SNOWMASS, COLO. – Recent data seem to refute the 2013 American Heart Association/American College of Cardiology class III recommendation to avoid multivessel percutaneous coronary intervention at the time of primary PCI for ST-elevation MI, Dr. David R. Holmes Jr. observed at the Annual Cardiovascular Conference at Snowmass.

“The current AHA/ACC guidelines for STEMI should be and are being reevaluated regarding clarifications for the indications and timing of non–infarct artery revascularization,” according to Dr. Holmes, a cardiologist at the Mayo Clinic in Rochester, Minn., and an ACC past president.

Indeed, the ACC has already withdrawn from its ‘Choosing Wisely’ campaign its former recommendation discouraging multivessel revascularization at the time of primary PCI for STEMI. The college cited “new science showing that complete revascularization of all significant blocked arteries leads to better outcomes in some heart attack patients.”

Dr. Holmes was coauthor of a meta-analysis of 4 prospective and 14 retrospective studies involving more than 40,000 patients that concluded multivessel PCI for STEMI should be discouraged, and that significant nonculprit lesions should only be treated during staged procedures (J. Am. Coll. Cardiol. 2011;58:692-703). This meta-analysis was influential in the creation of the class III ‘don’t do it’ recommendation in the AHA/ACC guidelines. But Dr. Holmes said that in hindsight, the data included in the meta-analysis were something of a mishmash and “wound up being very hard to interpret.”

Greater clarity has been brought by two more recent randomized trials: PRAMI and CvLPRIT. Both were relatively small by cardiology standards, but they ended up showing similarly striking advantages in favor of using the STEMI hospitalization to perform preventive PCI of both the infarct-related artery and non–infarct arteries with major stenoses.

PRAMI included 465 acute STEMI patients who underwent infarct artery PCI and were then randomized to preventive PCI or infarct artery–only PCI. At a mean follow-up of 23 months, the preventive multivessel PCI group had a 65% reduction in the relative risk of the primary outcome, a composite of cardiac death, nonfatal MI, or refractory angina (N. Engl. J. Med. 2013;369:1115-23).

The yet-to-be-published CvLPRIT study was presented at the 2014 European Society of Cardiology meeting in Barcelona. The multicenter study included 296 STEMI patients with angiographically established significant multivessel disease who were randomized to primary PCI of the culprit vessel only or to complete revascularization. The primary outcome, the 12-month composite of all-cause mortality, recurrent MI, heart failure, or ischemia-driven revascularization, occurred in 10% of the complete revascularization group, compared with 21.2% of patients assigned to culprit artery–only PCI.

Also at the ESC conference, CvLPRIT investigator Dr. Anthony Gershlick of the University of Leicester (England) presented a meta-analysis combining the weighted results of PRAMI, CvLPRIT, and two earlier randomized trials: HELP AMI (Int. J. Cardiovasc. Intervent. 2004;6:128-33) and an Italian trial (Heart 2010;96:662-7). The results strongly favored multivessel PCI, with a 45% reduction in mortality and a 61% decrease in recurrent MI, compared with culprit vessel–only PCI at the time of admission for STEMI.

“Maybe there aren’t any innocent bystanders,” commented Dr. Holmes. “Maybe if you have somebody who has multivessel disease and you see something you think might be an innocent bystander but is a significant lesion, maybe it’s not so innocent. Maybe by treating them all at the time of the initial intervention the patient is going to do better.”

He reported having no financial conflicts of interest regarding his presentation.

[email protected]

SNOWMASS, COLO. – Recent data seem to refute the 2013 American Heart Association/American College of Cardiology class III recommendation to avoid multivessel percutaneous coronary intervention at the time of primary PCI for ST-elevation MI, Dr. David R. Holmes Jr. observed at the Annual Cardiovascular Conference at Snowmass.

“The current AHA/ACC guidelines for STEMI should be and are being reevaluated regarding clarifications for the indications and timing of non–infarct artery revascularization,” according to Dr. Holmes, a cardiologist at the Mayo Clinic in Rochester, Minn., and an ACC past president.

Indeed, the ACC has already withdrawn from its ‘Choosing Wisely’ campaign its former recommendation discouraging multivessel revascularization at the time of primary PCI for STEMI. The college cited “new science showing that complete revascularization of all significant blocked arteries leads to better outcomes in some heart attack patients.”

Dr. Holmes was coauthor of a meta-analysis of 4 prospective and 14 retrospective studies involving more than 40,000 patients that concluded multivessel PCI for STEMI should be discouraged, and that significant nonculprit lesions should only be treated during staged procedures (J. Am. Coll. Cardiol. 2011;58:692-703). This meta-analysis was influential in the creation of the class III ‘don’t do it’ recommendation in the AHA/ACC guidelines. But Dr. Holmes said that in hindsight, the data included in the meta-analysis were something of a mishmash and “wound up being very hard to interpret.”

Greater clarity has been brought by two more recent randomized trials: PRAMI and CvLPRIT. Both were relatively small by cardiology standards, but they ended up showing similarly striking advantages in favor of using the STEMI hospitalization to perform preventive PCI of both the infarct-related artery and non–infarct arteries with major stenoses.

PRAMI included 465 acute STEMI patients who underwent infarct artery PCI and were then randomized to preventive PCI or infarct artery–only PCI. At a mean follow-up of 23 months, the preventive multivessel PCI group had a 65% reduction in the relative risk of the primary outcome, a composite of cardiac death, nonfatal MI, or refractory angina (N. Engl. J. Med. 2013;369:1115-23).

The yet-to-be-published CvLPRIT study was presented at the 2014 European Society of Cardiology meeting in Barcelona. The multicenter study included 296 STEMI patients with angiographically established significant multivessel disease who were randomized to primary PCI of the culprit vessel only or to complete revascularization. The primary outcome, the 12-month composite of all-cause mortality, recurrent MI, heart failure, or ischemia-driven revascularization, occurred in 10% of the complete revascularization group, compared with 21.2% of patients assigned to culprit artery–only PCI.

Also at the ESC conference, CvLPRIT investigator Dr. Anthony Gershlick of the University of Leicester (England) presented a meta-analysis combining the weighted results of PRAMI, CvLPRIT, and two earlier randomized trials: HELP AMI (Int. J. Cardiovasc. Intervent. 2004;6:128-33) and an Italian trial (Heart 2010;96:662-7). The results strongly favored multivessel PCI, with a 45% reduction in mortality and a 61% decrease in recurrent MI, compared with culprit vessel–only PCI at the time of admission for STEMI.

“Maybe there aren’t any innocent bystanders,” commented Dr. Holmes. “Maybe if you have somebody who has multivessel disease and you see something you think might be an innocent bystander but is a significant lesion, maybe it’s not so innocent. Maybe by treating them all at the time of the initial intervention the patient is going to do better.”

He reported having no financial conflicts of interest regarding his presentation.

[email protected]

SNOWMASS, COLO. – Recent data seem to refute the 2013 American Heart Association/American College of Cardiology class III recommendation to avoid multivessel percutaneous coronary intervention at the time of primary PCI for ST-elevation MI, Dr. David R. Holmes Jr. observed at the Annual Cardiovascular Conference at Snowmass.

“The current AHA/ACC guidelines for STEMI should be and are being reevaluated regarding clarifications for the indications and timing of non–infarct artery revascularization,” according to Dr. Holmes, a cardiologist at the Mayo Clinic in Rochester, Minn., and an ACC past president.

Indeed, the ACC has already withdrawn from its ‘Choosing Wisely’ campaign its former recommendation discouraging multivessel revascularization at the time of primary PCI for STEMI. The college cited “new science showing that complete revascularization of all significant blocked arteries leads to better outcomes in some heart attack patients.”

Dr. Holmes was coauthor of a meta-analysis of 4 prospective and 14 retrospective studies involving more than 40,000 patients that concluded multivessel PCI for STEMI should be discouraged, and that significant nonculprit lesions should only be treated during staged procedures (J. Am. Coll. Cardiol. 2011;58:692-703). This meta-analysis was influential in the creation of the class III ‘don’t do it’ recommendation in the AHA/ACC guidelines. But Dr. Holmes said that in hindsight, the data included in the meta-analysis were something of a mishmash and “wound up being very hard to interpret.”

Greater clarity has been brought by two more recent randomized trials: PRAMI and CvLPRIT. Both were relatively small by cardiology standards, but they ended up showing similarly striking advantages in favor of using the STEMI hospitalization to perform preventive PCI of both the infarct-related artery and non–infarct arteries with major stenoses.

PRAMI included 465 acute STEMI patients who underwent infarct artery PCI and were then randomized to preventive PCI or infarct artery–only PCI. At a mean follow-up of 23 months, the preventive multivessel PCI group had a 65% reduction in the relative risk of the primary outcome, a composite of cardiac death, nonfatal MI, or refractory angina (N. Engl. J. Med. 2013;369:1115-23).

The yet-to-be-published CvLPRIT study was presented at the 2014 European Society of Cardiology meeting in Barcelona. The multicenter study included 296 STEMI patients with angiographically established significant multivessel disease who were randomized to primary PCI of the culprit vessel only or to complete revascularization. The primary outcome, the 12-month composite of all-cause mortality, recurrent MI, heart failure, or ischemia-driven revascularization, occurred in 10% of the complete revascularization group, compared with 21.2% of patients assigned to culprit artery–only PCI.

Also at the ESC conference, CvLPRIT investigator Dr. Anthony Gershlick of the University of Leicester (England) presented a meta-analysis combining the weighted results of PRAMI, CvLPRIT, and two earlier randomized trials: HELP AMI (Int. J. Cardiovasc. Intervent. 2004;6:128-33) and an Italian trial (Heart 2010;96:662-7). The results strongly favored multivessel PCI, with a 45% reduction in mortality and a 61% decrease in recurrent MI, compared with culprit vessel–only PCI at the time of admission for STEMI.

“Maybe there aren’t any innocent bystanders,” commented Dr. Holmes. “Maybe if you have somebody who has multivessel disease and you see something you think might be an innocent bystander but is a significant lesion, maybe it’s not so innocent. Maybe by treating them all at the time of the initial intervention the patient is going to do better.”

He reported having no financial conflicts of interest regarding his presentation.

[email protected]

Can photographs be as good as clinical examination for counting actinic keratoses?

Depending on the physician, AK counts varied widely on clinical assessment as well as in photos, reported Dr. Sudipta Sinnya of the Dermatology Research Centre at the University of Queensland, Brisbane, and associates. However, based on current two-dimensional technology, clinical counting yields superior results, said the researchers, who studied the counts of five trained observers carried out in two sessions with six patients.

“As technological advancements occur, three-dimensional photography will largely supersede two-dimensional photographs in clinical practice, and more robust image-capturing techniques should improve the accuracy of photogra­phic counting,” the researchers noted.

Read the full article from Acta Dermato-Venereologica (2015 [doi:10.2340/00015555-2040]) here.

Can photographs be as good as clinical examination for counting actinic keratoses?

Depending on the physician, AK counts varied widely on clinical assessment as well as in photos, reported Dr. Sudipta Sinnya of the Dermatology Research Centre at the University of Queensland, Brisbane, and associates. However, based on current two-dimensional technology, clinical counting yields superior results, said the researchers, who studied the counts of five trained observers carried out in two sessions with six patients.

“As technological advancements occur, three-dimensional photography will largely supersede two-dimensional photographs in clinical practice, and more robust image-capturing techniques should improve the accuracy of photogra­phic counting,” the researchers noted.

Read the full article from Acta Dermato-Venereologica (2015 [doi:10.2340/00015555-2040]) here.

Can photographs be as good as clinical examination for counting actinic keratoses?

Depending on the physician, AK counts varied widely on clinical assessment as well as in photos, reported Dr. Sudipta Sinnya of the Dermatology Research Centre at the University of Queensland, Brisbane, and associates. However, based on current two-dimensional technology, clinical counting yields superior results, said the researchers, who studied the counts of five trained observers carried out in two sessions with six patients.

“As technological advancements occur, three-dimensional photography will largely supersede two-dimensional photographs in clinical practice, and more robust image-capturing techniques should improve the accuracy of photogra­phic counting,” the researchers noted.

Read the full article from Acta Dermato-Venereologica (2015 [doi:10.2340/00015555-2040]) here.

NASHVILLE, TENN. – Patients with upper limbs affected by ischemic stroke who paired traditional rehabilitation exercises with pulsed vagus nerve stimulation boosted functional scores significantly higher than did those who performed exercises alone in a small, randomized pilot trial.

Taken together with the low rate of adverse events associated with device implantation, the study suggests that coupling the interventions is feasible and likely to be beneficial, Dr. Jesse Dawson of the University of Glasgow, Scotland, said at the International Stroke Conference, sponsored by the American Heart Association.

The vagus nerve stimulator (VNS) is typically used to suppress epileptiform discharges and circumvent seizures. The usual stimulation pattern is continuous cycles of 30 seconds on and 5 minutes off. In his randomized, controlled trial, Dr. Dawson set the device to deliver 0.5-second pulses that coincided with each repetition of a rehabilitative movement. When simulated, the nerve releases two proneuroplastic neurotransmitters, acetylcholine and norepinephrine, which then disperse over the cerebral cortex.

“Our theory was that if we timed these releases at specific periods during rehabilitation therapy, we might be able to drive neuroplasticity toward those specific tasks,” Dr. Dawson said at the conference. The technique has proved effective in both aged rats and rat stroke models, he added.

The trial comprised 20 patients who had experienced an ischemic stroke about 2 years prior. Each was left with residual dysfunction in an upper extremity; seven had a paretic limb. The mean Action Research Arm Test (ARAT) score was 33, and the mean upper extremity Fugl-Meyer score was 43, indicating moderate impairment.

Ten patients underwent VNS implantation. Nine completed the trial. One withdrew after 2 weeks because of a transient vocal cord palsy. This later resolved spontaneously.

Other adverse events related to the VNS were also transient. They included taste disturbance, chest pain, mild dysphagia, and nausea after a therapy session.

The 6-week intervention consisted of 18 sessions, each lasting 2 hours. In each, the rehabilitative movement was repeated 300-400 times.

In a per-protocol analysis, there was no significant difference in the upper extremity Fugl-Meyer score at the study’s end. However, when the patient who had withdrawn was excluded from the analysis, the results did become statistically significant. Patients in the dual-therapy group gained almost 10 points, compared with a 3-point gain in the exercise-only group. The ARAT scores were not different at study’s end.

In light of the positive initial results, a sham-controlled, randomized trial is in the works. The trial will randomize 20-25 patients to either the VNS-paired exercise or exercise-only interventions. All participants will receive the VNS device, but only the paired intervention group will receive actual stimuli.

Patricia Smith, Ph.D., the Doris E. Porter Professor in Physical Therapy at the University of Texas Southwestern, Dallas, is the lead investigator.

MicroTransponder, which makes the VNS unit, is sponsoring both the studies. Neither Dr. Dawson nor Dr. Smith have any financial ties to the company.

[email protected]

On Twitter @alz_gal

NASHVILLE, TENN. – Patients with upper limbs affected by ischemic stroke who paired traditional rehabilitation exercises with pulsed vagus nerve stimulation boosted functional scores significantly higher than did those who performed exercises alone in a small, randomized pilot trial.

Taken together with the low rate of adverse events associated with device implantation, the study suggests that coupling the interventions is feasible and likely to be beneficial, Dr. Jesse Dawson of the University of Glasgow, Scotland, said at the International Stroke Conference, sponsored by the American Heart Association.

The vagus nerve stimulator (VNS) is typically used to suppress epileptiform discharges and circumvent seizures. The usual stimulation pattern is continuous cycles of 30 seconds on and 5 minutes off. In his randomized, controlled trial, Dr. Dawson set the device to deliver 0.5-second pulses that coincided with each repetition of a rehabilitative movement. When simulated, the nerve releases two proneuroplastic neurotransmitters, acetylcholine and norepinephrine, which then disperse over the cerebral cortex.

“Our theory was that if we timed these releases at specific periods during rehabilitation therapy, we might be able to drive neuroplasticity toward those specific tasks,” Dr. Dawson said at the conference. The technique has proved effective in both aged rats and rat stroke models, he added.

The trial comprised 20 patients who had experienced an ischemic stroke about 2 years prior. Each was left with residual dysfunction in an upper extremity; seven had a paretic limb. The mean Action Research Arm Test (ARAT) score was 33, and the mean upper extremity Fugl-Meyer score was 43, indicating moderate impairment.

Ten patients underwent VNS implantation. Nine completed the trial. One withdrew after 2 weeks because of a transient vocal cord palsy. This later resolved spontaneously.

Other adverse events related to the VNS were also transient. They included taste disturbance, chest pain, mild dysphagia, and nausea after a therapy session.

The 6-week intervention consisted of 18 sessions, each lasting 2 hours. In each, the rehabilitative movement was repeated 300-400 times.

In a per-protocol analysis, there was no significant difference in the upper extremity Fugl-Meyer score at the study’s end. However, when the patient who had withdrawn was excluded from the analysis, the results did become statistically significant. Patients in the dual-therapy group gained almost 10 points, compared with a 3-point gain in the exercise-only group. The ARAT scores were not different at study’s end.

In light of the positive initial results, a sham-controlled, randomized trial is in the works. The trial will randomize 20-25 patients to either the VNS-paired exercise or exercise-only interventions. All participants will receive the VNS device, but only the paired intervention group will receive actual stimuli.

Patricia Smith, Ph.D., the Doris E. Porter Professor in Physical Therapy at the University of Texas Southwestern, Dallas, is the lead investigator.

MicroTransponder, which makes the VNS unit, is sponsoring both the studies. Neither Dr. Dawson nor Dr. Smith have any financial ties to the company.

[email protected]

On Twitter @alz_gal

NASHVILLE, TENN. – Patients with upper limbs affected by ischemic stroke who paired traditional rehabilitation exercises with pulsed vagus nerve stimulation boosted functional scores significantly higher than did those who performed exercises alone in a small, randomized pilot trial.

Taken together with the low rate of adverse events associated with device implantation, the study suggests that coupling the interventions is feasible and likely to be beneficial, Dr. Jesse Dawson of the University of Glasgow, Scotland, said at the International Stroke Conference, sponsored by the American Heart Association.

The vagus nerve stimulator (VNS) is typically used to suppress epileptiform discharges and circumvent seizures. The usual stimulation pattern is continuous cycles of 30 seconds on and 5 minutes off. In his randomized, controlled trial, Dr. Dawson set the device to deliver 0.5-second pulses that coincided with each repetition of a rehabilitative movement. When simulated, the nerve releases two proneuroplastic neurotransmitters, acetylcholine and norepinephrine, which then disperse over the cerebral cortex.

“Our theory was that if we timed these releases at specific periods during rehabilitation therapy, we might be able to drive neuroplasticity toward those specific tasks,” Dr. Dawson said at the conference. The technique has proved effective in both aged rats and rat stroke models, he added.

The trial comprised 20 patients who had experienced an ischemic stroke about 2 years prior. Each was left with residual dysfunction in an upper extremity; seven had a paretic limb. The mean Action Research Arm Test (ARAT) score was 33, and the mean upper extremity Fugl-Meyer score was 43, indicating moderate impairment.

Ten patients underwent VNS implantation. Nine completed the trial. One withdrew after 2 weeks because of a transient vocal cord palsy. This later resolved spontaneously.

Other adverse events related to the VNS were also transient. They included taste disturbance, chest pain, mild dysphagia, and nausea after a therapy session.

The 6-week intervention consisted of 18 sessions, each lasting 2 hours. In each, the rehabilitative movement was repeated 300-400 times.

In a per-protocol analysis, there was no significant difference in the upper extremity Fugl-Meyer score at the study’s end. However, when the patient who had withdrawn was excluded from the analysis, the results did become statistically significant. Patients in the dual-therapy group gained almost 10 points, compared with a 3-point gain in the exercise-only group. The ARAT scores were not different at study’s end.

In light of the positive initial results, a sham-controlled, randomized trial is in the works. The trial will randomize 20-25 patients to either the VNS-paired exercise or exercise-only interventions. All participants will receive the VNS device, but only the paired intervention group will receive actual stimuli.

Patricia Smith, Ph.D., the Doris E. Porter Professor in Physical Therapy at the University of Texas Southwestern, Dallas, is the lead investigator.

MicroTransponder, which makes the VNS unit, is sponsoring both the studies. Neither Dr. Dawson nor Dr. Smith have any financial ties to the company.

[email protected]

On Twitter @alz_gal

Clinical question

Did the 2011 Accreditation Council for Graduate Medical Education resident work hour reforms affect patient outcomes?

Bottom line

Resident work hour reforms were proposed by the Accreditation Council for Graduate Medical Education (ACGME) to reduce resident fatigue (and thus potentially reduce the risk of medical errors), but implementation of the work hour changes also led to concerns over patient safety because of increased handoffs in care. This study shows that work hour reforms had no impact, either positive or negative, on the important patient outcomes of mortality and readmission rates. Other outcomes such as length of stay and number of intensive care unit transfers may need to be examined in future studies to detect more subtle differences. (LOE = 2b)

Reference

Patel MS, Volpp KG, Small DS, et al. Association of the 2011 ACGME resident duty hour reforms with mortality and readmissions among hospitalized Medicare patients. JAMA 2014;312(22):2364-2373.

Study design: Cohort (retrospective)

Funding source: Government

Allocation: Uncertain

Setting: Inpatient (any location)

Synopsis

In 2011, the ACGME instituted work hour reforms for residents that reduced the work hour limit from 30 consecutive hours to 16 hours for first-year residents and 24 hours for all other residents. Investigators in this study evaluated the effect of the 2011 ACGME reforms on 30-day all-location mortality and 30-day all-cause readmissions. Patients included in the study were Medicare patients who were admitted to acute care US hospitals from 2009 to 2012 with acute myocardial infarction, stroke, gastrointestinal bleeding, or congestive heart failure, or those admitted for general, orthopedic, or vascular surgery. Hospitals were classified by their level of teaching intensity using a resident-to-bed ratio defined as the number of residents divided by the number of staffed beds.

In an analysis that adjusted for demographics, co-morbidities, and the presence of surgical complications, the implementation of work hour reforms did not affect 30-day mortality or readmissions in more-intensive teaching hospitals relative to less-intensive teaching hospitals during the postreform year as compared with 2 years before the reform. Multiple factors beyond the implementation of work hour reforms, may have contributed to this lack of effect. First, adherence to the new reforms by residency programs in the first year is unclear. Second, concurrent initiatives to improve patient outcomes during this time may have affected all hospitals, teaching and nonteaching. Finally, the authors suggest that the greater emphasis on resident supervision with the new reforms may have counterbalanced any negative effects of increased resident handoffs.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Did the 2011 Accreditation Council for Graduate Medical Education resident work hour reforms affect patient outcomes?

Bottom line

Resident work hour reforms were proposed by the Accreditation Council for Graduate Medical Education (ACGME) to reduce resident fatigue (and thus potentially reduce the risk of medical errors), but implementation of the work hour changes also led to concerns over patient safety because of increased handoffs in care. This study shows that work hour reforms had no impact, either positive or negative, on the important patient outcomes of mortality and readmission rates. Other outcomes such as length of stay and number of intensive care unit transfers may need to be examined in future studies to detect more subtle differences. (LOE = 2b)

Reference

Patel MS, Volpp KG, Small DS, et al. Association of the 2011 ACGME resident duty hour reforms with mortality and readmissions among hospitalized Medicare patients. JAMA 2014;312(22):2364-2373.

Study design: Cohort (retrospective)

Funding source: Government

Allocation: Uncertain

Setting: Inpatient (any location)

Synopsis

In 2011, the ACGME instituted work hour reforms for residents that reduced the work hour limit from 30 consecutive hours to 16 hours for first-year residents and 24 hours for all other residents. Investigators in this study evaluated the effect of the 2011 ACGME reforms on 30-day all-location mortality and 30-day all-cause readmissions. Patients included in the study were Medicare patients who were admitted to acute care US hospitals from 2009 to 2012 with acute myocardial infarction, stroke, gastrointestinal bleeding, or congestive heart failure, or those admitted for general, orthopedic, or vascular surgery. Hospitals were classified by their level of teaching intensity using a resident-to-bed ratio defined as the number of residents divided by the number of staffed beds.

In an analysis that adjusted for demographics, co-morbidities, and the presence of surgical complications, the implementation of work hour reforms did not affect 30-day mortality or readmissions in more-intensive teaching hospitals relative to less-intensive teaching hospitals during the postreform year as compared with 2 years before the reform. Multiple factors beyond the implementation of work hour reforms, may have contributed to this lack of effect. First, adherence to the new reforms by residency programs in the first year is unclear. Second, concurrent initiatives to improve patient outcomes during this time may have affected all hospitals, teaching and nonteaching. Finally, the authors suggest that the greater emphasis on resident supervision with the new reforms may have counterbalanced any negative effects of increased resident handoffs.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Did the 2011 Accreditation Council for Graduate Medical Education resident work hour reforms affect patient outcomes?

Bottom line

Resident work hour reforms were proposed by the Accreditation Council for Graduate Medical Education (ACGME) to reduce resident fatigue (and thus potentially reduce the risk of medical errors), but implementation of the work hour changes also led to concerns over patient safety because of increased handoffs in care. This study shows that work hour reforms had no impact, either positive or negative, on the important patient outcomes of mortality and readmission rates. Other outcomes such as length of stay and number of intensive care unit transfers may need to be examined in future studies to detect more subtle differences. (LOE = 2b)

Reference

Patel MS, Volpp KG, Small DS, et al. Association of the 2011 ACGME resident duty hour reforms with mortality and readmissions among hospitalized Medicare patients. JAMA 2014;312(22):2364-2373.

Study design: Cohort (retrospective)

Funding source: Government

Allocation: Uncertain

Setting: Inpatient (any location)

Synopsis

In 2011, the ACGME instituted work hour reforms for residents that reduced the work hour limit from 30 consecutive hours to 16 hours for first-year residents and 24 hours for all other residents. Investigators in this study evaluated the effect of the 2011 ACGME reforms on 30-day all-location mortality and 30-day all-cause readmissions. Patients included in the study were Medicare patients who were admitted to acute care US hospitals from 2009 to 2012 with acute myocardial infarction, stroke, gastrointestinal bleeding, or congestive heart failure, or those admitted for general, orthopedic, or vascular surgery. Hospitals were classified by their level of teaching intensity using a resident-to-bed ratio defined as the number of residents divided by the number of staffed beds.

In an analysis that adjusted for demographics, co-morbidities, and the presence of surgical complications, the implementation of work hour reforms did not affect 30-day mortality or readmissions in more-intensive teaching hospitals relative to less-intensive teaching hospitals during the postreform year as compared with 2 years before the reform. Multiple factors beyond the implementation of work hour reforms, may have contributed to this lack of effect. First, adherence to the new reforms by residency programs in the first year is unclear. Second, concurrent initiatives to improve patient outcomes during this time may have affected all hospitals, teaching and nonteaching. Finally, the authors suggest that the greater emphasis on resident supervision with the new reforms may have counterbalanced any negative effects of increased resident handoffs.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: For critically ill patients, does daily bathing with chlorhexidine reduce health care–associated infections?

Bottom line

These results show that daily chlorhexidine bathing does not significantly affect the incidence of health care–associated infections. These data conflict with data from prior research, suggesting that more investigation is needed before incorporating chlorhexidine bathing into routine practice, especially given the increased cost with its use and the possibility of the development of chlorhexidine resistance. (LOE = 1b)

Reference: Noto MJ, Domenico HJ, Byrne DW, et al. Chlorhexidine bathing and health care-associated infections. JAMA 2015;313(4):369-378.

Study design: Cross-over trial (randomized)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (ICU only)

Synopsis

Previous studies have shown benefit of daily chlorhexidine bathing in patients at high risk of nosocomial blood stream infections (Daily POEM 7-31-2013; Daily POEM 4-26-2013). In this study, investigators randomized 5 intensive care units at a tertiary care hospital to provide daily bathing of all patients with either 2% chlorhexidine-impregnated cloths or with nonantimicrobial cloths. Each unit followed the assigned protocol for 10 weeks, followed by a 2-week washout period, and then crossed over to the alternate protocol for another 10 weeks. All units crossed over 3 times during the study. Almost 10,000 patients were included in the study. The primary outcome was a composite of health-care associated infections, including central-line associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and Clostridium difficile infections. There was no significant difference detected in the rate of the primary outcome between the chlorhexidine group and the control group with approximately 3 infections per 1000 patient-days in both groups. Adjusting for factors including demographics, co-morbidities, and the unit of admission also did not reveal a difference.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: For critically ill patients, does daily bathing with chlorhexidine reduce health care–associated infections?

Bottom line

These results show that daily chlorhexidine bathing does not significantly affect the incidence of health care–associated infections. These data conflict with data from prior research, suggesting that more investigation is needed before incorporating chlorhexidine bathing into routine practice, especially given the increased cost with its use and the possibility of the development of chlorhexidine resistance. (LOE = 1b)

Reference: Noto MJ, Domenico HJ, Byrne DW, et al. Chlorhexidine bathing and health care-associated infections. JAMA 2015;313(4):369-378.

Study design: Cross-over trial (randomized)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (ICU only)

Synopsis

Previous studies have shown benefit of daily chlorhexidine bathing in patients at high risk of nosocomial blood stream infections (Daily POEM 7-31-2013; Daily POEM 4-26-2013). In this study, investigators randomized 5 intensive care units at a tertiary care hospital to provide daily bathing of all patients with either 2% chlorhexidine-impregnated cloths or with nonantimicrobial cloths. Each unit followed the assigned protocol for 10 weeks, followed by a 2-week washout period, and then crossed over to the alternate protocol for another 10 weeks. All units crossed over 3 times during the study. Almost 10,000 patients were included in the study. The primary outcome was a composite of health-care associated infections, including central-line associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and Clostridium difficile infections. There was no significant difference detected in the rate of the primary outcome between the chlorhexidine group and the control group with approximately 3 infections per 1000 patient-days in both groups. Adjusting for factors including demographics, co-morbidities, and the unit of admission also did not reveal a difference.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: For critically ill patients, does daily bathing with chlorhexidine reduce health care–associated infections?

Bottom line

These results show that daily chlorhexidine bathing does not significantly affect the incidence of health care–associated infections. These data conflict with data from prior research, suggesting that more investigation is needed before incorporating chlorhexidine bathing into routine practice, especially given the increased cost with its use and the possibility of the development of chlorhexidine resistance. (LOE = 1b)

Reference: Noto MJ, Domenico HJ, Byrne DW, et al. Chlorhexidine bathing and health care-associated infections. JAMA 2015;313(4):369-378.

Study design: Cross-over trial (randomized)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (ICU only)

Synopsis

Previous studies have shown benefit of daily chlorhexidine bathing in patients at high risk of nosocomial blood stream infections (Daily POEM 7-31-2013; Daily POEM 4-26-2013). In this study, investigators randomized 5 intensive care units at a tertiary care hospital to provide daily bathing of all patients with either 2% chlorhexidine-impregnated cloths or with nonantimicrobial cloths. Each unit followed the assigned protocol for 10 weeks, followed by a 2-week washout period, and then crossed over to the alternate protocol for another 10 weeks. All units crossed over 3 times during the study. Almost 10,000 patients were included in the study. The primary outcome was a composite of health-care associated infections, including central-line associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and Clostridium difficile infections. There was no significant difference detected in the rate of the primary outcome between the chlorhexidine group and the control group with approximately 3 infections per 1000 patient-days in both groups. Adjusting for factors including demographics, co-morbidities, and the unit of admission also did not reveal a difference.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Sleeping infant

Photo by Vera Kratochvil

Infants who have acute lymphoblastic leukemia (ALL) with MLL rearrangements have few other mutations, according to new research.

The findings suggest that targeting MLL rearrangements in these patients is likely the key to improving their survival.

“We frequently associate a cancer’s aggressiveness with its mutation rate, but this work indicates that the two don’t always go hand-in-hand,” said Richard K. Wilson, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“Still, our findings provide a new direction for developing more effective treatments for these very young patients.”

Dr Wilson and his colleagues reported their findings in Nature Genetics.

The researchers performed whole-genome, exome, RNA, and targeted DNA sequencing to identify genetic alterations in 65 infants with ALL, including 47 with the MLL rearrangement.

The team was surprised to find that, despite being an aggressive leukemia, the MLL-rearranged subtype had among the lowest mutation rates reported for any cancer. The predominant leukemic clone carried a mean of 1.3 non-silent mutations.

“These results show that, to improve survival for patients with this aggressive leukemia, we need to develop drugs that target the abnormal proteins produced by the MLL fusion gene or that interact with the abnormal MLL fusion protein to shut down the cellular machinery that drives their tumors,” said James R. Downing, MD, of St Jude Research Hospital in Memphis, Tennessee. “That will not be easy, but this study found no obvious cooperating mutations to target.”

Almost half of infants with MLL-rearranged ALL (47%) had activating mutations in the kinase-PI3K-RAS signaling pathway. But the mutations were often present in only some of the leukemic cells.

Furthermore, the researchers analyzed leukemia cells in infants whose cancer returned after treatment and found that, at the time of relapse, the cells lacked these mutations.

“The fact that the mutations were often lost at relapse suggests that patients are unlikely to benefit from therapeutically targeting these mutations at diagnosis,” Dr Downing said.

The researchers also found that older children with MLL-rearranged leukemia had significantly more mutations than infants—a mean of 6.5 mutations per case (P=7.15 × 10⁻⁵).

Furthermore, 45% of the older children had mutations in genes that encode epigenetic regulatory proteins. And, aside from MLL, epigenetic regulators were rarely mutated in infants with MLL-rearranged ALL.

“While MLL belongs to a family of genes that encode epigenetic regulatory proteins, there was a striking difference between infants and older children regarding the frequency of mutations in other epigenetic regulatory genes,” said Anna Andersson, PhD, of Lund University in Sweden.

“This observation raises the possibility of a fundamental difference in the cell targeted for transformation in infants versus older patients,” said Tanja Gruber, MD, PhD, of St Jude.

“Our working hypothesis is that, in infants, the MLL rearrangement occurs in a developing blood cell, a prenatal progenitor cell, which requires fewer additional mutations to fully transform into leukemia. In contrast, in older patients, the MLL rearrangement isn’t enough on its own.”

Sleeping infant

Photo by Vera Kratochvil

Infants who have acute lymphoblastic leukemia (ALL) with MLL rearrangements have few other mutations, according to new research.

The findings suggest that targeting MLL rearrangements in these patients is likely the key to improving their survival.

“We frequently associate a cancer’s aggressiveness with its mutation rate, but this work indicates that the two don’t always go hand-in-hand,” said Richard K. Wilson, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“Still, our findings provide a new direction for developing more effective treatments for these very young patients.”

Dr Wilson and his colleagues reported their findings in Nature Genetics.

The researchers performed whole-genome, exome, RNA, and targeted DNA sequencing to identify genetic alterations in 65 infants with ALL, including 47 with the MLL rearrangement.

The team was surprised to find that, despite being an aggressive leukemia, the MLL-rearranged subtype had among the lowest mutation rates reported for any cancer. The predominant leukemic clone carried a mean of 1.3 non-silent mutations.

“These results show that, to improve survival for patients with this aggressive leukemia, we need to develop drugs that target the abnormal proteins produced by the MLL fusion gene or that interact with the abnormal MLL fusion protein to shut down the cellular machinery that drives their tumors,” said James R. Downing, MD, of St Jude Research Hospital in Memphis, Tennessee. “That will not be easy, but this study found no obvious cooperating mutations to target.”

Almost half of infants with MLL-rearranged ALL (47%) had activating mutations in the kinase-PI3K-RAS signaling pathway. But the mutations were often present in only some of the leukemic cells.

Furthermore, the researchers analyzed leukemia cells in infants whose cancer returned after treatment and found that, at the time of relapse, the cells lacked these mutations.

“The fact that the mutations were often lost at relapse suggests that patients are unlikely to benefit from therapeutically targeting these mutations at diagnosis,” Dr Downing said.

The researchers also found that older children with MLL-rearranged leukemia had significantly more mutations than infants—a mean of 6.5 mutations per case (P=7.15 × 10⁻⁵).

Furthermore, 45% of the older children had mutations in genes that encode epigenetic regulatory proteins. And, aside from MLL, epigenetic regulators were rarely mutated in infants with MLL-rearranged ALL.

“While MLL belongs to a family of genes that encode epigenetic regulatory proteins, there was a striking difference between infants and older children regarding the frequency of mutations in other epigenetic regulatory genes,” said Anna Andersson, PhD, of Lund University in Sweden.

“This observation raises the possibility of a fundamental difference in the cell targeted for transformation in infants versus older patients,” said Tanja Gruber, MD, PhD, of St Jude.

“Our working hypothesis is that, in infants, the MLL rearrangement occurs in a developing blood cell, a prenatal progenitor cell, which requires fewer additional mutations to fully transform into leukemia. In contrast, in older patients, the MLL rearrangement isn’t enough on its own.”

Sleeping infant

Photo by Vera Kratochvil

Infants who have acute lymphoblastic leukemia (ALL) with MLL rearrangements have few other mutations, according to new research.

The findings suggest that targeting MLL rearrangements in these patients is likely the key to improving their survival.

“We frequently associate a cancer’s aggressiveness with its mutation rate, but this work indicates that the two don’t always go hand-in-hand,” said Richard K. Wilson, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“Still, our findings provide a new direction for developing more effective treatments for these very young patients.”

Dr Wilson and his colleagues reported their findings in Nature Genetics.

The researchers performed whole-genome, exome, RNA, and targeted DNA sequencing to identify genetic alterations in 65 infants with ALL, including 47 with the MLL rearrangement.

The team was surprised to find that, despite being an aggressive leukemia, the MLL-rearranged subtype had among the lowest mutation rates reported for any cancer. The predominant leukemic clone carried a mean of 1.3 non-silent mutations.

“These results show that, to improve survival for patients with this aggressive leukemia, we need to develop drugs that target the abnormal proteins produced by the MLL fusion gene or that interact with the abnormal MLL fusion protein to shut down the cellular machinery that drives their tumors,” said James R. Downing, MD, of St Jude Research Hospital in Memphis, Tennessee. “That will not be easy, but this study found no obvious cooperating mutations to target.”

Almost half of infants with MLL-rearranged ALL (47%) had activating mutations in the kinase-PI3K-RAS signaling pathway. But the mutations were often present in only some of the leukemic cells.

Furthermore, the researchers analyzed leukemia cells in infants whose cancer returned after treatment and found that, at the time of relapse, the cells lacked these mutations.

“The fact that the mutations were often lost at relapse suggests that patients are unlikely to benefit from therapeutically targeting these mutations at diagnosis,” Dr Downing said.

The researchers also found that older children with MLL-rearranged leukemia had significantly more mutations than infants—a mean of 6.5 mutations per case (P=7.15 × 10⁻⁵).

Furthermore, 45% of the older children had mutations in genes that encode epigenetic regulatory proteins. And, aside from MLL, epigenetic regulators were rarely mutated in infants with MLL-rearranged ALL.

“While MLL belongs to a family of genes that encode epigenetic regulatory proteins, there was a striking difference between infants and older children regarding the frequency of mutations in other epigenetic regulatory genes,” said Anna Andersson, PhD, of Lund University in Sweden.

“This observation raises the possibility of a fundamental difference in the cell targeted for transformation in infants versus older patients,” said Tanja Gruber, MD, PhD, of St Jude.

“Our working hypothesis is that, in infants, the MLL rearrangement occurs in a developing blood cell, a prenatal progenitor cell, which requires fewer additional mutations to fully transform into leukemia. In contrast, in older patients, the MLL rearrangement isn’t enough on its own.”

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to be approved in the US.

A biosimilar product is approved based on data showing that it is highly similar to an already-approved biological product.

Sandoz Inc’s Zarxio is biosimilar to Amgen Inc’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is now approved for the same indications as Neupogen.

Zarxio can be prescribed for:

• patients with cancer receiving myelosuppressive chemotherapy
• patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
• patients with cancer undergoing bone marrow transplant
• patients undergoing autologous peripheral blood progenitor cell collection and therapy
• patients with severe chronic neutropenia.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD.

“Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”

Zarxio data

The FDA’s approval of Zarxio is based on a review of evidence that included structural and functional characterization, in vivo data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.

The PIONEER study was the final piece of data the FDA used to approve Zarxio as biosimilar to Neupogen. The data was sufficient to allow extrapolation of the use of Zarxio to all indications of Neupogen.

In the PIONEER study, Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy—1.17 and 1.20 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The most common side effects of Zarxio are aching in the bones or muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

About biosimilar approval

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Barack Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, known as the reference product.

This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and it enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.

A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.

There must be no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable.

Zarxio has been approved as a biosimilar, not an interchangeable product. Under the BPCI Act, a biological product that has been approved as “interchangeable” may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.

For Zarxio’s approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilars and other biological products.

While the FDA has not yet issued draft guidance on how current and future biological products marketed in the US should be named, the agency intends to do so in the near future.

For more details on Zarxio, see the full prescribing information.

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to be approved in the US.

A biosimilar product is approved based on data showing that it is highly similar to an already-approved biological product.

Sandoz Inc’s Zarxio is biosimilar to Amgen Inc’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is now approved for the same indications as Neupogen.

Zarxio can be prescribed for:

• patients with cancer receiving myelosuppressive chemotherapy
• patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
• patients with cancer undergoing bone marrow transplant
• patients undergoing autologous peripheral blood progenitor cell collection and therapy
• patients with severe chronic neutropenia.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD.

“Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”

Zarxio data

The FDA’s approval of Zarxio is based on a review of evidence that included structural and functional characterization, in vivo data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.

The PIONEER study was the final piece of data the FDA used to approve Zarxio as biosimilar to Neupogen. The data was sufficient to allow extrapolation of the use of Zarxio to all indications of Neupogen.

In the PIONEER study, Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy—1.17 and 1.20 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The most common side effects of Zarxio are aching in the bones or muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

About biosimilar approval

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Barack Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, known as the reference product.

This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and it enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.

A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.

There must be no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable.

Zarxio has been approved as a biosimilar, not an interchangeable product. Under the BPCI Act, a biological product that has been approved as “interchangeable” may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.

For Zarxio’s approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilars and other biological products.

While the FDA has not yet issued draft guidance on how current and future biological products marketed in the US should be named, the agency intends to do so in the near future.

For more details on Zarxio, see the full prescribing information.

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to be approved in the US.

A biosimilar product is approved based on data showing that it is highly similar to an already-approved biological product.

Sandoz Inc’s Zarxio is biosimilar to Amgen Inc’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is now approved for the same indications as Neupogen.

Zarxio can be prescribed for:

• patients with cancer receiving myelosuppressive chemotherapy
• patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
• patients with cancer undergoing bone marrow transplant
• patients undergoing autologous peripheral blood progenitor cell collection and therapy
• patients with severe chronic neutropenia.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD.

“Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”

Zarxio data

The FDA’s approval of Zarxio is based on a review of evidence that included structural and functional characterization, in vivo data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.

The PIONEER study was the final piece of data the FDA used to approve Zarxio as biosimilar to Neupogen. The data was sufficient to allow extrapolation of the use of Zarxio to all indications of Neupogen.

In the PIONEER study, Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy—1.17 and 1.20 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The most common side effects of Zarxio are aching in the bones or muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

About biosimilar approval

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Barack Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, known as the reference product.

This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and it enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.

A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.

There must be no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable.

Zarxio has been approved as a biosimilar, not an interchangeable product. Under the BPCI Act, a biological product that has been approved as “interchangeable” may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.

For Zarxio’s approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilars and other biological products.

While the FDA has not yet issued draft guidance on how current and future biological products marketed in the US should be named, the agency intends to do so in the near future.

For more details on Zarxio, see the full prescribing information.

Thrombus

Image by Andre E.X. Brown

The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending the anticoagulant apixaban (Eliquis) as an option for treating and preventing venous thromboembolism (VTE) in adults.

A NICE committee concluded that apixaban is clinically and cost-effective for this indication.

The draft guidance is now with consultees, who can appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.

“Apixaban, like the other newer oral anticoagulants already recommended by NICE for the treatment and secondary prevention of VTE, does not require frequent blood tests to monitor treatment and so represents a potential benefit for many people who have had a VTE,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The committee also heard that apixaban is the only oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE. This could also be of potential benefit in terms of reducing the risk of bleeding where treatment is continued and therefore increase the chance that a person would take apixaban long-term.”

Clinical effectiveness

The NICE committee assessed the clinical effectiveness of apixaban based on results of the AMPLIFY and AMPLIFY-EXT studies.

Results of the AMPLIFY study indicated that apixaban is noninferior to standard treatment for recurrent VTE—initial parenteral enoxaparin overlapped with warfarin. Apixaban was comparable in efficacy to standard therapy and induced significantly less bleeding.

In AMPLIFY-EXT, researchers compared 12 months of treatment with apixaban at 2 doses—2.5 mg and 5 mg—to placebo in patients who had previously received anticoagulant therapy for 6 to 12 months to treat a prior VTE.

Both doses of apixaban effectively prevented VTE, VTE-related events, and death. And the incidence of bleeding events was low in all treatment arms.

The NICE committee noted that there were limited data in these trials pertaining to patients who needed less than 6 months of treatment and for patients still at high risk of recurrent VTE after 6 months of treatment.

However, the committee concluded that, despite these limitations, the AMPLIFY trials were the pivotal trials that informed the marketing authorization for apixaban. As such, they were sufficient to inform a recommendation for the whole population covered by the marketing authorization.

The committee did point out that there were no head-to-head trials evaluating the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE.

In addition, there were insufficient data to assess the effectiveness and safety of apixaban in patients with active cancer who had VTE, so it was not possible to make a specific recommendation for this group.

Cost-effectiveness

The recommended dose of apixaban as VTE treatment is 10 mg twice a day for the first 7 days, followed by 5 mg twice a day for at least 3 months. To prevent recurrent VTE, patients who have completed 6 months of VTE treatment should take apixaban at 2.5 mg twice a day.

The cost of apixaban is £1.10 per tablet for either the 2.5 mg or 5 mg dose (excluding tax). The daily cost of apixaban is £2.20. (Costs may vary in different settings because of negotiated procurement discounts.)

Analyses suggested that the incremental cost-effectiveness ratio of apixaban was less than £20,000 per quality-adjusted life-year gained for either 6 months or life-long treatment. Therefore, NICE concluded that apixaban is a cost-effective use of National Health Service resources. 

Thrombus

Image by Andre E.X. Brown

The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending the anticoagulant apixaban (Eliquis) as an option for treating and preventing venous thromboembolism (VTE) in adults.

A NICE committee concluded that apixaban is clinically and cost-effective for this indication.

The draft guidance is now with consultees, who can appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.

“Apixaban, like the other newer oral anticoagulants already recommended by NICE for the treatment and secondary prevention of VTE, does not require frequent blood tests to monitor treatment and so represents a potential benefit for many people who have had a VTE,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The committee also heard that apixaban is the only oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE. This could also be of potential benefit in terms of reducing the risk of bleeding where treatment is continued and therefore increase the chance that a person would take apixaban long-term.”

Clinical effectiveness

The NICE committee assessed the clinical effectiveness of apixaban based on results of the AMPLIFY and AMPLIFY-EXT studies.

Results of the AMPLIFY study indicated that apixaban is noninferior to standard treatment for recurrent VTE—initial parenteral enoxaparin overlapped with warfarin. Apixaban was comparable in efficacy to standard therapy and induced significantly less bleeding.

In AMPLIFY-EXT, researchers compared 12 months of treatment with apixaban at 2 doses—2.5 mg and 5 mg—to placebo in patients who had previously received anticoagulant therapy for 6 to 12 months to treat a prior VTE.

Both doses of apixaban effectively prevented VTE, VTE-related events, and death. And the incidence of bleeding events was low in all treatment arms.

The NICE committee noted that there were limited data in these trials pertaining to patients who needed less than 6 months of treatment and for patients still at high risk of recurrent VTE after 6 months of treatment.

However, the committee concluded that, despite these limitations, the AMPLIFY trials were the pivotal trials that informed the marketing authorization for apixaban. As such, they were sufficient to inform a recommendation for the whole population covered by the marketing authorization.

The committee did point out that there were no head-to-head trials evaluating the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE.

In addition, there were insufficient data to assess the effectiveness and safety of apixaban in patients with active cancer who had VTE, so it was not possible to make a specific recommendation for this group.

Cost-effectiveness

The recommended dose of apixaban as VTE treatment is 10 mg twice a day for the first 7 days, followed by 5 mg twice a day for at least 3 months. To prevent recurrent VTE, patients who have completed 6 months of VTE treatment should take apixaban at 2.5 mg twice a day.

The cost of apixaban is £1.10 per tablet for either the 2.5 mg or 5 mg dose (excluding tax). The daily cost of apixaban is £2.20. (Costs may vary in different settings because of negotiated procurement discounts.)

Analyses suggested that the incremental cost-effectiveness ratio of apixaban was less than £20,000 per quality-adjusted life-year gained for either 6 months or life-long treatment. Therefore, NICE concluded that apixaban is a cost-effective use of National Health Service resources. 

Thrombus

Image by Andre E.X. Brown

The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending the anticoagulant apixaban (Eliquis) as an option for treating and preventing venous thromboembolism (VTE) in adults.

A NICE committee concluded that apixaban is clinically and cost-effective for this indication.

The draft guidance is now with consultees, who can appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.

“Apixaban, like the other newer oral anticoagulants already recommended by NICE for the treatment and secondary prevention of VTE, does not require frequent blood tests to monitor treatment and so represents a potential benefit for many people who have had a VTE,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The committee also heard that apixaban is the only oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE. This could also be of potential benefit in terms of reducing the risk of bleeding where treatment is continued and therefore increase the chance that a person would take apixaban long-term.”

Clinical effectiveness

The NICE committee assessed the clinical effectiveness of apixaban based on results of the AMPLIFY and AMPLIFY-EXT studies.

Results of the AMPLIFY study indicated that apixaban is noninferior to standard treatment for recurrent VTE—initial parenteral enoxaparin overlapped with warfarin. Apixaban was comparable in efficacy to standard therapy and induced significantly less bleeding.

In AMPLIFY-EXT, researchers compared 12 months of treatment with apixaban at 2 doses—2.5 mg and 5 mg—to placebo in patients who had previously received anticoagulant therapy for 6 to 12 months to treat a prior VTE.

Both doses of apixaban effectively prevented VTE, VTE-related events, and death. And the incidence of bleeding events was low in all treatment arms.

The NICE committee noted that there were limited data in these trials pertaining to patients who needed less than 6 months of treatment and for patients still at high risk of recurrent VTE after 6 months of treatment.

However, the committee concluded that, despite these limitations, the AMPLIFY trials were the pivotal trials that informed the marketing authorization for apixaban. As such, they were sufficient to inform a recommendation for the whole population covered by the marketing authorization.

The committee did point out that there were no head-to-head trials evaluating the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE.

In addition, there were insufficient data to assess the effectiveness and safety of apixaban in patients with active cancer who had VTE, so it was not possible to make a specific recommendation for this group.

Cost-effectiveness

The recommended dose of apixaban as VTE treatment is 10 mg twice a day for the first 7 days, followed by 5 mg twice a day for at least 3 months. To prevent recurrent VTE, patients who have completed 6 months of VTE treatment should take apixaban at 2.5 mg twice a day.

The cost of apixaban is £1.10 per tablet for either the 2.5 mg or 5 mg dose (excluding tax). The daily cost of apixaban is £2.20. (Costs may vary in different settings because of negotiated procurement discounts.)

Analyses suggested that the incremental cost-effectiveness ratio of apixaban was less than £20,000 per quality-adjusted life-year gained for either 6 months or life-long treatment. Therefore, NICE concluded that apixaban is a cost-effective use of National Health Service resources.