"Seriously? ... Okay. Get a stat x-ray of the pelvis and hips and tell the family I’ll be up within 5 minutes."

You hang up the phone incredulous! After 4 weeks in the critical care unit, 2 weeks in a step-down unit, and an additional 8 days on the general medical ward, your patient was finally on the launching pad.

You had spent 90 minutes the night before meticulously reviewing every nursing note, physical therapy recommendation, and a myriad of consultants notes to make sure your discharge summary thoroughly reflected her very complicated hospital course. Last night, she was alert and chatting up a storm. At times, she did not even know if she would ever make it out of the hospital (and neither did you), and here it was, the long-awaited day of discharge, and she wakes up groggy and takes a bad fall on her way to the bathroom.

The list of possible explanations for her new-onset grogginess race through your mind. The likelihood of a stroke is remote. Her vital signs and morning labs are all normal. She was weaned off pain meds weeks ago, and her only complaint for the past few days had been insomnia, for which you ordered zolpidem PRN. Surely that could not be the culprit ... or could it?

Recent evidence shows that sleep aids containing the popular drug zolpidem may be linked to decreased alertness the morning after use, particularly the long-acting formulations. In some patients, blood levels of the drug may remain high enough to put patients at risk when performing tasks that require mental alertness. Evidence of this association was so compelling, the Food and Drug Administration recently announced that it is requiring manufacturers of Ambien, Ambien CR, Zolpimist, and Edluar, sleep aids that contain zolpidem, to lower recommended doses. Women are at particular risk, since they eliminate the drug more slowly than do men. Accordingly, the new FDA-recommended dose for women was cut in half – 5 mg for immediate-release products and 6.25 mg for extended-release products.

Of course, zolpidem is not alone in its propensity to cause grogginess. Virtually any sleep aid can do so because, well, that is what it they are designed to do – make patients sleepy.

This recent drug-safety information was so interesting because we often have a false sense of security when prescribing this drug, and we prescribe it very often. It is our "safer" alternative to valium-type medications. We are now encouraged to order a safer dose of this frequently prescribed drug.

I ordered a lower dose myself right after reading the latest FDA report.

The bottom line is that we need to be aware what this study showed so we can alter our prescribing habits and order the lower dose. All medications have the potential to have side effects in a minority of patients, but it is very important for us to know and react when new recommendations come out that have the potential to be so far reaching.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care.

"Seriously? ... Okay. Get a stat x-ray of the pelvis and hips and tell the family I’ll be up within 5 minutes."

You hang up the phone incredulous! After 4 weeks in the critical care unit, 2 weeks in a step-down unit, and an additional 8 days on the general medical ward, your patient was finally on the launching pad.

You had spent 90 minutes the night before meticulously reviewing every nursing note, physical therapy recommendation, and a myriad of consultants notes to make sure your discharge summary thoroughly reflected her very complicated hospital course. Last night, she was alert and chatting up a storm. At times, she did not even know if she would ever make it out of the hospital (and neither did you), and here it was, the long-awaited day of discharge, and she wakes up groggy and takes a bad fall on her way to the bathroom.

The list of possible explanations for her new-onset grogginess race through your mind. The likelihood of a stroke is remote. Her vital signs and morning labs are all normal. She was weaned off pain meds weeks ago, and her only complaint for the past few days had been insomnia, for which you ordered zolpidem PRN. Surely that could not be the culprit ... or could it?

Recent evidence shows that sleep aids containing the popular drug zolpidem may be linked to decreased alertness the morning after use, particularly the long-acting formulations. In some patients, blood levels of the drug may remain high enough to put patients at risk when performing tasks that require mental alertness. Evidence of this association was so compelling, the Food and Drug Administration recently announced that it is requiring manufacturers of Ambien, Ambien CR, Zolpimist, and Edluar, sleep aids that contain zolpidem, to lower recommended doses. Women are at particular risk, since they eliminate the drug more slowly than do men. Accordingly, the new FDA-recommended dose for women was cut in half – 5 mg for immediate-release products and 6.25 mg for extended-release products.

Of course, zolpidem is not alone in its propensity to cause grogginess. Virtually any sleep aid can do so because, well, that is what it they are designed to do – make patients sleepy.

This recent drug-safety information was so interesting because we often have a false sense of security when prescribing this drug, and we prescribe it very often. It is our "safer" alternative to valium-type medications. We are now encouraged to order a safer dose of this frequently prescribed drug.

I ordered a lower dose myself right after reading the latest FDA report.

The bottom line is that we need to be aware what this study showed so we can alter our prescribing habits and order the lower dose. All medications have the potential to have side effects in a minority of patients, but it is very important for us to know and react when new recommendations come out that have the potential to be so far reaching.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care.

"Seriously? ... Okay. Get a stat x-ray of the pelvis and hips and tell the family I’ll be up within 5 minutes."

You hang up the phone incredulous! After 4 weeks in the critical care unit, 2 weeks in a step-down unit, and an additional 8 days on the general medical ward, your patient was finally on the launching pad.

You had spent 90 minutes the night before meticulously reviewing every nursing note, physical therapy recommendation, and a myriad of consultants notes to make sure your discharge summary thoroughly reflected her very complicated hospital course. Last night, she was alert and chatting up a storm. At times, she did not even know if she would ever make it out of the hospital (and neither did you), and here it was, the long-awaited day of discharge, and she wakes up groggy and takes a bad fall on her way to the bathroom.

The list of possible explanations for her new-onset grogginess race through your mind. The likelihood of a stroke is remote. Her vital signs and morning labs are all normal. She was weaned off pain meds weeks ago, and her only complaint for the past few days had been insomnia, for which you ordered zolpidem PRN. Surely that could not be the culprit ... or could it?

Recent evidence shows that sleep aids containing the popular drug zolpidem may be linked to decreased alertness the morning after use, particularly the long-acting formulations. In some patients, blood levels of the drug may remain high enough to put patients at risk when performing tasks that require mental alertness. Evidence of this association was so compelling, the Food and Drug Administration recently announced that it is requiring manufacturers of Ambien, Ambien CR, Zolpimist, and Edluar, sleep aids that contain zolpidem, to lower recommended doses. Women are at particular risk, since they eliminate the drug more slowly than do men. Accordingly, the new FDA-recommended dose for women was cut in half – 5 mg for immediate-release products and 6.25 mg for extended-release products.

Of course, zolpidem is not alone in its propensity to cause grogginess. Virtually any sleep aid can do so because, well, that is what it they are designed to do – make patients sleepy.

This recent drug-safety information was so interesting because we often have a false sense of security when prescribing this drug, and we prescribe it very often. It is our "safer" alternative to valium-type medications. We are now encouraged to order a safer dose of this frequently prescribed drug.

I ordered a lower dose myself right after reading the latest FDA report.

The bottom line is that we need to be aware what this study showed so we can alter our prescribing habits and order the lower dose. All medications have the potential to have side effects in a minority of patients, but it is very important for us to know and react when new recommendations come out that have the potential to be so far reaching.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care.

Physicians who rank poorly in their communication skills with patients were associated with reduced rates of medication adherence in a new report.

A cross-sectional study of nearly 9,4000 patients in the Diabetes Study of Northern California (DISTANCE) found roughly 30% of patients who gave their physicians poor ratings when it came to involving them in decisions, understanding their problems with medications, and eliciting their trust were less likely to refill their cardiometabolic medications than those whose doctors were deemed to be good communicators, researchers found. For each 10-point decrease in the Consumer Assessment of Healthcare Providers and Systems Survey (CAHPS), the prevalence of poor medication adherence increased by 0.9% (P +0.1), the researchers added.

“One of the tricks is that medication adherence is an inherently physician-centric concept,” says lead author Neda Ratanawongsa, MD, MPH, assistant professor in the department of medicine at the University of California at San Francisco (UCSF). “We’re asking you to take medicine that we think will be best for you. That’s been the way that physicians operate for years, often appropriately so. But part of this is figuring out how to encourage the patients to disclose their decision that ‘Yes, I do want to take that medicine’ or ‘No, here’s why I don’t want to take that medicine.’”

Dr. Ratanawongsa adds that hospitalists and other physicians have to develop a sense of trust with patients to build relationships. Future studies could then track patient satisfaction and adherence over time to see if a corollary exists. Also, she says, hospitalists shouldn’t be discouraged that most of their relationships aren’t long-term ones like those found in other specialties.

“I wouldn’t underestimate the impact a hospitalist could have, whether one-time interaction or not, to change an existing therapy program,” Dr. Ratanawongsa says. “It’s important for hospitalists to understand the power of their words.”

Visit our website for more information about medication reconciliation.

Physicians who rank poorly in their communication skills with patients were associated with reduced rates of medication adherence in a new report.

A cross-sectional study of nearly 9,4000 patients in the Diabetes Study of Northern California (DISTANCE) found roughly 30% of patients who gave their physicians poor ratings when it came to involving them in decisions, understanding their problems with medications, and eliciting their trust were less likely to refill their cardiometabolic medications than those whose doctors were deemed to be good communicators, researchers found. For each 10-point decrease in the Consumer Assessment of Healthcare Providers and Systems Survey (CAHPS), the prevalence of poor medication adherence increased by 0.9% (P +0.1), the researchers added.

“One of the tricks is that medication adherence is an inherently physician-centric concept,” says lead author Neda Ratanawongsa, MD, MPH, assistant professor in the department of medicine at the University of California at San Francisco (UCSF). “We’re asking you to take medicine that we think will be best for you. That’s been the way that physicians operate for years, often appropriately so. But part of this is figuring out how to encourage the patients to disclose their decision that ‘Yes, I do want to take that medicine’ or ‘No, here’s why I don’t want to take that medicine.’”

Dr. Ratanawongsa adds that hospitalists and other physicians have to develop a sense of trust with patients to build relationships. Future studies could then track patient satisfaction and adherence over time to see if a corollary exists. Also, she says, hospitalists shouldn’t be discouraged that most of their relationships aren’t long-term ones like those found in other specialties.

“I wouldn’t underestimate the impact a hospitalist could have, whether one-time interaction or not, to change an existing therapy program,” Dr. Ratanawongsa says. “It’s important for hospitalists to understand the power of their words.”

Visit our website for more information about medication reconciliation.

Physicians who rank poorly in their communication skills with patients were associated with reduced rates of medication adherence in a new report.

A cross-sectional study of nearly 9,4000 patients in the Diabetes Study of Northern California (DISTANCE) found roughly 30% of patients who gave their physicians poor ratings when it came to involving them in decisions, understanding their problems with medications, and eliciting their trust were less likely to refill their cardiometabolic medications than those whose doctors were deemed to be good communicators, researchers found. For each 10-point decrease in the Consumer Assessment of Healthcare Providers and Systems Survey (CAHPS), the prevalence of poor medication adherence increased by 0.9% (P +0.1), the researchers added.

“One of the tricks is that medication adherence is an inherently physician-centric concept,” says lead author Neda Ratanawongsa, MD, MPH, assistant professor in the department of medicine at the University of California at San Francisco (UCSF). “We’re asking you to take medicine that we think will be best for you. That’s been the way that physicians operate for years, often appropriately so. But part of this is figuring out how to encourage the patients to disclose their decision that ‘Yes, I do want to take that medicine’ or ‘No, here’s why I don’t want to take that medicine.’”

Dr. Ratanawongsa adds that hospitalists and other physicians have to develop a sense of trust with patients to build relationships. Future studies could then track patient satisfaction and adherence over time to see if a corollary exists. Also, she says, hospitalists shouldn’t be discouraged that most of their relationships aren’t long-term ones like those found in other specialties.

“I wouldn’t underestimate the impact a hospitalist could have, whether one-time interaction or not, to change an existing therapy program,” Dr. Ratanawongsa says. “It’s important for hospitalists to understand the power of their words.”

Visit our website for more information about medication reconciliation.

A healthy collaboration between hospitalists and pharmacists can generate cost savings and promote positive outcomes, such as preventing adverse drug events and improving care transitions, says Jonathan Edwards, PharmD, BCPS, a clinical pharmacy specialist at Huntsville Hospital in Alabama.

At the 2012 national conference of the American College of Clinical Pharmacy in Hollywood, Fla., Edwards presented a poster that detailed the effectiveness of such interdisciplinary collaboration at Huntsville Hospital, where pharmacists and physicians developed six order sets, a collaborative practice, and a patient interaction program from November 2011 to February 2012. During the study period, researchers documented a total cost savings of $9,825 resulting from 156 patient interventions.

Edwards’ collaborative study at Huntsville started with two physicians who had launched a service teaching hospitalists what pharmacists do, and how they could help in their efforts.

“We got together and developed an order set for treating acute alcohol withdrawal. That went well, so we did five more order sets,” Edwards says. “Then we thought: What if pharmacists got more involved by meeting directly with patients in the hospital to optimize their medication management and help them reach their goals for treatment? We now evaluate patients on the hospitalist service in three units.”

For Edwards, key factors that make the hospitalist-pharmacist relationship work include communicating the pharmacist’s availability to help with the hospitalist’s patients, identifying the physician’s openness to help, and clarifying how the physician prefers to be contacted.

Last October, the American Society of Health-System Pharmacists (ASHP) and the American Pharmacists Association (APhA) recognized eight care-transitions programs for best practices that improved patient outcomes and reduced hospital readmissions as part of the Medication Management in Care Transitions (MMCT) Project.

“The MMCT project highlights the valuable role pharmacists can play in addressing medication-related problems that can lead to hospital readmissions,” APhA chief executive officer Thomas E. Menighan, BSPharm, MBA, ScD (Hon), FAPhA, said in a news release. “By putting together these best practices, our goal is to provide a model for better coordination of care and better connectivity between pharmacists and healthcare providers in different practice settings that leads to improved patient health.”

Visit our website for more information about maximizing patient care through pharmacist-hospitalist collaboration.

A healthy collaboration between hospitalists and pharmacists can generate cost savings and promote positive outcomes, such as preventing adverse drug events and improving care transitions, says Jonathan Edwards, PharmD, BCPS, a clinical pharmacy specialist at Huntsville Hospital in Alabama.

At the 2012 national conference of the American College of Clinical Pharmacy in Hollywood, Fla., Edwards presented a poster that detailed the effectiveness of such interdisciplinary collaboration at Huntsville Hospital, where pharmacists and physicians developed six order sets, a collaborative practice, and a patient interaction program from November 2011 to February 2012. During the study period, researchers documented a total cost savings of $9,825 resulting from 156 patient interventions.

Edwards’ collaborative study at Huntsville started with two physicians who had launched a service teaching hospitalists what pharmacists do, and how they could help in their efforts.

“We got together and developed an order set for treating acute alcohol withdrawal. That went well, so we did five more order sets,” Edwards says. “Then we thought: What if pharmacists got more involved by meeting directly with patients in the hospital to optimize their medication management and help them reach their goals for treatment? We now evaluate patients on the hospitalist service in three units.”

For Edwards, key factors that make the hospitalist-pharmacist relationship work include communicating the pharmacist’s availability to help with the hospitalist’s patients, identifying the physician’s openness to help, and clarifying how the physician prefers to be contacted.

Last October, the American Society of Health-System Pharmacists (ASHP) and the American Pharmacists Association (APhA) recognized eight care-transitions programs for best practices that improved patient outcomes and reduced hospital readmissions as part of the Medication Management in Care Transitions (MMCT) Project.

“The MMCT project highlights the valuable role pharmacists can play in addressing medication-related problems that can lead to hospital readmissions,” APhA chief executive officer Thomas E. Menighan, BSPharm, MBA, ScD (Hon), FAPhA, said in a news release. “By putting together these best practices, our goal is to provide a model for better coordination of care and better connectivity between pharmacists and healthcare providers in different practice settings that leads to improved patient health.”

Visit our website for more information about maximizing patient care through pharmacist-hospitalist collaboration.

A healthy collaboration between hospitalists and pharmacists can generate cost savings and promote positive outcomes, such as preventing adverse drug events and improving care transitions, says Jonathan Edwards, PharmD, BCPS, a clinical pharmacy specialist at Huntsville Hospital in Alabama.

At the 2012 national conference of the American College of Clinical Pharmacy in Hollywood, Fla., Edwards presented a poster that detailed the effectiveness of such interdisciplinary collaboration at Huntsville Hospital, where pharmacists and physicians developed six order sets, a collaborative practice, and a patient interaction program from November 2011 to February 2012. During the study period, researchers documented a total cost savings of $9,825 resulting from 156 patient interventions.

Edwards’ collaborative study at Huntsville started with two physicians who had launched a service teaching hospitalists what pharmacists do, and how they could help in their efforts.

“We got together and developed an order set for treating acute alcohol withdrawal. That went well, so we did five more order sets,” Edwards says. “Then we thought: What if pharmacists got more involved by meeting directly with patients in the hospital to optimize their medication management and help them reach their goals for treatment? We now evaluate patients on the hospitalist service in three units.”

For Edwards, key factors that make the hospitalist-pharmacist relationship work include communicating the pharmacist’s availability to help with the hospitalist’s patients, identifying the physician’s openness to help, and clarifying how the physician prefers to be contacted.

Last October, the American Society of Health-System Pharmacists (ASHP) and the American Pharmacists Association (APhA) recognized eight care-transitions programs for best practices that improved patient outcomes and reduced hospital readmissions as part of the Medication Management in Care Transitions (MMCT) Project.

“The MMCT project highlights the valuable role pharmacists can play in addressing medication-related problems that can lead to hospital readmissions,” APhA chief executive officer Thomas E. Menighan, BSPharm, MBA, ScD (Hon), FAPhA, said in a news release. “By putting together these best practices, our goal is to provide a model for better coordination of care and better connectivity between pharmacists and healthcare providers in different practice settings that leads to improved patient health.”

Visit our website for more information about maximizing patient care through pharmacist-hospitalist collaboration.

The infusion of donor feces into the duodenum of patients with recurrent, often intractable Clostridium difficile infection led to a much higher rate of cure than did either vancomycin therapy or bowel lavage in a small, randomized, open-label clinical trial.

The trial was closed early to new enrollment after only 43 of its planned 120 patients had undergone randomization because an interim analysis by the trial’s data safety and monitoring board found that almost all patients in the two control groups had a recurrence, compared with ultimate resolution of diarrhea in 15 of 16 patients treated with fecal infusion.

There were no infectious complications from the fecal infusions, and the only adverse event was transient diarrhea immediately following the procedure, which resolved in all patients within 3 hours, according to Dr. Els van Nood of the University of Amsterdam Academic Medical Center and her associates. They reported their findings online Jan. 16 in the New England Journal of Medicine.

"We found that the infusion of donor feces is a potential therapeutic strategy against recurrent C. difficile infection. In our study, infusion of a relatively large amount of feces through a nasoduodenal tube had an acceptable adverse-event profile and was logistically manageable," they noted.

Currently there is no effective therapy for recurrent C. difficile infection of the gastrointestinal tract. Extended and repeated courses of vancomycin usually are prescribed, but the antibiotic’s efficacy is estimated to be only 60% for the first recurrence and declines substantially with each subsequent recurrence.

The reason for the waning of antibiotic effectiveness is not known for certain. Experts have proposed that C. difficile spores may persist in the gut and get reactivated over time; that antibody responses to Clostridium toxins diminish over time; or that persistent disturbance of the native intestinal microbiota causes reduced diversity, which in turn reduces natural resistance to C. difficile.

It was hoped that infusion of feces from healthy donors would address the last mechanism, restoring the normal microbiota and boosting host defenses against C. difficile. Several preliminary studies have produced promising results, but "experience with this procedure is limited by a lack of randomized trials supporting its efficacy and the unappealing nature of the treatment," Dr. van Nood and her colleagues said.

All the study subjects had persistent C. difficile infection, as evidenced by severe diarrhea with positive stool tests for the organism, after multiple courses of vancomycin and/or metronidazole.

Both patients and physicians are reluctant to choose donor-feces infusion until other measures have failed repeatedly. "It seems reasonable to initiate treatment with donor-feces infusion after the second or third relapse," the investigators wrote.

A total of 41 patients completed the study protocol. The trial compared the infusion of donor feces after pretreatment with a brief (4-day) course of vancomycin and bowel lavage (16 patients), a standard vancomycin regimen (12 patients), and a standard vancomycin regimen plus bowel lavage (13 patients). Bowel lavage was included because it has been used in previous studies of this new treatment and is thought to "reduce the pathogenic bowel content, facilitating colonization of healthy donor microbiota."

Most of the study subjects were elderly, with mean ages of 73 years, 66 years, and 69 years, respectively, in the three study arms.

Feces donors included 15 healthy volunteers aged 60 years and older who were screened for numerous potentially transmissible diseases. Fecal samples were collected just before the infusion was scheduled, and they were screened for parasites, C. difficile, and enteropathogenic bacteria. The samples were diluted with 500 mL of sterile saline, and the mixture was strained and poured into a sterile bottle.

A mean of 141 g of feces was infused through a nasoduodenal tube, and patients were monitored for 2 hours. Analysis of patients’ phylogenetic microarray profiles before and after treatment demonstrated "a major shift in the patients’ microbiota" from abnormal to normal diversity of organisms, Dr. van Nood and her associates said (N. Engl. J. Med. 2013 Jan. 16 [doi: 10.1056/NEJMoa1205037]).

The primary endpoint was cure without relapse within 10 weeks of treatment. Thirteen patients in the infusion group (81%) reached this endpoint after a single infusion. The remaining 3 patients had a second treatment, and 2 of them were cured, for an overall cure rate of 94% (15 of 16 patients).

In comparison, the cure rate with vancomycin alone was 31% (4 of 13 patients), and with vancomycin plus bowel lavage it was 23% (3 of 13).

At an interim follow-up of 5 weeks following initial treatment, C. difficile infection recurred in 1 patient (6%) in the infusion group, compared with 8 (62%) in the vancomycin-only group and 7 (54%) in the vancomycin-plus-lavage group.

Eighteen patients from the two control groups who relapsed after antibiotic treatment switched to off-protocol infusions of donor feces. Fifteen of them (83%) were cured: 11 after a single fecal infusion and 4 after two infusions.

All but one of the patients who received fecal infusions experienced immediate diarrhea, sometimes with cramping (31%) and belching (19%). These symptoms resolved in all of them within 3 hours. The only other adverse event that may have been related to the treatment was constipation, which developed in three patients.

Although the exact mechanism of action of this "unconventional" therapy is not yet known, Dr. van Nood and her colleagues speculated that donor-feces infusion probably restores the normal intestinal microbiota, enhancing the host defense against C. difficile.

Future research must determine the optimal protocol for donor-feces infusion, including the amount of feces required. Alternative routes of infusion, such as via enema or colonoscopy, also should be explored, they added.

This study was supported by the Netherlands Organization for Health Research and Development and the Netherlands Organization for Scientific Research. Four of the study’s 13 authors reported ties to Astellas. Two of those four also reported ties to Microbex.

The infusion of donor feces into the duodenum of patients with recurrent, often intractable Clostridium difficile infection led to a much higher rate of cure than did either vancomycin therapy or bowel lavage in a small, randomized, open-label clinical trial.

The trial was closed early to new enrollment after only 43 of its planned 120 patients had undergone randomization because an interim analysis by the trial’s data safety and monitoring board found that almost all patients in the two control groups had a recurrence, compared with ultimate resolution of diarrhea in 15 of 16 patients treated with fecal infusion.

There were no infectious complications from the fecal infusions, and the only adverse event was transient diarrhea immediately following the procedure, which resolved in all patients within 3 hours, according to Dr. Els van Nood of the University of Amsterdam Academic Medical Center and her associates. They reported their findings online Jan. 16 in the New England Journal of Medicine.

"We found that the infusion of donor feces is a potential therapeutic strategy against recurrent C. difficile infection. In our study, infusion of a relatively large amount of feces through a nasoduodenal tube had an acceptable adverse-event profile and was logistically manageable," they noted.

Currently there is no effective therapy for recurrent C. difficile infection of the gastrointestinal tract. Extended and repeated courses of vancomycin usually are prescribed, but the antibiotic’s efficacy is estimated to be only 60% for the first recurrence and declines substantially with each subsequent recurrence.

The reason for the waning of antibiotic effectiveness is not known for certain. Experts have proposed that C. difficile spores may persist in the gut and get reactivated over time; that antibody responses to Clostridium toxins diminish over time; or that persistent disturbance of the native intestinal microbiota causes reduced diversity, which in turn reduces natural resistance to C. difficile.

It was hoped that infusion of feces from healthy donors would address the last mechanism, restoring the normal microbiota and boosting host defenses against C. difficile. Several preliminary studies have produced promising results, but "experience with this procedure is limited by a lack of randomized trials supporting its efficacy and the unappealing nature of the treatment," Dr. van Nood and her colleagues said.

All the study subjects had persistent C. difficile infection, as evidenced by severe diarrhea with positive stool tests for the organism, after multiple courses of vancomycin and/or metronidazole.

Both patients and physicians are reluctant to choose donor-feces infusion until other measures have failed repeatedly. "It seems reasonable to initiate treatment with donor-feces infusion after the second or third relapse," the investigators wrote.

A total of 41 patients completed the study protocol. The trial compared the infusion of donor feces after pretreatment with a brief (4-day) course of vancomycin and bowel lavage (16 patients), a standard vancomycin regimen (12 patients), and a standard vancomycin regimen plus bowel lavage (13 patients). Bowel lavage was included because it has been used in previous studies of this new treatment and is thought to "reduce the pathogenic bowel content, facilitating colonization of healthy donor microbiota."

Most of the study subjects were elderly, with mean ages of 73 years, 66 years, and 69 years, respectively, in the three study arms.

Feces donors included 15 healthy volunteers aged 60 years and older who were screened for numerous potentially transmissible diseases. Fecal samples were collected just before the infusion was scheduled, and they were screened for parasites, C. difficile, and enteropathogenic bacteria. The samples were diluted with 500 mL of sterile saline, and the mixture was strained and poured into a sterile bottle.

A mean of 141 g of feces was infused through a nasoduodenal tube, and patients were monitored for 2 hours. Analysis of patients’ phylogenetic microarray profiles before and after treatment demonstrated "a major shift in the patients’ microbiota" from abnormal to normal diversity of organisms, Dr. van Nood and her associates said (N. Engl. J. Med. 2013 Jan. 16 [doi: 10.1056/NEJMoa1205037]).

The primary endpoint was cure without relapse within 10 weeks of treatment. Thirteen patients in the infusion group (81%) reached this endpoint after a single infusion. The remaining 3 patients had a second treatment, and 2 of them were cured, for an overall cure rate of 94% (15 of 16 patients).

In comparison, the cure rate with vancomycin alone was 31% (4 of 13 patients), and with vancomycin plus bowel lavage it was 23% (3 of 13).

At an interim follow-up of 5 weeks following initial treatment, C. difficile infection recurred in 1 patient (6%) in the infusion group, compared with 8 (62%) in the vancomycin-only group and 7 (54%) in the vancomycin-plus-lavage group.

Eighteen patients from the two control groups who relapsed after antibiotic treatment switched to off-protocol infusions of donor feces. Fifteen of them (83%) were cured: 11 after a single fecal infusion and 4 after two infusions.

All but one of the patients who received fecal infusions experienced immediate diarrhea, sometimes with cramping (31%) and belching (19%). These symptoms resolved in all of them within 3 hours. The only other adverse event that may have been related to the treatment was constipation, which developed in three patients.

Although the exact mechanism of action of this "unconventional" therapy is not yet known, Dr. van Nood and her colleagues speculated that donor-feces infusion probably restores the normal intestinal microbiota, enhancing the host defense against C. difficile.

Future research must determine the optimal protocol for donor-feces infusion, including the amount of feces required. Alternative routes of infusion, such as via enema or colonoscopy, also should be explored, they added.

This study was supported by the Netherlands Organization for Health Research and Development and the Netherlands Organization for Scientific Research. Four of the study’s 13 authors reported ties to Astellas. Two of those four also reported ties to Microbex.

The infusion of donor feces into the duodenum of patients with recurrent, often intractable Clostridium difficile infection led to a much higher rate of cure than did either vancomycin therapy or bowel lavage in a small, randomized, open-label clinical trial.

The trial was closed early to new enrollment after only 43 of its planned 120 patients had undergone randomization because an interim analysis by the trial’s data safety and monitoring board found that almost all patients in the two control groups had a recurrence, compared with ultimate resolution of diarrhea in 15 of 16 patients treated with fecal infusion.

There were no infectious complications from the fecal infusions, and the only adverse event was transient diarrhea immediately following the procedure, which resolved in all patients within 3 hours, according to Dr. Els van Nood of the University of Amsterdam Academic Medical Center and her associates. They reported their findings online Jan. 16 in the New England Journal of Medicine.

"We found that the infusion of donor feces is a potential therapeutic strategy against recurrent C. difficile infection. In our study, infusion of a relatively large amount of feces through a nasoduodenal tube had an acceptable adverse-event profile and was logistically manageable," they noted.

Currently there is no effective therapy for recurrent C. difficile infection of the gastrointestinal tract. Extended and repeated courses of vancomycin usually are prescribed, but the antibiotic’s efficacy is estimated to be only 60% for the first recurrence and declines substantially with each subsequent recurrence.

The reason for the waning of antibiotic effectiveness is not known for certain. Experts have proposed that C. difficile spores may persist in the gut and get reactivated over time; that antibody responses to Clostridium toxins diminish over time; or that persistent disturbance of the native intestinal microbiota causes reduced diversity, which in turn reduces natural resistance to C. difficile.

It was hoped that infusion of feces from healthy donors would address the last mechanism, restoring the normal microbiota and boosting host defenses against C. difficile. Several preliminary studies have produced promising results, but "experience with this procedure is limited by a lack of randomized trials supporting its efficacy and the unappealing nature of the treatment," Dr. van Nood and her colleagues said.

All the study subjects had persistent C. difficile infection, as evidenced by severe diarrhea with positive stool tests for the organism, after multiple courses of vancomycin and/or metronidazole.

Both patients and physicians are reluctant to choose donor-feces infusion until other measures have failed repeatedly. "It seems reasonable to initiate treatment with donor-feces infusion after the second or third relapse," the investigators wrote.

A total of 41 patients completed the study protocol. The trial compared the infusion of donor feces after pretreatment with a brief (4-day) course of vancomycin and bowel lavage (16 patients), a standard vancomycin regimen (12 patients), and a standard vancomycin regimen plus bowel lavage (13 patients). Bowel lavage was included because it has been used in previous studies of this new treatment and is thought to "reduce the pathogenic bowel content, facilitating colonization of healthy donor microbiota."

Most of the study subjects were elderly, with mean ages of 73 years, 66 years, and 69 years, respectively, in the three study arms.

Feces donors included 15 healthy volunteers aged 60 years and older who were screened for numerous potentially transmissible diseases. Fecal samples were collected just before the infusion was scheduled, and they were screened for parasites, C. difficile, and enteropathogenic bacteria. The samples were diluted with 500 mL of sterile saline, and the mixture was strained and poured into a sterile bottle.

A mean of 141 g of feces was infused through a nasoduodenal tube, and patients were monitored for 2 hours. Analysis of patients’ phylogenetic microarray profiles before and after treatment demonstrated "a major shift in the patients’ microbiota" from abnormal to normal diversity of organisms, Dr. van Nood and her associates said (N. Engl. J. Med. 2013 Jan. 16 [doi: 10.1056/NEJMoa1205037]).

The primary endpoint was cure without relapse within 10 weeks of treatment. Thirteen patients in the infusion group (81%) reached this endpoint after a single infusion. The remaining 3 patients had a second treatment, and 2 of them were cured, for an overall cure rate of 94% (15 of 16 patients).

In comparison, the cure rate with vancomycin alone was 31% (4 of 13 patients), and with vancomycin plus bowel lavage it was 23% (3 of 13).

At an interim follow-up of 5 weeks following initial treatment, C. difficile infection recurred in 1 patient (6%) in the infusion group, compared with 8 (62%) in the vancomycin-only group and 7 (54%) in the vancomycin-plus-lavage group.

Eighteen patients from the two control groups who relapsed after antibiotic treatment switched to off-protocol infusions of donor feces. Fifteen of them (83%) were cured: 11 after a single fecal infusion and 4 after two infusions.

All but one of the patients who received fecal infusions experienced immediate diarrhea, sometimes with cramping (31%) and belching (19%). These symptoms resolved in all of them within 3 hours. The only other adverse event that may have been related to the treatment was constipation, which developed in three patients.

Although the exact mechanism of action of this "unconventional" therapy is not yet known, Dr. van Nood and her colleagues speculated that donor-feces infusion probably restores the normal intestinal microbiota, enhancing the host defense against C. difficile.

Future research must determine the optimal protocol for donor-feces infusion, including the amount of feces required. Alternative routes of infusion, such as via enema or colonoscopy, also should be explored, they added.

This study was supported by the Netherlands Organization for Health Research and Development and the Netherlands Organization for Scientific Research. Four of the study’s 13 authors reported ties to Astellas. Two of those four also reported ties to Microbex.

A newly identified interferon gene known as IFNL4 is associated with impaired clearance of hepatitis C virus, results from a novel study demonstrated.

In an article published online Jan. 6 in Nature Genetics, the results of the study suggest that therapeutic inhibition of IFNL4 "might represent a novel biological strategy for the treatment of HCV and HBV infection and possibly other diseases, and IFNL4 genotype could be used to select patients for this therapy," wrote Ludmila Prokunina-Olsson, Ph.D., and her colleagues.

Courtesy US. Dept of Veterans Affairs

They described IFNL4 as "related to but distinct from known IFNs and other class 2 cytokines. The 179 amino acid open reading frame of the IFNL4 transcript is created by a common deletion frameshift allele of ss469415590, which is a dinucleotide variant strongly linked with rs12979860" – a genetic marker strongly associated with HCV clearance. The gene is located upstream of IFNL3 on chromosome 19q13.13.

Dr. Prokunina-Olsson, of the Laboratory of Translational Genomics in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and her associates performed the RNA sequencing experiment in a sample of primary human hepatocytes treated with polyinosinic:polycytidylic acid, a synthetic mimic of double-stranded HCV RNA. The sample was taken from a liver donor who was heterozygous for rs12979860 and uninfected with HCV (Nature Genetics 2013 Jan. 6 [doi: 10.1038/ng.2521]).

The researchers found that compared with rs12979860, ss469415590 was more strongly associated with HCV clearance in individuals of African ancestry (P = .015), while these variants behaved similarly in individuals of European ancestry.

They also discovered that IFNL4 "induces STAT1 and STAT2 phosphorylation, activates ISRE-Luc reporter and ISGs, and generates antiviral response in hepatoma cells," they wrote. "The mechanisms by which IFNL4 induces these responses but nevertheless impairs HCV clearance are currently under investigation."

The study was funded by grants from the National Cancer Institute and the National Institute of Diabetes, Digestive, and Kidney Diseases.

[email protected]

A newly identified interferon gene known as IFNL4 is associated with impaired clearance of hepatitis C virus, results from a novel study demonstrated.

In an article published online Jan. 6 in Nature Genetics, the results of the study suggest that therapeutic inhibition of IFNL4 "might represent a novel biological strategy for the treatment of HCV and HBV infection and possibly other diseases, and IFNL4 genotype could be used to select patients for this therapy," wrote Ludmila Prokunina-Olsson, Ph.D., and her colleagues.

Courtesy US. Dept of Veterans Affairs

They described IFNL4 as "related to but distinct from known IFNs and other class 2 cytokines. The 179 amino acid open reading frame of the IFNL4 transcript is created by a common deletion frameshift allele of ss469415590, which is a dinucleotide variant strongly linked with rs12979860" – a genetic marker strongly associated with HCV clearance. The gene is located upstream of IFNL3 on chromosome 19q13.13.

Dr. Prokunina-Olsson, of the Laboratory of Translational Genomics in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and her associates performed the RNA sequencing experiment in a sample of primary human hepatocytes treated with polyinosinic:polycytidylic acid, a synthetic mimic of double-stranded HCV RNA. The sample was taken from a liver donor who was heterozygous for rs12979860 and uninfected with HCV (Nature Genetics 2013 Jan. 6 [doi: 10.1038/ng.2521]).

The researchers found that compared with rs12979860, ss469415590 was more strongly associated with HCV clearance in individuals of African ancestry (P = .015), while these variants behaved similarly in individuals of European ancestry.

They also discovered that IFNL4 "induces STAT1 and STAT2 phosphorylation, activates ISRE-Luc reporter and ISGs, and generates antiviral response in hepatoma cells," they wrote. "The mechanisms by which IFNL4 induces these responses but nevertheless impairs HCV clearance are currently under investigation."

The study was funded by grants from the National Cancer Institute and the National Institute of Diabetes, Digestive, and Kidney Diseases.

[email protected]

A newly identified interferon gene known as IFNL4 is associated with impaired clearance of hepatitis C virus, results from a novel study demonstrated.

In an article published online Jan. 6 in Nature Genetics, the results of the study suggest that therapeutic inhibition of IFNL4 "might represent a novel biological strategy for the treatment of HCV and HBV infection and possibly other diseases, and IFNL4 genotype could be used to select patients for this therapy," wrote Ludmila Prokunina-Olsson, Ph.D., and her colleagues.

Courtesy US. Dept of Veterans Affairs

They described IFNL4 as "related to but distinct from known IFNs and other class 2 cytokines. The 179 amino acid open reading frame of the IFNL4 transcript is created by a common deletion frameshift allele of ss469415590, which is a dinucleotide variant strongly linked with rs12979860" – a genetic marker strongly associated with HCV clearance. The gene is located upstream of IFNL3 on chromosome 19q13.13.

Dr. Prokunina-Olsson, of the Laboratory of Translational Genomics in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and her associates performed the RNA sequencing experiment in a sample of primary human hepatocytes treated with polyinosinic:polycytidylic acid, a synthetic mimic of double-stranded HCV RNA. The sample was taken from a liver donor who was heterozygous for rs12979860 and uninfected with HCV (Nature Genetics 2013 Jan. 6 [doi: 10.1038/ng.2521]).

The researchers found that compared with rs12979860, ss469415590 was more strongly associated with HCV clearance in individuals of African ancestry (P = .015), while these variants behaved similarly in individuals of European ancestry.

They also discovered that IFNL4 "induces STAT1 and STAT2 phosphorylation, activates ISRE-Luc reporter and ISGs, and generates antiviral response in hepatoma cells," they wrote. "The mechanisms by which IFNL4 induces these responses but nevertheless impairs HCV clearance are currently under investigation."

The study was funded by grants from the National Cancer Institute and the National Institute of Diabetes, Digestive, and Kidney Diseases.

[email protected]

Cyclosporine was no more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids, according to an open-label, randomized controlled trial of 115 patients.

However, the authors, led by Dr. David Laharie of the hepatology and gastroenterology service at Bordeaux (France) Hospital Center, said that their findings should be interpreted with caution because of the sample size. They added that treatment choice should be guided by physician and center experience.

As many as 40% of patients with acute severe ulcerative colitis who are admitted to the hospital are resistant to intravenous corticosteroids. For these patients, two drugs, cyclosporine or infliximab, have been used as rescue drugs to avoid colectomy.

Meanwhile, there haven’t been many studies comparing the two drugs. A 2012 systematic review of studies on cyclosporine and infliximab showed that the two were comparable, but randomized trials were needed, the review authors noted (Int. J. Colorectal. Dis. 2012 Nov. 1 [Epub ahead of print]). The current study, according to Dr. Laharie and his colleagues, is the first randomized trial to address the issue (Lancet 2012;380:1909-15).

For the 98-day open-label study, researchers randomized 115 patients to cyclosporine (58 patients) or infliximab (57). The patients were admitted for acute severe flare of ulcerative colitis (Lichtiger score greater than 10 points) to one of the 27 European centers participating in the study between June 1, 2007, and Aug. 31, 2010. They were 18 years or older (mean, 37.5 years), and had never received cyclosporine or infliximab. Contraception during the trial and for 3 months after was mandatory for patients of childbearing age.

The primary endpoint was treatment failure at any time, including absence of clinical response on day 7, relapse between day 7 and day 98, absence of steroid-free remission at day 98, or a severe adverse event leading to interruption of treatment, colectomy, or death. The secondary endpoints included clinical response at day 7, time to clinical response, mucosal healing at day 98, colectomy-free survival, and safety.

Treatment failed in 35 patients (60%) who were receiving cyclosporine, and in 31 patients (54%) who were given infliximab (absolute risk difference of 6%, P = .52). There were no significant differences between the two groups’ suboutcomes, such as responses at day 7 and colectomy rates at day 98. Both drugs were well tolerated, and there were no serious infections or deaths during the trial period.

The authors noted several limitations of the study. Treatment assignments were open label. The use of composite criteria as a primary outcome, rather than colectomy alone, "probably restricted the effect of unmasking on therapeutic decisions," they wrote. Also, the study was powered to detect a large difference between the effect of the two drugs. In addition, they said that because of the sample size, the study’s findings needed to be interpreted with caution.

The authors listed disclosures with several companies, including Merck Sharp & Dohme, Abbott, and Ferring, but they said that no commercial entity had any role in the study, and that the funding sources had no role in the study design, data collection, analysis, or interpretation.

[email protected]

On Twitter @naseemsmiller

Cyclosporine was no more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids, according to an open-label, randomized controlled trial of 115 patients.

However, the authors, led by Dr. David Laharie of the hepatology and gastroenterology service at Bordeaux (France) Hospital Center, said that their findings should be interpreted with caution because of the sample size. They added that treatment choice should be guided by physician and center experience.

As many as 40% of patients with acute severe ulcerative colitis who are admitted to the hospital are resistant to intravenous corticosteroids. For these patients, two drugs, cyclosporine or infliximab, have been used as rescue drugs to avoid colectomy.

Meanwhile, there haven’t been many studies comparing the two drugs. A 2012 systematic review of studies on cyclosporine and infliximab showed that the two were comparable, but randomized trials were needed, the review authors noted (Int. J. Colorectal. Dis. 2012 Nov. 1 [Epub ahead of print]). The current study, according to Dr. Laharie and his colleagues, is the first randomized trial to address the issue (Lancet 2012;380:1909-15).

For the 98-day open-label study, researchers randomized 115 patients to cyclosporine (58 patients) or infliximab (57). The patients were admitted for acute severe flare of ulcerative colitis (Lichtiger score greater than 10 points) to one of the 27 European centers participating in the study between June 1, 2007, and Aug. 31, 2010. They were 18 years or older (mean, 37.5 years), and had never received cyclosporine or infliximab. Contraception during the trial and for 3 months after was mandatory for patients of childbearing age.

The primary endpoint was treatment failure at any time, including absence of clinical response on day 7, relapse between day 7 and day 98, absence of steroid-free remission at day 98, or a severe adverse event leading to interruption of treatment, colectomy, or death. The secondary endpoints included clinical response at day 7, time to clinical response, mucosal healing at day 98, colectomy-free survival, and safety.

Treatment failed in 35 patients (60%) who were receiving cyclosporine, and in 31 patients (54%) who were given infliximab (absolute risk difference of 6%, P = .52). There were no significant differences between the two groups’ suboutcomes, such as responses at day 7 and colectomy rates at day 98. Both drugs were well tolerated, and there were no serious infections or deaths during the trial period.

The authors noted several limitations of the study. Treatment assignments were open label. The use of composite criteria as a primary outcome, rather than colectomy alone, "probably restricted the effect of unmasking on therapeutic decisions," they wrote. Also, the study was powered to detect a large difference between the effect of the two drugs. In addition, they said that because of the sample size, the study’s findings needed to be interpreted with caution.

The authors listed disclosures with several companies, including Merck Sharp & Dohme, Abbott, and Ferring, but they said that no commercial entity had any role in the study, and that the funding sources had no role in the study design, data collection, analysis, or interpretation.

[email protected]

On Twitter @naseemsmiller

Cyclosporine was no more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids, according to an open-label, randomized controlled trial of 115 patients.

However, the authors, led by Dr. David Laharie of the hepatology and gastroenterology service at Bordeaux (France) Hospital Center, said that their findings should be interpreted with caution because of the sample size. They added that treatment choice should be guided by physician and center experience.

As many as 40% of patients with acute severe ulcerative colitis who are admitted to the hospital are resistant to intravenous corticosteroids. For these patients, two drugs, cyclosporine or infliximab, have been used as rescue drugs to avoid colectomy.

Meanwhile, there haven’t been many studies comparing the two drugs. A 2012 systematic review of studies on cyclosporine and infliximab showed that the two were comparable, but randomized trials were needed, the review authors noted (Int. J. Colorectal. Dis. 2012 Nov. 1 [Epub ahead of print]). The current study, according to Dr. Laharie and his colleagues, is the first randomized trial to address the issue (Lancet 2012;380:1909-15).

For the 98-day open-label study, researchers randomized 115 patients to cyclosporine (58 patients) or infliximab (57). The patients were admitted for acute severe flare of ulcerative colitis (Lichtiger score greater than 10 points) to one of the 27 European centers participating in the study between June 1, 2007, and Aug. 31, 2010. They were 18 years or older (mean, 37.5 years), and had never received cyclosporine or infliximab. Contraception during the trial and for 3 months after was mandatory for patients of childbearing age.

The primary endpoint was treatment failure at any time, including absence of clinical response on day 7, relapse between day 7 and day 98, absence of steroid-free remission at day 98, or a severe adverse event leading to interruption of treatment, colectomy, or death. The secondary endpoints included clinical response at day 7, time to clinical response, mucosal healing at day 98, colectomy-free survival, and safety.

Treatment failed in 35 patients (60%) who were receiving cyclosporine, and in 31 patients (54%) who were given infliximab (absolute risk difference of 6%, P = .52). There were no significant differences between the two groups’ suboutcomes, such as responses at day 7 and colectomy rates at day 98. Both drugs were well tolerated, and there were no serious infections or deaths during the trial period.

The authors noted several limitations of the study. Treatment assignments were open label. The use of composite criteria as a primary outcome, rather than colectomy alone, "probably restricted the effect of unmasking on therapeutic decisions," they wrote. Also, the study was powered to detect a large difference between the effect of the two drugs. In addition, they said that because of the sample size, the study’s findings needed to be interpreted with caution.

The authors listed disclosures with several companies, including Merck Sharp & Dohme, Abbott, and Ferring, but they said that no commercial entity had any role in the study, and that the funding sources had no role in the study design, data collection, analysis, or interpretation.

[email protected]

On Twitter @naseemsmiller

Clinical question

For patients with acute variceal bleeds, does the use of vasoactive agents improve outcomes?

Bottom line

The use of vasoactive agents such as vasopressin, somatostatin, and octreotide decreases the risk of all-cause mortality in patients with acute variceal bleeding. LOE = 1a-

Reference

Wells M, Chande N, Adams P, et al. Meta-analysis: vasoactive medications for the management of acute variceal bleeds. Aliment Pharmacol Ther. 2012;35(11):1267-1278.

Study Design

Meta-analysis (randomized controlled trials)

Funding Source

Self-funded or unfunded

Allocation

Uncertain

Setting

Inpatient (any location)

Synopsis

Vasoactive agents such as vasopressin and somatostatin and their analogues (terlipressin, vapreotide and octreotide) are used to treat acute variceal bleeding. These investigators searched EMBASE, MEDLINE, and the EBM Reviews databases to identify randomized controlled trials that compared the intravenous use of these vasoactive agents with each other or with placebo in adults presenting with variceal bleeding. Two investigators independently selected the studies, abstracted data, and assessed study quality. The final selection included 30 studies that compared vasoactive medications with placebo (n = 3111) and 27 studies that compared different vasoactive agents with each other (n = 2293). Moderate-quality evidence showed that vasoactive agents decreased 7-day mortality risk compared with placebo or routine medical management (relative risk = 0.74; 95% CI, 0.57-0.95; P = .02). There was also evidence of decreased risk of rebleeding, decreased transfusion requirements, and shorter hospital stays with the use of vasoactive agents although the quality of this evidence was low to moderate. For the studies comparing different agents with each other, there was no difference in mortality detected.

Clinical question

For patients with acute variceal bleeds, does the use of vasoactive agents improve outcomes?

Bottom line

The use of vasoactive agents such as vasopressin, somatostatin, and octreotide decreases the risk of all-cause mortality in patients with acute variceal bleeding. LOE = 1a-

Reference

Wells M, Chande N, Adams P, et al. Meta-analysis: vasoactive medications for the management of acute variceal bleeds. Aliment Pharmacol Ther. 2012;35(11):1267-1278.

Study Design

Meta-analysis (randomized controlled trials)

Funding Source

Self-funded or unfunded

Allocation

Uncertain

Setting

Inpatient (any location)

Synopsis

Vasoactive agents such as vasopressin and somatostatin and their analogues (terlipressin, vapreotide and octreotide) are used to treat acute variceal bleeding. These investigators searched EMBASE, MEDLINE, and the EBM Reviews databases to identify randomized controlled trials that compared the intravenous use of these vasoactive agents with each other or with placebo in adults presenting with variceal bleeding. Two investigators independently selected the studies, abstracted data, and assessed study quality. The final selection included 30 studies that compared vasoactive medications with placebo (n = 3111) and 27 studies that compared different vasoactive agents with each other (n = 2293). Moderate-quality evidence showed that vasoactive agents decreased 7-day mortality risk compared with placebo or routine medical management (relative risk = 0.74; 95% CI, 0.57-0.95; P = .02). There was also evidence of decreased risk of rebleeding, decreased transfusion requirements, and shorter hospital stays with the use of vasoactive agents although the quality of this evidence was low to moderate. For the studies comparing different agents with each other, there was no difference in mortality detected.

Clinical question

For patients with acute variceal bleeds, does the use of vasoactive agents improve outcomes?

Bottom line

The use of vasoactive agents such as vasopressin, somatostatin, and octreotide decreases the risk of all-cause mortality in patients with acute variceal bleeding. LOE = 1a-

Reference

Wells M, Chande N, Adams P, et al. Meta-analysis: vasoactive medications for the management of acute variceal bleeds. Aliment Pharmacol Ther. 2012;35(11):1267-1278.

Study Design

Meta-analysis (randomized controlled trials)

Funding Source

Self-funded or unfunded

Allocation

Uncertain

Setting

Inpatient (any location)

Synopsis

Vasoactive agents such as vasopressin and somatostatin and their analogues (terlipressin, vapreotide and octreotide) are used to treat acute variceal bleeding. These investigators searched EMBASE, MEDLINE, and the EBM Reviews databases to identify randomized controlled trials that compared the intravenous use of these vasoactive agents with each other or with placebo in adults presenting with variceal bleeding. Two investigators independently selected the studies, abstracted data, and assessed study quality. The final selection included 30 studies that compared vasoactive medications with placebo (n = 3111) and 27 studies that compared different vasoactive agents with each other (n = 2293). Moderate-quality evidence showed that vasoactive agents decreased 7-day mortality risk compared with placebo or routine medical management (relative risk = 0.74; 95% CI, 0.57-0.95; P = .02). There was also evidence of decreased risk of rebleeding, decreased transfusion requirements, and shorter hospital stays with the use of vasoactive agents although the quality of this evidence was low to moderate. For the studies comparing different agents with each other, there was no difference in mortality detected.

Clinical question

For patients with diabetes and multivessel coronary artery disease, which revascularization strategy provides better outcomes?

Bottom line

Revascularization using coronary artery bypass grafting (CABG), as compared with percutaneous coronary intervention (PCI), significantly reduces long-term mortality as well as decreases the rate of myocardial infarctions in diabetic patients with multivessel coronary artery disease (CAD). The number needed to treat is 13. Of note, patients who undergo CABG are more likely to have a stroke, but this occurs mostly during the 30-day period following the procedure. LOE = 1b-

Reference

Farkouh ME, Domanski M, Sleeper LA, et al, for the FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012 Nov 4 [Epub ahead of print].

Study Design

Randomized controlled trial (nonblinded)

Funding Source

Industry + govt

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Using concealed allocation, these investigators enrolled 1900 patients with diabetes and multivessel CAD to receive either PCI with drug-eluting stents or CABG surgery. Most enrolled patients were men, had a mean age of 63 years, and 83% of the total group had evidence of 3-vessel disease. The use of appropriate cardiac medications, including statins and beta-blockers, was similar in the 2 groups, although patients in the PCI group were more likely to receive thienopyridines such as clopidogrel after 5 years of follow-up. Analysis was by intention to treat. Five years after revascularization, the primary composite outcome of all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke was more likely in the PCI group than in the CABG group (26.6% vs 18.7%; P = .005). This was due to increased rates of death and myocardial infarction in the PCI group (for death: 16.3% vs 10.9%; P = .049; for MI: 13.9% vs 6%; P < .001). The CABG group did, however, have a higher rate of stroke at 5 years (5.2% vs 2.4%; P = .03). The majority of these strokes occurred during the first 30 days following revascularization.

Clinical question

For patients with diabetes and multivessel coronary artery disease, which revascularization strategy provides better outcomes?

Bottom line

Revascularization using coronary artery bypass grafting (CABG), as compared with percutaneous coronary intervention (PCI), significantly reduces long-term mortality as well as decreases the rate of myocardial infarctions in diabetic patients with multivessel coronary artery disease (CAD). The number needed to treat is 13. Of note, patients who undergo CABG are more likely to have a stroke, but this occurs mostly during the 30-day period following the procedure. LOE = 1b-

Reference

Farkouh ME, Domanski M, Sleeper LA, et al, for the FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012 Nov 4 [Epub ahead of print].

Study Design

Randomized controlled trial (nonblinded)

Funding Source

Industry + govt

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Using concealed allocation, these investigators enrolled 1900 patients with diabetes and multivessel CAD to receive either PCI with drug-eluting stents or CABG surgery. Most enrolled patients were men, had a mean age of 63 years, and 83% of the total group had evidence of 3-vessel disease. The use of appropriate cardiac medications, including statins and beta-blockers, was similar in the 2 groups, although patients in the PCI group were more likely to receive thienopyridines such as clopidogrel after 5 years of follow-up. Analysis was by intention to treat. Five years after revascularization, the primary composite outcome of all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke was more likely in the PCI group than in the CABG group (26.6% vs 18.7%; P = .005). This was due to increased rates of death and myocardial infarction in the PCI group (for death: 16.3% vs 10.9%; P = .049; for MI: 13.9% vs 6%; P < .001). The CABG group did, however, have a higher rate of stroke at 5 years (5.2% vs 2.4%; P = .03). The majority of these strokes occurred during the first 30 days following revascularization.

Clinical question

For patients with diabetes and multivessel coronary artery disease, which revascularization strategy provides better outcomes?

Bottom line

Revascularization using coronary artery bypass grafting (CABG), as compared with percutaneous coronary intervention (PCI), significantly reduces long-term mortality as well as decreases the rate of myocardial infarctions in diabetic patients with multivessel coronary artery disease (CAD). The number needed to treat is 13. Of note, patients who undergo CABG are more likely to have a stroke, but this occurs mostly during the 30-day period following the procedure. LOE = 1b-

Reference

Farkouh ME, Domanski M, Sleeper LA, et al, for the FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012 Nov 4 [Epub ahead of print].

Study Design

Randomized controlled trial (nonblinded)

Funding Source

Industry + govt

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Using concealed allocation, these investigators enrolled 1900 patients with diabetes and multivessel CAD to receive either PCI with drug-eluting stents or CABG surgery. Most enrolled patients were men, had a mean age of 63 years, and 83% of the total group had evidence of 3-vessel disease. The use of appropriate cardiac medications, including statins and beta-blockers, was similar in the 2 groups, although patients in the PCI group were more likely to receive thienopyridines such as clopidogrel after 5 years of follow-up. Analysis was by intention to treat. Five years after revascularization, the primary composite outcome of all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke was more likely in the PCI group than in the CABG group (26.6% vs 18.7%; P = .005). This was due to increased rates of death and myocardial infarction in the PCI group (for death: 16.3% vs 10.9%; P = .049; for MI: 13.9% vs 6%; P < .001). The CABG group did, however, have a higher rate of stroke at 5 years (5.2% vs 2.4%; P = .03). The majority of these strokes occurred during the first 30 days following revascularization.