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Perioperative infliximab does not increase serious infection risk
Administration of infliximab within 4 weeks of elective knee or hip arthroplasty did not have any significant effect on patients’ risk of serious infection after surgery, whereas the use of glucocorticoids increased that risk, in an analysis of a Medicare claims database.
“This increased risk with glucocorticoids has been suggested by previous studies [and] although this risk may be related in part to increased disease severity among glucocorticoid treated patients, a direct medication effect is likely. [These data suggest] that prolonged interruptions in infliximab therapy prior to surgery may be counterproductive if higher dose glucocorticoid therapy is used in substitution,” wrote the authors of the new study, led by Michael D. George, MD, of the University of Pennsylvania in Philadelphia.
Dr. George and his colleagues examined data from the U.S. Medicare claims system on 4,288 elective knee or hip arthroplasties in individuals with rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, or ankylosing spondylitis who received infliximab within 6 months prior to the operation during 2007-2013 (Arthritis Care Res. 2017 Jan 27. doi: 10.1002/acr.23209).
The patients had to have received infliximab at least three times within a year of their procedure to establish that they were receiving stable therapy over a long-term period. The investigators also looked at oral prednisone, prednisolone, and methylprednisolone prescriptions and used data on average dosing to determine how much was administered to each subject.
“Although previous studies have treated TNF stopping vs. not stopping as a dichotomous exposure based on an arbitrary (and variable) stopping definition, in this study the primary analysis evaluated stop timing as a more general categorical exposure using 4-week intervals (half the standard rheumatoid arthritis dosing interval) to allow better assessment of the optimal stop timing,” the authors explained.
Stopping infliximab within 4 weeks of the operation did not significantly influence the rate of serious infection within 30 days (adjusted odds ratio, 0.90; 95% CI, 0.60-1.34) and neither did stopping within 4-8 weeks (OR, 0.95; 95% CI, 0.62-1.36) when compared against stopping 8-12 weeks before surgery. Of the 4,288 arthroplasties, 270 serious infections (6.3%) occurred within 30 days of the operation.
There also was no significant difference between stopping within 4 weeks and 8-12 weeks in the rate of prosthetic joint infection within 1 year of the operation (hazard ratio, 0.98; 95% CI, 0.52-1.87). Overall, prosthetic joint infection occurred 2.9 times per 100 person-years.
However, glucocorticoid doses of more than 10 mg per day were risky. The odds for a serious infection within 30 days after surgery more than doubled with that level of use (OR, 2.11; 95% CI, 1.30-3.40), while the risk for a prosthetic joint infection within 1 year of the surgery also rose significantly (HR, 2.70; 95% CI, 1.30-5.60).
“This is a very well done paper that adds important observational data to our understanding of perioperative medication risk,” Dr. Goodman said.
But the study results will not, at least initially, bring about any changes to the proposed guidelines for perioperative management of patients taking antirheumatic drugs that were described at the 2016 annual meeting of the American College of Rheumatology, she said.
“We were aware of the abstract, which was also presented at the ACR last fall at the time the current perioperative medication management guidelines were presented, and it won’t change guidelines at this point,” said Dr. Goodman, who is one of the lead authors of the proposed guidelines. “[But] I think [the study] could provide important background information to use in a randomized clinical trial to compare infection on [and] not on TNF inhibitors.”
The proposed guidelines conditionally recommend that all biologics should be withheld prior to surgery in patients with inflammatory arthritis, that surgery should be planned for the end of the dosing cycle, and that current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with rheumatoid arthritis, lupus, or inflammatory arthritis.
The National Institutes of Health, the Rheumatology Research Foundation, and the Department of Veterans Affairs funded the study. Dr. George did not report any relevant financial disclosures. Two coauthors disclosed receiving research grants or consulting fees from pharmaceutical companies for unrelated work.
Administration of infliximab within 4 weeks of elective knee or hip arthroplasty did not have any significant effect on patients’ risk of serious infection after surgery, whereas the use of glucocorticoids increased that risk, in an analysis of a Medicare claims database.
“This increased risk with glucocorticoids has been suggested by previous studies [and] although this risk may be related in part to increased disease severity among glucocorticoid treated patients, a direct medication effect is likely. [These data suggest] that prolonged interruptions in infliximab therapy prior to surgery may be counterproductive if higher dose glucocorticoid therapy is used in substitution,” wrote the authors of the new study, led by Michael D. George, MD, of the University of Pennsylvania in Philadelphia.
Dr. George and his colleagues examined data from the U.S. Medicare claims system on 4,288 elective knee or hip arthroplasties in individuals with rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, or ankylosing spondylitis who received infliximab within 6 months prior to the operation during 2007-2013 (Arthritis Care Res. 2017 Jan 27. doi: 10.1002/acr.23209).
The patients had to have received infliximab at least three times within a year of their procedure to establish that they were receiving stable therapy over a long-term period. The investigators also looked at oral prednisone, prednisolone, and methylprednisolone prescriptions and used data on average dosing to determine how much was administered to each subject.
“Although previous studies have treated TNF stopping vs. not stopping as a dichotomous exposure based on an arbitrary (and variable) stopping definition, in this study the primary analysis evaluated stop timing as a more general categorical exposure using 4-week intervals (half the standard rheumatoid arthritis dosing interval) to allow better assessment of the optimal stop timing,” the authors explained.
Stopping infliximab within 4 weeks of the operation did not significantly influence the rate of serious infection within 30 days (adjusted odds ratio, 0.90; 95% CI, 0.60-1.34) and neither did stopping within 4-8 weeks (OR, 0.95; 95% CI, 0.62-1.36) when compared against stopping 8-12 weeks before surgery. Of the 4,288 arthroplasties, 270 serious infections (6.3%) occurred within 30 days of the operation.
There also was no significant difference between stopping within 4 weeks and 8-12 weeks in the rate of prosthetic joint infection within 1 year of the operation (hazard ratio, 0.98; 95% CI, 0.52-1.87). Overall, prosthetic joint infection occurred 2.9 times per 100 person-years.
However, glucocorticoid doses of more than 10 mg per day were risky. The odds for a serious infection within 30 days after surgery more than doubled with that level of use (OR, 2.11; 95% CI, 1.30-3.40), while the risk for a prosthetic joint infection within 1 year of the surgery also rose significantly (HR, 2.70; 95% CI, 1.30-5.60).
“This is a very well done paper that adds important observational data to our understanding of perioperative medication risk,” Dr. Goodman said.
But the study results will not, at least initially, bring about any changes to the proposed guidelines for perioperative management of patients taking antirheumatic drugs that were described at the 2016 annual meeting of the American College of Rheumatology, she said.
“We were aware of the abstract, which was also presented at the ACR last fall at the time the current perioperative medication management guidelines were presented, and it won’t change guidelines at this point,” said Dr. Goodman, who is one of the lead authors of the proposed guidelines. “[But] I think [the study] could provide important background information to use in a randomized clinical trial to compare infection on [and] not on TNF inhibitors.”
The proposed guidelines conditionally recommend that all biologics should be withheld prior to surgery in patients with inflammatory arthritis, that surgery should be planned for the end of the dosing cycle, and that current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with rheumatoid arthritis, lupus, or inflammatory arthritis.
The National Institutes of Health, the Rheumatology Research Foundation, and the Department of Veterans Affairs funded the study. Dr. George did not report any relevant financial disclosures. Two coauthors disclosed receiving research grants or consulting fees from pharmaceutical companies for unrelated work.
Administration of infliximab within 4 weeks of elective knee or hip arthroplasty did not have any significant effect on patients’ risk of serious infection after surgery, whereas the use of glucocorticoids increased that risk, in an analysis of a Medicare claims database.
“This increased risk with glucocorticoids has been suggested by previous studies [and] although this risk may be related in part to increased disease severity among glucocorticoid treated patients, a direct medication effect is likely. [These data suggest] that prolonged interruptions in infliximab therapy prior to surgery may be counterproductive if higher dose glucocorticoid therapy is used in substitution,” wrote the authors of the new study, led by Michael D. George, MD, of the University of Pennsylvania in Philadelphia.
Dr. George and his colleagues examined data from the U.S. Medicare claims system on 4,288 elective knee or hip arthroplasties in individuals with rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, or ankylosing spondylitis who received infliximab within 6 months prior to the operation during 2007-2013 (Arthritis Care Res. 2017 Jan 27. doi: 10.1002/acr.23209).
The patients had to have received infliximab at least three times within a year of their procedure to establish that they were receiving stable therapy over a long-term period. The investigators also looked at oral prednisone, prednisolone, and methylprednisolone prescriptions and used data on average dosing to determine how much was administered to each subject.
“Although previous studies have treated TNF stopping vs. not stopping as a dichotomous exposure based on an arbitrary (and variable) stopping definition, in this study the primary analysis evaluated stop timing as a more general categorical exposure using 4-week intervals (half the standard rheumatoid arthritis dosing interval) to allow better assessment of the optimal stop timing,” the authors explained.
Stopping infliximab within 4 weeks of the operation did not significantly influence the rate of serious infection within 30 days (adjusted odds ratio, 0.90; 95% CI, 0.60-1.34) and neither did stopping within 4-8 weeks (OR, 0.95; 95% CI, 0.62-1.36) when compared against stopping 8-12 weeks before surgery. Of the 4,288 arthroplasties, 270 serious infections (6.3%) occurred within 30 days of the operation.
There also was no significant difference between stopping within 4 weeks and 8-12 weeks in the rate of prosthetic joint infection within 1 year of the operation (hazard ratio, 0.98; 95% CI, 0.52-1.87). Overall, prosthetic joint infection occurred 2.9 times per 100 person-years.
However, glucocorticoid doses of more than 10 mg per day were risky. The odds for a serious infection within 30 days after surgery more than doubled with that level of use (OR, 2.11; 95% CI, 1.30-3.40), while the risk for a prosthetic joint infection within 1 year of the surgery also rose significantly (HR, 2.70; 95% CI, 1.30-5.60).
“This is a very well done paper that adds important observational data to our understanding of perioperative medication risk,” Dr. Goodman said.
But the study results will not, at least initially, bring about any changes to the proposed guidelines for perioperative management of patients taking antirheumatic drugs that were described at the 2016 annual meeting of the American College of Rheumatology, she said.
“We were aware of the abstract, which was also presented at the ACR last fall at the time the current perioperative medication management guidelines were presented, and it won’t change guidelines at this point,” said Dr. Goodman, who is one of the lead authors of the proposed guidelines. “[But] I think [the study] could provide important background information to use in a randomized clinical trial to compare infection on [and] not on TNF inhibitors.”
The proposed guidelines conditionally recommend that all biologics should be withheld prior to surgery in patients with inflammatory arthritis, that surgery should be planned for the end of the dosing cycle, and that current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with rheumatoid arthritis, lupus, or inflammatory arthritis.
The National Institutes of Health, the Rheumatology Research Foundation, and the Department of Veterans Affairs funded the study. Dr. George did not report any relevant financial disclosures. Two coauthors disclosed receiving research grants or consulting fees from pharmaceutical companies for unrelated work.
FROM ARTHRITIS CARE & RESEARCH
Key clinical point:
Major finding: Subjects on glucocorticoids had an OR of 2.11 (95% CI 1.30-3.40) for serious infection within 30 days and an HR of 2.70 (95% CI 1.30-5.60) for prosthetic joint infection within 1 year.
Data source: Retrospective cohort study of 4,288 elective knee and hip arthroplasties in Medicare patients with rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, or ankylosing spondylitis during 2007-2013.
Disclosures: The National Institutes of Health, the Rheumatology Research Foundation, and the Department of Veterans Affairs funded the study. Dr. George did not report any relevant financial disclosures. Two coauthors disclosed receiving research grants or consulting fees from pharmaceutical companies for unrelated work.
Lower C. difficile mortality with vancomycin than metronidazole
Treating Clostridium difficile infection with vancomycin achieves the same recurrence rates as does treatment with metronidazole, but with a significantly lower 30-day mortality, new research suggests.
A retrospective, propensity-matched cohort study examined U.S. Department of Veterans Affairs health care system data from 47,471 patients with C. difficile infection who were treated with either vancomycin or metronidazole, according to a report published online Feb. 6 in JAMA Internal Medicine.
“Current guidelines recommend metronidazole hydrochloride as initial therapy for most cases of mild to moderate CDI [Clostridium difficile infection],” wrote Vanessa W. Stevens, PhD, of Veterans Affairs Salt Lake City Health Care System, and her coauthors. “Although an early clinical trial found no difference in cure rates between vancomycin hydrochloride and metronidazole, subsequent observational data and clinical trials suggest that metronidazole is inferior to vancomycin for primary clinical cure, especially in severe cases.”
Their study found patients treated with vancomycin had a similar risk of recurrence compared with those treated with metronidazole (relative risk, 0.98; 95% confidence interval, 0.87 to 1.10), with an overall recurrence rate of 16%.
However, patients treated with vancomycin had a 14% reduction in 30-day mortality compared to the metronidazole-treated group. This was after adjustment for factors such as comorbidity scores, hospitalization history, receipt of chemotherapy, receipt of immunosuppressive medication or proton pump inhibitor therapy in the prior 30-days, or antibiotic use on the day of diagnosis.
The 30-day mortality was not significantly different among patients with mild to moderate CDI, but there was a significant 21% reduction among patients with severe infection. The number needed to treat to prevent one death among patients with severe infection was 25 (JAMA Intern Med. 2017 Feb 6. doi: 10.1001/jamainternmed.2016.9045).
“This is the largest study to date to compare vancomycin and metronidazole in a real-world setting and one of the few studies focused on downstream outcomes of CDI,” researchers reported.
The authors noted that despite strong evidence and guidelines supporting the use of vancomycin for severe CDI – and the fact that 42% of episodes in the study were classified as severe – only 4%-6% of patients were prescribed vancomycin.
“Although the excess treatment costs of vancomycin relative to metronidazole and the concern for vancomycin-resistant Enterococcus will likely remain barriers, improved clinical cure and mortality rates may warrant reconsideration of current prescribing practices,” they wrote. “One approach to minimizing the effects of increasing vancomycin use is to target vancomycin treatment to patients with severe disease.”
The study was supported by researcher grants from the U.S. Department of Veterans Affairs. No conflicts of interest were declared.
Treating Clostridium difficile infection with vancomycin achieves the same recurrence rates as does treatment with metronidazole, but with a significantly lower 30-day mortality, new research suggests.
A retrospective, propensity-matched cohort study examined U.S. Department of Veterans Affairs health care system data from 47,471 patients with C. difficile infection who were treated with either vancomycin or metronidazole, according to a report published online Feb. 6 in JAMA Internal Medicine.
“Current guidelines recommend metronidazole hydrochloride as initial therapy for most cases of mild to moderate CDI [Clostridium difficile infection],” wrote Vanessa W. Stevens, PhD, of Veterans Affairs Salt Lake City Health Care System, and her coauthors. “Although an early clinical trial found no difference in cure rates between vancomycin hydrochloride and metronidazole, subsequent observational data and clinical trials suggest that metronidazole is inferior to vancomycin for primary clinical cure, especially in severe cases.”
Their study found patients treated with vancomycin had a similar risk of recurrence compared with those treated with metronidazole (relative risk, 0.98; 95% confidence interval, 0.87 to 1.10), with an overall recurrence rate of 16%.
However, patients treated with vancomycin had a 14% reduction in 30-day mortality compared to the metronidazole-treated group. This was after adjustment for factors such as comorbidity scores, hospitalization history, receipt of chemotherapy, receipt of immunosuppressive medication or proton pump inhibitor therapy in the prior 30-days, or antibiotic use on the day of diagnosis.
The 30-day mortality was not significantly different among patients with mild to moderate CDI, but there was a significant 21% reduction among patients with severe infection. The number needed to treat to prevent one death among patients with severe infection was 25 (JAMA Intern Med. 2017 Feb 6. doi: 10.1001/jamainternmed.2016.9045).
“This is the largest study to date to compare vancomycin and metronidazole in a real-world setting and one of the few studies focused on downstream outcomes of CDI,” researchers reported.
The authors noted that despite strong evidence and guidelines supporting the use of vancomycin for severe CDI – and the fact that 42% of episodes in the study were classified as severe – only 4%-6% of patients were prescribed vancomycin.
“Although the excess treatment costs of vancomycin relative to metronidazole and the concern for vancomycin-resistant Enterococcus will likely remain barriers, improved clinical cure and mortality rates may warrant reconsideration of current prescribing practices,” they wrote. “One approach to minimizing the effects of increasing vancomycin use is to target vancomycin treatment to patients with severe disease.”
The study was supported by researcher grants from the U.S. Department of Veterans Affairs. No conflicts of interest were declared.
Treating Clostridium difficile infection with vancomycin achieves the same recurrence rates as does treatment with metronidazole, but with a significantly lower 30-day mortality, new research suggests.
A retrospective, propensity-matched cohort study examined U.S. Department of Veterans Affairs health care system data from 47,471 patients with C. difficile infection who were treated with either vancomycin or metronidazole, according to a report published online Feb. 6 in JAMA Internal Medicine.
“Current guidelines recommend metronidazole hydrochloride as initial therapy for most cases of mild to moderate CDI [Clostridium difficile infection],” wrote Vanessa W. Stevens, PhD, of Veterans Affairs Salt Lake City Health Care System, and her coauthors. “Although an early clinical trial found no difference in cure rates between vancomycin hydrochloride and metronidazole, subsequent observational data and clinical trials suggest that metronidazole is inferior to vancomycin for primary clinical cure, especially in severe cases.”
Their study found patients treated with vancomycin had a similar risk of recurrence compared with those treated with metronidazole (relative risk, 0.98; 95% confidence interval, 0.87 to 1.10), with an overall recurrence rate of 16%.
However, patients treated with vancomycin had a 14% reduction in 30-day mortality compared to the metronidazole-treated group. This was after adjustment for factors such as comorbidity scores, hospitalization history, receipt of chemotherapy, receipt of immunosuppressive medication or proton pump inhibitor therapy in the prior 30-days, or antibiotic use on the day of diagnosis.
The 30-day mortality was not significantly different among patients with mild to moderate CDI, but there was a significant 21% reduction among patients with severe infection. The number needed to treat to prevent one death among patients with severe infection was 25 (JAMA Intern Med. 2017 Feb 6. doi: 10.1001/jamainternmed.2016.9045).
“This is the largest study to date to compare vancomycin and metronidazole in a real-world setting and one of the few studies focused on downstream outcomes of CDI,” researchers reported.
The authors noted that despite strong evidence and guidelines supporting the use of vancomycin for severe CDI – and the fact that 42% of episodes in the study were classified as severe – only 4%-6% of patients were prescribed vancomycin.
“Although the excess treatment costs of vancomycin relative to metronidazole and the concern for vancomycin-resistant Enterococcus will likely remain barriers, improved clinical cure and mortality rates may warrant reconsideration of current prescribing practices,” they wrote. “One approach to minimizing the effects of increasing vancomycin use is to target vancomycin treatment to patients with severe disease.”
The study was supported by researcher grants from the U.S. Department of Veterans Affairs. No conflicts of interest were declared.
FROM JAMA INTERNAL MEDICINE
Key clinical point: Vancomycin therapy is associated with significantly lower 30-day mortality from severe Clostridium difficile infection compared to metronidazole.
Major finding: Treatment with vancomycin prevented one death per 25 patients with severe C. difficile infection.
Data source: A retrospective, propensity-matched cohort study of 47,471 patients with C. difficile infection.
Disclosures: The study was supported by researcher grants from the U.S. Department of Veterans Affairs. No conflicts of interest were declared.
Ventilator use in patients with advanced dementia
Clinical question: Does the increasing number of ICU beds in the U.S. affect the use of mechanical ventilation in nursing home patients with advanced dementia?
Background: Some physicians are concerned that increases in ICU beds in the U.S. will translate to increased treatment of advanced dementia in the ICU, which might not line up with their preferences, nor improve mortality.
Study design: Retrospective cohort study.
Setting: Hospitals that completed the American Hospital Association (AHA) annual survey.
Synopsis: From 2000 to 2013, there were 635,008 hospitalizations of 380,060 Medicare patients with advanced dementia who had been in a nursing home in the 120 days prior to hospital admission. ICU admissions increased to 38.5% from 16.9% during the same period. The rate of mechanical ventilation per 1,000 hospital admissions increased to 78 from 39, and 1-year mortality for ventilation was unchanged.
For each increase in 10 ICU beds within a hospital, the adjusted odds ratio for receiving mechanical ventilation was 1.06 (95% CI, 1.05-1.07).
Limitations of the study include that only hospitals completing the AHA annual survey were studied, and also lacked information on individual patients.
Bottom line: The use of mechanical ventilation increased in hospitalized nursing home patients with advanced dementia, correlating with increased ICU bed capacity, yet with no changes in survival.
Citation: Teno JM, Gozalo P, Khandelwal N, et al. Association of increasing use of mechanical ventilation among nursing home residents with advanced dementia and intensive care unit beds [published online ahead of print, Oct. 10, 2016]. JAMA Int Med. 2016;176(12):1809-16.
Dr. Balch is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Clinical question: Does the increasing number of ICU beds in the U.S. affect the use of mechanical ventilation in nursing home patients with advanced dementia?
Background: Some physicians are concerned that increases in ICU beds in the U.S. will translate to increased treatment of advanced dementia in the ICU, which might not line up with their preferences, nor improve mortality.
Study design: Retrospective cohort study.
Setting: Hospitals that completed the American Hospital Association (AHA) annual survey.
Synopsis: From 2000 to 2013, there were 635,008 hospitalizations of 380,060 Medicare patients with advanced dementia who had been in a nursing home in the 120 days prior to hospital admission. ICU admissions increased to 38.5% from 16.9% during the same period. The rate of mechanical ventilation per 1,000 hospital admissions increased to 78 from 39, and 1-year mortality for ventilation was unchanged.
For each increase in 10 ICU beds within a hospital, the adjusted odds ratio for receiving mechanical ventilation was 1.06 (95% CI, 1.05-1.07).
Limitations of the study include that only hospitals completing the AHA annual survey were studied, and also lacked information on individual patients.
Bottom line: The use of mechanical ventilation increased in hospitalized nursing home patients with advanced dementia, correlating with increased ICU bed capacity, yet with no changes in survival.
Citation: Teno JM, Gozalo P, Khandelwal N, et al. Association of increasing use of mechanical ventilation among nursing home residents with advanced dementia and intensive care unit beds [published online ahead of print, Oct. 10, 2016]. JAMA Int Med. 2016;176(12):1809-16.
Dr. Balch is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Clinical question: Does the increasing number of ICU beds in the U.S. affect the use of mechanical ventilation in nursing home patients with advanced dementia?
Background: Some physicians are concerned that increases in ICU beds in the U.S. will translate to increased treatment of advanced dementia in the ICU, which might not line up with their preferences, nor improve mortality.
Study design: Retrospective cohort study.
Setting: Hospitals that completed the American Hospital Association (AHA) annual survey.
Synopsis: From 2000 to 2013, there were 635,008 hospitalizations of 380,060 Medicare patients with advanced dementia who had been in a nursing home in the 120 days prior to hospital admission. ICU admissions increased to 38.5% from 16.9% during the same period. The rate of mechanical ventilation per 1,000 hospital admissions increased to 78 from 39, and 1-year mortality for ventilation was unchanged.
For each increase in 10 ICU beds within a hospital, the adjusted odds ratio for receiving mechanical ventilation was 1.06 (95% CI, 1.05-1.07).
Limitations of the study include that only hospitals completing the AHA annual survey were studied, and also lacked information on individual patients.
Bottom line: The use of mechanical ventilation increased in hospitalized nursing home patients with advanced dementia, correlating with increased ICU bed capacity, yet with no changes in survival.
Citation: Teno JM, Gozalo P, Khandelwal N, et al. Association of increasing use of mechanical ventilation among nursing home residents with advanced dementia and intensive care unit beds [published online ahead of print, Oct. 10, 2016]. JAMA Int Med. 2016;176(12):1809-16.
Dr. Balch is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Consensus guidelines for calcium channel blocker poisoning
Clinical question: What is the best management approach for adults who are admitted to the hospital with a calcium channel blocker (CCB) overdose?
Background: There is significant morbidity and mortality from cardiac drug poisoning. Overall, the level of evidence in the literature on the treatment of CCB toxicity is very low. Prior to the current publication there were no guidelines for treating patients admitted to the hospital with a CCB overdose.
Setting: Panel members participated in online votes, telephone meetings, and two face-to-face meetings to develop the guidelines.
Synopsis: In symptomatic CCB poisoning, the following first-line measures are strongly recommended: IV calcium, with norepinephrine or epinephrine in the presence of shock, and high-dose IV insulin (with other first-line treatments) if there is myocardial dysfunction.
Further lower-strength suggestions were made: insulin therapy as monotherapy if cardiac dysfunction present, or in combination with other therapies if there is no cardiac dysfunction; atropine in the setting of symptomatic bradycardia; and dobutamine or epinephrine in the presence of cardiogenic shock.
For refractory CCB, toxicity suggestions included incremental doses of high-dose insulin (if myocardial dysfunction is present, or even if it is not present in periarrest situations), IV lipid emulsion therapy, and pacemaker for unstable bradycardia (if there is no evidence of cardiac dysfunction). If the patient is in refractory shock or periarrest, the panel suggests the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO).
Limitations included the limited availability of evidence.
Bottom line: Management of CCB toxicity should include IV calcium and high-dose IV insulin, with vasopressors for shock, and other additional therapies for refractory cases.
Citation: St-Onge M, Anseeuw K, Cantrell FL, et al. Experts’ consensus recommendations for the management of calcium channel blocker poisoning in adults [published online ahead of print, Oct. 3, 2016]. Crit Care Med. doi: 10.1097/CCM.0000000000002087.
Dr. Balch is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Clinical question: What is the best management approach for adults who are admitted to the hospital with a calcium channel blocker (CCB) overdose?
Background: There is significant morbidity and mortality from cardiac drug poisoning. Overall, the level of evidence in the literature on the treatment of CCB toxicity is very low. Prior to the current publication there were no guidelines for treating patients admitted to the hospital with a CCB overdose.
Setting: Panel members participated in online votes, telephone meetings, and two face-to-face meetings to develop the guidelines.
Synopsis: In symptomatic CCB poisoning, the following first-line measures are strongly recommended: IV calcium, with norepinephrine or epinephrine in the presence of shock, and high-dose IV insulin (with other first-line treatments) if there is myocardial dysfunction.
Further lower-strength suggestions were made: insulin therapy as monotherapy if cardiac dysfunction present, or in combination with other therapies if there is no cardiac dysfunction; atropine in the setting of symptomatic bradycardia; and dobutamine or epinephrine in the presence of cardiogenic shock.
For refractory CCB, toxicity suggestions included incremental doses of high-dose insulin (if myocardial dysfunction is present, or even if it is not present in periarrest situations), IV lipid emulsion therapy, and pacemaker for unstable bradycardia (if there is no evidence of cardiac dysfunction). If the patient is in refractory shock or periarrest, the panel suggests the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO).
Limitations included the limited availability of evidence.
Bottom line: Management of CCB toxicity should include IV calcium and high-dose IV insulin, with vasopressors for shock, and other additional therapies for refractory cases.
Citation: St-Onge M, Anseeuw K, Cantrell FL, et al. Experts’ consensus recommendations for the management of calcium channel blocker poisoning in adults [published online ahead of print, Oct. 3, 2016]. Crit Care Med. doi: 10.1097/CCM.0000000000002087.
Dr. Balch is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Clinical question: What is the best management approach for adults who are admitted to the hospital with a calcium channel blocker (CCB) overdose?
Background: There is significant morbidity and mortality from cardiac drug poisoning. Overall, the level of evidence in the literature on the treatment of CCB toxicity is very low. Prior to the current publication there were no guidelines for treating patients admitted to the hospital with a CCB overdose.
Setting: Panel members participated in online votes, telephone meetings, and two face-to-face meetings to develop the guidelines.
Synopsis: In symptomatic CCB poisoning, the following first-line measures are strongly recommended: IV calcium, with norepinephrine or epinephrine in the presence of shock, and high-dose IV insulin (with other first-line treatments) if there is myocardial dysfunction.
Further lower-strength suggestions were made: insulin therapy as monotherapy if cardiac dysfunction present, or in combination with other therapies if there is no cardiac dysfunction; atropine in the setting of symptomatic bradycardia; and dobutamine or epinephrine in the presence of cardiogenic shock.
For refractory CCB, toxicity suggestions included incremental doses of high-dose insulin (if myocardial dysfunction is present, or even if it is not present in periarrest situations), IV lipid emulsion therapy, and pacemaker for unstable bradycardia (if there is no evidence of cardiac dysfunction). If the patient is in refractory shock or periarrest, the panel suggests the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO).
Limitations included the limited availability of evidence.
Bottom line: Management of CCB toxicity should include IV calcium and high-dose IV insulin, with vasopressors for shock, and other additional therapies for refractory cases.
Citation: St-Onge M, Anseeuw K, Cantrell FL, et al. Experts’ consensus recommendations for the management of calcium channel blocker poisoning in adults [published online ahead of print, Oct. 3, 2016]. Crit Care Med. doi: 10.1097/CCM.0000000000002087.
Dr. Balch is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Conservative oxygen therapy in critically ill patients
Clinical question: Does a conservative oxygenation strategy improve clinical outcomes, compared with standard clinical practice among critically ill patients?
Background: Supraphysiologic levels of oxygen have been linked to direct cellular injury through generation of reactive oxygen species. Hyperoxia is known to cause airway injury, including diffuse alveolar damage and tracheobronchitis; it also is linked to worse clinical outcomes in various cardiac and surgical patients. ICU patients have not been studied.
Setting: Single-center, academic hospital in Italy.
Synopsis: Investigators randomized 480 adults admitted to the ICU for at least 72 hours to either standard practice (allowing PaO2 up to 150 mmHg, SpO2 97%-100%) or the conservative protocol (PaO2 70-100 mmHg or SpO2 94%-98%). Patients who were pregnant, readmitted, immunosuppressed, neutropenic, with decompensated COPD or acute respiratory distress syndrome were excluded. Outcomes included ICU mortality, hospital mortality, new-onset organ failure, or new infection.
Enrollment was slow, the authors noted, partially due to an earthquake that damaged the facility, and the trial was stopped short of the planned 660 patient sample size.
In an intent-to-treat analysis, there was a statistically significant decrease in ICU and hospital mortality, shock, liver failure, and bacteremia among the conservative group.
Limitations included possible confounding from higher illness severity in the standard practice group, as well as the single-center focus that terminated early due to enrollment challenges.
Bottom line: A conservative oxygen strategy had a statistically significant decrease in ICU and hospital mortality, shock, liver failure, and bacteremia.
Citation: Girardis M, Busani S, Damiani E, et al. Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit. JAMA. 2016;316(15):1583-9.
Dr. Marr is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Clinical question: Does a conservative oxygenation strategy improve clinical outcomes, compared with standard clinical practice among critically ill patients?
Background: Supraphysiologic levels of oxygen have been linked to direct cellular injury through generation of reactive oxygen species. Hyperoxia is known to cause airway injury, including diffuse alveolar damage and tracheobronchitis; it also is linked to worse clinical outcomes in various cardiac and surgical patients. ICU patients have not been studied.
Setting: Single-center, academic hospital in Italy.
Synopsis: Investigators randomized 480 adults admitted to the ICU for at least 72 hours to either standard practice (allowing PaO2 up to 150 mmHg, SpO2 97%-100%) or the conservative protocol (PaO2 70-100 mmHg or SpO2 94%-98%). Patients who were pregnant, readmitted, immunosuppressed, neutropenic, with decompensated COPD or acute respiratory distress syndrome were excluded. Outcomes included ICU mortality, hospital mortality, new-onset organ failure, or new infection.
Enrollment was slow, the authors noted, partially due to an earthquake that damaged the facility, and the trial was stopped short of the planned 660 patient sample size.
In an intent-to-treat analysis, there was a statistically significant decrease in ICU and hospital mortality, shock, liver failure, and bacteremia among the conservative group.
Limitations included possible confounding from higher illness severity in the standard practice group, as well as the single-center focus that terminated early due to enrollment challenges.
Bottom line: A conservative oxygen strategy had a statistically significant decrease in ICU and hospital mortality, shock, liver failure, and bacteremia.
Citation: Girardis M, Busani S, Damiani E, et al. Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit. JAMA. 2016;316(15):1583-9.
Dr. Marr is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Clinical question: Does a conservative oxygenation strategy improve clinical outcomes, compared with standard clinical practice among critically ill patients?
Background: Supraphysiologic levels of oxygen have been linked to direct cellular injury through generation of reactive oxygen species. Hyperoxia is known to cause airway injury, including diffuse alveolar damage and tracheobronchitis; it also is linked to worse clinical outcomes in various cardiac and surgical patients. ICU patients have not been studied.
Setting: Single-center, academic hospital in Italy.
Synopsis: Investigators randomized 480 adults admitted to the ICU for at least 72 hours to either standard practice (allowing PaO2 up to 150 mmHg, SpO2 97%-100%) or the conservative protocol (PaO2 70-100 mmHg or SpO2 94%-98%). Patients who were pregnant, readmitted, immunosuppressed, neutropenic, with decompensated COPD or acute respiratory distress syndrome were excluded. Outcomes included ICU mortality, hospital mortality, new-onset organ failure, or new infection.
Enrollment was slow, the authors noted, partially due to an earthquake that damaged the facility, and the trial was stopped short of the planned 660 patient sample size.
In an intent-to-treat analysis, there was a statistically significant decrease in ICU and hospital mortality, shock, liver failure, and bacteremia among the conservative group.
Limitations included possible confounding from higher illness severity in the standard practice group, as well as the single-center focus that terminated early due to enrollment challenges.
Bottom line: A conservative oxygen strategy had a statistically significant decrease in ICU and hospital mortality, shock, liver failure, and bacteremia.
Citation: Girardis M, Busani S, Damiani E, et al. Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit. JAMA. 2016;316(15):1583-9.
Dr. Marr is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Prevalence of pulmonary embolism among syncope patients
Clinical question: What is the prevalence of acute pulmonary emboli (PE) in patients admitted for syncope?
Background: An acute pulmonary embolism is a differential consideration among patients admitted with syncope. However, current guidelines do not guide evaluation.
Study design: Cross-sectional study.
Setting: Two academic and nine non-academic hospitals in Italy.
Synopsis: Five hundred-sixty patients admitted with a first episode of syncope were evaluated for a PE. Patients with atrial fibrillation, treatment with anticoagulation, recurrent syncope, or who were pregnant were excluded. The simplified Wells score was used to stratify patients into low and high-risk groups, while low-risk groups received D-dimer testing; 230 patients had a positive D-dimer or a high-risk Wells score and received either CT pulmonary angiography or VQ scans.
Ninety-seven of the 230 patients were found to have a PE (42.2%), leading to a prevalence of 17.3% among the entire cohort. The study did not include the 1,867 patients who were discharged from the ED without admission, potentially leading to bias and overestimating the prevalence of pulmonary emboli (PE).
Bottom line: The prevalence of PE in patients with syncope is higher than previously thought, highlighting the importance of considering acute PE in patients hospitalized with syncope.
Citation: Prandoni P, Lensing AWA, Prins MH, et al. Prevalence of pulmonary embolism among patients hospitalized for syncope. N Engl J Med. 2016;375(16):1524-31.
Dr. Marr is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Clinical question: What is the prevalence of acute pulmonary emboli (PE) in patients admitted for syncope?
Background: An acute pulmonary embolism is a differential consideration among patients admitted with syncope. However, current guidelines do not guide evaluation.
Study design: Cross-sectional study.
Setting: Two academic and nine non-academic hospitals in Italy.
Synopsis: Five hundred-sixty patients admitted with a first episode of syncope were evaluated for a PE. Patients with atrial fibrillation, treatment with anticoagulation, recurrent syncope, or who were pregnant were excluded. The simplified Wells score was used to stratify patients into low and high-risk groups, while low-risk groups received D-dimer testing; 230 patients had a positive D-dimer or a high-risk Wells score and received either CT pulmonary angiography or VQ scans.
Ninety-seven of the 230 patients were found to have a PE (42.2%), leading to a prevalence of 17.3% among the entire cohort. The study did not include the 1,867 patients who were discharged from the ED without admission, potentially leading to bias and overestimating the prevalence of pulmonary emboli (PE).
Bottom line: The prevalence of PE in patients with syncope is higher than previously thought, highlighting the importance of considering acute PE in patients hospitalized with syncope.
Citation: Prandoni P, Lensing AWA, Prins MH, et al. Prevalence of pulmonary embolism among patients hospitalized for syncope. N Engl J Med. 2016;375(16):1524-31.
Dr. Marr is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Clinical question: What is the prevalence of acute pulmonary emboli (PE) in patients admitted for syncope?
Background: An acute pulmonary embolism is a differential consideration among patients admitted with syncope. However, current guidelines do not guide evaluation.
Study design: Cross-sectional study.
Setting: Two academic and nine non-academic hospitals in Italy.
Synopsis: Five hundred-sixty patients admitted with a first episode of syncope were evaluated for a PE. Patients with atrial fibrillation, treatment with anticoagulation, recurrent syncope, or who were pregnant were excluded. The simplified Wells score was used to stratify patients into low and high-risk groups, while low-risk groups received D-dimer testing; 230 patients had a positive D-dimer or a high-risk Wells score and received either CT pulmonary angiography or VQ scans.
Ninety-seven of the 230 patients were found to have a PE (42.2%), leading to a prevalence of 17.3% among the entire cohort. The study did not include the 1,867 patients who were discharged from the ED without admission, potentially leading to bias and overestimating the prevalence of pulmonary emboli (PE).
Bottom line: The prevalence of PE in patients with syncope is higher than previously thought, highlighting the importance of considering acute PE in patients hospitalized with syncope.
Citation: Prandoni P, Lensing AWA, Prins MH, et al. Prevalence of pulmonary embolism among patients hospitalized for syncope. N Engl J Med. 2016;375(16):1524-31.
Dr. Marr is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Evidence suggests fondaparinux is more effective than LMWH in prevention of VTE and total DVT in the postoperative setting
Clinical question: How do pentasaccharides compare to other anticoagulants in postoperative venous thromboembolism prevention?
Background: Venous thromboembolism (VTE) remains a leading cause of preventable hospital related death. Pentasaccharides selectively inhibit factor Xa to inhibit clotting and exhibit a lower risk of heparin induced thrombocytopenia (HIT) compared to low molecular weight heparin (LMWH) and unfractionated heparin. We lack a formal recommendation regarding the pentasaccharides superiority or inferiority, relative to other anticoagulants, in the perioperative setting.
Study design: Cochrane review.
Setting: Hospital and outpatient.
Synopsis: Authors searched randomized controlled trials involving pentasaccharides versus other VTE prophylaxis to obtain 25 studies totaling 21,004 subjects undergoing orthopedic, abdominal, cardiac bypass, thoracic, and bariatric surgery; hospitalized patients, immobilized patients, and those with superficial venous thrombosis. Selected studies pertained to fondaparinux and VTE prevention. Fondaparinux was superior to placebo in prevention of DVT and VTE. Compared to LMWH, fondaparinux reduced total VTE (RR, 0.55, 95% CI, 0.42-0.73) and DVT (RR, 0.54, 95% CI, 0.40-0.71), but carried a higher rate of major bleeding compared to placebo (RR, 2.56, 95% CI, 1.48-4.44) and LMWH (RR, 1.38, 95% CI, 1.09-1.75). The all cause death and major adverse events for fondaparinux versus placebo and LMWH were not statistically significant. Limitations of this review include the predominance of orthopedic patients, variable duration of treatment, and low-moderate quality data.
Bottom line: Fondaparinux demonstrates better perioperative total VTE and DVT reduction compared to LMWH, but it increases the incidence of major bleeding.
Reference: Dong K, Song Y, Li X, Ding J, Gao Z, Lu D, Zhu Y. Pentasaccharides for the prevention of venous thromboembolism. Cochrane Database Syst Rev. 2016 Oct 31;10:CD005134.
Dr. Coleman is an assistant professor of clinical medicine at Cooper Medical School at Rowan University. She works as a hospitalist at Cooper University Hospital in Camden, N.J.
Clinical question: How do pentasaccharides compare to other anticoagulants in postoperative venous thromboembolism prevention?
Background: Venous thromboembolism (VTE) remains a leading cause of preventable hospital related death. Pentasaccharides selectively inhibit factor Xa to inhibit clotting and exhibit a lower risk of heparin induced thrombocytopenia (HIT) compared to low molecular weight heparin (LMWH) and unfractionated heparin. We lack a formal recommendation regarding the pentasaccharides superiority or inferiority, relative to other anticoagulants, in the perioperative setting.
Study design: Cochrane review.
Setting: Hospital and outpatient.
Synopsis: Authors searched randomized controlled trials involving pentasaccharides versus other VTE prophylaxis to obtain 25 studies totaling 21,004 subjects undergoing orthopedic, abdominal, cardiac bypass, thoracic, and bariatric surgery; hospitalized patients, immobilized patients, and those with superficial venous thrombosis. Selected studies pertained to fondaparinux and VTE prevention. Fondaparinux was superior to placebo in prevention of DVT and VTE. Compared to LMWH, fondaparinux reduced total VTE (RR, 0.55, 95% CI, 0.42-0.73) and DVT (RR, 0.54, 95% CI, 0.40-0.71), but carried a higher rate of major bleeding compared to placebo (RR, 2.56, 95% CI, 1.48-4.44) and LMWH (RR, 1.38, 95% CI, 1.09-1.75). The all cause death and major adverse events for fondaparinux versus placebo and LMWH were not statistically significant. Limitations of this review include the predominance of orthopedic patients, variable duration of treatment, and low-moderate quality data.
Bottom line: Fondaparinux demonstrates better perioperative total VTE and DVT reduction compared to LMWH, but it increases the incidence of major bleeding.
Reference: Dong K, Song Y, Li X, Ding J, Gao Z, Lu D, Zhu Y. Pentasaccharides for the prevention of venous thromboembolism. Cochrane Database Syst Rev. 2016 Oct 31;10:CD005134.
Dr. Coleman is an assistant professor of clinical medicine at Cooper Medical School at Rowan University. She works as a hospitalist at Cooper University Hospital in Camden, N.J.
Clinical question: How do pentasaccharides compare to other anticoagulants in postoperative venous thromboembolism prevention?
Background: Venous thromboembolism (VTE) remains a leading cause of preventable hospital related death. Pentasaccharides selectively inhibit factor Xa to inhibit clotting and exhibit a lower risk of heparin induced thrombocytopenia (HIT) compared to low molecular weight heparin (LMWH) and unfractionated heparin. We lack a formal recommendation regarding the pentasaccharides superiority or inferiority, relative to other anticoagulants, in the perioperative setting.
Study design: Cochrane review.
Setting: Hospital and outpatient.
Synopsis: Authors searched randomized controlled trials involving pentasaccharides versus other VTE prophylaxis to obtain 25 studies totaling 21,004 subjects undergoing orthopedic, abdominal, cardiac bypass, thoracic, and bariatric surgery; hospitalized patients, immobilized patients, and those with superficial venous thrombosis. Selected studies pertained to fondaparinux and VTE prevention. Fondaparinux was superior to placebo in prevention of DVT and VTE. Compared to LMWH, fondaparinux reduced total VTE (RR, 0.55, 95% CI, 0.42-0.73) and DVT (RR, 0.54, 95% CI, 0.40-0.71), but carried a higher rate of major bleeding compared to placebo (RR, 2.56, 95% CI, 1.48-4.44) and LMWH (RR, 1.38, 95% CI, 1.09-1.75). The all cause death and major adverse events for fondaparinux versus placebo and LMWH were not statistically significant. Limitations of this review include the predominance of orthopedic patients, variable duration of treatment, and low-moderate quality data.
Bottom line: Fondaparinux demonstrates better perioperative total VTE and DVT reduction compared to LMWH, but it increases the incidence of major bleeding.
Reference: Dong K, Song Y, Li X, Ding J, Gao Z, Lu D, Zhu Y. Pentasaccharides for the prevention of venous thromboembolism. Cochrane Database Syst Rev. 2016 Oct 31;10:CD005134.
Dr. Coleman is an assistant professor of clinical medicine at Cooper Medical School at Rowan University. She works as a hospitalist at Cooper University Hospital in Camden, N.J.
Taking the hammer to sickle pain crises
Clinical question: Are any novel medicines designed to interrupt the pathophysiology of vaso-occlusion available to reduce the frequency and severity of pain crises in sickle cell anemia?
Background: Hypoxemia-dependent HbS polymerization is just the initiating step in a complex cascade of events leading to sickle pain crises. Animal studies have suggested that blockade of P-selectin, an adhesion molecule expressed by endothelium, blunts the aggregation of sickled erythrocytes, leukocytes and activated platelets and may reduce progression to vaso-occlusive crises. 
Study Design: Multicenter, double-blinded, randomized placebo-controlled trial.
Setting: International (60 study sites in 3 countries) from August 2013 to January 2015.
Synopsis: Crizanlizumab is a humanized monoclonal antibody directed against P-selectin. A total of 198 patients aged 16-65 with HbSS, HbSC, HbSbeta+ and select other genotypes experiencing 2-10 pain crises in the 12 months prior to trial were block randomized to receive high-dose crizanlizumab, low-dose crizanlizumab, or placebo. Roughly 62% of enrolled patients in all three arms were already taking hydroxyurea – for which dose changes during trial period were forbidden. Patients not already on hydroxyurea could not initiate treatment during the trial period. The primary outcome was annualized rate of sickle pain crises (defined as pain without other demonstrable cause requiring medical facility visit and treatment with oral or parenteral narcotics or NSAIDs), including acute chest, hepatic or splenic sequestration crises and priapism. Secondary outcomes were annualized rates of hospital days, rates of uncomplicated crises, time to first and second crises, rates of acute chest syndrome and Brief Pain Inventory questionnaire. Primary outcome data were processed via intention-to-treat analysis.
For high-dose crizanlizumab, there were a median 1.63 crises per year compared to 2.98 in the placebo group, representing a 45.3% lower rate (P = .01). The protective effect of crizanlizumab was more pronounced in the per-protocol analysis (1.04 crises per year for the high dose group). In the subgroup of patients on concomitant hydroxyurea, the median annualized crisis rate among high dose versus placebo was 2.43 compared to 3.58, representing a 32.1% lower rate. In the non-hydroxyurea subgroup, the median annualized crisis rate for high dose versus placebo was 1.0 vs. 2.0, representing a 50% lower rate. Secondary endpoints similarly trended in favor of crizanlizumab in a dose-dependent fashion, although statistical significance was mixed.
Bottom line: Crizanlizumab, a humanized monoclonal antibody that blocks the action of the endothelial adhesion molecule P-selectin, is promising as a novel medication to reduce frequency of vaso-occlusive crises in patients with HbS-related disease.
Citation: Ataga KI, Kutler A, Kanter J, et al. Crizanlizumab for prevention of pain crises in sickle cell disease. N Engl J Med. 2016 Dec. 3. doi: 10.1056/NEJMoa1611770.
Clinical question: Are any novel medicines designed to interrupt the pathophysiology of vaso-occlusion available to reduce the frequency and severity of pain crises in sickle cell anemia?
Background: Hypoxemia-dependent HbS polymerization is just the initiating step in a complex cascade of events leading to sickle pain crises. Animal studies have suggested that blockade of P-selectin, an adhesion molecule expressed by endothelium, blunts the aggregation of sickled erythrocytes, leukocytes and activated platelets and may reduce progression to vaso-occlusive crises.
Study Design: Multicenter, double-blinded, randomized placebo-controlled trial.
Setting: International (60 study sites in 3 countries) from August 2013 to January 2015.
Synopsis: Crizanlizumab is a humanized monoclonal antibody directed against P-selectin. A total of 198 patients aged 16-65 with HbSS, HbSC, HbSbeta+ and select other genotypes experiencing 2-10 pain crises in the 12 months prior to trial were block randomized to receive high-dose crizanlizumab, low-dose crizanlizumab, or placebo. Roughly 62% of enrolled patients in all three arms were already taking hydroxyurea – for which dose changes during trial period were forbidden. Patients not already on hydroxyurea could not initiate treatment during the trial period. The primary outcome was annualized rate of sickle pain crises (defined as pain without other demonstrable cause requiring medical facility visit and treatment with oral or parenteral narcotics or NSAIDs), including acute chest, hepatic or splenic sequestration crises and priapism. Secondary outcomes were annualized rates of hospital days, rates of uncomplicated crises, time to first and second crises, rates of acute chest syndrome and Brief Pain Inventory questionnaire. Primary outcome data were processed via intention-to-treat analysis.
For high-dose crizanlizumab, there were a median 1.63 crises per year compared to 2.98 in the placebo group, representing a 45.3% lower rate (P = .01). The protective effect of crizanlizumab was more pronounced in the per-protocol analysis (1.04 crises per year for the high dose group). In the subgroup of patients on concomitant hydroxyurea, the median annualized crisis rate among high dose versus placebo was 2.43 compared to 3.58, representing a 32.1% lower rate. In the non-hydroxyurea subgroup, the median annualized crisis rate for high dose versus placebo was 1.0 vs. 2.0, representing a 50% lower rate. Secondary endpoints similarly trended in favor of crizanlizumab in a dose-dependent fashion, although statistical significance was mixed.
Bottom line: Crizanlizumab, a humanized monoclonal antibody that blocks the action of the endothelial adhesion molecule P-selectin, is promising as a novel medication to reduce frequency of vaso-occlusive crises in patients with HbS-related disease.
Citation: Ataga KI, Kutler A, Kanter J, et al. Crizanlizumab for prevention of pain crises in sickle cell disease. N Engl J Med. 2016 Dec. 3. doi: 10.1056/NEJMoa1611770.
Clinical question: Are any novel medicines designed to interrupt the pathophysiology of vaso-occlusion available to reduce the frequency and severity of pain crises in sickle cell anemia?
Background: Hypoxemia-dependent HbS polymerization is just the initiating step in a complex cascade of events leading to sickle pain crises. Animal studies have suggested that blockade of P-selectin, an adhesion molecule expressed by endothelium, blunts the aggregation of sickled erythrocytes, leukocytes and activated platelets and may reduce progression to vaso-occlusive crises.
Study Design: Multicenter, double-blinded, randomized placebo-controlled trial.
Setting: International (60 study sites in 3 countries) from August 2013 to January 2015.
Synopsis: Crizanlizumab is a humanized monoclonal antibody directed against P-selectin. A total of 198 patients aged 16-65 with HbSS, HbSC, HbSbeta+ and select other genotypes experiencing 2-10 pain crises in the 12 months prior to trial were block randomized to receive high-dose crizanlizumab, low-dose crizanlizumab, or placebo. Roughly 62% of enrolled patients in all three arms were already taking hydroxyurea – for which dose changes during trial period were forbidden. Patients not already on hydroxyurea could not initiate treatment during the trial period. The primary outcome was annualized rate of sickle pain crises (defined as pain without other demonstrable cause requiring medical facility visit and treatment with oral or parenteral narcotics or NSAIDs), including acute chest, hepatic or splenic sequestration crises and priapism. Secondary outcomes were annualized rates of hospital days, rates of uncomplicated crises, time to first and second crises, rates of acute chest syndrome and Brief Pain Inventory questionnaire. Primary outcome data were processed via intention-to-treat analysis.
For high-dose crizanlizumab, there were a median 1.63 crises per year compared to 2.98 in the placebo group, representing a 45.3% lower rate (P = .01). The protective effect of crizanlizumab was more pronounced in the per-protocol analysis (1.04 crises per year for the high dose group). In the subgroup of patients on concomitant hydroxyurea, the median annualized crisis rate among high dose versus placebo was 2.43 compared to 3.58, representing a 32.1% lower rate. In the non-hydroxyurea subgroup, the median annualized crisis rate for high dose versus placebo was 1.0 vs. 2.0, representing a 50% lower rate. Secondary endpoints similarly trended in favor of crizanlizumab in a dose-dependent fashion, although statistical significance was mixed.
Bottom line: Crizanlizumab, a humanized monoclonal antibody that blocks the action of the endothelial adhesion molecule P-selectin, is promising as a novel medication to reduce frequency of vaso-occlusive crises in patients with HbS-related disease.
Citation: Ataga KI, Kutler A, Kanter J, et al. Crizanlizumab for prevention of pain crises in sickle cell disease. N Engl J Med. 2016 Dec. 3. doi: 10.1056/NEJMoa1611770.
DVT prophylaxis not needed after casting
Clinical question: Is DVT prophylaxis necessary with lower leg casting or after knee arthroscopy?
Background: Patients who undergo immobilization from casting or knee arthroscopic surgery are thought to be at increased risk for venous thromboembolism (VTE). Most patients who undergo orthopedic procedures receive thromboprophylaxis but controversy exists surrounding its use in low limb casting or knee arthroscopic surgery. Prior studies did not establish consensus because of methodologic weaknesses.
Study design: Two parallel randomized-controlled, open-label trials with blinded outcome (POD-KAST for knee arthroscopy and POD-CAST for casting lower leg.
Setting: International (32 pediatric intensive care units across Asia, Australia, Europe, and North America).
Synopsis: Patients were randomly assigned to receive either a prophylactic dose of low-molecular-weight heparin (either for the 8 days after arthroscopy or for the duration of casting-related immobilization) or no anticoagulant therapy. The primary outcomes were the cumulative incidences of symptomatic venous thromboembolism (VTE) and major bleeding within 3 months after the procedure. For the 1,543 patients undergoing knee arthroscopy, VTE occurred in 0.7% of the treatment group and 0.4% of the control group (relative risk, 1.6; 95% confidence interval [CI], 0.4-6.8; absolute difference in risk, 0.3 percentage points; 95% CI, −0.6 to 1.2) and major bleeding was seen in 0.1% of both groups.
For the 1,519 patients undergoing knee arthroscopy, VTE occurred in 1.4% of the treatment group and 1.8% of the control group (relative risk, 0.8; 95% CI, 0.3-1.7; absolute difference in risk, −0.4 percentage points; 95% CI, −1.8 to 1.0) and no episodes of major bleeding were reported in either group.
Bottom line: VTE prophylaxis either after arthroscopy or during immobilization from casting did not prevent DVT.
Citations: Van Adrichem RA, Nemeth B, Algra A, et al. Thromboprophylaxis after knee arthroscopy and low-leg casting. N Engl J Med. 2016 Dec 3. doi: 10.1056/NEJMoa1613303.
Dr. Cerceo is assistant professor in the division of hospital medicine, and associate director of the internal medicine residency program at Cooper Medical School of Rowan University, Camden, N.J.
Clinical question: Is DVT prophylaxis necessary with lower leg casting or after knee arthroscopy?
Background: Patients who undergo immobilization from casting or knee arthroscopic surgery are thought to be at increased risk for venous thromboembolism (VTE). Most patients who undergo orthopedic procedures receive thromboprophylaxis but controversy exists surrounding its use in low limb casting or knee arthroscopic surgery. Prior studies did not establish consensus because of methodologic weaknesses.
Study design: Two parallel randomized-controlled, open-label trials with blinded outcome (POD-KAST for knee arthroscopy and POD-CAST for casting lower leg.
Setting: International (32 pediatric intensive care units across Asia, Australia, Europe, and North America).
Synopsis: Patients were randomly assigned to receive either a prophylactic dose of low-molecular-weight heparin (either for the 8 days after arthroscopy or for the duration of casting-related immobilization) or no anticoagulant therapy. The primary outcomes were the cumulative incidences of symptomatic venous thromboembolism (VTE) and major bleeding within 3 months after the procedure. For the 1,543 patients undergoing knee arthroscopy, VTE occurred in 0.7% of the treatment group and 0.4% of the control group (relative risk, 1.6; 95% confidence interval [CI], 0.4-6.8; absolute difference in risk, 0.3 percentage points; 95% CI, −0.6 to 1.2) and major bleeding was seen in 0.1% of both groups.
For the 1,519 patients undergoing knee arthroscopy, VTE occurred in 1.4% of the treatment group and 1.8% of the control group (relative risk, 0.8; 95% CI, 0.3-1.7; absolute difference in risk, −0.4 percentage points; 95% CI, −1.8 to 1.0) and no episodes of major bleeding were reported in either group.
Bottom line: VTE prophylaxis either after arthroscopy or during immobilization from casting did not prevent DVT.
Citations: Van Adrichem RA, Nemeth B, Algra A, et al. Thromboprophylaxis after knee arthroscopy and low-leg casting. N Engl J Med. 2016 Dec 3. doi: 10.1056/NEJMoa1613303.
Dr. Cerceo is assistant professor in the division of hospital medicine, and associate director of the internal medicine residency program at Cooper Medical School of Rowan University, Camden, N.J.
Clinical question: Is DVT prophylaxis necessary with lower leg casting or after knee arthroscopy?
Background: Patients who undergo immobilization from casting or knee arthroscopic surgery are thought to be at increased risk for venous thromboembolism (VTE). Most patients who undergo orthopedic procedures receive thromboprophylaxis but controversy exists surrounding its use in low limb casting or knee arthroscopic surgery. Prior studies did not establish consensus because of methodologic weaknesses.
Study design: Two parallel randomized-controlled, open-label trials with blinded outcome (POD-KAST for knee arthroscopy and POD-CAST for casting lower leg.
Setting: International (32 pediatric intensive care units across Asia, Australia, Europe, and North America).
Synopsis: Patients were randomly assigned to receive either a prophylactic dose of low-molecular-weight heparin (either for the 8 days after arthroscopy or for the duration of casting-related immobilization) or no anticoagulant therapy. The primary outcomes were the cumulative incidences of symptomatic venous thromboembolism (VTE) and major bleeding within 3 months after the procedure. For the 1,543 patients undergoing knee arthroscopy, VTE occurred in 0.7% of the treatment group and 0.4% of the control group (relative risk, 1.6; 95% confidence interval [CI], 0.4-6.8; absolute difference in risk, 0.3 percentage points; 95% CI, −0.6 to 1.2) and major bleeding was seen in 0.1% of both groups.
For the 1,519 patients undergoing knee arthroscopy, VTE occurred in 1.4% of the treatment group and 1.8% of the control group (relative risk, 0.8; 95% CI, 0.3-1.7; absolute difference in risk, −0.4 percentage points; 95% CI, −1.8 to 1.0) and no episodes of major bleeding were reported in either group.
Bottom line: VTE prophylaxis either after arthroscopy or during immobilization from casting did not prevent DVT.
Citations: Van Adrichem RA, Nemeth B, Algra A, et al. Thromboprophylaxis after knee arthroscopy and low-leg casting. N Engl J Med. 2016 Dec 3. doi: 10.1056/NEJMoa1613303.
Dr. Cerceo is assistant professor in the division of hospital medicine, and associate director of the internal medicine residency program at Cooper Medical School of Rowan University, Camden, N.J.
Long-term oxygen for COPD with moderate desaturation
Clinical question: Does using supplemental oxygen in patients with stable chronic obstructive pulmonary disease (COPD) result in a longer time to death or first hospitalization?
Background: Previous trials have shown that use of long-term, supplemental oxygen in COPD and severe resting hypoxia reduced mortality, however, data is inconclusive if its use in mild-moderate COPD has the same effect.
Study design: Parallel-group, randomized, unblinded clinical trial.
Synopsis: Researchers randomized 738 patients from 42 outpatient centers with stable COPD and moderate resting desaturation (SpO2, 89%-93%) or moderate exercise induced desaturation (6-minute walk test, SpO2 greater than 80% for five minutes, and greater than 90% for 10 seconds) to long-term supplemental oxygen or no supplemental oxygen. Time-to-event analysis found no differences in the composite primary outcome of death or first hospitalization (HR, 0.94; 95% confidence interval, 0.79-1.12), or in any other secondary outcomes of COPD exacerbations, or COPD-related or all-cause hospitalizations.
Limitations included lack of blinding, possible exclusion of patients with higher COPD severity, and lack of assessment of immediate effects of oxygen on symptoms or exercise performance.
Bottom line: Long-term, supplemental oxygen provided no benefit in mortality or time to first hospitalization among other outcomes in patients with stable COPD and resting or exercise-induced moderate desaturations.
Citation: The Long-Term Oxygen Treatment Trial Research Group. A randomized trial of long-term oxygen for COPD with moderate desaturation. N Engl J Med. 2016;375:1617-27.
Dr. Ciarkowski is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Clinical question: Does using supplemental oxygen in patients with stable chronic obstructive pulmonary disease (COPD) result in a longer time to death or first hospitalization?
Background: Previous trials have shown that use of long-term, supplemental oxygen in COPD and severe resting hypoxia reduced mortality, however, data is inconclusive if its use in mild-moderate COPD has the same effect.
Study design: Parallel-group, randomized, unblinded clinical trial.
Synopsis: Researchers randomized 738 patients from 42 outpatient centers with stable COPD and moderate resting desaturation (SpO2, 89%-93%) or moderate exercise induced desaturation (6-minute walk test, SpO2 greater than 80% for five minutes, and greater than 90% for 10 seconds) to long-term supplemental oxygen or no supplemental oxygen. Time-to-event analysis found no differences in the composite primary outcome of death or first hospitalization (HR, 0.94; 95% confidence interval, 0.79-1.12), or in any other secondary outcomes of COPD exacerbations, or COPD-related or all-cause hospitalizations.
Limitations included lack of blinding, possible exclusion of patients with higher COPD severity, and lack of assessment of immediate effects of oxygen on symptoms or exercise performance.
Bottom line: Long-term, supplemental oxygen provided no benefit in mortality or time to first hospitalization among other outcomes in patients with stable COPD and resting or exercise-induced moderate desaturations.
Citation: The Long-Term Oxygen Treatment Trial Research Group. A randomized trial of long-term oxygen for COPD with moderate desaturation. N Engl J Med. 2016;375:1617-27.
Dr. Ciarkowski is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.
Clinical question: Does using supplemental oxygen in patients with stable chronic obstructive pulmonary disease (COPD) result in a longer time to death or first hospitalization?
Background: Previous trials have shown that use of long-term, supplemental oxygen in COPD and severe resting hypoxia reduced mortality, however, data is inconclusive if its use in mild-moderate COPD has the same effect.
Study design: Parallel-group, randomized, unblinded clinical trial.
Synopsis: Researchers randomized 738 patients from 42 outpatient centers with stable COPD and moderate resting desaturation (SpO2, 89%-93%) or moderate exercise induced desaturation (6-minute walk test, SpO2 greater than 80% for five minutes, and greater than 90% for 10 seconds) to long-term supplemental oxygen or no supplemental oxygen. Time-to-event analysis found no differences in the composite primary outcome of death or first hospitalization (HR, 0.94; 95% confidence interval, 0.79-1.12), or in any other secondary outcomes of COPD exacerbations, or COPD-related or all-cause hospitalizations.
Limitations included lack of blinding, possible exclusion of patients with higher COPD severity, and lack of assessment of immediate effects of oxygen on symptoms or exercise performance.
Bottom line: Long-term, supplemental oxygen provided no benefit in mortality or time to first hospitalization among other outcomes in patients with stable COPD and resting or exercise-induced moderate desaturations.
Citation: The Long-Term Oxygen Treatment Trial Research Group. A randomized trial of long-term oxygen for COPD with moderate desaturation. N Engl J Med. 2016;375:1617-27.
Dr. Ciarkowski is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.