOSPITAL score before incorporating it into practice.
Bottom line: A unique and simple seven-item prediction model identifies potentially avoidable 30-day readmissions but needs to be externally validated before being widely utilized.
Citation: Donze J, Drahomir A, Williams D, Schnipper JL. Potentially avoidable 30-day hospital readmissions in medical patients. JAMA Intern Med. 2013;137(8):632-638.
Clinical question: Can a prediction model based on administrative and clinical data identify potentially avoidable 30-day readmissions in medical patients prior to discharge?
Background: An estimated 18% of Medicare beneficiaries are readmitted to the hospital within 30 days of discharge, costing nearly $17 billion per year. Interventions to reduce readmission rates are costly and should be focused on high-risk patients. To date, using models to predict 30-day readmission has been problematic and unreliable.
Study design: Retrospective cohort.
Setting: Academic medical center in Boston.
Synopsis: Using consecutive discharges from all medical services of Brigham and Women’s Hospital occurring over one year, this study derived and internally validated a prediction model for potentially avoidable 30-day readmissions. Of 10,731 discharges, there were 2,399 (22%) 30-day readmissions, and 879 (8.5%) were deemed potentially avoidable. Seven independent predictors for readmission were identified and used to create a predictor score referred to as the HOSPITAL score. Predictors included hemoglobin and sodium levels at discharge, number of hospitalizations in the past year, and four features of the index hospitalization, including type, discharge from an oncology service, presence of procedures, and length of stay. The score was internally validated and found to predict potentially avoidable 30-day readmission in medical patients with fair discriminatory power and good calibration.
This study is unique in that none of the classic comorbidities (e.g. congestive heart failure) were associated with a higher risk of 30-day readmission. Previously unrecognized predictors, including hemoglobin, sodium, and number of procedures performed, were incorporated. This suggests that comorbidities are not as important as illness severity or clinical instability. Hospitalists should await studies that externally validate the HOSPITAL score before incorporating it into practice.
Bottom line: A unique and simple seven-item prediction model identifies potentially avoidable 30-day readmissions but needs to be externally validated before being widely utilized.
Citation: Donze J, Drahomir A, Williams D, Schnipper JL. Potentially avoidable 30-day hospital readmissions in medical patients. JAMA Intern Med. 2013;137(8):632-638.
Surgical-Site Infection Risk Not Associated with Prophylactic Antibiotic Timing
Clinical question: How does timing of surgical antibiotic prophylaxis affect risk of postoperative surgical-site infections (SSIs)?
Background: Antibiotic prophylaxis for major surgical procedures has been proven in clinical trials to reduce rates of SSI. The Centers for Medicare & Medicaid Services’ (CMS) Surgical Care Improvement Project (SCIP) has implemented quality metrics to ensure antibiotics are administered within 60 minutes of incision; however, studies have failed to show that a 60-minute pre-incision window is advantageous.
Study design: Retrospective cohort.
Setting: Veterans Affairs hospitals.
Synopsis: Using SCIP and VA Surgical Quality Improvement Program data from 112 VA hospitals, 32,459 cases of hip or knee arthroplasty, colorectal surgery, arterial vascular surgery, and hysterectomy from 2005-2009 were reviewed. A postoperative SSI occurred in 1,497 cases (4.6%). Using several statistical methods, the relationship between timing of prophylactic antibiotic administration and postoperative SSI within 30 days was evaluated. In unadjusted models, higher SSI rates were observed with antibiotic administration more than 60 minutes prior to incision (OR 1.34, 95% CI 1.08-1.66) but not after incision (OR 1.26, 95% CI 0.92-1.72), compared with procedures with antibiotics administered within 60 minutes pre-incision. However, after adjustment for patient, procedure, and antibiotic variables, no significant relationship between timing and SSI was observed (P=0.50 for all specialties).
The study sample was comprised primarily of older men and did not include patients who underwent cardiac procedures, limiting the generalizability of the findings. Nonetheless, the study is the largest of its kind and confirms previous studies that suggest there is no significant relationship between timing of antibiotics and SSI. Prophylactic antibiotics should still be used when indicated; however, using timing of prophylactic antibiotics as a quality measure is unlikely to improve outcomes.
Bottom line: Adherence to the empiric 60-minute window metric for timing of prophylactic antibiotics is not significantly associated with risk of SSI.
Citation: Hawn MT, Richman JS, Vick CC, et al. Timing of surgical antibiotic prophylaxis and the risk of surgical site infection. JAMA Surg. 2013 March 20:1-8. doi: 10.1001/jamasurg.2013.134 [Epub ahead of print].
Clinical question: How does timing of surgical antibiotic prophylaxis affect risk of postoperative surgical-site infections (SSIs)?
Background: Antibiotic prophylaxis for major surgical procedures has been proven in clinical trials to reduce rates of SSI. The Centers for Medicare & Medicaid Services’ (CMS) Surgical Care Improvement Project (SCIP) has implemented quality metrics to ensure antibiotics are administered within 60 minutes of incision; however, studies have failed to show that a 60-minute pre-incision window is advantageous.
Study design: Retrospective cohort.
Setting: Veterans Affairs hospitals.
Synopsis: Using SCIP and VA Surgical Quality Improvement Program data from 112 VA hospitals, 32,459 cases of hip or knee arthroplasty, colorectal surgery, arterial vascular surgery, and hysterectomy from 2005-2009 were reviewed. A postoperative SSI occurred in 1,497 cases (4.6%). Using several statistical methods, the relationship between timing of prophylactic antibiotic administration and postoperative SSI within 30 days was evaluated. In unadjusted models, higher SSI rates were observed with antibiotic administration more than 60 minutes prior to incision (OR 1.34, 95% CI 1.08-1.66) but not after incision (OR 1.26, 95% CI 0.92-1.72), compared with procedures with antibiotics administered within 60 minutes pre-incision. However, after adjustment for patient, procedure, and antibiotic variables, no significant relationship between timing and SSI was observed (P=0.50 for all specialties).
The study sample was comprised primarily of older men and did not include patients who underwent cardiac procedures, limiting the generalizability of the findings. Nonetheless, the study is the largest of its kind and confirms previous studies that suggest there is no significant relationship between timing of antibiotics and SSI. Prophylactic antibiotics should still be used when indicated; however, using timing of prophylactic antibiotics as a quality measure is unlikely to improve outcomes.
Bottom line: Adherence to the empiric 60-minute window metric for timing of prophylactic antibiotics is not significantly associated with risk of SSI.
Citation: Hawn MT, Richman JS, Vick CC, et al. Timing of surgical antibiotic prophylaxis and the risk of surgical site infection. JAMA Surg. 2013 March 20:1-8. doi: 10.1001/jamasurg.2013.134 [Epub ahead of print].
Clinical question: How does timing of surgical antibiotic prophylaxis affect risk of postoperative surgical-site infections (SSIs)?
Background: Antibiotic prophylaxis for major surgical procedures has been proven in clinical trials to reduce rates of SSI. The Centers for Medicare & Medicaid Services’ (CMS) Surgical Care Improvement Project (SCIP) has implemented quality metrics to ensure antibiotics are administered within 60 minutes of incision; however, studies have failed to show that a 60-minute pre-incision window is advantageous.
Study design: Retrospective cohort.
Setting: Veterans Affairs hospitals.
Synopsis: Using SCIP and VA Surgical Quality Improvement Program data from 112 VA hospitals, 32,459 cases of hip or knee arthroplasty, colorectal surgery, arterial vascular surgery, and hysterectomy from 2005-2009 were reviewed. A postoperative SSI occurred in 1,497 cases (4.6%). Using several statistical methods, the relationship between timing of prophylactic antibiotic administration and postoperative SSI within 30 days was evaluated. In unadjusted models, higher SSI rates were observed with antibiotic administration more than 60 minutes prior to incision (OR 1.34, 95% CI 1.08-1.66) but not after incision (OR 1.26, 95% CI 0.92-1.72), compared with procedures with antibiotics administered within 60 minutes pre-incision. However, after adjustment for patient, procedure, and antibiotic variables, no significant relationship between timing and SSI was observed (P=0.50 for all specialties).
The study sample was comprised primarily of older men and did not include patients who underwent cardiac procedures, limiting the generalizability of the findings. Nonetheless, the study is the largest of its kind and confirms previous studies that suggest there is no significant relationship between timing of antibiotics and SSI. Prophylactic antibiotics should still be used when indicated; however, using timing of prophylactic antibiotics as a quality measure is unlikely to improve outcomes.
Bottom line: Adherence to the empiric 60-minute window metric for timing of prophylactic antibiotics is not significantly associated with risk of SSI.
Citation: Hawn MT, Richman JS, Vick CC, et al. Timing of surgical antibiotic prophylaxis and the risk of surgical site infection. JAMA Surg. 2013 March 20:1-8. doi: 10.1001/jamasurg.2013.134 [Epub ahead of print].
One-Year Survival Nearly 60% for Elderly Survivors of In-Hospital Cardiac Arrest
Clinical question: What is the long-term outcome of elderly survivors of in-hospital cardiac arrest?
Background: Previous studies have examined in-hospital survival from in-hospital cardiac arrest but have not looked at long-term outcomes and readmission of in-hospital cardiac arrest survivors.
Study design: Retrospective cohort.
Setting: Acute-care hospitals that submitted data to the Get with the Guidelines—Resuscitation registry between 2000 and 2008.
Synopsis: Using the Get with the Guidelines—Resuscitation registry from 401 acute-care hospitals, data from 6,972 Medicare patients aged 65 years or older who had a pulseless in-hospital cardiac arrest and survived to discharge were analyzed. Survival rates were 82% at 30 days, 72% at three months, 58.5% at one year, and 49.6% at two years. Survival at three years was 43.5%, similar to patients discharged with heart failure.
One-year survival decreased with increasing age. Survival also decreased with black race (52.5% vs. 60.4% for white patients, P=0.001) and male sex (58.6% vs. 60.9% for women, P=0.03). Patients with mild or no neurologic disability at discharge had a higher survival rate at one year than patients with moderate, severe, or coma state. Readmission rates at one year after discharge were 65.6% and 76.2% at two years. Black patients, women, and patients with neurologic disability at discharge were more likely to be readmitted.
Because this is an observational study looking at a quality database of Medicare patients, it excludes patients at VA hospitals and non-Medicare facilities. This data excludes assessments of quality of life after discharge and health status among those with long-term survival, and does not include cause of death.
Bottom line: One-year survival following in-hospital cardiac arrest for patients over age 65 approaches 60% and decreases with increasing age, male sex, and black race.
Citation: Chan PS, Nallamothu BK, Krumholz HM, et al. Long-term outcomes in elderly survivors of in-hospital cardiac arrest. N Engl J Med. 2013;368:1019-1026.
Clinical question: What is the long-term outcome of elderly survivors of in-hospital cardiac arrest?
Background: Previous studies have examined in-hospital survival from in-hospital cardiac arrest but have not looked at long-term outcomes and readmission of in-hospital cardiac arrest survivors.
Study design: Retrospective cohort.
Setting: Acute-care hospitals that submitted data to the Get with the Guidelines—Resuscitation registry between 2000 and 2008.
Synopsis: Using the Get with the Guidelines—Resuscitation registry from 401 acute-care hospitals, data from 6,972 Medicare patients aged 65 years or older who had a pulseless in-hospital cardiac arrest and survived to discharge were analyzed. Survival rates were 82% at 30 days, 72% at three months, 58.5% at one year, and 49.6% at two years. Survival at three years was 43.5%, similar to patients discharged with heart failure.
One-year survival decreased with increasing age. Survival also decreased with black race (52.5% vs. 60.4% for white patients, P=0.001) and male sex (58.6% vs. 60.9% for women, P=0.03). Patients with mild or no neurologic disability at discharge had a higher survival rate at one year than patients with moderate, severe, or coma state. Readmission rates at one year after discharge were 65.6% and 76.2% at two years. Black patients, women, and patients with neurologic disability at discharge were more likely to be readmitted.
Because this is an observational study looking at a quality database of Medicare patients, it excludes patients at VA hospitals and non-Medicare facilities. This data excludes assessments of quality of life after discharge and health status among those with long-term survival, and does not include cause of death.
Bottom line: One-year survival following in-hospital cardiac arrest for patients over age 65 approaches 60% and decreases with increasing age, male sex, and black race.
Citation: Chan PS, Nallamothu BK, Krumholz HM, et al. Long-term outcomes in elderly survivors of in-hospital cardiac arrest. N Engl J Med. 2013;368:1019-1026.
Clinical question: What is the long-term outcome of elderly survivors of in-hospital cardiac arrest?
Background: Previous studies have examined in-hospital survival from in-hospital cardiac arrest but have not looked at long-term outcomes and readmission of in-hospital cardiac arrest survivors.
Study design: Retrospective cohort.
Setting: Acute-care hospitals that submitted data to the Get with the Guidelines—Resuscitation registry between 2000 and 2008.
Synopsis: Using the Get with the Guidelines—Resuscitation registry from 401 acute-care hospitals, data from 6,972 Medicare patients aged 65 years or older who had a pulseless in-hospital cardiac arrest and survived to discharge were analyzed. Survival rates were 82% at 30 days, 72% at three months, 58.5% at one year, and 49.6% at two years. Survival at three years was 43.5%, similar to patients discharged with heart failure.
One-year survival decreased with increasing age. Survival also decreased with black race (52.5% vs. 60.4% for white patients, P=0.001) and male sex (58.6% vs. 60.9% for women, P=0.03). Patients with mild or no neurologic disability at discharge had a higher survival rate at one year than patients with moderate, severe, or coma state. Readmission rates at one year after discharge were 65.6% and 76.2% at two years. Black patients, women, and patients with neurologic disability at discharge were more likely to be readmitted.
Because this is an observational study looking at a quality database of Medicare patients, it excludes patients at VA hospitals and non-Medicare facilities. This data excludes assessments of quality of life after discharge and health status among those with long-term survival, and does not include cause of death.
Bottom line: One-year survival following in-hospital cardiac arrest for patients over age 65 approaches 60% and decreases with increasing age, male sex, and black race.
Citation: Chan PS, Nallamothu BK, Krumholz HM, et al. Long-term outcomes in elderly survivors of in-hospital cardiac arrest. N Engl J Med. 2013;368:1019-1026.
FDA’s Draft Guidance Targets Drug Development for Early Stages of Alzheimer’s Disease
The FDA has issued a draft guidance designed to assist pharmaceutical companies in developing new drugs for patients who are in the early stages of Alzheimer’s disease. The proposed recommendations address patient selection and end points for clinical trials, as well as the manner in which disease modification may be demonstrated.
“The scientific community and the FDA believe that it is critical to identify and study patients with very early Alzheimer’s disease before there is too much irreversible injury to the brain,” said Russell Katz, MD, Director of the Division of Neurology Products at the FDA’s Center for Drug Evaluation and Research in Silver Spring, Maryland.
One theory for why previous Alzheimer’s disease drugs have failed is that they were tested too late in the disease process, noted Nicholas A. Kozauer, MD, Acting Clinical Team Lead at the FDA’s Division of Neurology Products. “If the treatment is earlier, the patient may have more benefit from it,” he said.
The research group did not endorse a particular set of diagnostic criteria for early-stage Alzheimer’s disease, and instead emphasized the importance of identifying the correct patients for trial enrollment. The group also noted that many assessment tools used to measure functional or global impairment in patients with dementia have not been validated in early-stage patients. Therefore, “we consider the use of a composite scale, validated in early-stage patients to assess both cognition and function as a single primary efficacy outcome measure, to be appropriate,” stated the authors.
Regarding biomarkers, the committee noted that until there is widespread agreement that an effect on a particular biomarker is reasonably likely to predict clinical benefit, it would not consider an approval based on use of a biomarker as a surrogate outcome measure in any stage of Alzheimer’s disease.
“We are open to considering the argument that a positive biomarker result (generally included as a secondary outcome measure in a trial) in combination with a positive finding on a primary clinical outcome measure may support a claim of disease modification in Alzheimer’s disease,” stated the committee.
The recommendations were open for a public comment period, which ended on April 9.
—Colby Stong
Editor
Suggested Reading
FDA. Guidance for industry—Alzheimer’s disease: developing drugs for the treatment of early stage disease. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM338287.pdf
The FDA has issued a draft guidance designed to assist pharmaceutical companies in developing new drugs for patients who are in the early stages of Alzheimer’s disease. The proposed recommendations address patient selection and end points for clinical trials, as well as the manner in which disease modification may be demonstrated.
“The scientific community and the FDA believe that it is critical to identify and study patients with very early Alzheimer’s disease before there is too much irreversible injury to the brain,” said Russell Katz, MD, Director of the Division of Neurology Products at the FDA’s Center for Drug Evaluation and Research in Silver Spring, Maryland.
One theory for why previous Alzheimer’s disease drugs have failed is that they were tested too late in the disease process, noted Nicholas A. Kozauer, MD, Acting Clinical Team Lead at the FDA’s Division of Neurology Products. “If the treatment is earlier, the patient may have more benefit from it,” he said.
The research group did not endorse a particular set of diagnostic criteria for early-stage Alzheimer’s disease, and instead emphasized the importance of identifying the correct patients for trial enrollment. The group also noted that many assessment tools used to measure functional or global impairment in patients with dementia have not been validated in early-stage patients. Therefore, “we consider the use of a composite scale, validated in early-stage patients to assess both cognition and function as a single primary efficacy outcome measure, to be appropriate,” stated the authors.
Regarding biomarkers, the committee noted that until there is widespread agreement that an effect on a particular biomarker is reasonably likely to predict clinical benefit, it would not consider an approval based on use of a biomarker as a surrogate outcome measure in any stage of Alzheimer’s disease.
“We are open to considering the argument that a positive biomarker result (generally included as a secondary outcome measure in a trial) in combination with a positive finding on a primary clinical outcome measure may support a claim of disease modification in Alzheimer’s disease,” stated the committee.
The recommendations were open for a public comment period, which ended on April 9.
—Colby Stong
Editor
Suggested Reading
FDA. Guidance for industry—Alzheimer’s disease: developing drugs for the treatment of early stage disease. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM338287.pdf
The FDA has issued a draft guidance designed to assist pharmaceutical companies in developing new drugs for patients who are in the early stages of Alzheimer’s disease. The proposed recommendations address patient selection and end points for clinical trials, as well as the manner in which disease modification may be demonstrated.
“The scientific community and the FDA believe that it is critical to identify and study patients with very early Alzheimer’s disease before there is too much irreversible injury to the brain,” said Russell Katz, MD, Director of the Division of Neurology Products at the FDA’s Center for Drug Evaluation and Research in Silver Spring, Maryland.
One theory for why previous Alzheimer’s disease drugs have failed is that they were tested too late in the disease process, noted Nicholas A. Kozauer, MD, Acting Clinical Team Lead at the FDA’s Division of Neurology Products. “If the treatment is earlier, the patient may have more benefit from it,” he said.
The research group did not endorse a particular set of diagnostic criteria for early-stage Alzheimer’s disease, and instead emphasized the importance of identifying the correct patients for trial enrollment. The group also noted that many assessment tools used to measure functional or global impairment in patients with dementia have not been validated in early-stage patients. Therefore, “we consider the use of a composite scale, validated in early-stage patients to assess both cognition and function as a single primary efficacy outcome measure, to be appropriate,” stated the authors.
Regarding biomarkers, the committee noted that until there is widespread agreement that an effect on a particular biomarker is reasonably likely to predict clinical benefit, it would not consider an approval based on use of a biomarker as a surrogate outcome measure in any stage of Alzheimer’s disease.
“We are open to considering the argument that a positive biomarker result (generally included as a secondary outcome measure in a trial) in combination with a positive finding on a primary clinical outcome measure may support a claim of disease modification in Alzheimer’s disease,” stated the committee.
The recommendations were open for a public comment period, which ended on April 9.
—Colby Stong
Editor
Suggested Reading
FDA. Guidance for industry—Alzheimer’s disease: developing drugs for the treatment of early stage disease. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM338287.pdf
Childhood Migraine Tied to History of Infantile Colic
Children and adolescents who presented to the emergency department with migraine headache were six times more likely to have a history of colic during infancy than were those who presented for other reasons, according to a report in the April 17 JAMA.
In contrast, children and adolescents who presented to the emergency department with tension-type headache showed no increase in the likelihood that they had experienced infantile colic. This confirms the specificity of the association between migraine—not other types of headache—and colic, said lead author Silvia Romanello, MD, of the Department of Pediatric Emergency Care and the Pediatric Migraine and Neurovascular Diseases Unit at Robert Debré Hospital, Paris, and her associates.
Researchers and clinicians have long suspected an association between the two pain syndromes of colic and migraine, but such a link has not been well studied. Dr. Romanello and colleagues at three tertiary-care hospitals in France and Italy examined the association in a case-control study involving 328 pediatric patients and 471 controls.
Subjects were between the ages of 6 and 18 and presented to emergency departments with primary headaches during a three-month study period. A total of 208 patients were diagnosed by a pediatric neurologist as having primary migraine (142 without aura and 66 with aura), and 120 were diagnosed as having tension-type headache. The control subjects were patients of the same age who presented during the same period with minor trauma.
A total of 72.6% of the patients with primary migraine had a history of infantile colic. The prevalence of colic was similarly high between those who had migraine with aura (69.7%) and those who had migraine without aura (73.9%). In contrast, only 35% of the patients with tension-type headache had a history of infantile colic. This prevalence was similar to that in the control group (26.5%), the investigators said.
In a further statistical analysis of the data, the association between infantile colic and migraine was highly significant, with an odds ratio (OR) of 6.61. No association was seen between infantile colic and tension-type headache or infantile colic and minor trauma.
A subgroup analysis showed that the association between infantile colic and migraine with aura was highly significant, with an OR of 5.73, as was the association between infantile colic and migraine without aura, which had an OR of 7.01. This finding indicates that the two pain disorders, colic and migraine, share a common pathophysiology, Dr. Romanello and her associates said.
Given that diagnosing headache in children can be challenging, another subgroup analysis was performed to explore any possible age-related bias in diagnosis. The results confirmed those of the main study: The association between migraine and infantile colic remained highly significant in both children ages 6 through 12 and adolescents ages 13 through 18.
The investigators noted that colic might result from a sensitization of the perivascular nerve terminals in the gut.
Another possibility is that “molecules known to be involved in the modulation of sensory activity, such as calcitonin-gene-related peptide (CGRP),” which is released during migraine episodes, also may be involved in modulation of abdominal pain “by inducing the neurogenic inflammation of sensory neurons in the gut.”
In addition, triptans have proved extremely effective against acute attacks of both migraine and abdominal migraine, and they eventually may be found useful for infantile colic. “It is currently difficult to imagine that clinical trials will be conducted with such off-label drugs for the treatment of a benign condition such as infantile colic,” Dr. Romanello and her associates said.
—Mary Ann Moon
IMNG Medical News
Suggested Reading
Romanello S, Spiri D, Marcuzzi E, et al. Association between childhood migraine and history of infantile colic. JAMA. 2013;309(15):1607-1612.
Children and adolescents who presented to the emergency department with migraine headache were six times more likely to have a history of colic during infancy than were those who presented for other reasons, according to a report in the April 17 JAMA.
In contrast, children and adolescents who presented to the emergency department with tension-type headache showed no increase in the likelihood that they had experienced infantile colic. This confirms the specificity of the association between migraine—not other types of headache—and colic, said lead author Silvia Romanello, MD, of the Department of Pediatric Emergency Care and the Pediatric Migraine and Neurovascular Diseases Unit at Robert Debré Hospital, Paris, and her associates.
Researchers and clinicians have long suspected an association between the two pain syndromes of colic and migraine, but such a link has not been well studied. Dr. Romanello and colleagues at three tertiary-care hospitals in France and Italy examined the association in a case-control study involving 328 pediatric patients and 471 controls.
Subjects were between the ages of 6 and 18 and presented to emergency departments with primary headaches during a three-month study period. A total of 208 patients were diagnosed by a pediatric neurologist as having primary migraine (142 without aura and 66 with aura), and 120 were diagnosed as having tension-type headache. The control subjects were patients of the same age who presented during the same period with minor trauma.
A total of 72.6% of the patients with primary migraine had a history of infantile colic. The prevalence of colic was similarly high between those who had migraine with aura (69.7%) and those who had migraine without aura (73.9%). In contrast, only 35% of the patients with tension-type headache had a history of infantile colic. This prevalence was similar to that in the control group (26.5%), the investigators said.
In a further statistical analysis of the data, the association between infantile colic and migraine was highly significant, with an odds ratio (OR) of 6.61. No association was seen between infantile colic and tension-type headache or infantile colic and minor trauma.
A subgroup analysis showed that the association between infantile colic and migraine with aura was highly significant, with an OR of 5.73, as was the association between infantile colic and migraine without aura, which had an OR of 7.01. This finding indicates that the two pain disorders, colic and migraine, share a common pathophysiology, Dr. Romanello and her associates said.
Given that diagnosing headache in children can be challenging, another subgroup analysis was performed to explore any possible age-related bias in diagnosis. The results confirmed those of the main study: The association between migraine and infantile colic remained highly significant in both children ages 6 through 12 and adolescents ages 13 through 18.
The investigators noted that colic might result from a sensitization of the perivascular nerve terminals in the gut.
Another possibility is that “molecules known to be involved in the modulation of sensory activity, such as calcitonin-gene-related peptide (CGRP),” which is released during migraine episodes, also may be involved in modulation of abdominal pain “by inducing the neurogenic inflammation of sensory neurons in the gut.”
In addition, triptans have proved extremely effective against acute attacks of both migraine and abdominal migraine, and they eventually may be found useful for infantile colic. “It is currently difficult to imagine that clinical trials will be conducted with such off-label drugs for the treatment of a benign condition such as infantile colic,” Dr. Romanello and her associates said.
—Mary Ann Moon
IMNG Medical News
Suggested Reading
Romanello S, Spiri D, Marcuzzi E, et al. Association between childhood migraine and history of infantile colic. JAMA. 2013;309(15):1607-1612.
Children and adolescents who presented to the emergency department with migraine headache were six times more likely to have a history of colic during infancy than were those who presented for other reasons, according to a report in the April 17 JAMA.
In contrast, children and adolescents who presented to the emergency department with tension-type headache showed no increase in the likelihood that they had experienced infantile colic. This confirms the specificity of the association between migraine—not other types of headache—and colic, said lead author Silvia Romanello, MD, of the Department of Pediatric Emergency Care and the Pediatric Migraine and Neurovascular Diseases Unit at Robert Debré Hospital, Paris, and her associates.
Researchers and clinicians have long suspected an association between the two pain syndromes of colic and migraine, but such a link has not been well studied. Dr. Romanello and colleagues at three tertiary-care hospitals in France and Italy examined the association in a case-control study involving 328 pediatric patients and 471 controls.
Subjects were between the ages of 6 and 18 and presented to emergency departments with primary headaches during a three-month study period. A total of 208 patients were diagnosed by a pediatric neurologist as having primary migraine (142 without aura and 66 with aura), and 120 were diagnosed as having tension-type headache. The control subjects were patients of the same age who presented during the same period with minor trauma.
A total of 72.6% of the patients with primary migraine had a history of infantile colic. The prevalence of colic was similarly high between those who had migraine with aura (69.7%) and those who had migraine without aura (73.9%). In contrast, only 35% of the patients with tension-type headache had a history of infantile colic. This prevalence was similar to that in the control group (26.5%), the investigators said.
In a further statistical analysis of the data, the association between infantile colic and migraine was highly significant, with an odds ratio (OR) of 6.61. No association was seen between infantile colic and tension-type headache or infantile colic and minor trauma.
A subgroup analysis showed that the association between infantile colic and migraine with aura was highly significant, with an OR of 5.73, as was the association between infantile colic and migraine without aura, which had an OR of 7.01. This finding indicates that the two pain disorders, colic and migraine, share a common pathophysiology, Dr. Romanello and her associates said.
Given that diagnosing headache in children can be challenging, another subgroup analysis was performed to explore any possible age-related bias in diagnosis. The results confirmed those of the main study: The association between migraine and infantile colic remained highly significant in both children ages 6 through 12 and adolescents ages 13 through 18.
The investigators noted that colic might result from a sensitization of the perivascular nerve terminals in the gut.
Another possibility is that “molecules known to be involved in the modulation of sensory activity, such as calcitonin-gene-related peptide (CGRP),” which is released during migraine episodes, also may be involved in modulation of abdominal pain “by inducing the neurogenic inflammation of sensory neurons in the gut.”
In addition, triptans have proved extremely effective against acute attacks of both migraine and abdominal migraine, and they eventually may be found useful for infantile colic. “It is currently difficult to imagine that clinical trials will be conducted with such off-label drugs for the treatment of a benign condition such as infantile colic,” Dr. Romanello and her associates said.
—Mary Ann Moon
IMNG Medical News
Suggested Reading
Romanello S, Spiri D, Marcuzzi E, et al. Association between childhood migraine and history of infantile colic. JAMA. 2013;309(15):1607-1612.
New Guideline Proposes Treatment for Neurocysticercosis
A new evidence-based guideline for adults and children with neurocysticercosis—tapeworm larvae seeded in the brain parenchyma—suggests that clinicians should consider treating patients with albendazole and either dexamethasone or prednisolone.
The combination of the cysticidal drug albendazole and a corticosteroid is intended to reduce the number of active brain lesions and the frequency of the seizures they cause, according to Ruth Ann Baird, MD, Professor of Neurology at Indiana University in Indianapolis, lead author of the guideline. The American Academy of Neurology’s guideline development subcommittee drafted the document.
The optimal treatment for neurocysticercosis has been controversial, and experts have debated the usefulness and potential dangers of cysticidal therapy, steroid therapy, and antiepileptic therapy. Dr. Baird and her colleagues performed a systematic review of the English- and Spanish-language medical literature to clarify the issue.
Unfortunately, even a close review of the best 123 articles available did little to resolve the controversy. The studies used widely varying methodologies and different criteria for judging improvement on brain imaging, thus making comparisons and data pooling difficult. Also, the quality of the data in most of the available studies was suboptimal.
The committee, however, was able to reach some conclusions. “Based on imaging findings in four class I studies (three concordant, one underpowered study failing to show an effect) and a meta-analysis of two class I and four class II studies, albendazole (400 mg b.i.d. for adults or weight-based dosing for either adults or children) is probably safe and effective in reducing both the number of cysts and long-term seizure frequency,” said Dr. Baird.
“In most studies, corticosteroids were coadministered in varying dosages, and this combination appears effective, [but] the evidence is insufficient to support or refute the use of steroid treatment alone in patients with intraparenchymal neurocysticercosis,” noted the committee. The group also found no evidence on which to base a recommendation regarding the optimal timing of steroid therapy.
—Mary Ann Moon
IMNG Medical News
Suggested Reading
Baird RA, Wiebe S, Zunt JR, et al. Evidence-based guideline: Treatment of parenchymal neurocysticercosis: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;80(15):1424-1429.
A new evidence-based guideline for adults and children with neurocysticercosis—tapeworm larvae seeded in the brain parenchyma—suggests that clinicians should consider treating patients with albendazole and either dexamethasone or prednisolone.
The combination of the cysticidal drug albendazole and a corticosteroid is intended to reduce the number of active brain lesions and the frequency of the seizures they cause, according to Ruth Ann Baird, MD, Professor of Neurology at Indiana University in Indianapolis, lead author of the guideline. The American Academy of Neurology’s guideline development subcommittee drafted the document.
The optimal treatment for neurocysticercosis has been controversial, and experts have debated the usefulness and potential dangers of cysticidal therapy, steroid therapy, and antiepileptic therapy. Dr. Baird and her colleagues performed a systematic review of the English- and Spanish-language medical literature to clarify the issue.
Unfortunately, even a close review of the best 123 articles available did little to resolve the controversy. The studies used widely varying methodologies and different criteria for judging improvement on brain imaging, thus making comparisons and data pooling difficult. Also, the quality of the data in most of the available studies was suboptimal.
The committee, however, was able to reach some conclusions. “Based on imaging findings in four class I studies (three concordant, one underpowered study failing to show an effect) and a meta-analysis of two class I and four class II studies, albendazole (400 mg b.i.d. for adults or weight-based dosing for either adults or children) is probably safe and effective in reducing both the number of cysts and long-term seizure frequency,” said Dr. Baird.
“In most studies, corticosteroids were coadministered in varying dosages, and this combination appears effective, [but] the evidence is insufficient to support or refute the use of steroid treatment alone in patients with intraparenchymal neurocysticercosis,” noted the committee. The group also found no evidence on which to base a recommendation regarding the optimal timing of steroid therapy.
—Mary Ann Moon
IMNG Medical News
Suggested Reading
Baird RA, Wiebe S, Zunt JR, et al. Evidence-based guideline: Treatment of parenchymal neurocysticercosis: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;80(15):1424-1429.
A new evidence-based guideline for adults and children with neurocysticercosis—tapeworm larvae seeded in the brain parenchyma—suggests that clinicians should consider treating patients with albendazole and either dexamethasone or prednisolone.
The combination of the cysticidal drug albendazole and a corticosteroid is intended to reduce the number of active brain lesions and the frequency of the seizures they cause, according to Ruth Ann Baird, MD, Professor of Neurology at Indiana University in Indianapolis, lead author of the guideline. The American Academy of Neurology’s guideline development subcommittee drafted the document.
The optimal treatment for neurocysticercosis has been controversial, and experts have debated the usefulness and potential dangers of cysticidal therapy, steroid therapy, and antiepileptic therapy. Dr. Baird and her colleagues performed a systematic review of the English- and Spanish-language medical literature to clarify the issue.
Unfortunately, even a close review of the best 123 articles available did little to resolve the controversy. The studies used widely varying methodologies and different criteria for judging improvement on brain imaging, thus making comparisons and data pooling difficult. Also, the quality of the data in most of the available studies was suboptimal.
The committee, however, was able to reach some conclusions. “Based on imaging findings in four class I studies (three concordant, one underpowered study failing to show an effect) and a meta-analysis of two class I and four class II studies, albendazole (400 mg b.i.d. for adults or weight-based dosing for either adults or children) is probably safe and effective in reducing both the number of cysts and long-term seizure frequency,” said Dr. Baird.
“In most studies, corticosteroids were coadministered in varying dosages, and this combination appears effective, [but] the evidence is insufficient to support or refute the use of steroid treatment alone in patients with intraparenchymal neurocysticercosis,” noted the committee. The group also found no evidence on which to base a recommendation regarding the optimal timing of steroid therapy.
—Mary Ann Moon
IMNG Medical News
Suggested Reading
Baird RA, Wiebe S, Zunt JR, et al. Evidence-based guideline: Treatment of parenchymal neurocysticercosis: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;80(15):1424-1429.
Unexplained Widespread Pain Syndrome? It May Be Small-Fiber Polyneuropathy
In a large series of adult and pediatric patients with juvenile-onset, unexplained, chronic widespread pain, more than half met rigorous, multi-test diagnostic criteria for small-fiber polyneuropathy (SFPN), according to a report in the April issue of Pediatrics. This finding, said lead author Anne Louise Oaklander, MD, PhD, extends the age range of acquired SFPN into young adulthood, adolescence, and even early childhood.
Dr. Oaklander and coauthor Max M. Klein, PhD, both affiliated with Massachusetts General Hospital and Harvard Medical School in Boston, evaluated 41 consecutive patients with unexplained widespread pain beginning before age 21. Most had extensive medical records that were extracted for the results of objective diagnostic testing for SFPN, which consisted of neurodiagnostic skin biopsy, nerve biopsy, and autonomic function testing. Secondary information came from subjects’ histories, symptoms, examinations, all other tests, and treatments. Healthy, demographically matched volunteers served as controls for SFPN tests.
“We chose for this initial characterization paper to focus on the youngest group with this disease, because they lacked potentially confounding conditions,” Dr. Oaklander told Neurology Reviews. “It can be hard to ascertain the specific cause of peripheral neuropathy in older adults because they have so many potentially neuropathic exposures and conditions. Here, by focusing on children, we were able to study a pure population in whom exposure to alcohol, toxins, nutritional deficiencies, cancer, and diabetes, were absent. The high signal-to-noise ratio enabled us to home in on the likelihood of autoimmune causality in most. Because of the different age-range and causality, we call this juvenile-onset small-fiber polyneuropathy, or JOSeFINE, to distinguish it from classical SFPN of older adults.”
Subjects included children from other countries and various races, demonstrating that JOSeFINE is present outside the US. Seventy-three percent of patients were female. Nearly 70% had been chronically disabled from school or work, and the same number (68%) had hospitalizations. Objective testing diagnosed definite SFPN in 59% and probable SFPN in 17%. Only one of the 41 subjects had entirely normal SFPN test results. Ninety-eight percent of patients also had other complaints thought to represent autonomic symptoms of SFPN (90% had cardiovascular, 82% had gastrointestinal, and 34% had urologic complaints). In addition, 83% reported chronic fatigue and 63% had chronic headache. Neurologic examinations identified reduced sensation in 68% and vasomotor abnormalities in 55%, including 23% with the erythromelalgia variant that produces areas of redness and burning that patients treat by cooling.
In addition, this study investigated the underlying causes of SFPN in this cohort. Several lines of evidence suggested immunologic problems. For example, past histories for 33% of subjects were notable only for history of other autoimmune illness, and extensive blood and urine tests revealed only serologic markers of disordered immunity in 89% of patients. In addition, some patients improved after immunomodulatory treatments. Corticosteroids or IV immune globulin objectively and subjectively benefited 12 of 15 patients (80%).
“This case series provides a new hypothesis about juvenile-onset, unexplained, acquired chronic widespread pain syndromes, implicating acquired SFPN, a biologically plausible diagnosis not previously recognized in children,” Drs. Oaklander and Klein wrote in their published paper. The data, they contend, suggest that SFPN can develop in children as young as preschool age and that juvenile-onset SFPN can persist for decades into adulthood.
“I would like to emphasize that this is not a disease only of children,” said Dr. Oaklander. “In fact, most patients were young adults by the time they reached us for diagnosis. Additionally, we have other patients who were not included in this study whose illness began when they were in their 20s, 30s, and even 40s. We have one older man in his 60s, but clearly the age range of JOSeFINE is different from the type of neuropathy that we associate with diabetes, cancers, and toxic exposures.
“Perhaps the most common label for these patients was pediatric fibromyalgia,” Dr. Oaklander continued. “Others had been called sero-negative Lyme or other vague descriptors. Basically, these are patients who kick around every hospital and pain clinic without a diagnosis. Now, for the first time, we’re offering a framework in which to organize care, with recommended examinations to perform, recommended diagnostic tests, and nonrecommended diagnostic tests—lumbar puncture is not useful, MRI is not useful. We homed in on the tests that are useful—skin biopsy, autonomic function testing—and we identified the blood tests that were most likely to provide supportive evidence—four specific blood tests associated with dysimmunity. Having a specific diagnosis to test for and treat when present may reduce ineffective, costly, and potentially harmful tests and treatments and permit objective testing and definitive treatment of some patients.”
In addition, the researchers said their results “demonstrate the need for pediatric norms for tests of SFPN, and they provide new testable hypotheses for clinical and basic research study that we are now engaged in.”
—Glenn S. Williams
Vice President, Group Editor
Suggested Reading
Oaklander AL, Klein MM. Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes. Pediatrics. 2013;131(4):e1091-1100.
In a large series of adult and pediatric patients with juvenile-onset, unexplained, chronic widespread pain, more than half met rigorous, multi-test diagnostic criteria for small-fiber polyneuropathy (SFPN), according to a report in the April issue of Pediatrics. This finding, said lead author Anne Louise Oaklander, MD, PhD, extends the age range of acquired SFPN into young adulthood, adolescence, and even early childhood.
Dr. Oaklander and coauthor Max M. Klein, PhD, both affiliated with Massachusetts General Hospital and Harvard Medical School in Boston, evaluated 41 consecutive patients with unexplained widespread pain beginning before age 21. Most had extensive medical records that were extracted for the results of objective diagnostic testing for SFPN, which consisted of neurodiagnostic skin biopsy, nerve biopsy, and autonomic function testing. Secondary information came from subjects’ histories, symptoms, examinations, all other tests, and treatments. Healthy, demographically matched volunteers served as controls for SFPN tests.
“We chose for this initial characterization paper to focus on the youngest group with this disease, because they lacked potentially confounding conditions,” Dr. Oaklander told Neurology Reviews. “It can be hard to ascertain the specific cause of peripheral neuropathy in older adults because they have so many potentially neuropathic exposures and conditions. Here, by focusing on children, we were able to study a pure population in whom exposure to alcohol, toxins, nutritional deficiencies, cancer, and diabetes, were absent. The high signal-to-noise ratio enabled us to home in on the likelihood of autoimmune causality in most. Because of the different age-range and causality, we call this juvenile-onset small-fiber polyneuropathy, or JOSeFINE, to distinguish it from classical SFPN of older adults.”
Subjects included children from other countries and various races, demonstrating that JOSeFINE is present outside the US. Seventy-three percent of patients were female. Nearly 70% had been chronically disabled from school or work, and the same number (68%) had hospitalizations. Objective testing diagnosed definite SFPN in 59% and probable SFPN in 17%. Only one of the 41 subjects had entirely normal SFPN test results. Ninety-eight percent of patients also had other complaints thought to represent autonomic symptoms of SFPN (90% had cardiovascular, 82% had gastrointestinal, and 34% had urologic complaints). In addition, 83% reported chronic fatigue and 63% had chronic headache. Neurologic examinations identified reduced sensation in 68% and vasomotor abnormalities in 55%, including 23% with the erythromelalgia variant that produces areas of redness and burning that patients treat by cooling.
In addition, this study investigated the underlying causes of SFPN in this cohort. Several lines of evidence suggested immunologic problems. For example, past histories for 33% of subjects were notable only for history of other autoimmune illness, and extensive blood and urine tests revealed only serologic markers of disordered immunity in 89% of patients. In addition, some patients improved after immunomodulatory treatments. Corticosteroids or IV immune globulin objectively and subjectively benefited 12 of 15 patients (80%).
“This case series provides a new hypothesis about juvenile-onset, unexplained, acquired chronic widespread pain syndromes, implicating acquired SFPN, a biologically plausible diagnosis not previously recognized in children,” Drs. Oaklander and Klein wrote in their published paper. The data, they contend, suggest that SFPN can develop in children as young as preschool age and that juvenile-onset SFPN can persist for decades into adulthood.
“I would like to emphasize that this is not a disease only of children,” said Dr. Oaklander. “In fact, most patients were young adults by the time they reached us for diagnosis. Additionally, we have other patients who were not included in this study whose illness began when they were in their 20s, 30s, and even 40s. We have one older man in his 60s, but clearly the age range of JOSeFINE is different from the type of neuropathy that we associate with diabetes, cancers, and toxic exposures.
“Perhaps the most common label for these patients was pediatric fibromyalgia,” Dr. Oaklander continued. “Others had been called sero-negative Lyme or other vague descriptors. Basically, these are patients who kick around every hospital and pain clinic without a diagnosis. Now, for the first time, we’re offering a framework in which to organize care, with recommended examinations to perform, recommended diagnostic tests, and nonrecommended diagnostic tests—lumbar puncture is not useful, MRI is not useful. We homed in on the tests that are useful—skin biopsy, autonomic function testing—and we identified the blood tests that were most likely to provide supportive evidence—four specific blood tests associated with dysimmunity. Having a specific diagnosis to test for and treat when present may reduce ineffective, costly, and potentially harmful tests and treatments and permit objective testing and definitive treatment of some patients.”
In addition, the researchers said their results “demonstrate the need for pediatric norms for tests of SFPN, and they provide new testable hypotheses for clinical and basic research study that we are now engaged in.”
—Glenn S. Williams
Vice President, Group Editor
Suggested Reading
Oaklander AL, Klein MM. Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes. Pediatrics. 2013;131(4):e1091-1100.
In a large series of adult and pediatric patients with juvenile-onset, unexplained, chronic widespread pain, more than half met rigorous, multi-test diagnostic criteria for small-fiber polyneuropathy (SFPN), according to a report in the April issue of Pediatrics. This finding, said lead author Anne Louise Oaklander, MD, PhD, extends the age range of acquired SFPN into young adulthood, adolescence, and even early childhood.
Dr. Oaklander and coauthor Max M. Klein, PhD, both affiliated with Massachusetts General Hospital and Harvard Medical School in Boston, evaluated 41 consecutive patients with unexplained widespread pain beginning before age 21. Most had extensive medical records that were extracted for the results of objective diagnostic testing for SFPN, which consisted of neurodiagnostic skin biopsy, nerve biopsy, and autonomic function testing. Secondary information came from subjects’ histories, symptoms, examinations, all other tests, and treatments. Healthy, demographically matched volunteers served as controls for SFPN tests.
“We chose for this initial characterization paper to focus on the youngest group with this disease, because they lacked potentially confounding conditions,” Dr. Oaklander told Neurology Reviews. “It can be hard to ascertain the specific cause of peripheral neuropathy in older adults because they have so many potentially neuropathic exposures and conditions. Here, by focusing on children, we were able to study a pure population in whom exposure to alcohol, toxins, nutritional deficiencies, cancer, and diabetes, were absent. The high signal-to-noise ratio enabled us to home in on the likelihood of autoimmune causality in most. Because of the different age-range and causality, we call this juvenile-onset small-fiber polyneuropathy, or JOSeFINE, to distinguish it from classical SFPN of older adults.”
Subjects included children from other countries and various races, demonstrating that JOSeFINE is present outside the US. Seventy-three percent of patients were female. Nearly 70% had been chronically disabled from school or work, and the same number (68%) had hospitalizations. Objective testing diagnosed definite SFPN in 59% and probable SFPN in 17%. Only one of the 41 subjects had entirely normal SFPN test results. Ninety-eight percent of patients also had other complaints thought to represent autonomic symptoms of SFPN (90% had cardiovascular, 82% had gastrointestinal, and 34% had urologic complaints). In addition, 83% reported chronic fatigue and 63% had chronic headache. Neurologic examinations identified reduced sensation in 68% and vasomotor abnormalities in 55%, including 23% with the erythromelalgia variant that produces areas of redness and burning that patients treat by cooling.
In addition, this study investigated the underlying causes of SFPN in this cohort. Several lines of evidence suggested immunologic problems. For example, past histories for 33% of subjects were notable only for history of other autoimmune illness, and extensive blood and urine tests revealed only serologic markers of disordered immunity in 89% of patients. In addition, some patients improved after immunomodulatory treatments. Corticosteroids or IV immune globulin objectively and subjectively benefited 12 of 15 patients (80%).
“This case series provides a new hypothesis about juvenile-onset, unexplained, acquired chronic widespread pain syndromes, implicating acquired SFPN, a biologically plausible diagnosis not previously recognized in children,” Drs. Oaklander and Klein wrote in their published paper. The data, they contend, suggest that SFPN can develop in children as young as preschool age and that juvenile-onset SFPN can persist for decades into adulthood.
“I would like to emphasize that this is not a disease only of children,” said Dr. Oaklander. “In fact, most patients were young adults by the time they reached us for diagnosis. Additionally, we have other patients who were not included in this study whose illness began when they were in their 20s, 30s, and even 40s. We have one older man in his 60s, but clearly the age range of JOSeFINE is different from the type of neuropathy that we associate with diabetes, cancers, and toxic exposures.
“Perhaps the most common label for these patients was pediatric fibromyalgia,” Dr. Oaklander continued. “Others had been called sero-negative Lyme or other vague descriptors. Basically, these are patients who kick around every hospital and pain clinic without a diagnosis. Now, for the first time, we’re offering a framework in which to organize care, with recommended examinations to perform, recommended diagnostic tests, and nonrecommended diagnostic tests—lumbar puncture is not useful, MRI is not useful. We homed in on the tests that are useful—skin biopsy, autonomic function testing—and we identified the blood tests that were most likely to provide supportive evidence—four specific blood tests associated with dysimmunity. Having a specific diagnosis to test for and treat when present may reduce ineffective, costly, and potentially harmful tests and treatments and permit objective testing and definitive treatment of some patients.”
In addition, the researchers said their results “demonstrate the need for pediatric norms for tests of SFPN, and they provide new testable hypotheses for clinical and basic research study that we are now engaged in.”
—Glenn S. Williams
Vice President, Group Editor
Suggested Reading
Oaklander AL, Klein MM. Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes. Pediatrics. 2013;131(4):e1091-1100.
Start Planning Now for HM14
Whether you couldn’t make it to HM13 or you’re bringing back all the energy from the conference back to your hospital, now is the time to start planning for the next national conference exclusively designed for the nation’s 40,000 hospitalists.
For newcomers, HM14 will offer unprecedented access, networking, and CME-accredited educational sessions for hospitalists in all career stages. And for veterans of SHM’s annual meeting, 2014 will introduce two new pre-courses: “Cardiology and Evidence-Based Medicine” and “Bending the Cost Curve,” one of the hottest topics in public health, which will have its own dedicated track as well.
In addition to offering the best CME-accredited educational experience, HM14 will also give hospitalists the chance to enjoy an all-new official headquarters for the meeting: Mandalay Bay Hotel & Casino in Las Vegas.
Pre-Courses
Enhance the HM14 educational experience, broaden your skills, and earn additional CME credits. Choose from one of the following HM-focused topics:
- Medical Procedures for the Hospitalist;
- Portable Ultrasound for the Hospitalist;
- Perioperative Medicine;
- ABIM Maintenance of Certification;
- Practice Management;
- Neurology;
- Cardiology (new); and
- Evidence-Based Medicine (new).
Content Areas
The educational tracks offered at HM14 enable attendees to take courses in various designated tracks designed to better focus and enrich the annual meeting for attendees.
Tracks focus on the following cutting-edge content areas:
- Clinical;
- Rapid Fire;
- Practice Management;
- Academic/Research;
- Quality;
- Bending the Cost Curve (new);
- Pediatric;
- Potpourri;
- Comanagement; and
- Workshops.
Brendon Shank is SHM’s associate vice president of communications.
HM14 HEADQUARTERS: THE MANDALAY BAY HOTEL & CASINO
Enjoy casual elegance and comfort in the main tower’s rooms and suites, or relax in unparalleled sophistication and style at The Hotel at Mandalay Bay. At HM14 in March, hospitalists will:
- Bask in ultimate aquatic relaxation at the unforgettable, 11-acre Mandalay Bay Beach;
- Explore the Shark Reef Aquarium, featuring more than 2,000 exotic animals in a breathtaking 1.6-million-gallon habitat; and
- Taste the variety of foods at the 20-plus restaurants Mandalay Bay has to offer, including beach dining.
Whether you couldn’t make it to HM13 or you’re bringing back all the energy from the conference back to your hospital, now is the time to start planning for the next national conference exclusively designed for the nation’s 40,000 hospitalists.
For newcomers, HM14 will offer unprecedented access, networking, and CME-accredited educational sessions for hospitalists in all career stages. And for veterans of SHM’s annual meeting, 2014 will introduce two new pre-courses: “Cardiology and Evidence-Based Medicine” and “Bending the Cost Curve,” one of the hottest topics in public health, which will have its own dedicated track as well.
In addition to offering the best CME-accredited educational experience, HM14 will also give hospitalists the chance to enjoy an all-new official headquarters for the meeting: Mandalay Bay Hotel & Casino in Las Vegas.
Pre-Courses
Enhance the HM14 educational experience, broaden your skills, and earn additional CME credits. Choose from one of the following HM-focused topics:
- Medical Procedures for the Hospitalist;
- Portable Ultrasound for the Hospitalist;
- Perioperative Medicine;
- ABIM Maintenance of Certification;
- Practice Management;
- Neurology;
- Cardiology (new); and
- Evidence-Based Medicine (new).
Content Areas
The educational tracks offered at HM14 enable attendees to take courses in various designated tracks designed to better focus and enrich the annual meeting for attendees.
Tracks focus on the following cutting-edge content areas:
- Clinical;
- Rapid Fire;
- Practice Management;
- Academic/Research;
- Quality;
- Bending the Cost Curve (new);
- Pediatric;
- Potpourri;
- Comanagement; and
- Workshops.
Brendon Shank is SHM’s associate vice president of communications.
HM14 HEADQUARTERS: THE MANDALAY BAY HOTEL & CASINO
Enjoy casual elegance and comfort in the main tower’s rooms and suites, or relax in unparalleled sophistication and style at The Hotel at Mandalay Bay. At HM14 in March, hospitalists will:
- Bask in ultimate aquatic relaxation at the unforgettable, 11-acre Mandalay Bay Beach;
- Explore the Shark Reef Aquarium, featuring more than 2,000 exotic animals in a breathtaking 1.6-million-gallon habitat; and
- Taste the variety of foods at the 20-plus restaurants Mandalay Bay has to offer, including beach dining.
Whether you couldn’t make it to HM13 or you’re bringing back all the energy from the conference back to your hospital, now is the time to start planning for the next national conference exclusively designed for the nation’s 40,000 hospitalists.
For newcomers, HM14 will offer unprecedented access, networking, and CME-accredited educational sessions for hospitalists in all career stages. And for veterans of SHM’s annual meeting, 2014 will introduce two new pre-courses: “Cardiology and Evidence-Based Medicine” and “Bending the Cost Curve,” one of the hottest topics in public health, which will have its own dedicated track as well.
In addition to offering the best CME-accredited educational experience, HM14 will also give hospitalists the chance to enjoy an all-new official headquarters for the meeting: Mandalay Bay Hotel & Casino in Las Vegas.
Pre-Courses
Enhance the HM14 educational experience, broaden your skills, and earn additional CME credits. Choose from one of the following HM-focused topics:
- Medical Procedures for the Hospitalist;
- Portable Ultrasound for the Hospitalist;
- Perioperative Medicine;
- ABIM Maintenance of Certification;
- Practice Management;
- Neurology;
- Cardiology (new); and
- Evidence-Based Medicine (new).
Content Areas
The educational tracks offered at HM14 enable attendees to take courses in various designated tracks designed to better focus and enrich the annual meeting for attendees.
Tracks focus on the following cutting-edge content areas:
- Clinical;
- Rapid Fire;
- Practice Management;
- Academic/Research;
- Quality;
- Bending the Cost Curve (new);
- Pediatric;
- Potpourri;
- Comanagement; and
- Workshops.
Brendon Shank is SHM’s associate vice president of communications.
HM14 HEADQUARTERS: THE MANDALAY BAY HOTEL & CASINO
Enjoy casual elegance and comfort in the main tower’s rooms and suites, or relax in unparalleled sophistication and style at The Hotel at Mandalay Bay. At HM14 in March, hospitalists will:
- Bask in ultimate aquatic relaxation at the unforgettable, 11-acre Mandalay Bay Beach;
- Explore the Shark Reef Aquarium, featuring more than 2,000 exotic animals in a breathtaking 1.6-million-gallon habitat; and
- Taste the variety of foods at the 20-plus restaurants Mandalay Bay has to offer, including beach dining.
Physician Reviews of Hospital Medicine-Related Research
In This Edition
Literature At A Glance
A guide to this month’s studies
- Prices for common hospital procedures not readily available
- Antibiotics associated with decreased mortality in acute COPD exacerbation
- Endovascular therapy has no benefit to systemic t-PA in acute stroke
- Net harm observed with rivaroxaban for thromboprophylaxis
- Noninvasive ventilation more effective, safer for AECOPD patients
- Synthetic cannabinoid use and acute kidney injury
- Dabigatran vs. warfarin in the extended treatment of VTE
- Spironolactone improves diastolic function
- Real-time EMR-based prediction tool for clinical deterioration
- Hypothermia protocol and cardiac arrest
Prices for Common Hospital Procedures Not Readily Available
Clinical question: Are patients able to select health-care providers based on price of service?
Background: With health-care costs rising, patients are encouraged to take a more active role in cost containment. Many initiatives call for greater pricing transparency in the health-care system. This study evaluated price availability for a common surgical procedure.
Study design: Telephone inquiries with standardized interview script.
Setting: Twenty top-ranked orthopedic hospitals and 102 non-top-ranked U.S. hospitals.
Synopsis: Hospitals were contacted by phone with a standardized, scripted request for their price of an elective total hip arthroplasty. The script described the patient as a 62-year-old grandmother without insurance who is able to pay out of pocket and wishes to compare hospital prices. On the first or second attempt, 40% of top-ranked and 32% of non-top-ranked hospitals were able to provide their price; after five attempts, authors were unable to obtain full pricing information (both hospital and physician fee) from 40% of top-ranked and 37% of non-top-ranked hospitals. Neither fee was made available by 15% of top-ranked and 16% of non-top-ranked hospitals. Wide variation of pricing was found across hospitals. The authors commented on the difficulties they encountered, such as the transfer of calls between departments and the uncertainty of representatives on how to assist.
Bottom line: For individual patients, applying basic economic principles as a consumer might be tiresome and often impossible, with no major differences between top-ranked and non-top-ranked hospitals.
Citation: Rosenthal JA, Lu X, Cram P. Availability of consumer prices from US hospitals for a common surgical procedure. JAMA Intern Med. 2013;173(6):427-432.
Antibiotics Associated with Decreased Mortality in Acute COPD Exacerbation
Clinical question: Do antibiotics when added to systemic steroids provide clinical benefit for patients with acute COPD exacerbation?
Background: Despite widespread use of antibiotics in the treatment of acute COPD, their benefit is not clear.
Study design: Retrospective cohort study.Setting: Four hundred ten U.S. hospitals participating in Perspective, an inpatient administrative database.
Synopsis: More than 50,000 patients treated with systemic steroids for acute COPD exacerbation were included in this study; 85% of them received empiric antibiotics within the first two hospital days. They were compared with those treated with systemic steroids alone. In-hospital mortality was 1.02% for patients on steroids plus antibiotics versus 1.78% on steroids alone. Use of antibiotics was associated with a 40% reduction in the odds of in-hospital mortality (OR, 0.60; 95% CI, 0.50-0.74) and reduced readmissions. In an analysis of matched cohorts, hospital mortality was 1% for patients on antibiotics and 1.8% for patients without antibiotics (OR, 0.53; 95% CI, 0.40-0.71). The risk for readmission for Clostridium difficile colitis was not different between the groups, but other potential adverse effects of antibiotic use, such as development of resistant micro-organisms, were not studied. In a subset analysis, three groups of antibiotics were compared: macrolides, quinolones, and cephalosporins. None was better than another, but those treated with macrolides had a lower readmission rate for C. diff.
Bottom line: Treatment with antibiotics when added to systemic steroids is associated with improved outcomes in acute COPD exacerbations, but there is no clear advantage of one antibiotic class over another.
Citation: Stefan MS, Rothberg MB, Shieh M, Pekow PS, Lindenauer PK. Association between antibiotic treatment and outcomes in patients hospitalized with acute exacerbation of COPD treated with systemic steroids. Chest. 2013;143(1):82-90.
Endovascular Therapy Added to Systemic t-PA Has No Benefit in Acute Stroke
Clinical question: Does adding endovascular therapy to intravenous tissue plasminogen activator (t-PA) reduce disability in acute stroke?
Background: Early systemic t-PA is the only proven reperfusion therapy in acute stroke, but it is unknown if adding localized endovascular therapy is beneficial.
Study design: Randomized, open-label, blinded-outcome trial.
Setting: Fifty-eight centers in North America, Europe, and Australia.
Synopsis: Patients aged 18 to 82 with acute ischemic stroke were eligible if they received t-PA within three hours of enrollment and had moderate to severe neurologic deficit (National Institutes of Health Stroke Scale [NIHSS] >10, or NIHSS 8 or 9 with CT angiographic evidence of specific major artery occlusion). All patients received standard-dose t-PA; those randomized to endovascular treatment underwent angiography, and, if indicated, underwent one of the endovascular treatments chosen by the neurointerventionalist. The primary outcome measure was a modified Rankin score of 2 or lower (indicating functional independence) at 90 days (assessed by a neurologist).
After enrollment of 656 patients, the trial was terminated early for futility. There was no significant difference in the primary outcome, with 40.8% of patients in the endovascular intervention group and 38.7% in the t-PA-only group having a modified Rankin score of 2 or lower. There was also no difference in mortality or other secondary outcomes, even when the analysis was limited to patients presenting with more severe neurologic deficits.
Bottom line: The addition of endovascular therapy to systemic t-PA in acute ischemic stroke does not improve functional outcomes or mortality.
Citation: Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893-903.
Rivaroxaban Compared with Enoxaparin for Thromboprophylaxis
Clinical question: Is extended-duration rivaroxaban more effective than standard-duration enoxaparin in preventing deep venous thrombosis in acutely ill medical patients?
Background: Trials have shown benefits of thromboprophylaxis in acutely ill medical patients at increased risk of venous thrombosis, but the optimal duration and type of anticoagulation is unknown.
Study design: Prospective, randomized, double-blinded, active-comparator controlled trial.
Setting: Five hundred fifty-two centers in 52 countries.
Synopsis: The trial enrolled 8,428 patients hospitalized with an acute medical condition and reduced mobility. Patients were randomized to receive either enoxaparin for 10 (+/-4) days or rivaroxaban for 35 (+/-4) days. The co-primary composite outcomes were the incidence of asymptomatic proximal deep venous thrombosis, symptomatic deep venous thrombosis, pulmonary embolism, or death related to venous thromboembolism over 10 days and over 35 days.
Both groups had a 2.7% incidence of the primary endpoint over 10 days; over 35 days, the extended-duration rivaroxaban group had a reduced incidence of the primary endpoint of 4.4% compared with 5.7% for enoxaparin. However, there was an increase of clinically relevant bleeding in the rivaroxaban group, occurring in 2.8% and 4.1% of patients over 10 and 35 days, respectively, compared with 1.2% and 1.7% for enoxaparin.
Overall, there was net harm with rivaroxaban over both time periods: 6.6% and 9.4% of patients in the rivaroxaban group had a negative outcome at 10 and 35 days, compared with 4.4% and 7.8% with enoxaparin.
Bottom line: There was net harm with extended-duration rivaroxaban versus standard-duration enoxaparin for thromboprophylaxis in hospitalized medical patients.
Citation: Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368:513-523.
Noninvasive Ventilation More Effective, Safer for Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)
Clinical question: What are the patterns in use of noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) in patients with AECOPD, and which method produces better outcomes?
Background: Multiple randomized controlled trials and meta-analyses have suggested a mortality benefit with NIV compared to standard medical care in AECOPD. However, little evidence exists on head-to-head comparisons of NIV and IMV.
Study design: Retrospective cohort study.
Setting: Non-federal, short-term, general, and other specialty hospitals nationwide.
Synopsis: A sample of 67,651 ED visits for AECOPD with acute respiratory failure was analyzed from the National Emergency Department Sample (NEDS) database between 2006 and 2008. The study found that NIV use increased to 16% in 2008 from 14% in 2006. Use varied widely between hospitals and was more utilized in higher-case-volume, nonmetropolitan, and Northeastern hospitals. Compared with IMV, NIV was associated with 46% lower inpatient mortality (risk ratio 0.54, 95% confidence interval [CI] 0.50-0.59), shortened hospital length of stay (-3.2 days, 95% CI -3.4 to -2.9), lower hospital charges (-$35,012, 95% CI -$36,848 to -$33,176), and lower risk of iatrogenic pneumothorax (0.05% vs. 0.5%, P<0.001). Causality could not be established given the observational study design.
Bottom line: NIV is associated with better outcomes than IMV in the management of AECOPD, and might be underutilized.
Citation: Tsai CL, Lee WY, Delclos GL, Hanania NA, Camargo CA Jr. Comparative effectiveness of noninvasive ventilation vs. invasive mechanical ventilation in chronic obstructive pulmonary disease patients with acute respiratory failure. J Hosp Med. 2013;8(4):165-172.
Synthetic Cannabinoid Use May Cause Acute Kidney Injury
Clinical question: Are synthetic cannabinoids associated with acute kidney injury (AKI)?
Background: Synthetic cannabinoids are designer drugs of abuse with a growing popularity in the U.S.
Study design: Retrospective case series.
Setting: Hospitals in Wyoming, Oklahoma, Rhode Island, New York, Kansas, and Oregon.
Synopsis: The Centers for Disease Control and Prevention (CDC) issued an alert when 16 cases of unexplained AKI after exposure to synthetic cannabinoids were reported between March and December 2012. Synthetic cannabinoid use is associated with neurologic, sympathomimetic, and cardiovascular toxicity; however, this is the first case series reporting renal toxicity. The 16 patients included 15 males and one female, aged 15-33 years, with no pre-existing renal disease or nephrotoxic medication consumption. All used synthetic cannabinoids within hours to days before developing nausea, vomiting, abdominal, and flank and/or back pain.
Creatinine peaked one to six days after symptom onset. Five patients required hemodialysis, and all 16 recovered. There was no finding specific for all cases on ultrasound and/or biopsy. Toxicologic analysis of specimens was possible in seven cases and revealed a previously unreported fluorinated synthetic cannabinoid compound XLR-11 in all clinical specimens of patients who used the drug within two days of being tested.
Overall, the analysis did not reveal any single compound or brand that could explain all cases.
Bottom line: Clinicians should be aware of the potential for renal or other toxicities in users of synthetic cannabinoid products and should ask about their use in cases of unexplained AKI.
Citation: Murphy TD, Weidenbach KN, Van Houten C, et al. Centers for Disease Control and Prevention. Acute kidney injury associated with synthetic cannabinoid use—multiple states, 2012. MMWR Morb Mortal Wkly Rep. 2013;62(6):93-98.
Dabigatran versus Warfarin in Extended VTE Treatment
Clinical question: Is dabigatran suitable for extended treatment VTE?
Background: In contrast to warfarin (Coumadin), dabigatran (Pradaxa) is given in a fixed dose and does not require frequent laboratory monitoring. Dabigatran has been shown to be noninferior to warfarin in the initial six-month treatment of VTE.
Study design: Two double-blinded, randomized trials: an active-control study and a placebo-control study.
Setting: Two hundred sixty-five sites in 33 countries for the active-control study, and 147 sites in 21 countries for the placebo-control study.
Synopsis: This study enrolled 4,299 adult patients with objectively confirmed, symptomatic, proximal deep vein thrombosis or pulmonary embolism. In the active-control study comparing warfarin and dabigatran, recurrent objectively confirmed symptomatic or fatal VTE was observed in 1.8% of patients in the dabigatran group compared with 1.3% of patients in the warfarin group (P=0.01 for noninferiority). While major or clinically relevant bleeding was less frequent with dabigatran compared to warfarin (hazard ratio, 0.54), more acute coronary syndromes were observed with dabigatran (0.9% vs. 0.2%, P=0.02). In the placebo-control study, symptomatic or fatal VTE was observed in 0.4% of patients in the dabigatran group compared with 5.6% in the placebo group. Clinically relevant bleeding was more common with dabigatran (5.3% vs. 1.8%; hazard ratio 2.92).
Bottom line: Treatment with dabigatran met the pre-specified noninferiority margin in this study. However, it is worth noting that patients with VTE given extended treatment with dabigatran had significantly higher rates of recurrent symptomatic or fatal VTE than patients treated with warfarin.
Citation: Schulman S, Kearson C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718.
Spironolactone Improves Diastolic Function
Clinical question: What is the efficacy of aldosterone receptor blockers on diastolic function and exercise capacity?
Background: Mineralocorticoid receptor activation by aldosterone contributes to the pathophysiology of heart failure (HF) in patients with and without reduced ejection fraction (EF). Aldosterone receptor blockers (spironolactone) reduce overall and cardiovascular mortality in HF patients with reduced EF; however, its effect on HF patients with preserved EF is unknown.
Study design: Prospective, randomized, double-blinded, placebo-controlled trial.
Setting: Ten ambulatory sites in Germany and Austria.
Synopsis: This study enrolled 422 men and women, aged 50 or older, with New York Heart Association (NYHA) Class II or III HF and preserved EF, and randomized them to receive spironolactone 25 mg daily or placebo for one year.
The endpoints included echocardiographic measures of diastolic function and remodeling; N-terminal pro b-type natriuretic peptide (NT pro-BNP) levels; exercise capacity; quality of life; and HF symptoms.
In the spironolactone group, there was significant improvement in echocardiographic measures of diastolic function and remodeling as well as NT pro-BNP levels. However, there was no difference in exercise capacity, quality of life, or HF symptoms when compared to placebo.
The spironolactone group had significantly lower blood pressure than the control group, which may account for some of the remodeling effects. The study may have been underpowered, and the study population might not have had severe enough disease to detect a difference in clinical measures. It remains unknown if structural changes on echocardiography will translate into clinical benefits.
Bottom line: Compared to placebo, spironolactone did improve diastolic function by echo but did not improve exercise capacity.
Citation: Edelmann F, Wachter R, Schmidt A, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013;309(8):781-791.
Real-Time, EMR-Based Prediction Tool Accurately Predicts ICU Transfer Risks
Clinical question: Can clinical deterioration be accurately predicted using real-time data from an electronic medical record (EMR), and can it lead to better outcomes using a floor-based intervention?
Background: Research has shown that EMR-based prediction tools can help identify real-time clinical deterioration in ward patients, but an intervention based on these computer-based alerts has not been shown to be effective.
Study design: Randomized controlled crossover study.
Setting: Eight adult medicine wards in an academic medical center in the Midwest.
Synopsis: There were 20,031 patients assigned to intervention versus control based on their floor location. Computerized alerts were generated using a prediction algorithm. For patients admitted to intervention wards, the alerts were sent to the charge nurse via pager. Patients meeting the alert threshold based on the computerized prediction tool had five times higher risk of ICU transfer, and nine times higher risk of death than patients not meeting the alert threshold. Intervention of charge nurse notification via pager did not result in any significant change in length of stay (LOS), ICU transfer, or mortality. Charge nurses in the intervention group were supposed to alert a physician after receiving the computer alert, but the authors did not measure how often this occurred.
Bottom line: A real-time EMR-based prediction tool accurately predicts higher risk of ICU transfer and death, as well as LOS, but a floor-based intervention to alert the charge nurse in real time did not lead to better outcomes.
Citation: Bailey TC, Chen Y, Mao Y, et al. A trial of a real-time alert for clinical deterioration in patients hospitalized on general medicine wards. J Hosp Med. 2013 Feb 25. doi: 10.1002/jhm.2009 [Epub ahead of print].
Hypothermia Protocol and Cardiac Arrest
Clinical question: Is mild therapeutic hypothermia (MTH) following cardiac arrest beneficial and safe?
Background: Those with sudden cardiac arrest often have poor neurologic outcome. There are some studies that show benefit with hypothermia, but information on safety is limited.
Study design: Meta-analysis.
Setting: Europe, the United Kingdom, the U.S., Canada, Japan, and South Korea.
Synopsis: This study pooled data from 63 studies that looked at MTH protocols in the setting of comatose patients as a result of cardiac arrest. The end points included mortality and any complication potentially attributed to the MTH.
When restricting the analysis to include only randomized controlled trials, MTH was associated with decreased risk of in-hospital mortality (RR=0.75, 95% CI: 0.62-0.92), 30-day mortality (RR=0.61, 95% CI 0.45-0.81), and six-month mortality (RR=0.73, 95% CI 0.61-0.88). MTH was associated with increased risk of arrhythmia (RR=1.25, 95% CI: 1.00-1.55) and hypokalemia (RR=2.35, 95% CI: 1.35-4.11); all other complications were similar between groups.
There were inconsistent results regarding benefit in pediatric patients, as well as comatose patients with non-ventricular fibrillation (non-v-fib) arrest (i.e. asystole or pulseless electrical activity).
Bottom line: Mild therapeutic hypothermia can improve survival of comatose patients after v-fib cardiac arrest and is generally safe.
Citation: Xiao G, Guo Q, Xie X, et al. Safety profile and outcome of mild therapeutic hypothermia in patients following cardiac arrest: systematic review and meta-analysis. Emerg Med J. 2013;30:90-100.
In This Edition
Literature At A Glance
A guide to this month’s studies
- Prices for common hospital procedures not readily available
- Antibiotics associated with decreased mortality in acute COPD exacerbation
- Endovascular therapy has no benefit to systemic t-PA in acute stroke
- Net harm observed with rivaroxaban for thromboprophylaxis
- Noninvasive ventilation more effective, safer for AECOPD patients
- Synthetic cannabinoid use and acute kidney injury
- Dabigatran vs. warfarin in the extended treatment of VTE
- Spironolactone improves diastolic function
- Real-time EMR-based prediction tool for clinical deterioration
- Hypothermia protocol and cardiac arrest
Prices for Common Hospital Procedures Not Readily Available
Clinical question: Are patients able to select health-care providers based on price of service?
Background: With health-care costs rising, patients are encouraged to take a more active role in cost containment. Many initiatives call for greater pricing transparency in the health-care system. This study evaluated price availability for a common surgical procedure.
Study design: Telephone inquiries with standardized interview script.
Setting: Twenty top-ranked orthopedic hospitals and 102 non-top-ranked U.S. hospitals.
Synopsis: Hospitals were contacted by phone with a standardized, scripted request for their price of an elective total hip arthroplasty. The script described the patient as a 62-year-old grandmother without insurance who is able to pay out of pocket and wishes to compare hospital prices. On the first or second attempt, 40% of top-ranked and 32% of non-top-ranked hospitals were able to provide their price; after five attempts, authors were unable to obtain full pricing information (both hospital and physician fee) from 40% of top-ranked and 37% of non-top-ranked hospitals. Neither fee was made available by 15% of top-ranked and 16% of non-top-ranked hospitals. Wide variation of pricing was found across hospitals. The authors commented on the difficulties they encountered, such as the transfer of calls between departments and the uncertainty of representatives on how to assist.
Bottom line: For individual patients, applying basic economic principles as a consumer might be tiresome and often impossible, with no major differences between top-ranked and non-top-ranked hospitals.
Citation: Rosenthal JA, Lu X, Cram P. Availability of consumer prices from US hospitals for a common surgical procedure. JAMA Intern Med. 2013;173(6):427-432.
Antibiotics Associated with Decreased Mortality in Acute COPD Exacerbation
Clinical question: Do antibiotics when added to systemic steroids provide clinical benefit for patients with acute COPD exacerbation?
Background: Despite widespread use of antibiotics in the treatment of acute COPD, their benefit is not clear.
Study design: Retrospective cohort study.Setting: Four hundred ten U.S. hospitals participating in Perspective, an inpatient administrative database.
Synopsis: More than 50,000 patients treated with systemic steroids for acute COPD exacerbation were included in this study; 85% of them received empiric antibiotics within the first two hospital days. They were compared with those treated with systemic steroids alone. In-hospital mortality was 1.02% for patients on steroids plus antibiotics versus 1.78% on steroids alone. Use of antibiotics was associated with a 40% reduction in the odds of in-hospital mortality (OR, 0.60; 95% CI, 0.50-0.74) and reduced readmissions. In an analysis of matched cohorts, hospital mortality was 1% for patients on antibiotics and 1.8% for patients without antibiotics (OR, 0.53; 95% CI, 0.40-0.71). The risk for readmission for Clostridium difficile colitis was not different between the groups, but other potential adverse effects of antibiotic use, such as development of resistant micro-organisms, were not studied. In a subset analysis, three groups of antibiotics were compared: macrolides, quinolones, and cephalosporins. None was better than another, but those treated with macrolides had a lower readmission rate for C. diff.
Bottom line: Treatment with antibiotics when added to systemic steroids is associated with improved outcomes in acute COPD exacerbations, but there is no clear advantage of one antibiotic class over another.
Citation: Stefan MS, Rothberg MB, Shieh M, Pekow PS, Lindenauer PK. Association between antibiotic treatment and outcomes in patients hospitalized with acute exacerbation of COPD treated with systemic steroids. Chest. 2013;143(1):82-90.
Endovascular Therapy Added to Systemic t-PA Has No Benefit in Acute Stroke
Clinical question: Does adding endovascular therapy to intravenous tissue plasminogen activator (t-PA) reduce disability in acute stroke?
Background: Early systemic t-PA is the only proven reperfusion therapy in acute stroke, but it is unknown if adding localized endovascular therapy is beneficial.
Study design: Randomized, open-label, blinded-outcome trial.
Setting: Fifty-eight centers in North America, Europe, and Australia.
Synopsis: Patients aged 18 to 82 with acute ischemic stroke were eligible if they received t-PA within three hours of enrollment and had moderate to severe neurologic deficit (National Institutes of Health Stroke Scale [NIHSS] >10, or NIHSS 8 or 9 with CT angiographic evidence of specific major artery occlusion). All patients received standard-dose t-PA; those randomized to endovascular treatment underwent angiography, and, if indicated, underwent one of the endovascular treatments chosen by the neurointerventionalist. The primary outcome measure was a modified Rankin score of 2 or lower (indicating functional independence) at 90 days (assessed by a neurologist).
After enrollment of 656 patients, the trial was terminated early for futility. There was no significant difference in the primary outcome, with 40.8% of patients in the endovascular intervention group and 38.7% in the t-PA-only group having a modified Rankin score of 2 or lower. There was also no difference in mortality or other secondary outcomes, even when the analysis was limited to patients presenting with more severe neurologic deficits.
Bottom line: The addition of endovascular therapy to systemic t-PA in acute ischemic stroke does not improve functional outcomes or mortality.
Citation: Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893-903.
Rivaroxaban Compared with Enoxaparin for Thromboprophylaxis
Clinical question: Is extended-duration rivaroxaban more effective than standard-duration enoxaparin in preventing deep venous thrombosis in acutely ill medical patients?
Background: Trials have shown benefits of thromboprophylaxis in acutely ill medical patients at increased risk of venous thrombosis, but the optimal duration and type of anticoagulation is unknown.
Study design: Prospective, randomized, double-blinded, active-comparator controlled trial.
Setting: Five hundred fifty-two centers in 52 countries.
Synopsis: The trial enrolled 8,428 patients hospitalized with an acute medical condition and reduced mobility. Patients were randomized to receive either enoxaparin for 10 (+/-4) days or rivaroxaban for 35 (+/-4) days. The co-primary composite outcomes were the incidence of asymptomatic proximal deep venous thrombosis, symptomatic deep venous thrombosis, pulmonary embolism, or death related to venous thromboembolism over 10 days and over 35 days.
Both groups had a 2.7% incidence of the primary endpoint over 10 days; over 35 days, the extended-duration rivaroxaban group had a reduced incidence of the primary endpoint of 4.4% compared with 5.7% for enoxaparin. However, there was an increase of clinically relevant bleeding in the rivaroxaban group, occurring in 2.8% and 4.1% of patients over 10 and 35 days, respectively, compared with 1.2% and 1.7% for enoxaparin.
Overall, there was net harm with rivaroxaban over both time periods: 6.6% and 9.4% of patients in the rivaroxaban group had a negative outcome at 10 and 35 days, compared with 4.4% and 7.8% with enoxaparin.
Bottom line: There was net harm with extended-duration rivaroxaban versus standard-duration enoxaparin for thromboprophylaxis in hospitalized medical patients.
Citation: Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368:513-523.
Noninvasive Ventilation More Effective, Safer for Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)
Clinical question: What are the patterns in use of noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) in patients with AECOPD, and which method produces better outcomes?
Background: Multiple randomized controlled trials and meta-analyses have suggested a mortality benefit with NIV compared to standard medical care in AECOPD. However, little evidence exists on head-to-head comparisons of NIV and IMV.
Study design: Retrospective cohort study.
Setting: Non-federal, short-term, general, and other specialty hospitals nationwide.
Synopsis: A sample of 67,651 ED visits for AECOPD with acute respiratory failure was analyzed from the National Emergency Department Sample (NEDS) database between 2006 and 2008. The study found that NIV use increased to 16% in 2008 from 14% in 2006. Use varied widely between hospitals and was more utilized in higher-case-volume, nonmetropolitan, and Northeastern hospitals. Compared with IMV, NIV was associated with 46% lower inpatient mortality (risk ratio 0.54, 95% confidence interval [CI] 0.50-0.59), shortened hospital length of stay (-3.2 days, 95% CI -3.4 to -2.9), lower hospital charges (-$35,012, 95% CI -$36,848 to -$33,176), and lower risk of iatrogenic pneumothorax (0.05% vs. 0.5%, P<0.001). Causality could not be established given the observational study design.
Bottom line: NIV is associated with better outcomes than IMV in the management of AECOPD, and might be underutilized.
Citation: Tsai CL, Lee WY, Delclos GL, Hanania NA, Camargo CA Jr. Comparative effectiveness of noninvasive ventilation vs. invasive mechanical ventilation in chronic obstructive pulmonary disease patients with acute respiratory failure. J Hosp Med. 2013;8(4):165-172.
Synthetic Cannabinoid Use May Cause Acute Kidney Injury
Clinical question: Are synthetic cannabinoids associated with acute kidney injury (AKI)?
Background: Synthetic cannabinoids are designer drugs of abuse with a growing popularity in the U.S.
Study design: Retrospective case series.
Setting: Hospitals in Wyoming, Oklahoma, Rhode Island, New York, Kansas, and Oregon.
Synopsis: The Centers for Disease Control and Prevention (CDC) issued an alert when 16 cases of unexplained AKI after exposure to synthetic cannabinoids were reported between March and December 2012. Synthetic cannabinoid use is associated with neurologic, sympathomimetic, and cardiovascular toxicity; however, this is the first case series reporting renal toxicity. The 16 patients included 15 males and one female, aged 15-33 years, with no pre-existing renal disease or nephrotoxic medication consumption. All used synthetic cannabinoids within hours to days before developing nausea, vomiting, abdominal, and flank and/or back pain.
Creatinine peaked one to six days after symptom onset. Five patients required hemodialysis, and all 16 recovered. There was no finding specific for all cases on ultrasound and/or biopsy. Toxicologic analysis of specimens was possible in seven cases and revealed a previously unreported fluorinated synthetic cannabinoid compound XLR-11 in all clinical specimens of patients who used the drug within two days of being tested.
Overall, the analysis did not reveal any single compound or brand that could explain all cases.
Bottom line: Clinicians should be aware of the potential for renal or other toxicities in users of synthetic cannabinoid products and should ask about their use in cases of unexplained AKI.
Citation: Murphy TD, Weidenbach KN, Van Houten C, et al. Centers for Disease Control and Prevention. Acute kidney injury associated with synthetic cannabinoid use—multiple states, 2012. MMWR Morb Mortal Wkly Rep. 2013;62(6):93-98.
Dabigatran versus Warfarin in Extended VTE Treatment
Clinical question: Is dabigatran suitable for extended treatment VTE?
Background: In contrast to warfarin (Coumadin), dabigatran (Pradaxa) is given in a fixed dose and does not require frequent laboratory monitoring. Dabigatran has been shown to be noninferior to warfarin in the initial six-month treatment of VTE.
Study design: Two double-blinded, randomized trials: an active-control study and a placebo-control study.
Setting: Two hundred sixty-five sites in 33 countries for the active-control study, and 147 sites in 21 countries for the placebo-control study.
Synopsis: This study enrolled 4,299 adult patients with objectively confirmed, symptomatic, proximal deep vein thrombosis or pulmonary embolism. In the active-control study comparing warfarin and dabigatran, recurrent objectively confirmed symptomatic or fatal VTE was observed in 1.8% of patients in the dabigatran group compared with 1.3% of patients in the warfarin group (P=0.01 for noninferiority). While major or clinically relevant bleeding was less frequent with dabigatran compared to warfarin (hazard ratio, 0.54), more acute coronary syndromes were observed with dabigatran (0.9% vs. 0.2%, P=0.02). In the placebo-control study, symptomatic or fatal VTE was observed in 0.4% of patients in the dabigatran group compared with 5.6% in the placebo group. Clinically relevant bleeding was more common with dabigatran (5.3% vs. 1.8%; hazard ratio 2.92).
Bottom line: Treatment with dabigatran met the pre-specified noninferiority margin in this study. However, it is worth noting that patients with VTE given extended treatment with dabigatran had significantly higher rates of recurrent symptomatic or fatal VTE than patients treated with warfarin.
Citation: Schulman S, Kearson C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718.
Spironolactone Improves Diastolic Function
Clinical question: What is the efficacy of aldosterone receptor blockers on diastolic function and exercise capacity?
Background: Mineralocorticoid receptor activation by aldosterone contributes to the pathophysiology of heart failure (HF) in patients with and without reduced ejection fraction (EF). Aldosterone receptor blockers (spironolactone) reduce overall and cardiovascular mortality in HF patients with reduced EF; however, its effect on HF patients with preserved EF is unknown.
Study design: Prospective, randomized, double-blinded, placebo-controlled trial.
Setting: Ten ambulatory sites in Germany and Austria.
Synopsis: This study enrolled 422 men and women, aged 50 or older, with New York Heart Association (NYHA) Class II or III HF and preserved EF, and randomized them to receive spironolactone 25 mg daily or placebo for one year.
The endpoints included echocardiographic measures of diastolic function and remodeling; N-terminal pro b-type natriuretic peptide (NT pro-BNP) levels; exercise capacity; quality of life; and HF symptoms.
In the spironolactone group, there was significant improvement in echocardiographic measures of diastolic function and remodeling as well as NT pro-BNP levels. However, there was no difference in exercise capacity, quality of life, or HF symptoms when compared to placebo.
The spironolactone group had significantly lower blood pressure than the control group, which may account for some of the remodeling effects. The study may have been underpowered, and the study population might not have had severe enough disease to detect a difference in clinical measures. It remains unknown if structural changes on echocardiography will translate into clinical benefits.
Bottom line: Compared to placebo, spironolactone did improve diastolic function by echo but did not improve exercise capacity.
Citation: Edelmann F, Wachter R, Schmidt A, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013;309(8):781-791.
Real-Time, EMR-Based Prediction Tool Accurately Predicts ICU Transfer Risks
Clinical question: Can clinical deterioration be accurately predicted using real-time data from an electronic medical record (EMR), and can it lead to better outcomes using a floor-based intervention?
Background: Research has shown that EMR-based prediction tools can help identify real-time clinical deterioration in ward patients, but an intervention based on these computer-based alerts has not been shown to be effective.
Study design: Randomized controlled crossover study.
Setting: Eight adult medicine wards in an academic medical center in the Midwest.
Synopsis: There were 20,031 patients assigned to intervention versus control based on their floor location. Computerized alerts were generated using a prediction algorithm. For patients admitted to intervention wards, the alerts were sent to the charge nurse via pager. Patients meeting the alert threshold based on the computerized prediction tool had five times higher risk of ICU transfer, and nine times higher risk of death than patients not meeting the alert threshold. Intervention of charge nurse notification via pager did not result in any significant change in length of stay (LOS), ICU transfer, or mortality. Charge nurses in the intervention group were supposed to alert a physician after receiving the computer alert, but the authors did not measure how often this occurred.
Bottom line: A real-time EMR-based prediction tool accurately predicts higher risk of ICU transfer and death, as well as LOS, but a floor-based intervention to alert the charge nurse in real time did not lead to better outcomes.
Citation: Bailey TC, Chen Y, Mao Y, et al. A trial of a real-time alert for clinical deterioration in patients hospitalized on general medicine wards. J Hosp Med. 2013 Feb 25. doi: 10.1002/jhm.2009 [Epub ahead of print].
Hypothermia Protocol and Cardiac Arrest
Clinical question: Is mild therapeutic hypothermia (MTH) following cardiac arrest beneficial and safe?
Background: Those with sudden cardiac arrest often have poor neurologic outcome. There are some studies that show benefit with hypothermia, but information on safety is limited.
Study design: Meta-analysis.
Setting: Europe, the United Kingdom, the U.S., Canada, Japan, and South Korea.
Synopsis: This study pooled data from 63 studies that looked at MTH protocols in the setting of comatose patients as a result of cardiac arrest. The end points included mortality and any complication potentially attributed to the MTH.
When restricting the analysis to include only randomized controlled trials, MTH was associated with decreased risk of in-hospital mortality (RR=0.75, 95% CI: 0.62-0.92), 30-day mortality (RR=0.61, 95% CI 0.45-0.81), and six-month mortality (RR=0.73, 95% CI 0.61-0.88). MTH was associated with increased risk of arrhythmia (RR=1.25, 95% CI: 1.00-1.55) and hypokalemia (RR=2.35, 95% CI: 1.35-4.11); all other complications were similar between groups.
There were inconsistent results regarding benefit in pediatric patients, as well as comatose patients with non-ventricular fibrillation (non-v-fib) arrest (i.e. asystole or pulseless electrical activity).
Bottom line: Mild therapeutic hypothermia can improve survival of comatose patients after v-fib cardiac arrest and is generally safe.
Citation: Xiao G, Guo Q, Xie X, et al. Safety profile and outcome of mild therapeutic hypothermia in patients following cardiac arrest: systematic review and meta-analysis. Emerg Med J. 2013;30:90-100.
In This Edition
Literature At A Glance
A guide to this month’s studies
- Prices for common hospital procedures not readily available
- Antibiotics associated with decreased mortality in acute COPD exacerbation
- Endovascular therapy has no benefit to systemic t-PA in acute stroke
- Net harm observed with rivaroxaban for thromboprophylaxis
- Noninvasive ventilation more effective, safer for AECOPD patients
- Synthetic cannabinoid use and acute kidney injury
- Dabigatran vs. warfarin in the extended treatment of VTE
- Spironolactone improves diastolic function
- Real-time EMR-based prediction tool for clinical deterioration
- Hypothermia protocol and cardiac arrest
Prices for Common Hospital Procedures Not Readily Available
Clinical question: Are patients able to select health-care providers based on price of service?
Background: With health-care costs rising, patients are encouraged to take a more active role in cost containment. Many initiatives call for greater pricing transparency in the health-care system. This study evaluated price availability for a common surgical procedure.
Study design: Telephone inquiries with standardized interview script.
Setting: Twenty top-ranked orthopedic hospitals and 102 non-top-ranked U.S. hospitals.
Synopsis: Hospitals were contacted by phone with a standardized, scripted request for their price of an elective total hip arthroplasty. The script described the patient as a 62-year-old grandmother without insurance who is able to pay out of pocket and wishes to compare hospital prices. On the first or second attempt, 40% of top-ranked and 32% of non-top-ranked hospitals were able to provide their price; after five attempts, authors were unable to obtain full pricing information (both hospital and physician fee) from 40% of top-ranked and 37% of non-top-ranked hospitals. Neither fee was made available by 15% of top-ranked and 16% of non-top-ranked hospitals. Wide variation of pricing was found across hospitals. The authors commented on the difficulties they encountered, such as the transfer of calls between departments and the uncertainty of representatives on how to assist.
Bottom line: For individual patients, applying basic economic principles as a consumer might be tiresome and often impossible, with no major differences between top-ranked and non-top-ranked hospitals.
Citation: Rosenthal JA, Lu X, Cram P. Availability of consumer prices from US hospitals for a common surgical procedure. JAMA Intern Med. 2013;173(6):427-432.
Antibiotics Associated with Decreased Mortality in Acute COPD Exacerbation
Clinical question: Do antibiotics when added to systemic steroids provide clinical benefit for patients with acute COPD exacerbation?
Background: Despite widespread use of antibiotics in the treatment of acute COPD, their benefit is not clear.
Study design: Retrospective cohort study.Setting: Four hundred ten U.S. hospitals participating in Perspective, an inpatient administrative database.
Synopsis: More than 50,000 patients treated with systemic steroids for acute COPD exacerbation were included in this study; 85% of them received empiric antibiotics within the first two hospital days. They were compared with those treated with systemic steroids alone. In-hospital mortality was 1.02% for patients on steroids plus antibiotics versus 1.78% on steroids alone. Use of antibiotics was associated with a 40% reduction in the odds of in-hospital mortality (OR, 0.60; 95% CI, 0.50-0.74) and reduced readmissions. In an analysis of matched cohorts, hospital mortality was 1% for patients on antibiotics and 1.8% for patients without antibiotics (OR, 0.53; 95% CI, 0.40-0.71). The risk for readmission for Clostridium difficile colitis was not different between the groups, but other potential adverse effects of antibiotic use, such as development of resistant micro-organisms, were not studied. In a subset analysis, three groups of antibiotics were compared: macrolides, quinolones, and cephalosporins. None was better than another, but those treated with macrolides had a lower readmission rate for C. diff.
Bottom line: Treatment with antibiotics when added to systemic steroids is associated with improved outcomes in acute COPD exacerbations, but there is no clear advantage of one antibiotic class over another.
Citation: Stefan MS, Rothberg MB, Shieh M, Pekow PS, Lindenauer PK. Association between antibiotic treatment and outcomes in patients hospitalized with acute exacerbation of COPD treated with systemic steroids. Chest. 2013;143(1):82-90.
Endovascular Therapy Added to Systemic t-PA Has No Benefit in Acute Stroke
Clinical question: Does adding endovascular therapy to intravenous tissue plasminogen activator (t-PA) reduce disability in acute stroke?
Background: Early systemic t-PA is the only proven reperfusion therapy in acute stroke, but it is unknown if adding localized endovascular therapy is beneficial.
Study design: Randomized, open-label, blinded-outcome trial.
Setting: Fifty-eight centers in North America, Europe, and Australia.
Synopsis: Patients aged 18 to 82 with acute ischemic stroke were eligible if they received t-PA within three hours of enrollment and had moderate to severe neurologic deficit (National Institutes of Health Stroke Scale [NIHSS] >10, or NIHSS 8 or 9 with CT angiographic evidence of specific major artery occlusion). All patients received standard-dose t-PA; those randomized to endovascular treatment underwent angiography, and, if indicated, underwent one of the endovascular treatments chosen by the neurointerventionalist. The primary outcome measure was a modified Rankin score of 2 or lower (indicating functional independence) at 90 days (assessed by a neurologist).
After enrollment of 656 patients, the trial was terminated early for futility. There was no significant difference in the primary outcome, with 40.8% of patients in the endovascular intervention group and 38.7% in the t-PA-only group having a modified Rankin score of 2 or lower. There was also no difference in mortality or other secondary outcomes, even when the analysis was limited to patients presenting with more severe neurologic deficits.
Bottom line: The addition of endovascular therapy to systemic t-PA in acute ischemic stroke does not improve functional outcomes or mortality.
Citation: Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893-903.
Rivaroxaban Compared with Enoxaparin for Thromboprophylaxis
Clinical question: Is extended-duration rivaroxaban more effective than standard-duration enoxaparin in preventing deep venous thrombosis in acutely ill medical patients?
Background: Trials have shown benefits of thromboprophylaxis in acutely ill medical patients at increased risk of venous thrombosis, but the optimal duration and type of anticoagulation is unknown.
Study design: Prospective, randomized, double-blinded, active-comparator controlled trial.
Setting: Five hundred fifty-two centers in 52 countries.
Synopsis: The trial enrolled 8,428 patients hospitalized with an acute medical condition and reduced mobility. Patients were randomized to receive either enoxaparin for 10 (+/-4) days or rivaroxaban for 35 (+/-4) days. The co-primary composite outcomes were the incidence of asymptomatic proximal deep venous thrombosis, symptomatic deep venous thrombosis, pulmonary embolism, or death related to venous thromboembolism over 10 days and over 35 days.
Both groups had a 2.7% incidence of the primary endpoint over 10 days; over 35 days, the extended-duration rivaroxaban group had a reduced incidence of the primary endpoint of 4.4% compared with 5.7% for enoxaparin. However, there was an increase of clinically relevant bleeding in the rivaroxaban group, occurring in 2.8% and 4.1% of patients over 10 and 35 days, respectively, compared with 1.2% and 1.7% for enoxaparin.
Overall, there was net harm with rivaroxaban over both time periods: 6.6% and 9.4% of patients in the rivaroxaban group had a negative outcome at 10 and 35 days, compared with 4.4% and 7.8% with enoxaparin.
Bottom line: There was net harm with extended-duration rivaroxaban versus standard-duration enoxaparin for thromboprophylaxis in hospitalized medical patients.
Citation: Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368:513-523.
Noninvasive Ventilation More Effective, Safer for Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)
Clinical question: What are the patterns in use of noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) in patients with AECOPD, and which method produces better outcomes?
Background: Multiple randomized controlled trials and meta-analyses have suggested a mortality benefit with NIV compared to standard medical care in AECOPD. However, little evidence exists on head-to-head comparisons of NIV and IMV.
Study design: Retrospective cohort study.
Setting: Non-federal, short-term, general, and other specialty hospitals nationwide.
Synopsis: A sample of 67,651 ED visits for AECOPD with acute respiratory failure was analyzed from the National Emergency Department Sample (NEDS) database between 2006 and 2008. The study found that NIV use increased to 16% in 2008 from 14% in 2006. Use varied widely between hospitals and was more utilized in higher-case-volume, nonmetropolitan, and Northeastern hospitals. Compared with IMV, NIV was associated with 46% lower inpatient mortality (risk ratio 0.54, 95% confidence interval [CI] 0.50-0.59), shortened hospital length of stay (-3.2 days, 95% CI -3.4 to -2.9), lower hospital charges (-$35,012, 95% CI -$36,848 to -$33,176), and lower risk of iatrogenic pneumothorax (0.05% vs. 0.5%, P<0.001). Causality could not be established given the observational study design.
Bottom line: NIV is associated with better outcomes than IMV in the management of AECOPD, and might be underutilized.
Citation: Tsai CL, Lee WY, Delclos GL, Hanania NA, Camargo CA Jr. Comparative effectiveness of noninvasive ventilation vs. invasive mechanical ventilation in chronic obstructive pulmonary disease patients with acute respiratory failure. J Hosp Med. 2013;8(4):165-172.
Synthetic Cannabinoid Use May Cause Acute Kidney Injury
Clinical question: Are synthetic cannabinoids associated with acute kidney injury (AKI)?
Background: Synthetic cannabinoids are designer drugs of abuse with a growing popularity in the U.S.
Study design: Retrospective case series.
Setting: Hospitals in Wyoming, Oklahoma, Rhode Island, New York, Kansas, and Oregon.
Synopsis: The Centers for Disease Control and Prevention (CDC) issued an alert when 16 cases of unexplained AKI after exposure to synthetic cannabinoids were reported between March and December 2012. Synthetic cannabinoid use is associated with neurologic, sympathomimetic, and cardiovascular toxicity; however, this is the first case series reporting renal toxicity. The 16 patients included 15 males and one female, aged 15-33 years, with no pre-existing renal disease or nephrotoxic medication consumption. All used synthetic cannabinoids within hours to days before developing nausea, vomiting, abdominal, and flank and/or back pain.
Creatinine peaked one to six days after symptom onset. Five patients required hemodialysis, and all 16 recovered. There was no finding specific for all cases on ultrasound and/or biopsy. Toxicologic analysis of specimens was possible in seven cases and revealed a previously unreported fluorinated synthetic cannabinoid compound XLR-11 in all clinical specimens of patients who used the drug within two days of being tested.
Overall, the analysis did not reveal any single compound or brand that could explain all cases.
Bottom line: Clinicians should be aware of the potential for renal or other toxicities in users of synthetic cannabinoid products and should ask about their use in cases of unexplained AKI.
Citation: Murphy TD, Weidenbach KN, Van Houten C, et al. Centers for Disease Control and Prevention. Acute kidney injury associated with synthetic cannabinoid use—multiple states, 2012. MMWR Morb Mortal Wkly Rep. 2013;62(6):93-98.
Dabigatran versus Warfarin in Extended VTE Treatment
Clinical question: Is dabigatran suitable for extended treatment VTE?
Background: In contrast to warfarin (Coumadin), dabigatran (Pradaxa) is given in a fixed dose and does not require frequent laboratory monitoring. Dabigatran has been shown to be noninferior to warfarin in the initial six-month treatment of VTE.
Study design: Two double-blinded, randomized trials: an active-control study and a placebo-control study.
Setting: Two hundred sixty-five sites in 33 countries for the active-control study, and 147 sites in 21 countries for the placebo-control study.
Synopsis: This study enrolled 4,299 adult patients with objectively confirmed, symptomatic, proximal deep vein thrombosis or pulmonary embolism. In the active-control study comparing warfarin and dabigatran, recurrent objectively confirmed symptomatic or fatal VTE was observed in 1.8% of patients in the dabigatran group compared with 1.3% of patients in the warfarin group (P=0.01 for noninferiority). While major or clinically relevant bleeding was less frequent with dabigatran compared to warfarin (hazard ratio, 0.54), more acute coronary syndromes were observed with dabigatran (0.9% vs. 0.2%, P=0.02). In the placebo-control study, symptomatic or fatal VTE was observed in 0.4% of patients in the dabigatran group compared with 5.6% in the placebo group. Clinically relevant bleeding was more common with dabigatran (5.3% vs. 1.8%; hazard ratio 2.92).
Bottom line: Treatment with dabigatran met the pre-specified noninferiority margin in this study. However, it is worth noting that patients with VTE given extended treatment with dabigatran had significantly higher rates of recurrent symptomatic or fatal VTE than patients treated with warfarin.
Citation: Schulman S, Kearson C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718.
Spironolactone Improves Diastolic Function
Clinical question: What is the efficacy of aldosterone receptor blockers on diastolic function and exercise capacity?
Background: Mineralocorticoid receptor activation by aldosterone contributes to the pathophysiology of heart failure (HF) in patients with and without reduced ejection fraction (EF). Aldosterone receptor blockers (spironolactone) reduce overall and cardiovascular mortality in HF patients with reduced EF; however, its effect on HF patients with preserved EF is unknown.
Study design: Prospective, randomized, double-blinded, placebo-controlled trial.
Setting: Ten ambulatory sites in Germany and Austria.
Synopsis: This study enrolled 422 men and women, aged 50 or older, with New York Heart Association (NYHA) Class II or III HF and preserved EF, and randomized them to receive spironolactone 25 mg daily or placebo for one year.
The endpoints included echocardiographic measures of diastolic function and remodeling; N-terminal pro b-type natriuretic peptide (NT pro-BNP) levels; exercise capacity; quality of life; and HF symptoms.
In the spironolactone group, there was significant improvement in echocardiographic measures of diastolic function and remodeling as well as NT pro-BNP levels. However, there was no difference in exercise capacity, quality of life, or HF symptoms when compared to placebo.
The spironolactone group had significantly lower blood pressure than the control group, which may account for some of the remodeling effects. The study may have been underpowered, and the study population might not have had severe enough disease to detect a difference in clinical measures. It remains unknown if structural changes on echocardiography will translate into clinical benefits.
Bottom line: Compared to placebo, spironolactone did improve diastolic function by echo but did not improve exercise capacity.
Citation: Edelmann F, Wachter R, Schmidt A, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013;309(8):781-791.
Real-Time, EMR-Based Prediction Tool Accurately Predicts ICU Transfer Risks
Clinical question: Can clinical deterioration be accurately predicted using real-time data from an electronic medical record (EMR), and can it lead to better outcomes using a floor-based intervention?
Background: Research has shown that EMR-based prediction tools can help identify real-time clinical deterioration in ward patients, but an intervention based on these computer-based alerts has not been shown to be effective.
Study design: Randomized controlled crossover study.
Setting: Eight adult medicine wards in an academic medical center in the Midwest.
Synopsis: There were 20,031 patients assigned to intervention versus control based on their floor location. Computerized alerts were generated using a prediction algorithm. For patients admitted to intervention wards, the alerts were sent to the charge nurse via pager. Patients meeting the alert threshold based on the computerized prediction tool had five times higher risk of ICU transfer, and nine times higher risk of death than patients not meeting the alert threshold. Intervention of charge nurse notification via pager did not result in any significant change in length of stay (LOS), ICU transfer, or mortality. Charge nurses in the intervention group were supposed to alert a physician after receiving the computer alert, but the authors did not measure how often this occurred.
Bottom line: A real-time EMR-based prediction tool accurately predicts higher risk of ICU transfer and death, as well as LOS, but a floor-based intervention to alert the charge nurse in real time did not lead to better outcomes.
Citation: Bailey TC, Chen Y, Mao Y, et al. A trial of a real-time alert for clinical deterioration in patients hospitalized on general medicine wards. J Hosp Med. 2013 Feb 25. doi: 10.1002/jhm.2009 [Epub ahead of print].
Hypothermia Protocol and Cardiac Arrest
Clinical question: Is mild therapeutic hypothermia (MTH) following cardiac arrest beneficial and safe?
Background: Those with sudden cardiac arrest often have poor neurologic outcome. There are some studies that show benefit with hypothermia, but information on safety is limited.
Study design: Meta-analysis.
Setting: Europe, the United Kingdom, the U.S., Canada, Japan, and South Korea.
Synopsis: This study pooled data from 63 studies that looked at MTH protocols in the setting of comatose patients as a result of cardiac arrest. The end points included mortality and any complication potentially attributed to the MTH.
When restricting the analysis to include only randomized controlled trials, MTH was associated with decreased risk of in-hospital mortality (RR=0.75, 95% CI: 0.62-0.92), 30-day mortality (RR=0.61, 95% CI 0.45-0.81), and six-month mortality (RR=0.73, 95% CI 0.61-0.88). MTH was associated with increased risk of arrhythmia (RR=1.25, 95% CI: 1.00-1.55) and hypokalemia (RR=2.35, 95% CI: 1.35-4.11); all other complications were similar between groups.
There were inconsistent results regarding benefit in pediatric patients, as well as comatose patients with non-ventricular fibrillation (non-v-fib) arrest (i.e. asystole or pulseless electrical activity).
Bottom line: Mild therapeutic hypothermia can improve survival of comatose patients after v-fib cardiac arrest and is generally safe.
Citation: Xiao G, Guo Q, Xie X, et al. Safety profile and outcome of mild therapeutic hypothermia in patients following cardiac arrest: systematic review and meta-analysis. Emerg Med J. 2013;30:90-100.