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Fetal alcohol spectrum disorders and suicidality
As psychiatrists, we understand that behavior is complex and determined by multiple factors. However, despite our understanding that behavior is cultural, sociological, psychological, and biological, we often lose sight of the biological perspective because the brain is such a complex organ and because we are inundated with psychological theories of behavior. As I have said before, we cannot abdicate our role of being biologists in the reflection of mental health and wellness.
Accordingly, I feel it is my duty to bring our attention to a biologic etiology of suicidal behavior. I came across an article on the life expectancy of individuals afflicted with fetal alcohol syndrome in the Journal of Population Therapeutics and Clinical Pharmacology (2016;23[1]:e53-9). The findings were astonishing. As it turns out, the life expectancy of people with fetal alcohol syndrome is 34 years of age on average, and the leading causes of death were “external causes,” which accounted for 44% of the deaths. Suicide was responsible for 15% of those deaths, accidents for 14%, poisoning by illegal drugs or alcohol for 7%, and other external causes for another 7%, according to the article.
While working in a general hospital in a low-income African American environment where there are high rates of fetal alcohol exposure, I see at least 3-4 suicide attempts a week on the medical-surgical/psychiatric inpatient units where I serve. I am always looking for patients who have ND-PAE because determining such a diagnosis is critical to those patients’ medical-surgical care. For example, there was one woman with ND-PAE who had operable breast carcinoma but did not come in for a return visit until after her carcinoma had become inoperable (she forgot how important it was to get timely treatment). There was a patient who always had out-of-control diabetes because he did not know how to use his glucometer. There was a patient who was taking his antipsychotic medication during the day instead of as prescribed – at bedtime – because he could not read the instructions on his medication bottle. (I have altered several key aspects of my patients’ stories to protect their confidentiality.)
However, until I read that suicide was responsible for 15% of deaths with external causes among patients with fetal alcohol syndrome – patients whose life expectancy averages only 34 years – it did not occur to me that affect dysregulation also was likely to lead to suicide attempts among patients with ND-PAE.
When several of us who were working on the issue of suicide prevention while part of the Committee on Psychopathology & Prevention of Adolescent & Adult Suicide produced our report called “Reducing Suicide: A National Perspective” in 2002, the idea that paying attention to fetal environments and birth outcomes could inform the area of suicide prevention was an alien one. Now, it is a serious consideration because this dynamic just might explain part of the complex phenomena of some suicidal behaviors.
Dr. Bell is a staff psychiatrist at Jackson Park Hospital Family Medicine Clinic in Chicago; clinical psychiatrist emeritus in the department of psychiatry at the University of Illinois at Chicago; former president/CEO of Community Mental Health Council; and former director of the Institute for Juvenile Research (birthplace of child psychiatry), also in Chicago.
As psychiatrists, we understand that behavior is complex and determined by multiple factors. However, despite our understanding that behavior is cultural, sociological, psychological, and biological, we often lose sight of the biological perspective because the brain is such a complex organ and because we are inundated with psychological theories of behavior. As I have said before, we cannot abdicate our role of being biologists in the reflection of mental health and wellness.
Accordingly, I feel it is my duty to bring our attention to a biologic etiology of suicidal behavior. I came across an article on the life expectancy of individuals afflicted with fetal alcohol syndrome in the Journal of Population Therapeutics and Clinical Pharmacology (2016;23[1]:e53-9). The findings were astonishing. As it turns out, the life expectancy of people with fetal alcohol syndrome is 34 years of age on average, and the leading causes of death were “external causes,” which accounted for 44% of the deaths. Suicide was responsible for 15% of those deaths, accidents for 14%, poisoning by illegal drugs or alcohol for 7%, and other external causes for another 7%, according to the article.
While working in a general hospital in a low-income African American environment where there are high rates of fetal alcohol exposure, I see at least 3-4 suicide attempts a week on the medical-surgical/psychiatric inpatient units where I serve. I am always looking for patients who have ND-PAE because determining such a diagnosis is critical to those patients’ medical-surgical care. For example, there was one woman with ND-PAE who had operable breast carcinoma but did not come in for a return visit until after her carcinoma had become inoperable (she forgot how important it was to get timely treatment). There was a patient who always had out-of-control diabetes because he did not know how to use his glucometer. There was a patient who was taking his antipsychotic medication during the day instead of as prescribed – at bedtime – because he could not read the instructions on his medication bottle. (I have altered several key aspects of my patients’ stories to protect their confidentiality.)
However, until I read that suicide was responsible for 15% of deaths with external causes among patients with fetal alcohol syndrome – patients whose life expectancy averages only 34 years – it did not occur to me that affect dysregulation also was likely to lead to suicide attempts among patients with ND-PAE.
When several of us who were working on the issue of suicide prevention while part of the Committee on Psychopathology & Prevention of Adolescent & Adult Suicide produced our report called “Reducing Suicide: A National Perspective” in 2002, the idea that paying attention to fetal environments and birth outcomes could inform the area of suicide prevention was an alien one. Now, it is a serious consideration because this dynamic just might explain part of the complex phenomena of some suicidal behaviors.
Dr. Bell is a staff psychiatrist at Jackson Park Hospital Family Medicine Clinic in Chicago; clinical psychiatrist emeritus in the department of psychiatry at the University of Illinois at Chicago; former president/CEO of Community Mental Health Council; and former director of the Institute for Juvenile Research (birthplace of child psychiatry), also in Chicago.
As psychiatrists, we understand that behavior is complex and determined by multiple factors. However, despite our understanding that behavior is cultural, sociological, psychological, and biological, we often lose sight of the biological perspective because the brain is such a complex organ and because we are inundated with psychological theories of behavior. As I have said before, we cannot abdicate our role of being biologists in the reflection of mental health and wellness.
Accordingly, I feel it is my duty to bring our attention to a biologic etiology of suicidal behavior. I came across an article on the life expectancy of individuals afflicted with fetal alcohol syndrome in the Journal of Population Therapeutics and Clinical Pharmacology (2016;23[1]:e53-9). The findings were astonishing. As it turns out, the life expectancy of people with fetal alcohol syndrome is 34 years of age on average, and the leading causes of death were “external causes,” which accounted for 44% of the deaths. Suicide was responsible for 15% of those deaths, accidents for 14%, poisoning by illegal drugs or alcohol for 7%, and other external causes for another 7%, according to the article.
While working in a general hospital in a low-income African American environment where there are high rates of fetal alcohol exposure, I see at least 3-4 suicide attempts a week on the medical-surgical/psychiatric inpatient units where I serve. I am always looking for patients who have ND-PAE because determining such a diagnosis is critical to those patients’ medical-surgical care. For example, there was one woman with ND-PAE who had operable breast carcinoma but did not come in for a return visit until after her carcinoma had become inoperable (she forgot how important it was to get timely treatment). There was a patient who always had out-of-control diabetes because he did not know how to use his glucometer. There was a patient who was taking his antipsychotic medication during the day instead of as prescribed – at bedtime – because he could not read the instructions on his medication bottle. (I have altered several key aspects of my patients’ stories to protect their confidentiality.)
However, until I read that suicide was responsible for 15% of deaths with external causes among patients with fetal alcohol syndrome – patients whose life expectancy averages only 34 years – it did not occur to me that affect dysregulation also was likely to lead to suicide attempts among patients with ND-PAE.
When several of us who were working on the issue of suicide prevention while part of the Committee on Psychopathology & Prevention of Adolescent & Adult Suicide produced our report called “Reducing Suicide: A National Perspective” in 2002, the idea that paying attention to fetal environments and birth outcomes could inform the area of suicide prevention was an alien one. Now, it is a serious consideration because this dynamic just might explain part of the complex phenomena of some suicidal behaviors.
Dr. Bell is a staff psychiatrist at Jackson Park Hospital Family Medicine Clinic in Chicago; clinical psychiatrist emeritus in the department of psychiatry at the University of Illinois at Chicago; former president/CEO of Community Mental Health Council; and former director of the Institute for Juvenile Research (birthplace of child psychiatry), also in Chicago.
Pertuzumab approved for HER2-positive breast cancer
, according to the Food and Drug Administration.
The approval was based on results from the APHINITY trial, which included 4,804 patients who had HER2-positive early breast cancers that were excised prior to the study. After a median follow-up period of 45.4 months, an invasive disease event occurred in 7.1% of all patients who received pertuzumab (Perjeta) and in 8.7% of patients who received placebo. In patients with hormone receptor–negative disease, invasive events occurred in 8.2% of the pertuzumab group and in 10.6% of the placebo group. In patients with node-positive disease, the invasive event rate was 9.2% in the pertuzumab group and 12.1% in the placebo group.
“The initial pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30- to 60-minute intravenous infusion,” the FDA said in the statement.
Find the full statement on the FDA website.
, according to the Food and Drug Administration.
The approval was based on results from the APHINITY trial, which included 4,804 patients who had HER2-positive early breast cancers that were excised prior to the study. After a median follow-up period of 45.4 months, an invasive disease event occurred in 7.1% of all patients who received pertuzumab (Perjeta) and in 8.7% of patients who received placebo. In patients with hormone receptor–negative disease, invasive events occurred in 8.2% of the pertuzumab group and in 10.6% of the placebo group. In patients with node-positive disease, the invasive event rate was 9.2% in the pertuzumab group and 12.1% in the placebo group.
“The initial pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30- to 60-minute intravenous infusion,” the FDA said in the statement.
Find the full statement on the FDA website.
, according to the Food and Drug Administration.
The approval was based on results from the APHINITY trial, which included 4,804 patients who had HER2-positive early breast cancers that were excised prior to the study. After a median follow-up period of 45.4 months, an invasive disease event occurred in 7.1% of all patients who received pertuzumab (Perjeta) and in 8.7% of patients who received placebo. In patients with hormone receptor–negative disease, invasive events occurred in 8.2% of the pertuzumab group and in 10.6% of the placebo group. In patients with node-positive disease, the invasive event rate was 9.2% in the pertuzumab group and 12.1% in the placebo group.
“The initial pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30- to 60-minute intravenous infusion,” the FDA said in the statement.
Find the full statement on the FDA website.
Total Hip Arthroplasty and Hemiarthroplasty: US National Trends in the Treatment of Femoral Neck Fractures
Take-Home Points
- An increasing number of THAs and HAs were performed over time for FNF.
- HA patients tended to be older.
- Hospitalization and blood transfusion rates were higher for THA.
- Hospital size affected the rate of HAs, while hospital location affected the rate of THAs.
- A larger proportion of THA patients had private insurance.
Femoral neck fractures (FNFs) are a common source of morbidity and mortality worldwide. The increasing number of FNFs in the United States is attributed to increases in number of US residents >65 years old, the average life span, and the incidence of osteoporosis.1 Three hundred forty thousand hip fractures occurred in the United States in 1996, and the number is expected to double by 2050.2 By that year, an estimated 6.3 million hip fractures will occur worldwide.3 Given the 1-year mortality rate of 14% to 36%, optimizing the management of these fractures is an important public health issue that must be addressed.4
Treatment is based on preoperative ambulatory status, cognitive function, comorbidities, fracture type and displacement, and other factors. In physiologically elderly patients with displaced fractures, surgical treatment usually involves either hemiarthroplasty (HA) or total hip arthroplasty (THA). There is controversy regarding which modality is the preferred treatment.
Proponents of HA point to a higher rate of dislocation for FNFs treated with THAs,5,6 attributed to increased range of motion.7 Proponents of THA point to superior short-term clinical results and fewer complications, especially in mobile, independent patients.8
We conducted a study to assess recent US national trends in performing THA and HA for FNFs and to evaluate perioperative outcomes for each treatment group.
Materials and Methods
Data for this study were obtained from the National Center for Health Statistics (NCHS) National Hospital Discharge Survey (NHDS) and were imported into Microsoft Office Excel 2010.9 The NHDS examines patient discharges from various hospitals across the US, including federal, military, and Veterans Administration hospitals.9 Only short-stay hospitals (mean stay, <30 days) and hospitals with a general specialty are included in the survey. Each year, about 1% of all hospital admissions from across the US are abstracted and weighted to provide nationwide estimates. The information collected from each hospital record includes age, sex, race, marital status, discharge month, discharge status, days of care, hospital location, hospital size (number of beds), hospital type (proprietary or for-profit, government, nonprofit/church), and up to 15 discharge diagnoses and 8 procedures performed during admission.9
International Classification of Diseases, Ninth Revision (ICD-9) procedure codes were used to search the NHDS for patients admitted after FNF for each year from 2001 through 2010. These codes were then used to identify patients within this group who underwent THA or HA. We also collected data on patient demographics, hospitalization duration, discharge disposition, in-hospital adverse events (deep vein thrombosis [DVT], pulmonary embolism [PE], blood transfusion, mortality), form of primary medical insurance, number of hospital beds (0-99, 100-199, 200-299, 300-499, ≥500), hospital type (proprietary, government, nonprofit/church), and hospital region (Northeast, Midwest, South, West).
Trends were evaluated by linear regression with the Pearson correlation coefficient (r). Statistical comparisons were made using the Student t test for continuous data, and both the Fisher exact test and the χ2 test for categorical variables. Significance level was set at P < .05. All analyses were performed with IBM SPSS Statistics 22.
Results
Hospital stay was longer (P < .01) for THA patients (7.7 days; range, 1-312 days) than for HA patients (6.7 days; range, 1-118 days), and blood transfusion rate was higher (P = .02) for THA patients (30.4%) than for HA patients (25.7%), but the groups did not differ in their rates of DVT (THA, 1.2%; HA, 0.80%, P = .50), PE (THA, 0.52%; HA, 0.72%, P = .52), or mortality (THA, 1.8%; HA, 2.9%; P = .16). Discharge disposition varied with surgical status (P < .01): 23.2% of THA patients and 11.6% of HA patients were discharged directly home after their inpatient stay, and 76.8% of THA patients and 88.4% of HA patients were discharged or transferred to a short- or long-term care facility.
Private medical insurance provided coverage for 14.3% of THAs and 9.1% of HAs, and Medicare provided coverage for 80.9% of THAs and 86.0% of HAs (P < .01).
Discussion
The NHDS data showed a preference for HA over THA in the treatment of FNFs and suggested THA was favored for younger, healthier patients while HA was reserved for older patients with more comorbidities. Despite being younger and healthier, the THA group had higher transfusion rates and longer hospitalizations, possibly because of the increased complexity of THA procedures, which generally involve more operative time and increased blood loss. The resultant higher transfusion rate for THAs likely contributed to longer hospitalizations for FNFs. However, the THA and HA groups did not differ in their rates of DVT, PE, or mortality.
Multiple studies have noted no differences in mortality, infection, or general complications between THA and HA for FNF.8,10,11 THA patients have better functional outcomes, including Harris and Oxford hip scores and walking distance, but higher dislocation rates,8,10-12 and HA patients are at higher risk for reoperation because of progressive acetabular erosion.8,10,11
We noted an increase in use of both THA and HA for FNF over the study period (2001-2010). In a review of operative treatment for FNF by surgeons applying for the American Board of Orthopaedic Surgery certification between 1999 and 2011, Miller and colleagues13 found a similar increase in the THA rate over time, but decreases in the HA and internal fixation rates, with candidates in the “adult reconstruction” subspecialty showing a particularly strong trend toward THA use.
These findings reflect a general propensity toward femoral head replacement rather than preservation through open reduction and internal fixation (ORIF). Recent studies have found that ORIF carries a 39% to 43% rate of fixation failure and need for secondary revision, as well as risks of avascular necrosis, malunion, and nonunion.1,14-16 This need for secondary surgery makes ORIF ultimately less cost-effective than either THA or HA.16,17 Most authors would recommend arthroplasty for FNF in elderly patients with normal mental function1,16,18 and would reserve ORIF for young patients with good bone stock, joint space preservation, and reducible noncomminuted fractures.1,19
Our study results suggest that smaller hospitals (<100 beds) tend to have lower rates of HA (P < .01, significant) and THA (P = .10, not significant; Table), possibly because FNF patients who present to these hospitals may be referred elsewhere because of regional differences in the availability of orthopedic traumatologists and arthroplasty subspecialists. Surgeon volume affects postoperative outcomes and may play a role in referral patterns.20 Ames and colleagues20 found that HA performed for FNF by surgeons with high-volume THA experience (vs non-hip-arthroplasty surgeons) had lower rates of dislocation, superficial infection, and mortality.
Regional differences were significant for THA alone, with the highest THA rates in the South (5.2%) and the lowest in the West (3.3%; Figure 5). There were no clear regional trends for HA. Possible explanations include a propensity toward a more aggressive approach in these regions, increased regional prevalence of acetabular disease, regional surgeon preferences, and regional differences in patient characteristics (eg, increased prevalence of obesity in the South).21
HA rates were highest for nonprofit/church hospitals and lowest for proprietary hospitals, whereas THA rates did not differ by hospital type. Possible explanations include an older, less mobile nonprofit/church patient cohort that is more amenable to HA, and surgeon preference.
THA patients were more likely to be covered by private medical insurance than by Medicare—a finding in agreement with Hochfelder and colleagues,22 who found that, compared with federal insurance and self-pay patients, private insurance patients were 41% more likely to undergo THA than HA or internal fixation for FNF. We think that the age difference between our THA and HA groups contributed to the insurance variability in our study.
Our study had several limitations. It was conducted to examine the rates of THA and HA after FNF, not to survey treatment types, including ORIF and nonoperative management. The NHDS database does not provide information on HA implant type (unipolar, bipolar), use or nonuse of cement with HA, or surgical approach. Surgical approach could influence the rate of postoperative dislocation, an outcome measure that was not examined in this study. Last, the NHDS database tracks admissions and discharges, not patients. When a patient is discharged, collection of information on the patient’s postoperative course stops; a patient who returns even only 1 day later is recorded as a new or unique patient. Therefore, intermediate or long-term outcome information is unavailable, which likely led to an underrepresentation of DVT, PE, and mortality after these THA and HA procedures.
There was a trend toward femoral head replacement rather than ORIF in the treatment of FNF. Cognitively functional and independent elderly patients, and patients with osteoarthritis or rheumatoid arthritis, may benefit from THA, whereas HA may be better suited to cognitively dysfunctional patients.23,24 The NHDS reflects an increasing trend toward arthroplasty over ORIF, but the exact treatment choice is affected by hospital type, size, location and surgeon preference, training, and subspecialization.
1. Macaulay W, Pagnotto MR, Iorio R, Mont MA, Saleh KJ. Displaced femoral neck fractures in the elderly: hemiarthroplasty versus total hip arthroplasty. J Am Acad Orthop Surg. 2006;14(5):287-293.
2. Miyamoto RG, Kaplan KM, Levine BR, Egol KA, Zuckerman JD. Surgical management of hip fractures: an evidence-based review of the literature. I: femoral neck fractures. J Am Acad Orthop Surg. 2008;16(10):596-607.
3. Kannus P, Parkkari J, Sievänen H, Heinonen A, Vuori I, Järvinen M. Epidemiology of hip fractures. Bone. 1996;18(1 suppl):57S-63S.
4. Zuckerman JD. Hip fracture. N Engl J Med. 1996;334(23):1519-1525.
5. Papandrea RF, Froimson MI. Total hip arthroplasty after acute displaced femoral neck fractures. Am J Orthop. 1996;25(2):85-88.
6. Burgers PT, Van Geene AR, Van den Bekerom MP, et al. Total hip arthroplasty versus hemiarthroplasty for displaced femoral neck fractures in the healthy elderly: a meta-analysis and systematic review of randomized trials. Int Orthop. 2012;36(8):1549-1560.
7. Skinner P, Riley D, Ellery J, Beaumont A, Coumine R, Shafighian B. Displaced subcapital fractures of the femur: a prospective randomized comparison of internal fixation, hemiarthroplasty and total hip replacement. Injury. 1989;20(5):291-293.
8. Baker RP, Squires B, Gargan MF, Bannister GC. Total hip arthroplasty and hemiarthroplasty in mobile, independent patients with a displaced intracapsular fracture of the femoral neck. A randomized, controlled trial. J Bone Joint Surg Am. 2006;88(12):2583-2589.
9. Centers for Disease Control and Prevention, National Center for Health Statistics. National Hospital Discharge Survey. http://www.cdc.gov/nchs/nhds/about_nhds.htm. Last updated December 6, 2011. Accessed December 10, 2013.
10. Zi-Sheng A, You-Shui G, Zhi-Zhen J, Ting Y, Chang-Qing Z. Hemiarthroplasty vs primary total hip arthroplasty for displaced fractures of the femoral neck in the elderly: a meta-analysis. J Arthroplasty. 2012;27(4):583-590.
11. Yu L, Wang Y, Chen J. Total hip arthroplasty versus hemiarthroplasty for displaced femoral neck fractures: meta-analysis of randomized trials. Clin Orthop Relat Res. 2012;470(8):2235-2243.
12. Hopley C, Stengel D, Ekkernkamp A, Wich M. Primary total hip arthroplasty versus hemiarthroplasty for displaced intracapsular hip fractures in older patients: systematic review. BMJ. 2010;340:c2332.
13. Miller BJ, Callaghan JJ, Cram P, Karam M, Marsh JL, Noiseux NO. Changing trends in the treatment of femoral neck fractures: a review of the American Board of Orthopaedic Surgery database. J Bone Joint Surg Am. 2014;96(17):e149.
14. Rogmark C, Carlsson A, Johnell O, Sernbo I. A prospective randomised trial of internal fixation versus arthroplasty for displaced fractures of the neck of the femur. Functional outcome for 450 patients at two years. J Bone Joint Surg Br. 2002;84(2):183-188.
15. Bhandari M, Devereaux PJ, Swiontkowski MF, et al. Internal fixation compared with arthroplasty for displaced fractures of the femoral neck. A meta-analysis. J Bone Joint Surg Am. 2003;85(9):1673-1681.
16. Keating JF, Grant A, Masson M, Scott NW, Forbes JF. Randomized comparison of reduction and fixation, bipolar hemiarthroplasty, and total hip arthroplasty. Treatment of displaced intracapsular hip fractures in healthy older patients. J Bone Joint Surg Am. 2006;88(2):249-260.
17. Iorio R, Healy WL, Lemos DW, Appleby D, Lucchesi CA, Saleh KJ. Displaced femoral neck fractures in the elderly: outcomes and cost effectiveness. Clin Orthop Relat Res. 2001;(383):229-242.
18. Johansson T, Jacobsson SA, Ivarsson I, Knutsson A, Wahlström O. Internal fixation versus total hip arthroplasty in the treatment of displaced femoral neck fractures: a prospective randomized study of 100 hips. Acta Orthop Scand. 2000;71(6):597-602.
19. Shah AK, Eissler J, Radomisli T. Algorithms for the treatment of femoral neck fractures. Clin Orthop Relat Res. 2002;(399):28-34.
20. Ames JB, Lurie JD, Tomek IM, Zhou W, Koval KJ. Does surgeon volume for total hip arthroplasty affect outcomes after hemiarthroplasty for femoral neck fracture? Am J Orthop. 2010;39(8):E84-E89.
21. Le A, Judd SE, Allison DB, et al. The geographic distribution of obesity in the US and the potential regional differences in misreporting of obesity. Obesity. 2014;22(1):300-306.
22. Hochfelder JP, Khatib ON, Glait SA, Slover JD. Femoral neck fractures in New York state. Is the rate of THA increasing, and do race or payer influence decision making? J Orthop Trauma. 2014;28(7):422-426.
23. Lowe JA, Crist BD, Bhandari M, Ferguson TA. Optimal treatment of femoral neck fractures according to patient’s physiologic age: an evidence-based review. Orthop Clin North Am. 2010;41(2):157-166.
24. Callaghan JJ, Liu SS, Haidukewych GJ. Subcapital fractures: a changing paradigm. J Bone Joint Surg Br. 2012;94(11 suppl A):19-21.
Take-Home Points
- An increasing number of THAs and HAs were performed over time for FNF.
- HA patients tended to be older.
- Hospitalization and blood transfusion rates were higher for THA.
- Hospital size affected the rate of HAs, while hospital location affected the rate of THAs.
- A larger proportion of THA patients had private insurance.
Femoral neck fractures (FNFs) are a common source of morbidity and mortality worldwide. The increasing number of FNFs in the United States is attributed to increases in number of US residents >65 years old, the average life span, and the incidence of osteoporosis.1 Three hundred forty thousand hip fractures occurred in the United States in 1996, and the number is expected to double by 2050.2 By that year, an estimated 6.3 million hip fractures will occur worldwide.3 Given the 1-year mortality rate of 14% to 36%, optimizing the management of these fractures is an important public health issue that must be addressed.4
Treatment is based on preoperative ambulatory status, cognitive function, comorbidities, fracture type and displacement, and other factors. In physiologically elderly patients with displaced fractures, surgical treatment usually involves either hemiarthroplasty (HA) or total hip arthroplasty (THA). There is controversy regarding which modality is the preferred treatment.
Proponents of HA point to a higher rate of dislocation for FNFs treated with THAs,5,6 attributed to increased range of motion.7 Proponents of THA point to superior short-term clinical results and fewer complications, especially in mobile, independent patients.8
We conducted a study to assess recent US national trends in performing THA and HA for FNFs and to evaluate perioperative outcomes for each treatment group.
Materials and Methods
Data for this study were obtained from the National Center for Health Statistics (NCHS) National Hospital Discharge Survey (NHDS) and were imported into Microsoft Office Excel 2010.9 The NHDS examines patient discharges from various hospitals across the US, including federal, military, and Veterans Administration hospitals.9 Only short-stay hospitals (mean stay, <30 days) and hospitals with a general specialty are included in the survey. Each year, about 1% of all hospital admissions from across the US are abstracted and weighted to provide nationwide estimates. The information collected from each hospital record includes age, sex, race, marital status, discharge month, discharge status, days of care, hospital location, hospital size (number of beds), hospital type (proprietary or for-profit, government, nonprofit/church), and up to 15 discharge diagnoses and 8 procedures performed during admission.9
International Classification of Diseases, Ninth Revision (ICD-9) procedure codes were used to search the NHDS for patients admitted after FNF for each year from 2001 through 2010. These codes were then used to identify patients within this group who underwent THA or HA. We also collected data on patient demographics, hospitalization duration, discharge disposition, in-hospital adverse events (deep vein thrombosis [DVT], pulmonary embolism [PE], blood transfusion, mortality), form of primary medical insurance, number of hospital beds (0-99, 100-199, 200-299, 300-499, ≥500), hospital type (proprietary, government, nonprofit/church), and hospital region (Northeast, Midwest, South, West).
Trends were evaluated by linear regression with the Pearson correlation coefficient (r). Statistical comparisons were made using the Student t test for continuous data, and both the Fisher exact test and the χ2 test for categorical variables. Significance level was set at P < .05. All analyses were performed with IBM SPSS Statistics 22.
Results
Hospital stay was longer (P < .01) for THA patients (7.7 days; range, 1-312 days) than for HA patients (6.7 days; range, 1-118 days), and blood transfusion rate was higher (P = .02) for THA patients (30.4%) than for HA patients (25.7%), but the groups did not differ in their rates of DVT (THA, 1.2%; HA, 0.80%, P = .50), PE (THA, 0.52%; HA, 0.72%, P = .52), or mortality (THA, 1.8%; HA, 2.9%; P = .16). Discharge disposition varied with surgical status (P < .01): 23.2% of THA patients and 11.6% of HA patients were discharged directly home after their inpatient stay, and 76.8% of THA patients and 88.4% of HA patients were discharged or transferred to a short- or long-term care facility.
Private medical insurance provided coverage for 14.3% of THAs and 9.1% of HAs, and Medicare provided coverage for 80.9% of THAs and 86.0% of HAs (P < .01).
Discussion
The NHDS data showed a preference for HA over THA in the treatment of FNFs and suggested THA was favored for younger, healthier patients while HA was reserved for older patients with more comorbidities. Despite being younger and healthier, the THA group had higher transfusion rates and longer hospitalizations, possibly because of the increased complexity of THA procedures, which generally involve more operative time and increased blood loss. The resultant higher transfusion rate for THAs likely contributed to longer hospitalizations for FNFs. However, the THA and HA groups did not differ in their rates of DVT, PE, or mortality.
Multiple studies have noted no differences in mortality, infection, or general complications between THA and HA for FNF.8,10,11 THA patients have better functional outcomes, including Harris and Oxford hip scores and walking distance, but higher dislocation rates,8,10-12 and HA patients are at higher risk for reoperation because of progressive acetabular erosion.8,10,11
We noted an increase in use of both THA and HA for FNF over the study period (2001-2010). In a review of operative treatment for FNF by surgeons applying for the American Board of Orthopaedic Surgery certification between 1999 and 2011, Miller and colleagues13 found a similar increase in the THA rate over time, but decreases in the HA and internal fixation rates, with candidates in the “adult reconstruction” subspecialty showing a particularly strong trend toward THA use.
These findings reflect a general propensity toward femoral head replacement rather than preservation through open reduction and internal fixation (ORIF). Recent studies have found that ORIF carries a 39% to 43% rate of fixation failure and need for secondary revision, as well as risks of avascular necrosis, malunion, and nonunion.1,14-16 This need for secondary surgery makes ORIF ultimately less cost-effective than either THA or HA.16,17 Most authors would recommend arthroplasty for FNF in elderly patients with normal mental function1,16,18 and would reserve ORIF for young patients with good bone stock, joint space preservation, and reducible noncomminuted fractures.1,19
Our study results suggest that smaller hospitals (<100 beds) tend to have lower rates of HA (P < .01, significant) and THA (P = .10, not significant; Table), possibly because FNF patients who present to these hospitals may be referred elsewhere because of regional differences in the availability of orthopedic traumatologists and arthroplasty subspecialists. Surgeon volume affects postoperative outcomes and may play a role in referral patterns.20 Ames and colleagues20 found that HA performed for FNF by surgeons with high-volume THA experience (vs non-hip-arthroplasty surgeons) had lower rates of dislocation, superficial infection, and mortality.
Regional differences were significant for THA alone, with the highest THA rates in the South (5.2%) and the lowest in the West (3.3%; Figure 5). There were no clear regional trends for HA. Possible explanations include a propensity toward a more aggressive approach in these regions, increased regional prevalence of acetabular disease, regional surgeon preferences, and regional differences in patient characteristics (eg, increased prevalence of obesity in the South).21
HA rates were highest for nonprofit/church hospitals and lowest for proprietary hospitals, whereas THA rates did not differ by hospital type. Possible explanations include an older, less mobile nonprofit/church patient cohort that is more amenable to HA, and surgeon preference.
THA patients were more likely to be covered by private medical insurance than by Medicare—a finding in agreement with Hochfelder and colleagues,22 who found that, compared with federal insurance and self-pay patients, private insurance patients were 41% more likely to undergo THA than HA or internal fixation for FNF. We think that the age difference between our THA and HA groups contributed to the insurance variability in our study.
Our study had several limitations. It was conducted to examine the rates of THA and HA after FNF, not to survey treatment types, including ORIF and nonoperative management. The NHDS database does not provide information on HA implant type (unipolar, bipolar), use or nonuse of cement with HA, or surgical approach. Surgical approach could influence the rate of postoperative dislocation, an outcome measure that was not examined in this study. Last, the NHDS database tracks admissions and discharges, not patients. When a patient is discharged, collection of information on the patient’s postoperative course stops; a patient who returns even only 1 day later is recorded as a new or unique patient. Therefore, intermediate or long-term outcome information is unavailable, which likely led to an underrepresentation of DVT, PE, and mortality after these THA and HA procedures.
There was a trend toward femoral head replacement rather than ORIF in the treatment of FNF. Cognitively functional and independent elderly patients, and patients with osteoarthritis or rheumatoid arthritis, may benefit from THA, whereas HA may be better suited to cognitively dysfunctional patients.23,24 The NHDS reflects an increasing trend toward arthroplasty over ORIF, but the exact treatment choice is affected by hospital type, size, location and surgeon preference, training, and subspecialization.
Take-Home Points
- An increasing number of THAs and HAs were performed over time for FNF.
- HA patients tended to be older.
- Hospitalization and blood transfusion rates were higher for THA.
- Hospital size affected the rate of HAs, while hospital location affected the rate of THAs.
- A larger proportion of THA patients had private insurance.
Femoral neck fractures (FNFs) are a common source of morbidity and mortality worldwide. The increasing number of FNFs in the United States is attributed to increases in number of US residents >65 years old, the average life span, and the incidence of osteoporosis.1 Three hundred forty thousand hip fractures occurred in the United States in 1996, and the number is expected to double by 2050.2 By that year, an estimated 6.3 million hip fractures will occur worldwide.3 Given the 1-year mortality rate of 14% to 36%, optimizing the management of these fractures is an important public health issue that must be addressed.4
Treatment is based on preoperative ambulatory status, cognitive function, comorbidities, fracture type and displacement, and other factors. In physiologically elderly patients with displaced fractures, surgical treatment usually involves either hemiarthroplasty (HA) or total hip arthroplasty (THA). There is controversy regarding which modality is the preferred treatment.
Proponents of HA point to a higher rate of dislocation for FNFs treated with THAs,5,6 attributed to increased range of motion.7 Proponents of THA point to superior short-term clinical results and fewer complications, especially in mobile, independent patients.8
We conducted a study to assess recent US national trends in performing THA and HA for FNFs and to evaluate perioperative outcomes for each treatment group.
Materials and Methods
Data for this study were obtained from the National Center for Health Statistics (NCHS) National Hospital Discharge Survey (NHDS) and were imported into Microsoft Office Excel 2010.9 The NHDS examines patient discharges from various hospitals across the US, including federal, military, and Veterans Administration hospitals.9 Only short-stay hospitals (mean stay, <30 days) and hospitals with a general specialty are included in the survey. Each year, about 1% of all hospital admissions from across the US are abstracted and weighted to provide nationwide estimates. The information collected from each hospital record includes age, sex, race, marital status, discharge month, discharge status, days of care, hospital location, hospital size (number of beds), hospital type (proprietary or for-profit, government, nonprofit/church), and up to 15 discharge diagnoses and 8 procedures performed during admission.9
International Classification of Diseases, Ninth Revision (ICD-9) procedure codes were used to search the NHDS for patients admitted after FNF for each year from 2001 through 2010. These codes were then used to identify patients within this group who underwent THA or HA. We also collected data on patient demographics, hospitalization duration, discharge disposition, in-hospital adverse events (deep vein thrombosis [DVT], pulmonary embolism [PE], blood transfusion, mortality), form of primary medical insurance, number of hospital beds (0-99, 100-199, 200-299, 300-499, ≥500), hospital type (proprietary, government, nonprofit/church), and hospital region (Northeast, Midwest, South, West).
Trends were evaluated by linear regression with the Pearson correlation coefficient (r). Statistical comparisons were made using the Student t test for continuous data, and both the Fisher exact test and the χ2 test for categorical variables. Significance level was set at P < .05. All analyses were performed with IBM SPSS Statistics 22.
Results
Hospital stay was longer (P < .01) for THA patients (7.7 days; range, 1-312 days) than for HA patients (6.7 days; range, 1-118 days), and blood transfusion rate was higher (P = .02) for THA patients (30.4%) than for HA patients (25.7%), but the groups did not differ in their rates of DVT (THA, 1.2%; HA, 0.80%, P = .50), PE (THA, 0.52%; HA, 0.72%, P = .52), or mortality (THA, 1.8%; HA, 2.9%; P = .16). Discharge disposition varied with surgical status (P < .01): 23.2% of THA patients and 11.6% of HA patients were discharged directly home after their inpatient stay, and 76.8% of THA patients and 88.4% of HA patients were discharged or transferred to a short- or long-term care facility.
Private medical insurance provided coverage for 14.3% of THAs and 9.1% of HAs, and Medicare provided coverage for 80.9% of THAs and 86.0% of HAs (P < .01).
Discussion
The NHDS data showed a preference for HA over THA in the treatment of FNFs and suggested THA was favored for younger, healthier patients while HA was reserved for older patients with more comorbidities. Despite being younger and healthier, the THA group had higher transfusion rates and longer hospitalizations, possibly because of the increased complexity of THA procedures, which generally involve more operative time and increased blood loss. The resultant higher transfusion rate for THAs likely contributed to longer hospitalizations for FNFs. However, the THA and HA groups did not differ in their rates of DVT, PE, or mortality.
Multiple studies have noted no differences in mortality, infection, or general complications between THA and HA for FNF.8,10,11 THA patients have better functional outcomes, including Harris and Oxford hip scores and walking distance, but higher dislocation rates,8,10-12 and HA patients are at higher risk for reoperation because of progressive acetabular erosion.8,10,11
We noted an increase in use of both THA and HA for FNF over the study period (2001-2010). In a review of operative treatment for FNF by surgeons applying for the American Board of Orthopaedic Surgery certification between 1999 and 2011, Miller and colleagues13 found a similar increase in the THA rate over time, but decreases in the HA and internal fixation rates, with candidates in the “adult reconstruction” subspecialty showing a particularly strong trend toward THA use.
These findings reflect a general propensity toward femoral head replacement rather than preservation through open reduction and internal fixation (ORIF). Recent studies have found that ORIF carries a 39% to 43% rate of fixation failure and need for secondary revision, as well as risks of avascular necrosis, malunion, and nonunion.1,14-16 This need for secondary surgery makes ORIF ultimately less cost-effective than either THA or HA.16,17 Most authors would recommend arthroplasty for FNF in elderly patients with normal mental function1,16,18 and would reserve ORIF for young patients with good bone stock, joint space preservation, and reducible noncomminuted fractures.1,19
Our study results suggest that smaller hospitals (<100 beds) tend to have lower rates of HA (P < .01, significant) and THA (P = .10, not significant; Table), possibly because FNF patients who present to these hospitals may be referred elsewhere because of regional differences in the availability of orthopedic traumatologists and arthroplasty subspecialists. Surgeon volume affects postoperative outcomes and may play a role in referral patterns.20 Ames and colleagues20 found that HA performed for FNF by surgeons with high-volume THA experience (vs non-hip-arthroplasty surgeons) had lower rates of dislocation, superficial infection, and mortality.
Regional differences were significant for THA alone, with the highest THA rates in the South (5.2%) and the lowest in the West (3.3%; Figure 5). There were no clear regional trends for HA. Possible explanations include a propensity toward a more aggressive approach in these regions, increased regional prevalence of acetabular disease, regional surgeon preferences, and regional differences in patient characteristics (eg, increased prevalence of obesity in the South).21
HA rates were highest for nonprofit/church hospitals and lowest for proprietary hospitals, whereas THA rates did not differ by hospital type. Possible explanations include an older, less mobile nonprofit/church patient cohort that is more amenable to HA, and surgeon preference.
THA patients were more likely to be covered by private medical insurance than by Medicare—a finding in agreement with Hochfelder and colleagues,22 who found that, compared with federal insurance and self-pay patients, private insurance patients were 41% more likely to undergo THA than HA or internal fixation for FNF. We think that the age difference between our THA and HA groups contributed to the insurance variability in our study.
Our study had several limitations. It was conducted to examine the rates of THA and HA after FNF, not to survey treatment types, including ORIF and nonoperative management. The NHDS database does not provide information on HA implant type (unipolar, bipolar), use or nonuse of cement with HA, or surgical approach. Surgical approach could influence the rate of postoperative dislocation, an outcome measure that was not examined in this study. Last, the NHDS database tracks admissions and discharges, not patients. When a patient is discharged, collection of information on the patient’s postoperative course stops; a patient who returns even only 1 day later is recorded as a new or unique patient. Therefore, intermediate or long-term outcome information is unavailable, which likely led to an underrepresentation of DVT, PE, and mortality after these THA and HA procedures.
There was a trend toward femoral head replacement rather than ORIF in the treatment of FNF. Cognitively functional and independent elderly patients, and patients with osteoarthritis or rheumatoid arthritis, may benefit from THA, whereas HA may be better suited to cognitively dysfunctional patients.23,24 The NHDS reflects an increasing trend toward arthroplasty over ORIF, but the exact treatment choice is affected by hospital type, size, location and surgeon preference, training, and subspecialization.
1. Macaulay W, Pagnotto MR, Iorio R, Mont MA, Saleh KJ. Displaced femoral neck fractures in the elderly: hemiarthroplasty versus total hip arthroplasty. J Am Acad Orthop Surg. 2006;14(5):287-293.
2. Miyamoto RG, Kaplan KM, Levine BR, Egol KA, Zuckerman JD. Surgical management of hip fractures: an evidence-based review of the literature. I: femoral neck fractures. J Am Acad Orthop Surg. 2008;16(10):596-607.
3. Kannus P, Parkkari J, Sievänen H, Heinonen A, Vuori I, Järvinen M. Epidemiology of hip fractures. Bone. 1996;18(1 suppl):57S-63S.
4. Zuckerman JD. Hip fracture. N Engl J Med. 1996;334(23):1519-1525.
5. Papandrea RF, Froimson MI. Total hip arthroplasty after acute displaced femoral neck fractures. Am J Orthop. 1996;25(2):85-88.
6. Burgers PT, Van Geene AR, Van den Bekerom MP, et al. Total hip arthroplasty versus hemiarthroplasty for displaced femoral neck fractures in the healthy elderly: a meta-analysis and systematic review of randomized trials. Int Orthop. 2012;36(8):1549-1560.
7. Skinner P, Riley D, Ellery J, Beaumont A, Coumine R, Shafighian B. Displaced subcapital fractures of the femur: a prospective randomized comparison of internal fixation, hemiarthroplasty and total hip replacement. Injury. 1989;20(5):291-293.
8. Baker RP, Squires B, Gargan MF, Bannister GC. Total hip arthroplasty and hemiarthroplasty in mobile, independent patients with a displaced intracapsular fracture of the femoral neck. A randomized, controlled trial. J Bone Joint Surg Am. 2006;88(12):2583-2589.
9. Centers for Disease Control and Prevention, National Center for Health Statistics. National Hospital Discharge Survey. http://www.cdc.gov/nchs/nhds/about_nhds.htm. Last updated December 6, 2011. Accessed December 10, 2013.
10. Zi-Sheng A, You-Shui G, Zhi-Zhen J, Ting Y, Chang-Qing Z. Hemiarthroplasty vs primary total hip arthroplasty for displaced fractures of the femoral neck in the elderly: a meta-analysis. J Arthroplasty. 2012;27(4):583-590.
11. Yu L, Wang Y, Chen J. Total hip arthroplasty versus hemiarthroplasty for displaced femoral neck fractures: meta-analysis of randomized trials. Clin Orthop Relat Res. 2012;470(8):2235-2243.
12. Hopley C, Stengel D, Ekkernkamp A, Wich M. Primary total hip arthroplasty versus hemiarthroplasty for displaced intracapsular hip fractures in older patients: systematic review. BMJ. 2010;340:c2332.
13. Miller BJ, Callaghan JJ, Cram P, Karam M, Marsh JL, Noiseux NO. Changing trends in the treatment of femoral neck fractures: a review of the American Board of Orthopaedic Surgery database. J Bone Joint Surg Am. 2014;96(17):e149.
14. Rogmark C, Carlsson A, Johnell O, Sernbo I. A prospective randomised trial of internal fixation versus arthroplasty for displaced fractures of the neck of the femur. Functional outcome for 450 patients at two years. J Bone Joint Surg Br. 2002;84(2):183-188.
15. Bhandari M, Devereaux PJ, Swiontkowski MF, et al. Internal fixation compared with arthroplasty for displaced fractures of the femoral neck. A meta-analysis. J Bone Joint Surg Am. 2003;85(9):1673-1681.
16. Keating JF, Grant A, Masson M, Scott NW, Forbes JF. Randomized comparison of reduction and fixation, bipolar hemiarthroplasty, and total hip arthroplasty. Treatment of displaced intracapsular hip fractures in healthy older patients. J Bone Joint Surg Am. 2006;88(2):249-260.
17. Iorio R, Healy WL, Lemos DW, Appleby D, Lucchesi CA, Saleh KJ. Displaced femoral neck fractures in the elderly: outcomes and cost effectiveness. Clin Orthop Relat Res. 2001;(383):229-242.
18. Johansson T, Jacobsson SA, Ivarsson I, Knutsson A, Wahlström O. Internal fixation versus total hip arthroplasty in the treatment of displaced femoral neck fractures: a prospective randomized study of 100 hips. Acta Orthop Scand. 2000;71(6):597-602.
19. Shah AK, Eissler J, Radomisli T. Algorithms for the treatment of femoral neck fractures. Clin Orthop Relat Res. 2002;(399):28-34.
20. Ames JB, Lurie JD, Tomek IM, Zhou W, Koval KJ. Does surgeon volume for total hip arthroplasty affect outcomes after hemiarthroplasty for femoral neck fracture? Am J Orthop. 2010;39(8):E84-E89.
21. Le A, Judd SE, Allison DB, et al. The geographic distribution of obesity in the US and the potential regional differences in misreporting of obesity. Obesity. 2014;22(1):300-306.
22. Hochfelder JP, Khatib ON, Glait SA, Slover JD. Femoral neck fractures in New York state. Is the rate of THA increasing, and do race or payer influence decision making? J Orthop Trauma. 2014;28(7):422-426.
23. Lowe JA, Crist BD, Bhandari M, Ferguson TA. Optimal treatment of femoral neck fractures according to patient’s physiologic age: an evidence-based review. Orthop Clin North Am. 2010;41(2):157-166.
24. Callaghan JJ, Liu SS, Haidukewych GJ. Subcapital fractures: a changing paradigm. J Bone Joint Surg Br. 2012;94(11 suppl A):19-21.
1. Macaulay W, Pagnotto MR, Iorio R, Mont MA, Saleh KJ. Displaced femoral neck fractures in the elderly: hemiarthroplasty versus total hip arthroplasty. J Am Acad Orthop Surg. 2006;14(5):287-293.
2. Miyamoto RG, Kaplan KM, Levine BR, Egol KA, Zuckerman JD. Surgical management of hip fractures: an evidence-based review of the literature. I: femoral neck fractures. J Am Acad Orthop Surg. 2008;16(10):596-607.
3. Kannus P, Parkkari J, Sievänen H, Heinonen A, Vuori I, Järvinen M. Epidemiology of hip fractures. Bone. 1996;18(1 suppl):57S-63S.
4. Zuckerman JD. Hip fracture. N Engl J Med. 1996;334(23):1519-1525.
5. Papandrea RF, Froimson MI. Total hip arthroplasty after acute displaced femoral neck fractures. Am J Orthop. 1996;25(2):85-88.
6. Burgers PT, Van Geene AR, Van den Bekerom MP, et al. Total hip arthroplasty versus hemiarthroplasty for displaced femoral neck fractures in the healthy elderly: a meta-analysis and systematic review of randomized trials. Int Orthop. 2012;36(8):1549-1560.
7. Skinner P, Riley D, Ellery J, Beaumont A, Coumine R, Shafighian B. Displaced subcapital fractures of the femur: a prospective randomized comparison of internal fixation, hemiarthroplasty and total hip replacement. Injury. 1989;20(5):291-293.
8. Baker RP, Squires B, Gargan MF, Bannister GC. Total hip arthroplasty and hemiarthroplasty in mobile, independent patients with a displaced intracapsular fracture of the femoral neck. A randomized, controlled trial. J Bone Joint Surg Am. 2006;88(12):2583-2589.
9. Centers for Disease Control and Prevention, National Center for Health Statistics. National Hospital Discharge Survey. http://www.cdc.gov/nchs/nhds/about_nhds.htm. Last updated December 6, 2011. Accessed December 10, 2013.
10. Zi-Sheng A, You-Shui G, Zhi-Zhen J, Ting Y, Chang-Qing Z. Hemiarthroplasty vs primary total hip arthroplasty for displaced fractures of the femoral neck in the elderly: a meta-analysis. J Arthroplasty. 2012;27(4):583-590.
11. Yu L, Wang Y, Chen J. Total hip arthroplasty versus hemiarthroplasty for displaced femoral neck fractures: meta-analysis of randomized trials. Clin Orthop Relat Res. 2012;470(8):2235-2243.
12. Hopley C, Stengel D, Ekkernkamp A, Wich M. Primary total hip arthroplasty versus hemiarthroplasty for displaced intracapsular hip fractures in older patients: systematic review. BMJ. 2010;340:c2332.
13. Miller BJ, Callaghan JJ, Cram P, Karam M, Marsh JL, Noiseux NO. Changing trends in the treatment of femoral neck fractures: a review of the American Board of Orthopaedic Surgery database. J Bone Joint Surg Am. 2014;96(17):e149.
14. Rogmark C, Carlsson A, Johnell O, Sernbo I. A prospective randomised trial of internal fixation versus arthroplasty for displaced fractures of the neck of the femur. Functional outcome for 450 patients at two years. J Bone Joint Surg Br. 2002;84(2):183-188.
15. Bhandari M, Devereaux PJ, Swiontkowski MF, et al. Internal fixation compared with arthroplasty for displaced fractures of the femoral neck. A meta-analysis. J Bone Joint Surg Am. 2003;85(9):1673-1681.
16. Keating JF, Grant A, Masson M, Scott NW, Forbes JF. Randomized comparison of reduction and fixation, bipolar hemiarthroplasty, and total hip arthroplasty. Treatment of displaced intracapsular hip fractures in healthy older patients. J Bone Joint Surg Am. 2006;88(2):249-260.
17. Iorio R, Healy WL, Lemos DW, Appleby D, Lucchesi CA, Saleh KJ. Displaced femoral neck fractures in the elderly: outcomes and cost effectiveness. Clin Orthop Relat Res. 2001;(383):229-242.
18. Johansson T, Jacobsson SA, Ivarsson I, Knutsson A, Wahlström O. Internal fixation versus total hip arthroplasty in the treatment of displaced femoral neck fractures: a prospective randomized study of 100 hips. Acta Orthop Scand. 2000;71(6):597-602.
19. Shah AK, Eissler J, Radomisli T. Algorithms for the treatment of femoral neck fractures. Clin Orthop Relat Res. 2002;(399):28-34.
20. Ames JB, Lurie JD, Tomek IM, Zhou W, Koval KJ. Does surgeon volume for total hip arthroplasty affect outcomes after hemiarthroplasty for femoral neck fracture? Am J Orthop. 2010;39(8):E84-E89.
21. Le A, Judd SE, Allison DB, et al. The geographic distribution of obesity in the US and the potential regional differences in misreporting of obesity. Obesity. 2014;22(1):300-306.
22. Hochfelder JP, Khatib ON, Glait SA, Slover JD. Femoral neck fractures in New York state. Is the rate of THA increasing, and do race or payer influence decision making? J Orthop Trauma. 2014;28(7):422-426.
23. Lowe JA, Crist BD, Bhandari M, Ferguson TA. Optimal treatment of femoral neck fractures according to patient’s physiologic age: an evidence-based review. Orthop Clin North Am. 2010;41(2):157-166.
24. Callaghan JJ, Liu SS, Haidukewych GJ. Subcapital fractures: a changing paradigm. J Bone Joint Surg Br. 2012;94(11 suppl A):19-21.
FDA approves angiotensin II for shock patients
Angiotensin II has been approved for use in intravenous infusions to increase blood pressure in adults with septic or other distributive shock, the Food and Drug Administration announced.
Shock-related drops in blood pressure can restrict blood flow to vital organs and can result in organ failure and death. “There is a need for treatment options for critically ill hypotensive patients who do not adequately respond to available therapies,” Norman Stockbridge, MD, PhD, director of the division of cardiovascular and renal products in the FDA’s Center for Drug Evaluation and Research, said in a written statement.
The effectiveness of angiotensin II for treating critically low blood pressure was confirmed in a clinical trial of 321 patients who were in shock. A significant number of patients responded to angiotensin II treatment, compared with those given placebo. In combination with conventional treatments, angiotensin II increased blood pressure safely and effectively, according to the FDA statement.
Angiotensin II can cause serious blood clots, and prophylactic treatment for such issues is recommended.
The application for angiontensin II was received under Priority Review. The goal of Priority Review is for the FDA to take action on the application within 6 months if the agency determines that an approved drug would improve the safety and effectiveness of treating a serious medical condition.
Angiotensin II injections will be marketed as Giapreza by La Jolla Pharmaceutical Company.
Angiotensin II has been approved for use in intravenous infusions to increase blood pressure in adults with septic or other distributive shock, the Food and Drug Administration announced.
Shock-related drops in blood pressure can restrict blood flow to vital organs and can result in organ failure and death. “There is a need for treatment options for critically ill hypotensive patients who do not adequately respond to available therapies,” Norman Stockbridge, MD, PhD, director of the division of cardiovascular and renal products in the FDA’s Center for Drug Evaluation and Research, said in a written statement.
The effectiveness of angiotensin II for treating critically low blood pressure was confirmed in a clinical trial of 321 patients who were in shock. A significant number of patients responded to angiotensin II treatment, compared with those given placebo. In combination with conventional treatments, angiotensin II increased blood pressure safely and effectively, according to the FDA statement.
Angiotensin II can cause serious blood clots, and prophylactic treatment for such issues is recommended.
The application for angiontensin II was received under Priority Review. The goal of Priority Review is for the FDA to take action on the application within 6 months if the agency determines that an approved drug would improve the safety and effectiveness of treating a serious medical condition.
Angiotensin II injections will be marketed as Giapreza by La Jolla Pharmaceutical Company.
Angiotensin II has been approved for use in intravenous infusions to increase blood pressure in adults with septic or other distributive shock, the Food and Drug Administration announced.
Shock-related drops in blood pressure can restrict blood flow to vital organs and can result in organ failure and death. “There is a need for treatment options for critically ill hypotensive patients who do not adequately respond to available therapies,” Norman Stockbridge, MD, PhD, director of the division of cardiovascular and renal products in the FDA’s Center for Drug Evaluation and Research, said in a written statement.
The effectiveness of angiotensin II for treating critically low blood pressure was confirmed in a clinical trial of 321 patients who were in shock. A significant number of patients responded to angiotensin II treatment, compared with those given placebo. In combination with conventional treatments, angiotensin II increased blood pressure safely and effectively, according to the FDA statement.
Angiotensin II can cause serious blood clots, and prophylactic treatment for such issues is recommended.
The application for angiontensin II was received under Priority Review. The goal of Priority Review is for the FDA to take action on the application within 6 months if the agency determines that an approved drug would improve the safety and effectiveness of treating a serious medical condition.
Angiotensin II injections will be marketed as Giapreza by La Jolla Pharmaceutical Company.
Study: Atopic dermatitis subgroups identified in children
Identification of subphenotypes of atopic dermatitis (AD) in children, with differing risk factors, prognoses, and comorbidities, could lead to a stratified approach to managing pediatric AD, said Lavinia Paternoster, PhD, of the University of Bristol, England, and her associates.
The study identified six classes of AD in these children. Early-onset/early-resolving AD, occurring in 13%-15% of the children, was most prevalent and was associated with male gender. Children in this class had a favorable prognosis, and there was only a very weak association with asthma in later life.
Two classes of persistent disease were identified: early-onset persistent AD (rash occurring in most of this class by 30 months and resolving in half by 16.5 years) and early-onset/late-resolving AD (rash occurring in most by 30 months and resolving in most by 16.5 years). These classes, occurring in about 7% of the children, had the strongest association with an AD genetic risk score; a strong link with personal and parental history of atopic disease; and a strong tie to asthma.
An unrecognized class of mid-onset-resolving AD, occurring in 7% of children, was not significantly linked to FLG mutations but was tied to asthma. In those children, AD prevalence rose sharply from 2.5 years of age and peaked at about 6 years, Dr. Paternoster and her associates said.
The investigators also found an unaffected/transient AD class in which children either had never reported rash; had one or two isolated occasions of rash; or reported a rash consistent with AD at 6-18 months that declined with age. In the two cohorts, 58%-63% children fell into this class. Late-onset-resolving AD occurred in 7%-8% of children, with most developing rash by 12 years and declining by 16.5 years.
There was a preponderance of females in the early-onset persistent AD and the late onset classes, and more males in the early-onset resolving class. “The associations with asthma at ages 7 and 11-13 years were strongest with the persistent class, but all AD classes showed evidence of some increased risk of asthma at these ages,” Dr. Paternoster and her associates wrote.
“There was evidence that FLG null mutations were associated with all classes, however ... the association was strongest in the group with early-onset-persistent disease,” the researchers said. The “heterogeneity of effect of genetic variants on different disease profiles, emphasizes the need for patient stratification in future genetic studies. Stratification may be used to increase the power to detect variants associated with specific classes; stratification could also allow the identification of phenotype-specific mechanistic pathways as future therapeutic targets.”
Read more at (J Allerg Clin Immunol. 2017 Nov 10. doi: 10.1016/j.jaci.2017.09.044).
Identification of subphenotypes of atopic dermatitis (AD) in children, with differing risk factors, prognoses, and comorbidities, could lead to a stratified approach to managing pediatric AD, said Lavinia Paternoster, PhD, of the University of Bristol, England, and her associates.
The study identified six classes of AD in these children. Early-onset/early-resolving AD, occurring in 13%-15% of the children, was most prevalent and was associated with male gender. Children in this class had a favorable prognosis, and there was only a very weak association with asthma in later life.
Two classes of persistent disease were identified: early-onset persistent AD (rash occurring in most of this class by 30 months and resolving in half by 16.5 years) and early-onset/late-resolving AD (rash occurring in most by 30 months and resolving in most by 16.5 years). These classes, occurring in about 7% of the children, had the strongest association with an AD genetic risk score; a strong link with personal and parental history of atopic disease; and a strong tie to asthma.
An unrecognized class of mid-onset-resolving AD, occurring in 7% of children, was not significantly linked to FLG mutations but was tied to asthma. In those children, AD prevalence rose sharply from 2.5 years of age and peaked at about 6 years, Dr. Paternoster and her associates said.
The investigators also found an unaffected/transient AD class in which children either had never reported rash; had one or two isolated occasions of rash; or reported a rash consistent with AD at 6-18 months that declined with age. In the two cohorts, 58%-63% children fell into this class. Late-onset-resolving AD occurred in 7%-8% of children, with most developing rash by 12 years and declining by 16.5 years.
There was a preponderance of females in the early-onset persistent AD and the late onset classes, and more males in the early-onset resolving class. “The associations with asthma at ages 7 and 11-13 years were strongest with the persistent class, but all AD classes showed evidence of some increased risk of asthma at these ages,” Dr. Paternoster and her associates wrote.
“There was evidence that FLG null mutations were associated with all classes, however ... the association was strongest in the group with early-onset-persistent disease,” the researchers said. The “heterogeneity of effect of genetic variants on different disease profiles, emphasizes the need for patient stratification in future genetic studies. Stratification may be used to increase the power to detect variants associated with specific classes; stratification could also allow the identification of phenotype-specific mechanistic pathways as future therapeutic targets.”
Read more at (J Allerg Clin Immunol. 2017 Nov 10. doi: 10.1016/j.jaci.2017.09.044).
Identification of subphenotypes of atopic dermatitis (AD) in children, with differing risk factors, prognoses, and comorbidities, could lead to a stratified approach to managing pediatric AD, said Lavinia Paternoster, PhD, of the University of Bristol, England, and her associates.
The study identified six classes of AD in these children. Early-onset/early-resolving AD, occurring in 13%-15% of the children, was most prevalent and was associated with male gender. Children in this class had a favorable prognosis, and there was only a very weak association with asthma in later life.
Two classes of persistent disease were identified: early-onset persistent AD (rash occurring in most of this class by 30 months and resolving in half by 16.5 years) and early-onset/late-resolving AD (rash occurring in most by 30 months and resolving in most by 16.5 years). These classes, occurring in about 7% of the children, had the strongest association with an AD genetic risk score; a strong link with personal and parental history of atopic disease; and a strong tie to asthma.
An unrecognized class of mid-onset-resolving AD, occurring in 7% of children, was not significantly linked to FLG mutations but was tied to asthma. In those children, AD prevalence rose sharply from 2.5 years of age and peaked at about 6 years, Dr. Paternoster and her associates said.
The investigators also found an unaffected/transient AD class in which children either had never reported rash; had one or two isolated occasions of rash; or reported a rash consistent with AD at 6-18 months that declined with age. In the two cohorts, 58%-63% children fell into this class. Late-onset-resolving AD occurred in 7%-8% of children, with most developing rash by 12 years and declining by 16.5 years.
There was a preponderance of females in the early-onset persistent AD and the late onset classes, and more males in the early-onset resolving class. “The associations with asthma at ages 7 and 11-13 years were strongest with the persistent class, but all AD classes showed evidence of some increased risk of asthma at these ages,” Dr. Paternoster and her associates wrote.
“There was evidence that FLG null mutations were associated with all classes, however ... the association was strongest in the group with early-onset-persistent disease,” the researchers said. The “heterogeneity of effect of genetic variants on different disease profiles, emphasizes the need for patient stratification in future genetic studies. Stratification may be used to increase the power to detect variants associated with specific classes; stratification could also allow the identification of phenotype-specific mechanistic pathways as future therapeutic targets.”
Read more at (J Allerg Clin Immunol. 2017 Nov 10. doi: 10.1016/j.jaci.2017.09.044).
FROM THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
FDA Boxed Warning Updates: December 2017
The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.
CODEINE SULFATE
- Edited and updated warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRARAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Codeine sulfate tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of codeine sulfate tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE):
- Edited warning August 2017
ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a CYP2D6 polymorphism. Tuxarin ER is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuxarin ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
Concomitant Use with Benzodiazepines, CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound
sedation, respiratory depression, coma, and death. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.
TUZISTRA XR (CHLORPHENIRAMINE POLISTIREX; CODEINE POLISTIREX):
- Edited warning August 2017
ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a
CYP2D6 polymorphism. Tuzistra XR is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuzistra XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
FIORICET W/CODEINE (ACETAMINOPHEN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):
- Edited warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and HEPATOTOXICITY
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
FIORINAL W/CODEINE (ASPIRIN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):
- Edited warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES.
Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.
- Reserve concomitant prescribing of Fiorinal with codeine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
- Limit dosages and durations to the minimum required.
- Follow patients for signs and symptoms of respiratory depression and sedation.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. Fiorinal with codeine is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Fiorinal with codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
PHENERGAN VC W/CODEINE (CODEINE PHOSPHATE; PHENYLEPHRINE HYDROCHLORIDE; PROMETHAZINE HYDROCHLORIDE): PHENERGAN W/CODEINE (CODEINE PHOSPHATE; PROMETHAZINE HYDROCHLORIDE):
- Edited warning August 2017
WARNING: ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Promethazine HCl and codeine phosphate oral solution is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of promethazine HCl and codeine phosphate oral solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
Promethazine and Respiratory Depression in Children
Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patients. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine.
SYNALGOS-DC (ASPIRIN; CAFFEINE; DIHYDROCODEINE BITARTRATE):
- Edited warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF DIHYDROCODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Synalgos-DC is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Synalgos-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine.
CONZIP (TRAMADOL HYDROCHLORIDE): ULTRAM (TRAMADOL HYDROCHLORIDE): ULTRACET (ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE):
- Edited warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; and at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. Ultram is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Ultram in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.
The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.
CODEINE SULFATE
- Edited and updated warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRARAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Codeine sulfate tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of codeine sulfate tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE):
- Edited warning August 2017
ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a CYP2D6 polymorphism. Tuxarin ER is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuxarin ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
Concomitant Use with Benzodiazepines, CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound
sedation, respiratory depression, coma, and death. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.
TUZISTRA XR (CHLORPHENIRAMINE POLISTIREX; CODEINE POLISTIREX):
- Edited warning August 2017
ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a
CYP2D6 polymorphism. Tuzistra XR is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuzistra XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
FIORICET W/CODEINE (ACETAMINOPHEN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):
- Edited warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and HEPATOTOXICITY
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
FIORINAL W/CODEINE (ASPIRIN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):
- Edited warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES.
Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.
- Reserve concomitant prescribing of Fiorinal with codeine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
- Limit dosages and durations to the minimum required.
- Follow patients for signs and symptoms of respiratory depression and sedation.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. Fiorinal with codeine is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Fiorinal with codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
PHENERGAN VC W/CODEINE (CODEINE PHOSPHATE; PHENYLEPHRINE HYDROCHLORIDE; PROMETHAZINE HYDROCHLORIDE): PHENERGAN W/CODEINE (CODEINE PHOSPHATE; PROMETHAZINE HYDROCHLORIDE):
- Edited warning August 2017
WARNING: ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Promethazine HCl and codeine phosphate oral solution is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of promethazine HCl and codeine phosphate oral solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
Promethazine and Respiratory Depression in Children
Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patients. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine.
SYNALGOS-DC (ASPIRIN; CAFFEINE; DIHYDROCODEINE BITARTRATE):
- Edited warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF DIHYDROCODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Synalgos-DC is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Synalgos-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine.
CONZIP (TRAMADOL HYDROCHLORIDE): ULTRAM (TRAMADOL HYDROCHLORIDE): ULTRACET (ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE):
- Edited warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; and at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. Ultram is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Ultram in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.
The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.
CODEINE SULFATE
- Edited and updated warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRARAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Codeine sulfate tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of codeine sulfate tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE):
- Edited warning August 2017
ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a CYP2D6 polymorphism. Tuxarin ER is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuxarin ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
Concomitant Use with Benzodiazepines, CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound
sedation, respiratory depression, coma, and death. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.
TUZISTRA XR (CHLORPHENIRAMINE POLISTIREX; CODEINE POLISTIREX):
- Edited warning August 2017
ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a
CYP2D6 polymorphism. Tuzistra XR is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuzistra XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
FIORICET W/CODEINE (ACETAMINOPHEN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):
- Edited warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and HEPATOTOXICITY
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
FIORINAL W/CODEINE (ASPIRIN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):
- Edited warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES.
Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.
- Reserve concomitant prescribing of Fiorinal with codeine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
- Limit dosages and durations to the minimum required.
- Follow patients for signs and symptoms of respiratory depression and sedation.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. Fiorinal with codeine is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Fiorinal with codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
PHENERGAN VC W/CODEINE (CODEINE PHOSPHATE; PHENYLEPHRINE HYDROCHLORIDE; PROMETHAZINE HYDROCHLORIDE): PHENERGAN W/CODEINE (CODEINE PHOSPHATE; PROMETHAZINE HYDROCHLORIDE):
- Edited warning August 2017
WARNING: ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Promethazine HCl and codeine phosphate oral solution is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of promethazine HCl and codeine phosphate oral solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
Promethazine and Respiratory Depression in Children
Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patients. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine.
SYNALGOS-DC (ASPIRIN; CAFFEINE; DIHYDROCODEINE BITARTRATE):
- Edited warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF DIHYDROCODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Synalgos-DC is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Synalgos-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine.
CONZIP (TRAMADOL HYDROCHLORIDE): ULTRAM (TRAMADOL HYDROCHLORIDE): ULTRACET (ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE):
- Edited warning August 2017
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; and at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. Ultram is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Ultram in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.
Study highlights need for induction strategy in elderly, frail MM patients
ATLANTA—Initial results of the phase 2 HOVON-126 trial in newly diagnosed multiple myeloma (MM) patients have highlighted the need for an induction strategy in elderly and frail patients.
The trial showed high overall response rates (ORRs) after induction with ixazomib, thalidomide, and low-dose dexamethasone.
However, 62% of patients older than 75 and 60% of frail patients discontinued therapy prior to starting maintenance.
HOVON-126 was designed to determine the ORR of induction therapy with ixazomib, thalidomide, and dexamethasone but also compare progression-free survival in patients who received ixazomib maintenance and those who received placebo.
Sonja Zweegman, MD, of VUmc in Amsterdam, The Netherlands, presented induction results from HOVON-126 at the 2017 ASH Annual Meeting (abstract 433).
The study was supported by Takeda and the Dutch Cancer Society. Dr Zweegman disclosed research funding from, and advisory board participation for, Takeda.
Study design
Investigators enrolled patients with previously untreated, symptomatic MM who were not eligible for stem cell transplant. Patients had to have measurable disease and a WHO performance status of 0 to 3 for patients younger than 75 and 0 to 2 for patients 75 or older.
Patients were not eligible if they had grade 3 neuropathy or grade 2 with pain. They were also ineligible if their creatinine clearance was less than 30 mL/minute.
All patients received ixazomib at 4 mg on days 1, 8, and 15; thalidomide at 100 mg on days 1 to 28; and dexamethasone at 40 mg on days 1, 8, 15, and 22 for nine 28-day cycles.
They could then be randomized to ixazomib maintenance (on the aforementioned schedule) or placebo for 28-day cycles until progression.
Investigators performed subgroup analyses based on cytogenetic risk and frailty.
They defined frailty according to the modified IMWG frailty index, which takes into account age, the Charlson Comorbidity Index, and the WHO performance scale as a proxy for Activities of Daily Living.
They defined high-risk cytogenetics as del17p, t(4;14), or t(14;16).
Investigators planned to enroll 142 patients and expected 94 patients to be randomized.
Patient demographics
The first 120 patients enrolled had a median age of 74 (range, 64–90). Thirty percent (n=38) were older than 75, and 8% (n=10) were older than 80.
More than two-thirds had an ISS score of I or II, and three-quarters had a WHO performance status of 0 or 1. Twenty-four percent had a performance status of 2, and 1% had a performance status of 3.
Eighty percent had lytic bone disease.
One hundred thirteen patients (94%) had FISH analysis performed. Of those, 10% had del17p, 7% had t(4;14), and 1% had t(14;16).
Eighty-one percent of patients fell into the standard-risk category and 19% into the high-risk category.
Almost half of patients (47%) were considered frail, 28% unfit, 21% fit, and 4% unknown.
Response
The ORR for induction was 81%. Ten percent of patients achieved a complete response (CR), 34% had a very good partial response (VGPR), and 37% had a partial response (PR).
The median time to response was 1.1 months, and the median time to maximum response was 4.7 months.
The response rate was independent of cytogenetic risk. Standard-risk patients achieved an ORR of 84%, a VGPR rate of 48%, and a CR rate of 10%. High-risk patients had an ORR of 79%, VGPR of 42%, and CR of 11%.
The response rate was also independent of frailty. Fit patients had an ORR of 88%, unfit patients 85%, and frail patients 75%. The VGPR rate was 36% for fit, 53% for unfit, and 43% for frail patients. The CR rate was 16% for fit, 9% for unfit, and 9% for frail patients.
Safety
“Grade 3 and 4 toxicities were found to be limited, with mainly infections, [gastrointestinal], and skin toxicity,” Dr Zweegman noted. “There was also a very low incidence of neuropathy, with only 3% grade 3 neuropathy and no grade 4 neuropathy.”
Grade 3 adverse events (AEs) occurred in 50% of patients and grade 4 in 11%.
Hematologic AEs of grade 3 and 4, respectively, included anemia (5%, 1%), thrombocytopenia (3%, 1%), and neutropenia (1%, 0).
Nonhematologic AEs of grade 3 and 4, respectively, included infections (12%, 3%), neuropathy (3%, 0), cardiac events (7%, 3%), gastrointestinal events (8%, 0), skin AEs (10%, 0), and venous thromboembolism (0, 2%).
The incidence of severe neuropathy was low. Fifty-eight percent of patients had grade 0 neuropathy, 24% grade 1, 14% grade 2, 3% grade 3, and no grade 4.
Discontinuation
Fifty-four patients (45%) discontinued therapy. The reasons for discontinuation were:
- Progressive disease, 13%
- Toxicity, 15%
- Death, 4%
- Noncompliance, 8%
- Not eligible for randomization, 0.8%
- Other, 4%.
“And when looking in detail into the toxicity, it was shown that it was mainly asthenia and neuropathy being judged by the treating physicians as caused by thalidomide,” Dr Zweegman explained.
Investigators also evaluated discontinuation according to age and found that 35% of patients 75 or younger discontinued therapy, compared with 62% of those older than 75.
However, there was no significant difference in discontinuation rate during the first 6 cycles. Seventy-seven percent of the younger patients and 69% of the older group completed 6 cycles.
Older patients who discontinued early had rates of progressive disease and toxicity comparable to the younger patients, but “there was a difference in early mortality,” Dr Zweegman added.
Nine percent of older patients discontinued before maintenance due to early mortality, compared with 1% of younger patients. And mortality in the older group was mainly due to infections and 1 cardiac arrest.
“So I think that highlights the need for antibiotic prophylaxis, which was not mandatory in this study,” Dr Zweegman said.
And finally, the investigators evaluated discontinuation according to frailty. Twenty-four percent of fit patients discontinued prior to maintenance, 32% of unfit, and 60% of frail.
Again, investigators found no significant difference in discontinuation rate during the first 6 cycles of induction. Eighty percent of fit patients completed 6 cycles, as did 79% of unfit patients and 70% of frail patients.
Despite the feasibility of the treatment and an ORR of 81%, the investigators say novel approaches are needed for frail patients and those older than 75.
“One possibility is to limit the duration of induction therapy . . . ,” Dr Zweegman said. “That would allow the start of long-term administration of maintenance treatment.”
The investigators also suggest evaluating less toxic combinations, such as ixazomib and daratumumab with lower doses of dexamethasone, the combination used in the HOVON-143 study.
Ixazomib is approved by the US Food and Drug Administration, Health Canada, and conditionally approved by the European Commission for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior therapy. 
ATLANTA—Initial results of the phase 2 HOVON-126 trial in newly diagnosed multiple myeloma (MM) patients have highlighted the need for an induction strategy in elderly and frail patients.
The trial showed high overall response rates (ORRs) after induction with ixazomib, thalidomide, and low-dose dexamethasone.
However, 62% of patients older than 75 and 60% of frail patients discontinued therapy prior to starting maintenance.
HOVON-126 was designed to determine the ORR of induction therapy with ixazomib, thalidomide, and dexamethasone but also compare progression-free survival in patients who received ixazomib maintenance and those who received placebo.
Sonja Zweegman, MD, of VUmc in Amsterdam, The Netherlands, presented induction results from HOVON-126 at the 2017 ASH Annual Meeting (abstract 433).
The study was supported by Takeda and the Dutch Cancer Society. Dr Zweegman disclosed research funding from, and advisory board participation for, Takeda.
Study design
Investigators enrolled patients with previously untreated, symptomatic MM who were not eligible for stem cell transplant. Patients had to have measurable disease and a WHO performance status of 0 to 3 for patients younger than 75 and 0 to 2 for patients 75 or older.
Patients were not eligible if they had grade 3 neuropathy or grade 2 with pain. They were also ineligible if their creatinine clearance was less than 30 mL/minute.
All patients received ixazomib at 4 mg on days 1, 8, and 15; thalidomide at 100 mg on days 1 to 28; and dexamethasone at 40 mg on days 1, 8, 15, and 22 for nine 28-day cycles.
They could then be randomized to ixazomib maintenance (on the aforementioned schedule) or placebo for 28-day cycles until progression.
Investigators performed subgroup analyses based on cytogenetic risk and frailty.
They defined frailty according to the modified IMWG frailty index, which takes into account age, the Charlson Comorbidity Index, and the WHO performance scale as a proxy for Activities of Daily Living.
They defined high-risk cytogenetics as del17p, t(4;14), or t(14;16).
Investigators planned to enroll 142 patients and expected 94 patients to be randomized.
Patient demographics
The first 120 patients enrolled had a median age of 74 (range, 64–90). Thirty percent (n=38) were older than 75, and 8% (n=10) were older than 80.
More than two-thirds had an ISS score of I or II, and three-quarters had a WHO performance status of 0 or 1. Twenty-four percent had a performance status of 2, and 1% had a performance status of 3.
Eighty percent had lytic bone disease.
One hundred thirteen patients (94%) had FISH analysis performed. Of those, 10% had del17p, 7% had t(4;14), and 1% had t(14;16).
Eighty-one percent of patients fell into the standard-risk category and 19% into the high-risk category.
Almost half of patients (47%) were considered frail, 28% unfit, 21% fit, and 4% unknown.
Response
The ORR for induction was 81%. Ten percent of patients achieved a complete response (CR), 34% had a very good partial response (VGPR), and 37% had a partial response (PR).
The median time to response was 1.1 months, and the median time to maximum response was 4.7 months.
The response rate was independent of cytogenetic risk. Standard-risk patients achieved an ORR of 84%, a VGPR rate of 48%, and a CR rate of 10%. High-risk patients had an ORR of 79%, VGPR of 42%, and CR of 11%.
The response rate was also independent of frailty. Fit patients had an ORR of 88%, unfit patients 85%, and frail patients 75%. The VGPR rate was 36% for fit, 53% for unfit, and 43% for frail patients. The CR rate was 16% for fit, 9% for unfit, and 9% for frail patients.
Safety
“Grade 3 and 4 toxicities were found to be limited, with mainly infections, [gastrointestinal], and skin toxicity,” Dr Zweegman noted. “There was also a very low incidence of neuropathy, with only 3% grade 3 neuropathy and no grade 4 neuropathy.”
Grade 3 adverse events (AEs) occurred in 50% of patients and grade 4 in 11%.
Hematologic AEs of grade 3 and 4, respectively, included anemia (5%, 1%), thrombocytopenia (3%, 1%), and neutropenia (1%, 0).
Nonhematologic AEs of grade 3 and 4, respectively, included infections (12%, 3%), neuropathy (3%, 0), cardiac events (7%, 3%), gastrointestinal events (8%, 0), skin AEs (10%, 0), and venous thromboembolism (0, 2%).
The incidence of severe neuropathy was low. Fifty-eight percent of patients had grade 0 neuropathy, 24% grade 1, 14% grade 2, 3% grade 3, and no grade 4.
Discontinuation
Fifty-four patients (45%) discontinued therapy. The reasons for discontinuation were:
- Progressive disease, 13%
- Toxicity, 15%
- Death, 4%
- Noncompliance, 8%
- Not eligible for randomization, 0.8%
- Other, 4%.
“And when looking in detail into the toxicity, it was shown that it was mainly asthenia and neuropathy being judged by the treating physicians as caused by thalidomide,” Dr Zweegman explained.
Investigators also evaluated discontinuation according to age and found that 35% of patients 75 or younger discontinued therapy, compared with 62% of those older than 75.
However, there was no significant difference in discontinuation rate during the first 6 cycles. Seventy-seven percent of the younger patients and 69% of the older group completed 6 cycles.
Older patients who discontinued early had rates of progressive disease and toxicity comparable to the younger patients, but “there was a difference in early mortality,” Dr Zweegman added.
Nine percent of older patients discontinued before maintenance due to early mortality, compared with 1% of younger patients. And mortality in the older group was mainly due to infections and 1 cardiac arrest.
“So I think that highlights the need for antibiotic prophylaxis, which was not mandatory in this study,” Dr Zweegman said.
And finally, the investigators evaluated discontinuation according to frailty. Twenty-four percent of fit patients discontinued prior to maintenance, 32% of unfit, and 60% of frail.
Again, investigators found no significant difference in discontinuation rate during the first 6 cycles of induction. Eighty percent of fit patients completed 6 cycles, as did 79% of unfit patients and 70% of frail patients.
Despite the feasibility of the treatment and an ORR of 81%, the investigators say novel approaches are needed for frail patients and those older than 75.
“One possibility is to limit the duration of induction therapy . . . ,” Dr Zweegman said. “That would allow the start of long-term administration of maintenance treatment.”
The investigators also suggest evaluating less toxic combinations, such as ixazomib and daratumumab with lower doses of dexamethasone, the combination used in the HOVON-143 study.
Ixazomib is approved by the US Food and Drug Administration, Health Canada, and conditionally approved by the European Commission for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior therapy.
ATLANTA—Initial results of the phase 2 HOVON-126 trial in newly diagnosed multiple myeloma (MM) patients have highlighted the need for an induction strategy in elderly and frail patients.
The trial showed high overall response rates (ORRs) after induction with ixazomib, thalidomide, and low-dose dexamethasone.
However, 62% of patients older than 75 and 60% of frail patients discontinued therapy prior to starting maintenance.
HOVON-126 was designed to determine the ORR of induction therapy with ixazomib, thalidomide, and dexamethasone but also compare progression-free survival in patients who received ixazomib maintenance and those who received placebo.
Sonja Zweegman, MD, of VUmc in Amsterdam, The Netherlands, presented induction results from HOVON-126 at the 2017 ASH Annual Meeting (abstract 433).
The study was supported by Takeda and the Dutch Cancer Society. Dr Zweegman disclosed research funding from, and advisory board participation for, Takeda.
Study design
Investigators enrolled patients with previously untreated, symptomatic MM who were not eligible for stem cell transplant. Patients had to have measurable disease and a WHO performance status of 0 to 3 for patients younger than 75 and 0 to 2 for patients 75 or older.
Patients were not eligible if they had grade 3 neuropathy or grade 2 with pain. They were also ineligible if their creatinine clearance was less than 30 mL/minute.
All patients received ixazomib at 4 mg on days 1, 8, and 15; thalidomide at 100 mg on days 1 to 28; and dexamethasone at 40 mg on days 1, 8, 15, and 22 for nine 28-day cycles.
They could then be randomized to ixazomib maintenance (on the aforementioned schedule) or placebo for 28-day cycles until progression.
Investigators performed subgroup analyses based on cytogenetic risk and frailty.
They defined frailty according to the modified IMWG frailty index, which takes into account age, the Charlson Comorbidity Index, and the WHO performance scale as a proxy for Activities of Daily Living.
They defined high-risk cytogenetics as del17p, t(4;14), or t(14;16).
Investigators planned to enroll 142 patients and expected 94 patients to be randomized.
Patient demographics
The first 120 patients enrolled had a median age of 74 (range, 64–90). Thirty percent (n=38) were older than 75, and 8% (n=10) were older than 80.
More than two-thirds had an ISS score of I or II, and three-quarters had a WHO performance status of 0 or 1. Twenty-four percent had a performance status of 2, and 1% had a performance status of 3.
Eighty percent had lytic bone disease.
One hundred thirteen patients (94%) had FISH analysis performed. Of those, 10% had del17p, 7% had t(4;14), and 1% had t(14;16).
Eighty-one percent of patients fell into the standard-risk category and 19% into the high-risk category.
Almost half of patients (47%) were considered frail, 28% unfit, 21% fit, and 4% unknown.
Response
The ORR for induction was 81%. Ten percent of patients achieved a complete response (CR), 34% had a very good partial response (VGPR), and 37% had a partial response (PR).
The median time to response was 1.1 months, and the median time to maximum response was 4.7 months.
The response rate was independent of cytogenetic risk. Standard-risk patients achieved an ORR of 84%, a VGPR rate of 48%, and a CR rate of 10%. High-risk patients had an ORR of 79%, VGPR of 42%, and CR of 11%.
The response rate was also independent of frailty. Fit patients had an ORR of 88%, unfit patients 85%, and frail patients 75%. The VGPR rate was 36% for fit, 53% for unfit, and 43% for frail patients. The CR rate was 16% for fit, 9% for unfit, and 9% for frail patients.
Safety
“Grade 3 and 4 toxicities were found to be limited, with mainly infections, [gastrointestinal], and skin toxicity,” Dr Zweegman noted. “There was also a very low incidence of neuropathy, with only 3% grade 3 neuropathy and no grade 4 neuropathy.”
Grade 3 adverse events (AEs) occurred in 50% of patients and grade 4 in 11%.
Hematologic AEs of grade 3 and 4, respectively, included anemia (5%, 1%), thrombocytopenia (3%, 1%), and neutropenia (1%, 0).
Nonhematologic AEs of grade 3 and 4, respectively, included infections (12%, 3%), neuropathy (3%, 0), cardiac events (7%, 3%), gastrointestinal events (8%, 0), skin AEs (10%, 0), and venous thromboembolism (0, 2%).
The incidence of severe neuropathy was low. Fifty-eight percent of patients had grade 0 neuropathy, 24% grade 1, 14% grade 2, 3% grade 3, and no grade 4.
Discontinuation
Fifty-four patients (45%) discontinued therapy. The reasons for discontinuation were:
- Progressive disease, 13%
- Toxicity, 15%
- Death, 4%
- Noncompliance, 8%
- Not eligible for randomization, 0.8%
- Other, 4%.
“And when looking in detail into the toxicity, it was shown that it was mainly asthenia and neuropathy being judged by the treating physicians as caused by thalidomide,” Dr Zweegman explained.
Investigators also evaluated discontinuation according to age and found that 35% of patients 75 or younger discontinued therapy, compared with 62% of those older than 75.
However, there was no significant difference in discontinuation rate during the first 6 cycles. Seventy-seven percent of the younger patients and 69% of the older group completed 6 cycles.
Older patients who discontinued early had rates of progressive disease and toxicity comparable to the younger patients, but “there was a difference in early mortality,” Dr Zweegman added.
Nine percent of older patients discontinued before maintenance due to early mortality, compared with 1% of younger patients. And mortality in the older group was mainly due to infections and 1 cardiac arrest.
“So I think that highlights the need for antibiotic prophylaxis, which was not mandatory in this study,” Dr Zweegman said.
And finally, the investigators evaluated discontinuation according to frailty. Twenty-four percent of fit patients discontinued prior to maintenance, 32% of unfit, and 60% of frail.
Again, investigators found no significant difference in discontinuation rate during the first 6 cycles of induction. Eighty percent of fit patients completed 6 cycles, as did 79% of unfit patients and 70% of frail patients.
Despite the feasibility of the treatment and an ORR of 81%, the investigators say novel approaches are needed for frail patients and those older than 75.
“One possibility is to limit the duration of induction therapy . . . ,” Dr Zweegman said. “That would allow the start of long-term administration of maintenance treatment.”
The investigators also suggest evaluating less toxic combinations, such as ixazomib and daratumumab with lower doses of dexamethasone, the combination used in the HOVON-143 study.
Ixazomib is approved by the US Food and Drug Administration, Health Canada, and conditionally approved by the European Commission for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior therapy.
Iron chelating agent could enhance chemo in AML
Chemotherapy for acute myeloid leukemia (AML) might be improved by the addition of deferoxamine, according to preclinical research published in Cell Stem Cell.
Researchers found that, when certain areas of the bone marrow are overtaken by AML cells, hematopoietic stem cells (HSCs) are lost, and the delivery of chemotherapy may be compromised.
However, the team also discovered that deferoxamine, a drug already approved to treat iron overload, can protect these areas of the bone marrow, allowing HSCs to survive and improving the efficacy of chemotherapy.
“Since the drug is already approved for human use for a different condition, we already know that it is safe,” said study author Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We still need to test it in the context of leukemia and chemotherapy, but, because it is already in use, we can progress to clinical trials much quicker than we could with a brand-new drug.”
For the current study, Dr Lo Celso and her colleagues used intravital microscopy to study AML cells, healthy hematopoietic cells, and the bone marrow microenvironment in mice.
The researchers found the endosteal microenvironment was hit particularly hard by AML. Specifically, AML progression led to endosteal remodeling, with AML cells degrading endosteal endothelium, stromal cells, and osteoblastic cells.
This remodeling resulted in the loss of nonleukemic HSCs, which hindered hematopoiesis. However, preserving endosteal vessels prevented the loss of HSCs.
Previous research had shown that deferoxamine could induce endosteal vessel expansion through enhancement of hypoxia-inducible factor 1a stability and activity. So the researchers administered deferoxamine to mice with AML.
The drug had a protective effect on endosteal vessels, which were able to support healthy HSCs and improve HSC homing.
The researchers also found that enhanced endosteal vessels improved the efficacy of chemotherapy (cytarabine and doxorubicin) in mice with AML.
The team compared Fbxw7iΔEC-mutant mice, in which the administration of tamoxifen increases the number of endosteal vessels and arterioles, to control mice. Both sets of mice had AML.
After confirming the mutant mice had increased numbers of endosteal vessels, the researchers treated the mutant mice and controls with cytarabine and doxorubicin.
Both sets of mice had significant chemotherapy-induced damage to the bone marrow vasculature, including endosteal vessels.
However, after treatment, the Fbxw7iΔEC-mutant mice had lower numbers of surviving AML cells in the bone marrow, delayed relapse, and longer survival than control mice.
The researchers therefore concluded that rescuing endosteal vessels before starting chemotherapy can improve the efficacy of treatment in AML.
“Our work suggests that therapies targeting these blood vessels may improve existing therapeutic regimens for AML and perhaps other leukemias too,” said study author Delfim Duarte, MD, of Imperial College London.
Based on this work, the researchers are hoping to start trials of deferoxamine in patients with AML.
Chemotherapy for acute myeloid leukemia (AML) might be improved by the addition of deferoxamine, according to preclinical research published in Cell Stem Cell.
Researchers found that, when certain areas of the bone marrow are overtaken by AML cells, hematopoietic stem cells (HSCs) are lost, and the delivery of chemotherapy may be compromised.
However, the team also discovered that deferoxamine, a drug already approved to treat iron overload, can protect these areas of the bone marrow, allowing HSCs to survive and improving the efficacy of chemotherapy.
“Since the drug is already approved for human use for a different condition, we already know that it is safe,” said study author Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We still need to test it in the context of leukemia and chemotherapy, but, because it is already in use, we can progress to clinical trials much quicker than we could with a brand-new drug.”
For the current study, Dr Lo Celso and her colleagues used intravital microscopy to study AML cells, healthy hematopoietic cells, and the bone marrow microenvironment in mice.
The researchers found the endosteal microenvironment was hit particularly hard by AML. Specifically, AML progression led to endosteal remodeling, with AML cells degrading endosteal endothelium, stromal cells, and osteoblastic cells.
This remodeling resulted in the loss of nonleukemic HSCs, which hindered hematopoiesis. However, preserving endosteal vessels prevented the loss of HSCs.
Previous research had shown that deferoxamine could induce endosteal vessel expansion through enhancement of hypoxia-inducible factor 1a stability and activity. So the researchers administered deferoxamine to mice with AML.
The drug had a protective effect on endosteal vessels, which were able to support healthy HSCs and improve HSC homing.
The researchers also found that enhanced endosteal vessels improved the efficacy of chemotherapy (cytarabine and doxorubicin) in mice with AML.
The team compared Fbxw7iΔEC-mutant mice, in which the administration of tamoxifen increases the number of endosteal vessels and arterioles, to control mice. Both sets of mice had AML.
After confirming the mutant mice had increased numbers of endosteal vessels, the researchers treated the mutant mice and controls with cytarabine and doxorubicin.
Both sets of mice had significant chemotherapy-induced damage to the bone marrow vasculature, including endosteal vessels.
However, after treatment, the Fbxw7iΔEC-mutant mice had lower numbers of surviving AML cells in the bone marrow, delayed relapse, and longer survival than control mice.
The researchers therefore concluded that rescuing endosteal vessels before starting chemotherapy can improve the efficacy of treatment in AML.
“Our work suggests that therapies targeting these blood vessels may improve existing therapeutic regimens for AML and perhaps other leukemias too,” said study author Delfim Duarte, MD, of Imperial College London.
Based on this work, the researchers are hoping to start trials of deferoxamine in patients with AML.
Chemotherapy for acute myeloid leukemia (AML) might be improved by the addition of deferoxamine, according to preclinical research published in Cell Stem Cell.
Researchers found that, when certain areas of the bone marrow are overtaken by AML cells, hematopoietic stem cells (HSCs) are lost, and the delivery of chemotherapy may be compromised.
However, the team also discovered that deferoxamine, a drug already approved to treat iron overload, can protect these areas of the bone marrow, allowing HSCs to survive and improving the efficacy of chemotherapy.
“Since the drug is already approved for human use for a different condition, we already know that it is safe,” said study author Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We still need to test it in the context of leukemia and chemotherapy, but, because it is already in use, we can progress to clinical trials much quicker than we could with a brand-new drug.”
For the current study, Dr Lo Celso and her colleagues used intravital microscopy to study AML cells, healthy hematopoietic cells, and the bone marrow microenvironment in mice.
The researchers found the endosteal microenvironment was hit particularly hard by AML. Specifically, AML progression led to endosteal remodeling, with AML cells degrading endosteal endothelium, stromal cells, and osteoblastic cells.
This remodeling resulted in the loss of nonleukemic HSCs, which hindered hematopoiesis. However, preserving endosteal vessels prevented the loss of HSCs.
Previous research had shown that deferoxamine could induce endosteal vessel expansion through enhancement of hypoxia-inducible factor 1a stability and activity. So the researchers administered deferoxamine to mice with AML.
The drug had a protective effect on endosteal vessels, which were able to support healthy HSCs and improve HSC homing.
The researchers also found that enhanced endosteal vessels improved the efficacy of chemotherapy (cytarabine and doxorubicin) in mice with AML.
The team compared Fbxw7iΔEC-mutant mice, in which the administration of tamoxifen increases the number of endosteal vessels and arterioles, to control mice. Both sets of mice had AML.
After confirming the mutant mice had increased numbers of endosteal vessels, the researchers treated the mutant mice and controls with cytarabine and doxorubicin.
Both sets of mice had significant chemotherapy-induced damage to the bone marrow vasculature, including endosteal vessels.
However, after treatment, the Fbxw7iΔEC-mutant mice had lower numbers of surviving AML cells in the bone marrow, delayed relapse, and longer survival than control mice.
The researchers therefore concluded that rescuing endosteal vessels before starting chemotherapy can improve the efficacy of treatment in AML.
“Our work suggests that therapies targeting these blood vessels may improve existing therapeutic regimens for AML and perhaps other leukemias too,” said study author Delfim Duarte, MD, of Imperial College London.
Based on this work, the researchers are hoping to start trials of deferoxamine in patients with AML.
Research explains why cisplatin causes hearing loss
Researchers have gained new insight into hearing loss caused by cisplatin.
By measuring and mapping cisplatin retention in mouse and human inner ear tissues, the researchers found that cisplatin builds up in the inner ear and can remain there for years.
The team also found that a region in the inner ear called the stria vascularis could be targeted to prevent hearing loss resulting from cisplatin.
Lisa L. Cunningham, PhD, of the National Institute on Deafness and other Communications Disorders (NIDCD) in Bethesda, Maryland, and her colleagues reported these findings in Nature Communications.
The researchers noted that cisplatin can cause permanent hearing loss in 40% to 80% of treated patients. The team’s new findings help explain why.
The researchers found that, in most areas of the body, cisplatin is eliminated within days or weeks of treatment, but, in the inner ear, the drug remains much longer.
The team developed a mouse model that represents cisplatin-induced hearing loss seen in human patients.
By looking at inner ear tissue of mice after the first, second, and third cisplatin treatment, the researchers saw that cisplatin remained in the mouse inner ear much longer than in most other body tissues, and the drug builds up with each successive treatment.
The team also studied inner ear tissue donated by deceased adults who had been treated with cisplatin and found the drug is retained in the inner ear months or years after treatment.
When the researchers examined inner ear tissue from a child, they found cisplatin buildup that was even higher than that seen in adults.
Taken together, these results suggest the inner ear readily takes up cisplatin but has limited ability to remove the drug.
In mice and human tissues, the researchers saw the highest buildup of cisplatin in a part of the inner ear called the stria vascularis, which helps maintain the positive electrical charge in inner ear fluid that certain cells need to detect sound.
The team found the accumulation of cisplatin in the stria vascularis contributed to cisplatin-related hearing loss.
“Our findings suggest that if we can prevent cisplatin from entering the stria vascularis in the inner ear during treatment, we may be able to protect cancer patients from developing cisplatin-induced hearing loss,” Dr Cunningham said.
Researchers have gained new insight into hearing loss caused by cisplatin.
By measuring and mapping cisplatin retention in mouse and human inner ear tissues, the researchers found that cisplatin builds up in the inner ear and can remain there for years.
The team also found that a region in the inner ear called the stria vascularis could be targeted to prevent hearing loss resulting from cisplatin.
Lisa L. Cunningham, PhD, of the National Institute on Deafness and other Communications Disorders (NIDCD) in Bethesda, Maryland, and her colleagues reported these findings in Nature Communications.
The researchers noted that cisplatin can cause permanent hearing loss in 40% to 80% of treated patients. The team’s new findings help explain why.
The researchers found that, in most areas of the body, cisplatin is eliminated within days or weeks of treatment, but, in the inner ear, the drug remains much longer.
The team developed a mouse model that represents cisplatin-induced hearing loss seen in human patients.
By looking at inner ear tissue of mice after the first, second, and third cisplatin treatment, the researchers saw that cisplatin remained in the mouse inner ear much longer than in most other body tissues, and the drug builds up with each successive treatment.
The team also studied inner ear tissue donated by deceased adults who had been treated with cisplatin and found the drug is retained in the inner ear months or years after treatment.
When the researchers examined inner ear tissue from a child, they found cisplatin buildup that was even higher than that seen in adults.
Taken together, these results suggest the inner ear readily takes up cisplatin but has limited ability to remove the drug.
In mice and human tissues, the researchers saw the highest buildup of cisplatin in a part of the inner ear called the stria vascularis, which helps maintain the positive electrical charge in inner ear fluid that certain cells need to detect sound.
The team found the accumulation of cisplatin in the stria vascularis contributed to cisplatin-related hearing loss.
“Our findings suggest that if we can prevent cisplatin from entering the stria vascularis in the inner ear during treatment, we may be able to protect cancer patients from developing cisplatin-induced hearing loss,” Dr Cunningham said.
Researchers have gained new insight into hearing loss caused by cisplatin.
By measuring and mapping cisplatin retention in mouse and human inner ear tissues, the researchers found that cisplatin builds up in the inner ear and can remain there for years.
The team also found that a region in the inner ear called the stria vascularis could be targeted to prevent hearing loss resulting from cisplatin.
Lisa L. Cunningham, PhD, of the National Institute on Deafness and other Communications Disorders (NIDCD) in Bethesda, Maryland, and her colleagues reported these findings in Nature Communications.
The researchers noted that cisplatin can cause permanent hearing loss in 40% to 80% of treated patients. The team’s new findings help explain why.
The researchers found that, in most areas of the body, cisplatin is eliminated within days or weeks of treatment, but, in the inner ear, the drug remains much longer.
The team developed a mouse model that represents cisplatin-induced hearing loss seen in human patients.
By looking at inner ear tissue of mice after the first, second, and third cisplatin treatment, the researchers saw that cisplatin remained in the mouse inner ear much longer than in most other body tissues, and the drug builds up with each successive treatment.
The team also studied inner ear tissue donated by deceased adults who had been treated with cisplatin and found the drug is retained in the inner ear months or years after treatment.
When the researchers examined inner ear tissue from a child, they found cisplatin buildup that was even higher than that seen in adults.
Taken together, these results suggest the inner ear readily takes up cisplatin but has limited ability to remove the drug.
In mice and human tissues, the researchers saw the highest buildup of cisplatin in a part of the inner ear called the stria vascularis, which helps maintain the positive electrical charge in inner ear fluid that certain cells need to detect sound.
The team found the accumulation of cisplatin in the stria vascularis contributed to cisplatin-related hearing loss.
“Our findings suggest that if we can prevent cisplatin from entering the stria vascularis in the inner ear during treatment, we may be able to protect cancer patients from developing cisplatin-induced hearing loss,” Dr Cunningham said.
Hypercalcemia, Parathyroid Disease, Vitamin D Deficiency
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This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.
