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Blood donation intervals of 8 weeks safe for most donors
Reducing the interval between blood donations from every 12 weeks to every 8 weeks increases blood units collected with little ill effects on donor quality of life other than symptoms related to iron deficiency, based on results reported by the INTERVAL Trial Group.
In the United States, men and women can donate blood every 8 weeks; the Food and Drug Administration and the AABB (formerly the American Association of Blood Banks) have considered lengthening the 8-week minimum inter-donation interval to reduce the risk of iron deficiency. The current practice in the United Kingdom is to allow men to donate every 12 weeks and women every 16 weeks, the authors noted.
The INTERVAL study examined hemoglobin levels, ferritin levels, and self-reported symptoms as well as the number of blood donations over a 2-year period among 22,466 men randomly assigned to either 8-, 10-, or 12-week blood donation intervals and 22,797 women randomly assigned to donation intervals of 12, 14, and 16 weeks.
Men in the 8-week interval group donated significantly more blood on a per-donor basis, contributing 1.69 and 7.9 units more than the men in the 10- and 12-week interval groups, respectively. Similarly, women in the 12-week interval group contributed approximately 0.84 and 0.46 units more than did women in the 14- and 16-week interval groups.
Hemoglobin and ferritin concentrations stayed relatively stable throughout the study in men and women in all donation interval groups. The baseline hemoglobin and ferritin averages were 149.7 g/L and 44.9 mcg/L in men, and 133.9 g/L and 24.6 mcg/L in women, respectively. Ultimately, mean hemoglobin level decreased by 1%-2%. Ferritin level decreased by 15%-30%, indicating that it is a more accurate marker of iron depletion, the study authors wrote. The report was published online in The Lancet.
The researchers also analyzed self-reported symptoms associated with blood donations derived from donor follow-up surveys sent at 6-, 12-, and 18-month intervals. At the end of the 2-year study, donors underwent a series of cognitive function tests and answered a physical activity questionnaire. Increased donation rates correlated with increased symptoms of iron deficiency such as tiredness, restless legs, and dizziness. This effect was reported more strongly in men.
About 10% of participants were allowed to donate despite having baseline hemoglobin concentrations below the minimum regulatory threshold, said the authors, who said that the screening method used in the United Kingdom to test eligibility to donate needs to be reviewed.
“In response to these findings, we have started the COMPARE study (ISRCTN90871183) to provide a systematic, within-person comparison of the relative merits of different haemoglobin screening methods,” they wrote
The study was funded by National Health Service Blood and Transplant and the National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024).
Donating blood serves an important function in medicine, but the practices associated with blood donations do not consider the effect it has on the donors. The amount of blood that most donors give is around 500 mL, or about 10% of total blood volume. The ratio of iron to blood is 1:1, meaning that for each milligram of blood drawn, one milligram of iron is lost. Considering that women only have 250 mg of iron reserves and men have 1,000 mg of reserves, many frequent donors are at risk of developing iron deficiency.
This study found that the total units of blood collected increased with shorter inter-donation intervals, while secondary safety outcomes of hemoglobin and ferritin levels remained similar between short and long inter-donation interval groups. While overall health did not decline, short inter-donation donors reported symptoms consistent with iron deficiency, including dizziness, tiredness, and restless legs. Researchers found that “about 25% of men and women at the most frequent inter-donation interval had iron deficiency and a third had at least one deferral for low hemoglobin.”
Iron deficiency can be mitigated by iron supplements or by lengthening the time between donations, but this does not fully correct the issue. Some blood centers have already introduced ferritin screening and lengthened the inter-donation interval for donors found to have low ferritin concentrations. Given the advances in automated laboratory testing, information technology, and the high compliance of blood donors, individualized approaches for prevention of iron deficiency could be feasible.
Alan E. Mast, MD , is the medical director for the Blood Center of Wisconsin, and an associate professor of pathology and cell biology at the Medical College of Wisconsin, Milwaukee. Edward L. Murphy, MD , is resident professor of laboratory medicine at University of California, San Francisco, and an affiliate of the Blood Systems Research Institute. They made their comments in an editorial that accompanied the study.
Donating blood serves an important function in medicine, but the practices associated with blood donations do not consider the effect it has on the donors. The amount of blood that most donors give is around 500 mL, or about 10% of total blood volume. The ratio of iron to blood is 1:1, meaning that for each milligram of blood drawn, one milligram of iron is lost. Considering that women only have 250 mg of iron reserves and men have 1,000 mg of reserves, many frequent donors are at risk of developing iron deficiency.
This study found that the total units of blood collected increased with shorter inter-donation intervals, while secondary safety outcomes of hemoglobin and ferritin levels remained similar between short and long inter-donation interval groups. While overall health did not decline, short inter-donation donors reported symptoms consistent with iron deficiency, including dizziness, tiredness, and restless legs. Researchers found that “about 25% of men and women at the most frequent inter-donation interval had iron deficiency and a third had at least one deferral for low hemoglobin.”
Iron deficiency can be mitigated by iron supplements or by lengthening the time between donations, but this does not fully correct the issue. Some blood centers have already introduced ferritin screening and lengthened the inter-donation interval for donors found to have low ferritin concentrations. Given the advances in automated laboratory testing, information technology, and the high compliance of blood donors, individualized approaches for prevention of iron deficiency could be feasible.
Alan E. Mast, MD , is the medical director for the Blood Center of Wisconsin, and an associate professor of pathology and cell biology at the Medical College of Wisconsin, Milwaukee. Edward L. Murphy, MD , is resident professor of laboratory medicine at University of California, San Francisco, and an affiliate of the Blood Systems Research Institute. They made their comments in an editorial that accompanied the study.
Donating blood serves an important function in medicine, but the practices associated with blood donations do not consider the effect it has on the donors. The amount of blood that most donors give is around 500 mL, or about 10% of total blood volume. The ratio of iron to blood is 1:1, meaning that for each milligram of blood drawn, one milligram of iron is lost. Considering that women only have 250 mg of iron reserves and men have 1,000 mg of reserves, many frequent donors are at risk of developing iron deficiency.
This study found that the total units of blood collected increased with shorter inter-donation intervals, while secondary safety outcomes of hemoglobin and ferritin levels remained similar between short and long inter-donation interval groups. While overall health did not decline, short inter-donation donors reported symptoms consistent with iron deficiency, including dizziness, tiredness, and restless legs. Researchers found that “about 25% of men and women at the most frequent inter-donation interval had iron deficiency and a third had at least one deferral for low hemoglobin.”
Iron deficiency can be mitigated by iron supplements or by lengthening the time between donations, but this does not fully correct the issue. Some blood centers have already introduced ferritin screening and lengthened the inter-donation interval for donors found to have low ferritin concentrations. Given the advances in automated laboratory testing, information technology, and the high compliance of blood donors, individualized approaches for prevention of iron deficiency could be feasible.
Alan E. Mast, MD , is the medical director for the Blood Center of Wisconsin, and an associate professor of pathology and cell biology at the Medical College of Wisconsin, Milwaukee. Edward L. Murphy, MD , is resident professor of laboratory medicine at University of California, San Francisco, and an affiliate of the Blood Systems Research Institute. They made their comments in an editorial that accompanied the study.
Reducing the interval between blood donations from every 12 weeks to every 8 weeks increases blood units collected with little ill effects on donor quality of life other than symptoms related to iron deficiency, based on results reported by the INTERVAL Trial Group.
In the United States, men and women can donate blood every 8 weeks; the Food and Drug Administration and the AABB (formerly the American Association of Blood Banks) have considered lengthening the 8-week minimum inter-donation interval to reduce the risk of iron deficiency. The current practice in the United Kingdom is to allow men to donate every 12 weeks and women every 16 weeks, the authors noted.
The INTERVAL study examined hemoglobin levels, ferritin levels, and self-reported symptoms as well as the number of blood donations over a 2-year period among 22,466 men randomly assigned to either 8-, 10-, or 12-week blood donation intervals and 22,797 women randomly assigned to donation intervals of 12, 14, and 16 weeks.
Men in the 8-week interval group donated significantly more blood on a per-donor basis, contributing 1.69 and 7.9 units more than the men in the 10- and 12-week interval groups, respectively. Similarly, women in the 12-week interval group contributed approximately 0.84 and 0.46 units more than did women in the 14- and 16-week interval groups.
Hemoglobin and ferritin concentrations stayed relatively stable throughout the study in men and women in all donation interval groups. The baseline hemoglobin and ferritin averages were 149.7 g/L and 44.9 mcg/L in men, and 133.9 g/L and 24.6 mcg/L in women, respectively. Ultimately, mean hemoglobin level decreased by 1%-2%. Ferritin level decreased by 15%-30%, indicating that it is a more accurate marker of iron depletion, the study authors wrote. The report was published online in The Lancet.
The researchers also analyzed self-reported symptoms associated with blood donations derived from donor follow-up surveys sent at 6-, 12-, and 18-month intervals. At the end of the 2-year study, donors underwent a series of cognitive function tests and answered a physical activity questionnaire. Increased donation rates correlated with increased symptoms of iron deficiency such as tiredness, restless legs, and dizziness. This effect was reported more strongly in men.
About 10% of participants were allowed to donate despite having baseline hemoglobin concentrations below the minimum regulatory threshold, said the authors, who said that the screening method used in the United Kingdom to test eligibility to donate needs to be reviewed.
“In response to these findings, we have started the COMPARE study (ISRCTN90871183) to provide a systematic, within-person comparison of the relative merits of different haemoglobin screening methods,” they wrote
The study was funded by National Health Service Blood and Transplant and the National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024).
Reducing the interval between blood donations from every 12 weeks to every 8 weeks increases blood units collected with little ill effects on donor quality of life other than symptoms related to iron deficiency, based on results reported by the INTERVAL Trial Group.
In the United States, men and women can donate blood every 8 weeks; the Food and Drug Administration and the AABB (formerly the American Association of Blood Banks) have considered lengthening the 8-week minimum inter-donation interval to reduce the risk of iron deficiency. The current practice in the United Kingdom is to allow men to donate every 12 weeks and women every 16 weeks, the authors noted.
The INTERVAL study examined hemoglobin levels, ferritin levels, and self-reported symptoms as well as the number of blood donations over a 2-year period among 22,466 men randomly assigned to either 8-, 10-, or 12-week blood donation intervals and 22,797 women randomly assigned to donation intervals of 12, 14, and 16 weeks.
Men in the 8-week interval group donated significantly more blood on a per-donor basis, contributing 1.69 and 7.9 units more than the men in the 10- and 12-week interval groups, respectively. Similarly, women in the 12-week interval group contributed approximately 0.84 and 0.46 units more than did women in the 14- and 16-week interval groups.
Hemoglobin and ferritin concentrations stayed relatively stable throughout the study in men and women in all donation interval groups. The baseline hemoglobin and ferritin averages were 149.7 g/L and 44.9 mcg/L in men, and 133.9 g/L and 24.6 mcg/L in women, respectively. Ultimately, mean hemoglobin level decreased by 1%-2%. Ferritin level decreased by 15%-30%, indicating that it is a more accurate marker of iron depletion, the study authors wrote. The report was published online in The Lancet.
The researchers also analyzed self-reported symptoms associated with blood donations derived from donor follow-up surveys sent at 6-, 12-, and 18-month intervals. At the end of the 2-year study, donors underwent a series of cognitive function tests and answered a physical activity questionnaire. Increased donation rates correlated with increased symptoms of iron deficiency such as tiredness, restless legs, and dizziness. This effect was reported more strongly in men.
About 10% of participants were allowed to donate despite having baseline hemoglobin concentrations below the minimum regulatory threshold, said the authors, who said that the screening method used in the United Kingdom to test eligibility to donate needs to be reviewed.
“In response to these findings, we have started the COMPARE study (ISRCTN90871183) to provide a systematic, within-person comparison of the relative merits of different haemoglobin screening methods,” they wrote
The study was funded by National Health Service Blood and Transplant and the National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024).
FROM THE LANCET
Key clinical point:
Major finding: Reducing inter-donation intervals increases blood collections by 33% in men and 24% in women.
Data source: Parallel group, pragmatic, randomized trial of 22,466 men and 22,797 women from the 25 donor centers of National Health Service Blood and Transplant.
Disclosures: The study was funded by National Health Service Blood and Transplant and the National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics.
PVC phlebitis rates varied widely, depending on assessment tool
Rates of phlebitis associated with peripheral venous catheters (PVC) ranged from less than 1% to 34% depending on which assessment tool researchers used in a large cross-sectional study.
Rates also varied within individual instruments because they included several possible case definitions, Katarina Göransson, PhD, and her associates reported in Lancet Haematology. “We find it concerning that our study shows variation of the proportion of PVCs causing phlebitis both within and across the instruments investigated,” they wrote. “How to best measure phlebitis outcomes is still unclear, since no universally accepted instrument exists that has had rigorous testing. From a work environment and patient safety perspective, clinical staff engaged in PVC management should be aware of the absence of adequately validated instruments for phlebitis assessment.”
There are many tools to measure PVC-related phlebitis, but no consensus on which to use, and past studies have reported rates of anywhere from 2% to 62%. Hypothesizing that instrument variability contributed to this discrepancy, the researchers tested 17 instruments in 1,032 patients who had 1,175 PVCs placed at 12 inpatient units in Sweden. Eight tools used clinical definitions, seven used severity rating systems, and two used scoring systems (Lancet Haematol. 2017 doi: 10.1016/S2352-3026[17]30122-9).
Rates of PVC-induced phlebitis reached 12% (137 cases) when the researchers used case definition tools, up to 31% when they used scoring systems (P less than .0001), and up to 34% when they used severity rating systems (P less than .0001, compared with the 12% rate). “The proportion within instruments ranged from less than 1% to 28%,” they added. “We [also] identified face validity issues, such as use of indistinct or complex measurements and inconsistent measurements or definitions.”
The investigators did not perform a systematic review to identify these instruments, and they did not necessarily use the most recent versions, they noted. Nevertheless, the findings have direct implications for hospital quality control measures, which require using a single validated instrument over time to generate meaningful results, they said. Hence, the investigators recommended developing a joint research program to develop reliable measures of PVC-related adverse events and better support clinicians who are trying to decide whether to remove PVCs.
The investigators reported having no funding sources and no competing interests.
Rates of phlebitis associated with peripheral venous catheters (PVC) ranged from less than 1% to 34% depending on which assessment tool researchers used in a large cross-sectional study.
Rates also varied within individual instruments because they included several possible case definitions, Katarina Göransson, PhD, and her associates reported in Lancet Haematology. “We find it concerning that our study shows variation of the proportion of PVCs causing phlebitis both within and across the instruments investigated,” they wrote. “How to best measure phlebitis outcomes is still unclear, since no universally accepted instrument exists that has had rigorous testing. From a work environment and patient safety perspective, clinical staff engaged in PVC management should be aware of the absence of adequately validated instruments for phlebitis assessment.”
There are many tools to measure PVC-related phlebitis, but no consensus on which to use, and past studies have reported rates of anywhere from 2% to 62%. Hypothesizing that instrument variability contributed to this discrepancy, the researchers tested 17 instruments in 1,032 patients who had 1,175 PVCs placed at 12 inpatient units in Sweden. Eight tools used clinical definitions, seven used severity rating systems, and two used scoring systems (Lancet Haematol. 2017 doi: 10.1016/S2352-3026[17]30122-9).
Rates of PVC-induced phlebitis reached 12% (137 cases) when the researchers used case definition tools, up to 31% when they used scoring systems (P less than .0001), and up to 34% when they used severity rating systems (P less than .0001, compared with the 12% rate). “The proportion within instruments ranged from less than 1% to 28%,” they added. “We [also] identified face validity issues, such as use of indistinct or complex measurements and inconsistent measurements or definitions.”
The investigators did not perform a systematic review to identify these instruments, and they did not necessarily use the most recent versions, they noted. Nevertheless, the findings have direct implications for hospital quality control measures, which require using a single validated instrument over time to generate meaningful results, they said. Hence, the investigators recommended developing a joint research program to develop reliable measures of PVC-related adverse events and better support clinicians who are trying to decide whether to remove PVCs.
The investigators reported having no funding sources and no competing interests.
Rates of phlebitis associated with peripheral venous catheters (PVC) ranged from less than 1% to 34% depending on which assessment tool researchers used in a large cross-sectional study.
Rates also varied within individual instruments because they included several possible case definitions, Katarina Göransson, PhD, and her associates reported in Lancet Haematology. “We find it concerning that our study shows variation of the proportion of PVCs causing phlebitis both within and across the instruments investigated,” they wrote. “How to best measure phlebitis outcomes is still unclear, since no universally accepted instrument exists that has had rigorous testing. From a work environment and patient safety perspective, clinical staff engaged in PVC management should be aware of the absence of adequately validated instruments for phlebitis assessment.”
There are many tools to measure PVC-related phlebitis, but no consensus on which to use, and past studies have reported rates of anywhere from 2% to 62%. Hypothesizing that instrument variability contributed to this discrepancy, the researchers tested 17 instruments in 1,032 patients who had 1,175 PVCs placed at 12 inpatient units in Sweden. Eight tools used clinical definitions, seven used severity rating systems, and two used scoring systems (Lancet Haematol. 2017 doi: 10.1016/S2352-3026[17]30122-9).
Rates of PVC-induced phlebitis reached 12% (137 cases) when the researchers used case definition tools, up to 31% when they used scoring systems (P less than .0001), and up to 34% when they used severity rating systems (P less than .0001, compared with the 12% rate). “The proportion within instruments ranged from less than 1% to 28%,” they added. “We [also] identified face validity issues, such as use of indistinct or complex measurements and inconsistent measurements or definitions.”
The investigators did not perform a systematic review to identify these instruments, and they did not necessarily use the most recent versions, they noted. Nevertheless, the findings have direct implications for hospital quality control measures, which require using a single validated instrument over time to generate meaningful results, they said. Hence, the investigators recommended developing a joint research program to develop reliable measures of PVC-related adverse events and better support clinicians who are trying to decide whether to remove PVCs.
The investigators reported having no funding sources and no competing interests.
FROM LANCET HAEMATOLOGY
Key clinical point: Rates of PVC-induced phlebitis varied widely within and between assessment instruments.
Major finding: Rates were as high as 12% (137 cases) based on the case definition tools, up to 31% based on the scoring systems (P less than .0001), and up to 34% based on the severity rating systems (P less than .0001, compared with the case definition rate).
Data source: A cross-sectional study of 17 instruments used to identify phlebitis associated with peripheral venous catheters.
Disclosures: The investigators reported having no funding sources and no competing interests.
Massive blood transfusions increase risk with CRS/HIPEC
Massive allogenic blood transfusion during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) increased the risk of major complications and reduced overall survival in a review of 936 cases at St. George Hospital near Sydney, Australia.
CRS/HIPEC is a long, complex procedure for peritoneal carcinomatosis, pseudomyxoma peritonei, peritoneal mesothelioma, and other abdominal cancers. The abdomen is opened, the cancer is debulked as much as possible, and the cavity is filled with heated chemotherapy drugs. Because CRS/HIPEC often requires multivisceral resection and dissection in multiple abdominal regions, up to 77% of patients require intraoperative transfusions, and up to 37% require massive allogenic blood transfusions (MABT) with five or more units.
Blood transfusions are known to be associated with poorer cancer surgery outcomes, but their effect in CRS/HIPEC hasn’t been much studied, which is “surprising given the extent to which blood products are used in” the procedure, said investigators led by Akshat Saxena, MD, a surgeon at St. George Hospital (J Gastrointest Surg. 2017 May 30. doi: 10.1007/s11605-017-3444-8).
Based on their findings, the researchers concluded that “there is a real need to evaluate new strategies to reduce the rate of MABT during CRS/HIPEC.”
The procedures in the study were performed from 1996 to 2016. The in-hospital mortality rate was 0.3% in patients who did not have MABT but 4.4% among the 337 patients (36%) who did. Even after adjusting for confounders on multivariate analysis, including the fact that MABT patients had more extensive disease and longer surgeries, MABT significantly increased the risk of in-hospital mortality (relative risk, 7.72; P = .021). In patients requiring MABT had a 5-year survival of 5%. In patients not requiring MABT, 5-year survival was at 36%. The difference remained significant on multivariate analysis.
MABT patients also had twice the risk of life-threatening complications and complications requiring surgical, endoscopic, or radiological intervention (62% versus 30%; RR, 2.05; P less than .001). MABT patients were more likely to stay in the ICU for 4 or more days and in the hospital for 28 or more days.
Worse overall survival with MABT was driven at least in part by patients who had CRS/HIPEC for colorectal cancer peritoneal carcinomatosis and pseudomyxoma peritonei. MABT did not seem to contribute to lower survival in patients who had the procedure for appendiceal or ovarian cancer. “It seems that the impact of long-term immunomodulation induced by blood transfusion” – the suspected mechanism through which transfusions cause problems – “varies according to the disease subtype. This warrants further investigation,” the investigators said.
Several strategies have been tried to reduce the need for transfusions during CRS/HIPEC. The study team previously reported that preemptive clotting factor replacement helps. Others have had success with preemptive tranexamic acid and cryoprecipitate to address low serum fibrinogen levels during CRS/HIPEC. “Further evaluation of both these strategies is warranted,” the researchers said.
Funding source and disclosure information were not included in the study report.
Massive allogenic blood transfusion during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) increased the risk of major complications and reduced overall survival in a review of 936 cases at St. George Hospital near Sydney, Australia.
CRS/HIPEC is a long, complex procedure for peritoneal carcinomatosis, pseudomyxoma peritonei, peritoneal mesothelioma, and other abdominal cancers. The abdomen is opened, the cancer is debulked as much as possible, and the cavity is filled with heated chemotherapy drugs. Because CRS/HIPEC often requires multivisceral resection and dissection in multiple abdominal regions, up to 77% of patients require intraoperative transfusions, and up to 37% require massive allogenic blood transfusions (MABT) with five or more units.
Blood transfusions are known to be associated with poorer cancer surgery outcomes, but their effect in CRS/HIPEC hasn’t been much studied, which is “surprising given the extent to which blood products are used in” the procedure, said investigators led by Akshat Saxena, MD, a surgeon at St. George Hospital (J Gastrointest Surg. 2017 May 30. doi: 10.1007/s11605-017-3444-8).
Based on their findings, the researchers concluded that “there is a real need to evaluate new strategies to reduce the rate of MABT during CRS/HIPEC.”
The procedures in the study were performed from 1996 to 2016. The in-hospital mortality rate was 0.3% in patients who did not have MABT but 4.4% among the 337 patients (36%) who did. Even after adjusting for confounders on multivariate analysis, including the fact that MABT patients had more extensive disease and longer surgeries, MABT significantly increased the risk of in-hospital mortality (relative risk, 7.72; P = .021). In patients requiring MABT had a 5-year survival of 5%. In patients not requiring MABT, 5-year survival was at 36%. The difference remained significant on multivariate analysis.
MABT patients also had twice the risk of life-threatening complications and complications requiring surgical, endoscopic, or radiological intervention (62% versus 30%; RR, 2.05; P less than .001). MABT patients were more likely to stay in the ICU for 4 or more days and in the hospital for 28 or more days.
Worse overall survival with MABT was driven at least in part by patients who had CRS/HIPEC for colorectal cancer peritoneal carcinomatosis and pseudomyxoma peritonei. MABT did not seem to contribute to lower survival in patients who had the procedure for appendiceal or ovarian cancer. “It seems that the impact of long-term immunomodulation induced by blood transfusion” – the suspected mechanism through which transfusions cause problems – “varies according to the disease subtype. This warrants further investigation,” the investigators said.
Several strategies have been tried to reduce the need for transfusions during CRS/HIPEC. The study team previously reported that preemptive clotting factor replacement helps. Others have had success with preemptive tranexamic acid and cryoprecipitate to address low serum fibrinogen levels during CRS/HIPEC. “Further evaluation of both these strategies is warranted,” the researchers said.
Funding source and disclosure information were not included in the study report.
Massive allogenic blood transfusion during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) increased the risk of major complications and reduced overall survival in a review of 936 cases at St. George Hospital near Sydney, Australia.
CRS/HIPEC is a long, complex procedure for peritoneal carcinomatosis, pseudomyxoma peritonei, peritoneal mesothelioma, and other abdominal cancers. The abdomen is opened, the cancer is debulked as much as possible, and the cavity is filled with heated chemotherapy drugs. Because CRS/HIPEC often requires multivisceral resection and dissection in multiple abdominal regions, up to 77% of patients require intraoperative transfusions, and up to 37% require massive allogenic blood transfusions (MABT) with five or more units.
Blood transfusions are known to be associated with poorer cancer surgery outcomes, but their effect in CRS/HIPEC hasn’t been much studied, which is “surprising given the extent to which blood products are used in” the procedure, said investigators led by Akshat Saxena, MD, a surgeon at St. George Hospital (J Gastrointest Surg. 2017 May 30. doi: 10.1007/s11605-017-3444-8).
Based on their findings, the researchers concluded that “there is a real need to evaluate new strategies to reduce the rate of MABT during CRS/HIPEC.”
The procedures in the study were performed from 1996 to 2016. The in-hospital mortality rate was 0.3% in patients who did not have MABT but 4.4% among the 337 patients (36%) who did. Even after adjusting for confounders on multivariate analysis, including the fact that MABT patients had more extensive disease and longer surgeries, MABT significantly increased the risk of in-hospital mortality (relative risk, 7.72; P = .021). In patients requiring MABT had a 5-year survival of 5%. In patients not requiring MABT, 5-year survival was at 36%. The difference remained significant on multivariate analysis.
MABT patients also had twice the risk of life-threatening complications and complications requiring surgical, endoscopic, or radiological intervention (62% versus 30%; RR, 2.05; P less than .001). MABT patients were more likely to stay in the ICU for 4 or more days and in the hospital for 28 or more days.
Worse overall survival with MABT was driven at least in part by patients who had CRS/HIPEC for colorectal cancer peritoneal carcinomatosis and pseudomyxoma peritonei. MABT did not seem to contribute to lower survival in patients who had the procedure for appendiceal or ovarian cancer. “It seems that the impact of long-term immunomodulation induced by blood transfusion” – the suspected mechanism through which transfusions cause problems – “varies according to the disease subtype. This warrants further investigation,” the investigators said.
Several strategies have been tried to reduce the need for transfusions during CRS/HIPEC. The study team previously reported that preemptive clotting factor replacement helps. Others have had success with preemptive tranexamic acid and cryoprecipitate to address low serum fibrinogen levels during CRS/HIPEC. “Further evaluation of both these strategies is warranted,” the researchers said.
Funding source and disclosure information were not included in the study report.
FROM THE JOURNAL OF GASTROINTESTINAL SURGERY
Key clinical point:
Major finding: Even after adjusting for confounders, MABT significantly increased the risk of in-hospital mortality (RR, 7.72; P = .021).
Data source: A single institution review of 936 cases.
Disclosures: Funding source and disclosure information were not included in the study report.
Blood donor age, sex do not affect recipient survival
The age and sex of blood donors do not affect the recipient’s survival and do not need to be considered in blood allocation, according to a report published online April 24 in JAMA Internal Medicine.
A recent observational Canadian study suggested that blood from young donors and female donors increased the recipients’ risk of death – a finding which, if confirmed, would have immediate implications for medical practice.
A separate group of Scandinavian researchers attempted to replicate these findings by performing a retrospective cohort study using similar but more nuanced statistical methods. Gustaf Edgren, MD, PhD, of the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and his associates analyzed information collected on 968,264 patients over a 10-year period from a Swedish and Danish transfusion database.
In initial, unadjusted analyses, both extremes of age (young and old) and female sex in the donor were associated with reduced survival in the recipient. However, that association disappeared when the data were adjusted to account for the total number of transfusions a patient received, a marker of their severity of illness. The hazard ratio per transfusion from a donor younger than age 20 was 0.98, and the hazard ratio per transfusion from a female donor was 0.99. This pattern also occurred in sensitivity analyses, the investigators noted (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0890).
“When studying associations between ... transfusions with a particular characteristic and the risk of death in the recipient, [the] underlying disease severity ... may still confound the association. However, with meticulous adjustment for total number of transfusions, it should be possible to block the confounding effect of patient disease severity entirely,” they noted.
“We believe that, rather than reflecting true biologic effects, the Canadian results can be explained by residual confounding (i.e., that the observations resulted from incomplete adjustment for the number of transfusions),” Dr. Edgren and his associates said.
“In addition, we believe these data reinforce the importance of extreme caution in assessing epidemiologic analyses in this field, given the tremendous clinical and logistical implications of false-positive findings,” they added.
The findings of Edgren et al. provide reassurance regarding the safety of current transfusion practice.
They present a convincing argument that differences in the statistical approach for controlling confounding likely explained the discrepant results of the Canadian study and their study.
This subtle confounding stems from the fact that increased transfusions expose the recipient to a greater total number of blood products, which in turn is associated with higher comorbidity, greater severity of illness, and higher mortality.
Nareg Roubinian, MD, is at the Blood Systems Research Institute, San Francisco, and in the division of research at Kaiser Permanente Northern California, Oakland. He and his associates reported having no relevant financial disclosures. They made these remarks in an invited commentary accompanying Dr. Edgren’s report (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0914).
The findings of Edgren et al. provide reassurance regarding the safety of current transfusion practice.
They present a convincing argument that differences in the statistical approach for controlling confounding likely explained the discrepant results of the Canadian study and their study.
This subtle confounding stems from the fact that increased transfusions expose the recipient to a greater total number of blood products, which in turn is associated with higher comorbidity, greater severity of illness, and higher mortality.
Nareg Roubinian, MD, is at the Blood Systems Research Institute, San Francisco, and in the division of research at Kaiser Permanente Northern California, Oakland. He and his associates reported having no relevant financial disclosures. They made these remarks in an invited commentary accompanying Dr. Edgren’s report (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0914).
The findings of Edgren et al. provide reassurance regarding the safety of current transfusion practice.
They present a convincing argument that differences in the statistical approach for controlling confounding likely explained the discrepant results of the Canadian study and their study.
This subtle confounding stems from the fact that increased transfusions expose the recipient to a greater total number of blood products, which in turn is associated with higher comorbidity, greater severity of illness, and higher mortality.
Nareg Roubinian, MD, is at the Blood Systems Research Institute, San Francisco, and in the division of research at Kaiser Permanente Northern California, Oakland. He and his associates reported having no relevant financial disclosures. They made these remarks in an invited commentary accompanying Dr. Edgren’s report (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0914).
The age and sex of blood donors do not affect the recipient’s survival and do not need to be considered in blood allocation, according to a report published online April 24 in JAMA Internal Medicine.
A recent observational Canadian study suggested that blood from young donors and female donors increased the recipients’ risk of death – a finding which, if confirmed, would have immediate implications for medical practice.
A separate group of Scandinavian researchers attempted to replicate these findings by performing a retrospective cohort study using similar but more nuanced statistical methods. Gustaf Edgren, MD, PhD, of the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and his associates analyzed information collected on 968,264 patients over a 10-year period from a Swedish and Danish transfusion database.
In initial, unadjusted analyses, both extremes of age (young and old) and female sex in the donor were associated with reduced survival in the recipient. However, that association disappeared when the data were adjusted to account for the total number of transfusions a patient received, a marker of their severity of illness. The hazard ratio per transfusion from a donor younger than age 20 was 0.98, and the hazard ratio per transfusion from a female donor was 0.99. This pattern also occurred in sensitivity analyses, the investigators noted (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0890).
“When studying associations between ... transfusions with a particular characteristic and the risk of death in the recipient, [the] underlying disease severity ... may still confound the association. However, with meticulous adjustment for total number of transfusions, it should be possible to block the confounding effect of patient disease severity entirely,” they noted.
“We believe that, rather than reflecting true biologic effects, the Canadian results can be explained by residual confounding (i.e., that the observations resulted from incomplete adjustment for the number of transfusions),” Dr. Edgren and his associates said.
“In addition, we believe these data reinforce the importance of extreme caution in assessing epidemiologic analyses in this field, given the tremendous clinical and logistical implications of false-positive findings,” they added.
The age and sex of blood donors do not affect the recipient’s survival and do not need to be considered in blood allocation, according to a report published online April 24 in JAMA Internal Medicine.
A recent observational Canadian study suggested that blood from young donors and female donors increased the recipients’ risk of death – a finding which, if confirmed, would have immediate implications for medical practice.
A separate group of Scandinavian researchers attempted to replicate these findings by performing a retrospective cohort study using similar but more nuanced statistical methods. Gustaf Edgren, MD, PhD, of the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and his associates analyzed information collected on 968,264 patients over a 10-year period from a Swedish and Danish transfusion database.
In initial, unadjusted analyses, both extremes of age (young and old) and female sex in the donor were associated with reduced survival in the recipient. However, that association disappeared when the data were adjusted to account for the total number of transfusions a patient received, a marker of their severity of illness. The hazard ratio per transfusion from a donor younger than age 20 was 0.98, and the hazard ratio per transfusion from a female donor was 0.99. This pattern also occurred in sensitivity analyses, the investigators noted (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0890).
“When studying associations between ... transfusions with a particular characteristic and the risk of death in the recipient, [the] underlying disease severity ... may still confound the association. However, with meticulous adjustment for total number of transfusions, it should be possible to block the confounding effect of patient disease severity entirely,” they noted.
“We believe that, rather than reflecting true biologic effects, the Canadian results can be explained by residual confounding (i.e., that the observations resulted from incomplete adjustment for the number of transfusions),” Dr. Edgren and his associates said.
“In addition, we believe these data reinforce the importance of extreme caution in assessing epidemiologic analyses in this field, given the tremendous clinical and logistical implications of false-positive findings,” they added.
Key clinical point: The age and sex of blood donors do not affect the recipient’s survival and do not need to be considered in blood allocation.
Major finding: The hazard ratio per transfusion from a donor younger than age 20 was 0.98, and the hazard ratio per transfusion from a female donor was 0.99.
Data source: A retrospective cohort study involving 968,264 transfusion recipients in Sweden and Denmark during a 10-year period.
Disclosures: The Swedish Research Council, the Swedish Heart-Lung Foundation, the Swedish Society for Medical Research, Karolinska Institutet’s Strategic Research Program, and the Danish Council for Independent Research supported the study. Dr. Edgren and his associates reported having no relevant financial disclosures.
Promising ibrutinib data prompt frontline cGVHD therapy study
ORLANDO – Ibrutinib was associated with clinically meaningful and durable responses in patients with chronic graft-versus-host disease that did not respond to frontline systemic therapy, based on the final results of a phase II study.
Preliminary findings from that study led in 2016 to a Food and Drug Administration Breakthrough Therapy Designation for ibrutinib for chronic graft-versus-host disease (cGVHD) after the failure of one or more lines of systemic therapy, and the responses seen in this pretreated, high-risk population support the study of ibrutinib for frontline treatment of cGVHD, said David Miklos, MD, of Stanford (Calif.) University.
Of 20 patients with multiple organ involvement, 25 (80%) had responses in at least two organs, and of 9 patients with three or more involved organs, 5 (56%) had responses in at least three organs, he reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation..
“We think that the responses across different organ involvement as well as multiple organ responses speaks to the underlying impact of ibrutinib on the pathogenic pathway and not to masking symptoms or indirect effect,” he said.
The median steroid dose among responders decreased from 0.29 mg/kg daily at baseline to 0.19 mg/kg daily and 0.12 mg/kg daily at weeks 25 and 49, respectively. Overall, 62% of all patients reached steroid doses less than 0.15 mg/kg daily, and five responders discontinued steroid treatment.
“Patients also had clinically meaningful improvement as assessed by the Lee symptoms scale,” he said, noting that scores improved in 61% of responders and 11% of nonresponders.
Study participants had a median age of 56 years and a median of 7.6 months from allogeneic transplant to diagnosis of cGVHD. All had been treated with up to three prior cGVHD regimens (median, two) and had either a rash that exceeded 25% of their body surface area or a National Institutes of Health consensus mouth score greater than 4. They were treated with ibrutinib at a dose of 420 mg/day until cGVHD progression or unacceptable toxicity. The cGVHD response – the primary endpoint of the study – was measured using 2005 NIH response criteria.
Adverse events occurring in at least 20% of patients included fatigue, diarrhea, muscle spasms, nausea, and bruising. Grade 3 or higher adverse events occurring in at least 10% of patients included pneumonia, fatigue, and diarrhea.
Serious adverse events occurred in 52% of patients. Grade 3 or higher serious adverse events occurred in 40% of patients and included pneumonia, septic shock, and pyrexia. Two fatal events were reported and included one case of multilobular pneumonia and one case of bronchopulmonary aspergillosis.
Twelve patients (29%) remained on ibrutinib at 14 months; Of those who discontinued therapy, 5 discontinued because of progressive cGVHD, and 14 because of adverse events.
Patients who have cGVHD and don’t respond to frontline therapy have previously had no effective options. Ibrutinib showed promise in preclinical models; it reduced the severity of cGVHD through inhibition of Bruton’s tyrosine kinase and interleukin-2–inducible T-cell kinase, Dr. Miklos explained, noting that both B and T cells play a role in the pathophysiology of cGVHD.
The findings from this phase II trial demonstrate that ibrutinib does indeed lead to durable improvement in this patient population, and its safety profile is consistent with that previously reported for B-cell malignancies treated with ibrutinib and for cGVHD patients treated with concomitant steroids, he said.
“We think the efficacy of ibrutinib in this population supports further study in frontline treatment of cGVHD in a randomized, double-blinded study,” he concluded.
A phase III study – the INTEGRATE clinical trial – is now open. The international study will compare ibrutinib and prednisone with placebo and prednisone as a frontline therapy for moderate and severe cGVHD with a primary endpoint of response rate at 24 weeks.
The study was sponsored by Pharmacyclics in collaboration with Janssen Research & Development. Dr. Miklos reported various financial relationships with Pharmacyclics (the maker of ibrutinib [Imbruvica]), Velos, Kite Pharma, Sanofi Oncology, Adaptive Biotechnologies, and Genentech.
sworcester@frontlinemedcom.com
ORLANDO – Ibrutinib was associated with clinically meaningful and durable responses in patients with chronic graft-versus-host disease that did not respond to frontline systemic therapy, based on the final results of a phase II study.
Preliminary findings from that study led in 2016 to a Food and Drug Administration Breakthrough Therapy Designation for ibrutinib for chronic graft-versus-host disease (cGVHD) after the failure of one or more lines of systemic therapy, and the responses seen in this pretreated, high-risk population support the study of ibrutinib for frontline treatment of cGVHD, said David Miklos, MD, of Stanford (Calif.) University.
Of 20 patients with multiple organ involvement, 25 (80%) had responses in at least two organs, and of 9 patients with three or more involved organs, 5 (56%) had responses in at least three organs, he reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation..
“We think that the responses across different organ involvement as well as multiple organ responses speaks to the underlying impact of ibrutinib on the pathogenic pathway and not to masking symptoms or indirect effect,” he said.
The median steroid dose among responders decreased from 0.29 mg/kg daily at baseline to 0.19 mg/kg daily and 0.12 mg/kg daily at weeks 25 and 49, respectively. Overall, 62% of all patients reached steroid doses less than 0.15 mg/kg daily, and five responders discontinued steroid treatment.
“Patients also had clinically meaningful improvement as assessed by the Lee symptoms scale,” he said, noting that scores improved in 61% of responders and 11% of nonresponders.
Study participants had a median age of 56 years and a median of 7.6 months from allogeneic transplant to diagnosis of cGVHD. All had been treated with up to three prior cGVHD regimens (median, two) and had either a rash that exceeded 25% of their body surface area or a National Institutes of Health consensus mouth score greater than 4. They were treated with ibrutinib at a dose of 420 mg/day until cGVHD progression or unacceptable toxicity. The cGVHD response – the primary endpoint of the study – was measured using 2005 NIH response criteria.
Adverse events occurring in at least 20% of patients included fatigue, diarrhea, muscle spasms, nausea, and bruising. Grade 3 or higher adverse events occurring in at least 10% of patients included pneumonia, fatigue, and diarrhea.
Serious adverse events occurred in 52% of patients. Grade 3 or higher serious adverse events occurred in 40% of patients and included pneumonia, septic shock, and pyrexia. Two fatal events were reported and included one case of multilobular pneumonia and one case of bronchopulmonary aspergillosis.
Twelve patients (29%) remained on ibrutinib at 14 months; Of those who discontinued therapy, 5 discontinued because of progressive cGVHD, and 14 because of adverse events.
Patients who have cGVHD and don’t respond to frontline therapy have previously had no effective options. Ibrutinib showed promise in preclinical models; it reduced the severity of cGVHD through inhibition of Bruton’s tyrosine kinase and interleukin-2–inducible T-cell kinase, Dr. Miklos explained, noting that both B and T cells play a role in the pathophysiology of cGVHD.
The findings from this phase II trial demonstrate that ibrutinib does indeed lead to durable improvement in this patient population, and its safety profile is consistent with that previously reported for B-cell malignancies treated with ibrutinib and for cGVHD patients treated with concomitant steroids, he said.
“We think the efficacy of ibrutinib in this population supports further study in frontline treatment of cGVHD in a randomized, double-blinded study,” he concluded.
A phase III study – the INTEGRATE clinical trial – is now open. The international study will compare ibrutinib and prednisone with placebo and prednisone as a frontline therapy for moderate and severe cGVHD with a primary endpoint of response rate at 24 weeks.
The study was sponsored by Pharmacyclics in collaboration with Janssen Research & Development. Dr. Miklos reported various financial relationships with Pharmacyclics (the maker of ibrutinib [Imbruvica]), Velos, Kite Pharma, Sanofi Oncology, Adaptive Biotechnologies, and Genentech.
sworcester@frontlinemedcom.com
ORLANDO – Ibrutinib was associated with clinically meaningful and durable responses in patients with chronic graft-versus-host disease that did not respond to frontline systemic therapy, based on the final results of a phase II study.
Preliminary findings from that study led in 2016 to a Food and Drug Administration Breakthrough Therapy Designation for ibrutinib for chronic graft-versus-host disease (cGVHD) after the failure of one or more lines of systemic therapy, and the responses seen in this pretreated, high-risk population support the study of ibrutinib for frontline treatment of cGVHD, said David Miklos, MD, of Stanford (Calif.) University.
Of 20 patients with multiple organ involvement, 25 (80%) had responses in at least two organs, and of 9 patients with three or more involved organs, 5 (56%) had responses in at least three organs, he reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation..
“We think that the responses across different organ involvement as well as multiple organ responses speaks to the underlying impact of ibrutinib on the pathogenic pathway and not to masking symptoms or indirect effect,” he said.
The median steroid dose among responders decreased from 0.29 mg/kg daily at baseline to 0.19 mg/kg daily and 0.12 mg/kg daily at weeks 25 and 49, respectively. Overall, 62% of all patients reached steroid doses less than 0.15 mg/kg daily, and five responders discontinued steroid treatment.
“Patients also had clinically meaningful improvement as assessed by the Lee symptoms scale,” he said, noting that scores improved in 61% of responders and 11% of nonresponders.
Study participants had a median age of 56 years and a median of 7.6 months from allogeneic transplant to diagnosis of cGVHD. All had been treated with up to three prior cGVHD regimens (median, two) and had either a rash that exceeded 25% of their body surface area or a National Institutes of Health consensus mouth score greater than 4. They were treated with ibrutinib at a dose of 420 mg/day until cGVHD progression or unacceptable toxicity. The cGVHD response – the primary endpoint of the study – was measured using 2005 NIH response criteria.
Adverse events occurring in at least 20% of patients included fatigue, diarrhea, muscle spasms, nausea, and bruising. Grade 3 or higher adverse events occurring in at least 10% of patients included pneumonia, fatigue, and diarrhea.
Serious adverse events occurred in 52% of patients. Grade 3 or higher serious adverse events occurred in 40% of patients and included pneumonia, septic shock, and pyrexia. Two fatal events were reported and included one case of multilobular pneumonia and one case of bronchopulmonary aspergillosis.
Twelve patients (29%) remained on ibrutinib at 14 months; Of those who discontinued therapy, 5 discontinued because of progressive cGVHD, and 14 because of adverse events.
Patients who have cGVHD and don’t respond to frontline therapy have previously had no effective options. Ibrutinib showed promise in preclinical models; it reduced the severity of cGVHD through inhibition of Bruton’s tyrosine kinase and interleukin-2–inducible T-cell kinase, Dr. Miklos explained, noting that both B and T cells play a role in the pathophysiology of cGVHD.
The findings from this phase II trial demonstrate that ibrutinib does indeed lead to durable improvement in this patient population, and its safety profile is consistent with that previously reported for B-cell malignancies treated with ibrutinib and for cGVHD patients treated with concomitant steroids, he said.
“We think the efficacy of ibrutinib in this population supports further study in frontline treatment of cGVHD in a randomized, double-blinded study,” he concluded.
A phase III study – the INTEGRATE clinical trial – is now open. The international study will compare ibrutinib and prednisone with placebo and prednisone as a frontline therapy for moderate and severe cGVHD with a primary endpoint of response rate at 24 weeks.
The study was sponsored by Pharmacyclics in collaboration with Janssen Research & Development. Dr. Miklos reported various financial relationships with Pharmacyclics (the maker of ibrutinib [Imbruvica]), Velos, Kite Pharma, Sanofi Oncology, Adaptive Biotechnologies, and Genentech.
sworcester@frontlinemedcom.com
AT THE 2017 BMT TANDEM MEETINGS
Key clinical point:
Major finding: At a median follow-up of 14 months, the overall response rate among 42 patients treated with ibrutinib for cGVHD was 67%, with a third of responders achieving a complete response.
Data source: A phase II study of 42 patients.
Disclosures: The study was sponsored by Pharmacyclics in collaboration with Janssen Research & Development. Dr. Miklos reported various financial relationships with Pharmacyclics (the maker of ibrutinib [Imbruvica]), Velos, Kite Pharma, Sanofi Oncology, Adaptive Biotechnologies, and Genentech.
Fewer post-transplant CMV infections with novel antiviral prophylaxis
ORLANDO – A first-in-class antiviral drug was safe and effective when used to prevent clinically significant cytomegalovirus infections in adults undergoing hematopoietic cell transplantation.
At 24 weeks post-transplant, 38% (122/325) of those receiving the novel antiviral letermovir were considered treatment failures, compared with 61% (103/170) of those receiving placebo (P less than .0001). All-cause mortality was 10% (n=32/325) for patients receiving letermovir and 16%, (n=27/170) for the placebo group (log rank two-sided P = 0.0317).
The study findings show that “we [can] prevent patients from getting CMV infections from the beginning of the transplant and that [result can] confer a mortality benefit,” lead author Francisco Marty, MD, said in an interview.
Dr. Marty said that letermovir has received fast-track status both from the Food and Drug Administration and from the European Medicines Agency.
HCT recipients who are CMV-positive but who do not have clinically significant disease are not preemptively treated in current practice. “Previously, there wasn’t a primary prevention strategy in bone marrow transplantation. When myelosuppressive drugs were tried such as ganciclovir, any benefit was offset by increased myelosuppression, with resulting increases in bacterial and fungal infections,” said Dr. Marty, professor of medicine at Harvard Medical School, Boston.
Letermovir was generally well-tolerated in the clinical trial; myelotoxicity and nephrotoxicity levels were comparable in patients receiving letermovir and placebo. Letermovir targets the terminase complex, which is a viral replication process specific to CMV and not otherwise present in humans. That fact may explain, in part, letermovir’s limited toxicity, Dr. Marty said. The primary outcome measure of the phase III randomized, double-blind, placebo-controlled trial was the stratum-adjusted proportion of patients who had clinically significant CMV at post-transplant week 24, examining only the patients in the trials who had no detectable CMV DNA at the time of randomization. If patients did not complete the study, or had missing data at week 24, they were considered to have failed the trial.
Overall, 31% of patients were considered at high risk for CMV disease. Half of the patients received myeloablative conditioning, and about a third (35%) received antithymocyte globulin. Donor sources, whose characteristics were balanced between study arms, included 14% mismatched unrelated donors, 13% haploidentical donors, and 4% cord blood.
The multinational study’s 24-week results were presented at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.
“This was an international study, conducted at multiple sites in multiple countries. We used two-to-one randomization, and stratified participants by their risk of CMV disease and by study sites. We wanted to make sure the groups were balanced by disease risk and by study sites, to account for regional variations in bone marrow transplant procedures and CMV treatment patterns,” said Dr. Marty.
For the study, clinically significant CMV infection was defined as either CMV disease, such as pneumonia, colitis, or hepatitis, or CMV viremia that would trigger preemptive treatment.
Letermovir, which can be administered orally or intravenously, was dosed at 480 mg per day. Because of the risk for a drug-drug interaction, patients on cyclosporine received 240 mg of letermovir per day. Having intravenous dosing as an option helped patients who were not tolerating oral intake to stay on the study drug during the post-transplant period, he said.
The study drug was begun a median of 9 days post-transplant. Some patients received letermovir or placebo as early as the day of transplant; all patients began the study drug by 28 days post-transplant. The study drug was continued through week 14, or until at least 100 days post-transplant. Overall, 37% of patients had engrafted at the time they began the study drug.
Patients had weekly serum CMV assays performed until week 14, with biweekly sampling done through week 24. If patients developed clinically significant CMV, or if their serum samples yielded CMV DNA warranting preemptive treatment, they discontinued the study drug and began treatment for CMV.
The safety analysis, which was carried through week 48, tracked adverse events from the first dose of study drug until 14 days after discontinuation. Adverse events that were more common with letermovir than placebo included vomiting (19% versus 14%), edema (15% versus 9%), atrial arrhythmias (10% versus 5%), and having alanine aspartate levels more than five times the upper limit of normal (4% versus 2%). Graft versus host disease occurred in 39% of patients in each group; diarrhea and nausea occurred in approximately one fourth of patients in each group.
In response to a question after the presentation, Dr. Marty said, “The higher the risk of CMV disease, the higher the benefit in terms of survival.” Answering another question, about who should receive letermovir. Dr. Marty replied, “Like acyclovir, we should give it during times of risk. And CMV risk is different for different populations. It’s a matter of managing risks and benefits.”
Though letermovir was safe and well-tolerated in this trial, it’s different from acyclovir in that “it’s not a one dollar a day drug,” Dr. Marty acknowledged.
Merck, which plans to market letermovir, was the sponsor of the study and plans to submit applications for approval in both the United States and in the European Union in 2017. Dr. Marty reported receiving research grants from Merck as well as Astellas, Chimerix, and Shire. Additionally, he has received honoraria from Alexion, Chimerix, LFB, Merck, Roche Molecular Diagnostics, and Shire.
This article was updated 2/27/17.
koakes@frontlinemedcom.com
On Twitter @karioakes
ORLANDO – A first-in-class antiviral drug was safe and effective when used to prevent clinically significant cytomegalovirus infections in adults undergoing hematopoietic cell transplantation.
At 24 weeks post-transplant, 38% (122/325) of those receiving the novel antiviral letermovir were considered treatment failures, compared with 61% (103/170) of those receiving placebo (P less than .0001). All-cause mortality was 10% (n=32/325) for patients receiving letermovir and 16%, (n=27/170) for the placebo group (log rank two-sided P = 0.0317).
The study findings show that “we [can] prevent patients from getting CMV infections from the beginning of the transplant and that [result can] confer a mortality benefit,” lead author Francisco Marty, MD, said in an interview.
Dr. Marty said that letermovir has received fast-track status both from the Food and Drug Administration and from the European Medicines Agency.
HCT recipients who are CMV-positive but who do not have clinically significant disease are not preemptively treated in current practice. “Previously, there wasn’t a primary prevention strategy in bone marrow transplantation. When myelosuppressive drugs were tried such as ganciclovir, any benefit was offset by increased myelosuppression, with resulting increases in bacterial and fungal infections,” said Dr. Marty, professor of medicine at Harvard Medical School, Boston.
Letermovir was generally well-tolerated in the clinical trial; myelotoxicity and nephrotoxicity levels were comparable in patients receiving letermovir and placebo. Letermovir targets the terminase complex, which is a viral replication process specific to CMV and not otherwise present in humans. That fact may explain, in part, letermovir’s limited toxicity, Dr. Marty said. The primary outcome measure of the phase III randomized, double-blind, placebo-controlled trial was the stratum-adjusted proportion of patients who had clinically significant CMV at post-transplant week 24, examining only the patients in the trials who had no detectable CMV DNA at the time of randomization. If patients did not complete the study, or had missing data at week 24, they were considered to have failed the trial.
Overall, 31% of patients were considered at high risk for CMV disease. Half of the patients received myeloablative conditioning, and about a third (35%) received antithymocyte globulin. Donor sources, whose characteristics were balanced between study arms, included 14% mismatched unrelated donors, 13% haploidentical donors, and 4% cord blood.
The multinational study’s 24-week results were presented at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.
“This was an international study, conducted at multiple sites in multiple countries. We used two-to-one randomization, and stratified participants by their risk of CMV disease and by study sites. We wanted to make sure the groups were balanced by disease risk and by study sites, to account for regional variations in bone marrow transplant procedures and CMV treatment patterns,” said Dr. Marty.
For the study, clinically significant CMV infection was defined as either CMV disease, such as pneumonia, colitis, or hepatitis, or CMV viremia that would trigger preemptive treatment.
Letermovir, which can be administered orally or intravenously, was dosed at 480 mg per day. Because of the risk for a drug-drug interaction, patients on cyclosporine received 240 mg of letermovir per day. Having intravenous dosing as an option helped patients who were not tolerating oral intake to stay on the study drug during the post-transplant period, he said.
The study drug was begun a median of 9 days post-transplant. Some patients received letermovir or placebo as early as the day of transplant; all patients began the study drug by 28 days post-transplant. The study drug was continued through week 14, or until at least 100 days post-transplant. Overall, 37% of patients had engrafted at the time they began the study drug.
Patients had weekly serum CMV assays performed until week 14, with biweekly sampling done through week 24. If patients developed clinically significant CMV, or if their serum samples yielded CMV DNA warranting preemptive treatment, they discontinued the study drug and began treatment for CMV.
The safety analysis, which was carried through week 48, tracked adverse events from the first dose of study drug until 14 days after discontinuation. Adverse events that were more common with letermovir than placebo included vomiting (19% versus 14%), edema (15% versus 9%), atrial arrhythmias (10% versus 5%), and having alanine aspartate levels more than five times the upper limit of normal (4% versus 2%). Graft versus host disease occurred in 39% of patients in each group; diarrhea and nausea occurred in approximately one fourth of patients in each group.
In response to a question after the presentation, Dr. Marty said, “The higher the risk of CMV disease, the higher the benefit in terms of survival.” Answering another question, about who should receive letermovir. Dr. Marty replied, “Like acyclovir, we should give it during times of risk. And CMV risk is different for different populations. It’s a matter of managing risks and benefits.”
Though letermovir was safe and well-tolerated in this trial, it’s different from acyclovir in that “it’s not a one dollar a day drug,” Dr. Marty acknowledged.
Merck, which plans to market letermovir, was the sponsor of the study and plans to submit applications for approval in both the United States and in the European Union in 2017. Dr. Marty reported receiving research grants from Merck as well as Astellas, Chimerix, and Shire. Additionally, he has received honoraria from Alexion, Chimerix, LFB, Merck, Roche Molecular Diagnostics, and Shire.
This article was updated 2/27/17.
koakes@frontlinemedcom.com
On Twitter @karioakes
ORLANDO – A first-in-class antiviral drug was safe and effective when used to prevent clinically significant cytomegalovirus infections in adults undergoing hematopoietic cell transplantation.
At 24 weeks post-transplant, 38% (122/325) of those receiving the novel antiviral letermovir were considered treatment failures, compared with 61% (103/170) of those receiving placebo (P less than .0001). All-cause mortality was 10% (n=32/325) for patients receiving letermovir and 16%, (n=27/170) for the placebo group (log rank two-sided P = 0.0317).
The study findings show that “we [can] prevent patients from getting CMV infections from the beginning of the transplant and that [result can] confer a mortality benefit,” lead author Francisco Marty, MD, said in an interview.
Dr. Marty said that letermovir has received fast-track status both from the Food and Drug Administration and from the European Medicines Agency.
HCT recipients who are CMV-positive but who do not have clinically significant disease are not preemptively treated in current practice. “Previously, there wasn’t a primary prevention strategy in bone marrow transplantation. When myelosuppressive drugs were tried such as ganciclovir, any benefit was offset by increased myelosuppression, with resulting increases in bacterial and fungal infections,” said Dr. Marty, professor of medicine at Harvard Medical School, Boston.
Letermovir was generally well-tolerated in the clinical trial; myelotoxicity and nephrotoxicity levels were comparable in patients receiving letermovir and placebo. Letermovir targets the terminase complex, which is a viral replication process specific to CMV and not otherwise present in humans. That fact may explain, in part, letermovir’s limited toxicity, Dr. Marty said. The primary outcome measure of the phase III randomized, double-blind, placebo-controlled trial was the stratum-adjusted proportion of patients who had clinically significant CMV at post-transplant week 24, examining only the patients in the trials who had no detectable CMV DNA at the time of randomization. If patients did not complete the study, or had missing data at week 24, they were considered to have failed the trial.
Overall, 31% of patients were considered at high risk for CMV disease. Half of the patients received myeloablative conditioning, and about a third (35%) received antithymocyte globulin. Donor sources, whose characteristics were balanced between study arms, included 14% mismatched unrelated donors, 13% haploidentical donors, and 4% cord blood.
The multinational study’s 24-week results were presented at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.
“This was an international study, conducted at multiple sites in multiple countries. We used two-to-one randomization, and stratified participants by their risk of CMV disease and by study sites. We wanted to make sure the groups were balanced by disease risk and by study sites, to account for regional variations in bone marrow transplant procedures and CMV treatment patterns,” said Dr. Marty.
For the study, clinically significant CMV infection was defined as either CMV disease, such as pneumonia, colitis, or hepatitis, or CMV viremia that would trigger preemptive treatment.
Letermovir, which can be administered orally or intravenously, was dosed at 480 mg per day. Because of the risk for a drug-drug interaction, patients on cyclosporine received 240 mg of letermovir per day. Having intravenous dosing as an option helped patients who were not tolerating oral intake to stay on the study drug during the post-transplant period, he said.
The study drug was begun a median of 9 days post-transplant. Some patients received letermovir or placebo as early as the day of transplant; all patients began the study drug by 28 days post-transplant. The study drug was continued through week 14, or until at least 100 days post-transplant. Overall, 37% of patients had engrafted at the time they began the study drug.
Patients had weekly serum CMV assays performed until week 14, with biweekly sampling done through week 24. If patients developed clinically significant CMV, or if their serum samples yielded CMV DNA warranting preemptive treatment, they discontinued the study drug and began treatment for CMV.
The safety analysis, which was carried through week 48, tracked adverse events from the first dose of study drug until 14 days after discontinuation. Adverse events that were more common with letermovir than placebo included vomiting (19% versus 14%), edema (15% versus 9%), atrial arrhythmias (10% versus 5%), and having alanine aspartate levels more than five times the upper limit of normal (4% versus 2%). Graft versus host disease occurred in 39% of patients in each group; diarrhea and nausea occurred in approximately one fourth of patients in each group.
In response to a question after the presentation, Dr. Marty said, “The higher the risk of CMV disease, the higher the benefit in terms of survival.” Answering another question, about who should receive letermovir. Dr. Marty replied, “Like acyclovir, we should give it during times of risk. And CMV risk is different for different populations. It’s a matter of managing risks and benefits.”
Though letermovir was safe and well-tolerated in this trial, it’s different from acyclovir in that “it’s not a one dollar a day drug,” Dr. Marty acknowledged.
Merck, which plans to market letermovir, was the sponsor of the study and plans to submit applications for approval in both the United States and in the European Union in 2017. Dr. Marty reported receiving research grants from Merck as well as Astellas, Chimerix, and Shire. Additionally, he has received honoraria from Alexion, Chimerix, LFB, Merck, Roche Molecular Diagnostics, and Shire.
This article was updated 2/27/17.
koakes@frontlinemedcom.com
On Twitter @karioakes
AT THE 2017 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Cytomegalovirus (CMV) infection or viremia occurred in 38% of patients receiving post-HCT letermovir, compared with 61% of controls.
Data source: Randomized, double-blind, placebo-controlled study of 495 patients seropositive for CMV with no detectable CMV DNA at the time of HCT.
Disclosures: Merck, which plans to market letermovir, was the sponsor of the study. Dr. Marty reported receiving research grants from Merck as well as Astellas, Chimerix, and Shire. Additionally, he has received honoraria from Alexion, Chimerix, LFB, Merck, Roche Molecular Diagnostics, and Shire.
Incompatible Type A plasma found safe for initial resuscitation of trauma patients
HOLLYWOOD, FLA. – Incompatible Type A plasma appears to be a safe and effective part of an initial resuscitation protocol for trauma patients who need a massive transfusion.
There were no increases in morbidity, mortality, or transfusion-related acute lung injury among 120 patients who received Type A plasma, compared with those who got compatible plasma, Bryan C. Morse, MD, said at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.
Type AB blood products are preferred for initial transfusions for trauma patients with unknown blood type. While type AB blood products are universally acceptable to patients, they are also in short supply. In an attempt to mitigate this shortage, some trauma centers are relying on anecdotal data, much drawn from real-life combat experience dating from World War II to present times, suggesting that Type A plasma is safe for initial resuscitation protocols. But the body of data from well-constructed trials is small, said Dr. Morse of Emory University, Atlanta. Thus, EAST sponsored this retrospective registry study, which examined outcomes in 1,536 trauma patients who received plasma transfusions as part of a massive transfusion protocol from 2012 to 2016.
The primary endpoints were overall morbidity, and mortality at four time points: 6 and 24 hours, and 7 and 28 days. Eight trauma centers contributed data to the study.
The group was largely male (75%) with a mean age of 37 years. Patients were seriously injured, with a mean Injury Severity Score (ISS) of 25. About 60% suffered from blunt-force trauma. Among the entire group, 120 (8%) received incompatible type A plasma.
About 28% of patients (434) experienced an adverse event. These were numerically but not significantly more common among the incompatible A plasma group (35% vs. 28%; P = .14). Events included acute respiratory distress syndrome (6% vs. 7.6%), thromboembolism (9% vs. 7%), pneumonia (19% vs. 15%), and acute kidney injury (8% each).
There were two cases of transfusion-related acute lung injury, both of which occurred in the compatible type A group.
Mortality was similar at every time point: 6 hours (16% vs. 15%), 24 hours (25% vs. 22%), 7 days (35% vs. 32%), and 28 days (38% vs. 35%).
A multivariate regression model controlled for treatment center, ISS, units of packed red cells given by 4 hours, mechanism of injury, Type A plasma incompatibility, and age.
In the morbidity analysis, only ISS and units of red blood cells at 4 hours were associated with a significant increase in risk (odd ratio 1.02). Incompatible Type A plasma did not significantly increase the risk of morbidity.
In the mortality analysis, units of red cells, ISS, and age were significantly associated with increased risk. Again, incompatible Type A plasma did not significantly increase the risk of death.
Dr. Morse had no financial declaration.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
HOLLYWOOD, FLA. – Incompatible Type A plasma appears to be a safe and effective part of an initial resuscitation protocol for trauma patients who need a massive transfusion.
There were no increases in morbidity, mortality, or transfusion-related acute lung injury among 120 patients who received Type A plasma, compared with those who got compatible plasma, Bryan C. Morse, MD, said at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.
Type AB blood products are preferred for initial transfusions for trauma patients with unknown blood type. While type AB blood products are universally acceptable to patients, they are also in short supply. In an attempt to mitigate this shortage, some trauma centers are relying on anecdotal data, much drawn from real-life combat experience dating from World War II to present times, suggesting that Type A plasma is safe for initial resuscitation protocols. But the body of data from well-constructed trials is small, said Dr. Morse of Emory University, Atlanta. Thus, EAST sponsored this retrospective registry study, which examined outcomes in 1,536 trauma patients who received plasma transfusions as part of a massive transfusion protocol from 2012 to 2016.
The primary endpoints were overall morbidity, and mortality at four time points: 6 and 24 hours, and 7 and 28 days. Eight trauma centers contributed data to the study.
The group was largely male (75%) with a mean age of 37 years. Patients were seriously injured, with a mean Injury Severity Score (ISS) of 25. About 60% suffered from blunt-force trauma. Among the entire group, 120 (8%) received incompatible type A plasma.
About 28% of patients (434) experienced an adverse event. These were numerically but not significantly more common among the incompatible A plasma group (35% vs. 28%; P = .14). Events included acute respiratory distress syndrome (6% vs. 7.6%), thromboembolism (9% vs. 7%), pneumonia (19% vs. 15%), and acute kidney injury (8% each).
There were two cases of transfusion-related acute lung injury, both of which occurred in the compatible type A group.
Mortality was similar at every time point: 6 hours (16% vs. 15%), 24 hours (25% vs. 22%), 7 days (35% vs. 32%), and 28 days (38% vs. 35%).
A multivariate regression model controlled for treatment center, ISS, units of packed red cells given by 4 hours, mechanism of injury, Type A plasma incompatibility, and age.
In the morbidity analysis, only ISS and units of red blood cells at 4 hours were associated with a significant increase in risk (odd ratio 1.02). Incompatible Type A plasma did not significantly increase the risk of morbidity.
In the mortality analysis, units of red cells, ISS, and age were significantly associated with increased risk. Again, incompatible Type A plasma did not significantly increase the risk of death.
Dr. Morse had no financial declaration.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
HOLLYWOOD, FLA. – Incompatible Type A plasma appears to be a safe and effective part of an initial resuscitation protocol for trauma patients who need a massive transfusion.
There were no increases in morbidity, mortality, or transfusion-related acute lung injury among 120 patients who received Type A plasma, compared with those who got compatible plasma, Bryan C. Morse, MD, said at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.
Type AB blood products are preferred for initial transfusions for trauma patients with unknown blood type. While type AB blood products are universally acceptable to patients, they are also in short supply. In an attempt to mitigate this shortage, some trauma centers are relying on anecdotal data, much drawn from real-life combat experience dating from World War II to present times, suggesting that Type A plasma is safe for initial resuscitation protocols. But the body of data from well-constructed trials is small, said Dr. Morse of Emory University, Atlanta. Thus, EAST sponsored this retrospective registry study, which examined outcomes in 1,536 trauma patients who received plasma transfusions as part of a massive transfusion protocol from 2012 to 2016.
The primary endpoints were overall morbidity, and mortality at four time points: 6 and 24 hours, and 7 and 28 days. Eight trauma centers contributed data to the study.
The group was largely male (75%) with a mean age of 37 years. Patients were seriously injured, with a mean Injury Severity Score (ISS) of 25. About 60% suffered from blunt-force trauma. Among the entire group, 120 (8%) received incompatible type A plasma.
About 28% of patients (434) experienced an adverse event. These were numerically but not significantly more common among the incompatible A plasma group (35% vs. 28%; P = .14). Events included acute respiratory distress syndrome (6% vs. 7.6%), thromboembolism (9% vs. 7%), pneumonia (19% vs. 15%), and acute kidney injury (8% each).
There were two cases of transfusion-related acute lung injury, both of which occurred in the compatible type A group.
Mortality was similar at every time point: 6 hours (16% vs. 15%), 24 hours (25% vs. 22%), 7 days (35% vs. 32%), and 28 days (38% vs. 35%).
A multivariate regression model controlled for treatment center, ISS, units of packed red cells given by 4 hours, mechanism of injury, Type A plasma incompatibility, and age.
In the morbidity analysis, only ISS and units of red blood cells at 4 hours were associated with a significant increase in risk (odd ratio 1.02). Incompatible Type A plasma did not significantly increase the risk of morbidity.
In the mortality analysis, units of red cells, ISS, and age were significantly associated with increased risk. Again, incompatible Type A plasma did not significantly increase the risk of death.
Dr. Morse had no financial declaration.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
AT THE EAST SCIENTIFIC ASSEMBLY
Key clinical point:
Major finding: Adverse events were not significantly more common among the incompatible A plasma group (35% vs. 28%; P = .14).
Data source: The retrospective study comprised 1,536 patients.
Disclosures: Dr. Morse had no financial disclosures.
Increased death rate with platelets for aspirin/clopidogrel GI bleed
Patients with normal platelet counts who have a GI bleed while on antiplatelets were almost six times more likely to die in the hospital if they had a platelet transfusion in a retrospective cohort study from the Yale University in New Haven, Conn.
Ten of the 14 deaths in the 204 transfused patients – versus none of the 3 deaths in the 204 nontransfused patients - were due to bleeding, so it’s possible that the mortality difference was simply because patients with worse bleeding were more likely to get transfused. “On the other hand, the adjusted [odds ratios] for mortality (4.5-6.8 with different sensitivity analyses) [were] large, increasing the likelihood of a cause-and-effect relationship,” said investigators led by gastroenterologist Liam Zakko, MD, now at the Mayo Clinic in Rochester, Minn. (Clin Gastroenterol Hepatol. 2016 Jul 25. doi: 10.1016/j.cgh.2016.07.017).
Current guidelines suggest platelet transfusions are an option for antiplatelet patients with serious GI bleeds, but the Yale team found that they did not reduce rebleeding. “The observation of increased mortality without documentation of clinical benefit suggests a very cautious approach to the use of platelet transfusion. ... We do not support the use of platelet transfusions in patients with GI [bleeds] who are taking antiplatelet agents,” the investigators wrote.
Subjects in the two groups were matched for sex, age, and GI bleed location, and all had platelet counts above 100 × 109/L. Almost everyone was on aspirin for cardiovascular protection, and 30% were on also on clopidogrel.
Just over half in both groups had upper GI bleeds, and about 40% in each group had colonic bleeds. Transfused patients had more-severe bleeding, with overall lower blood pressure and lower hemoglobin; a larger proportion was admitted to the ICU.
On univariate analyses, platelet patients had more cardiovascular events (23% vs. 13%) while in the hospital. They were also more likely to stay in the hospital for more than 4 days (47% vs. 33%) and more likely to die while there (7% vs. 1%). On multivariable analysis, only the greater risk for death during admission remained statistically significant (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was not significant.
Four patients in the platelet group died from cardiovascular causes. One patient in the control group had a fatal cardiovascular event.
Although counterintuitive, the authors said that it’s possible that platelet transfusions might actually increase the risk of severe and fatal GI bleeding. “Mechanisms by which platelet transfusion would increase mortality or [GI bleeding]–related mortality are not clear,” but “platelet transfusions are reported to be proinflammatory and alter recipient immunity,” they said.
At least for now, “the most prudent way to manage patients on antiplatelet agents with [GI bleeding] is to follow current evidence-based recommendations,” including early endoscopy, endoscopic hemostatic therapy for high-risk lesions, and intensive proton pump inhibitor therapy in patients with ulcers and high-risk endoscopic features.
“Although not based on high-quality evidence, we believe that hemostatic techniques that do not cause significant tissue damage (e.g., clips rather than thermal devices or sclerosants) should be used in patients on antiplatelet agents, especially if patients are expected to remain on these agents in the future,” they said.
The mean age in the study was 74 years, and about two-thirds of the subjects were men.
The authors had no disclosures.
The management of patients with gastrointestinal bleeding on antithrombotic drugs is a major challenge for gastroenterologists. Unfortunately, the use of aspirin alone has been shown to increase the risk of GI bleed twofold, and the addition of a thienopyridine additionally increases the risk of bleeding twofold. Furthermore, there is no available agent to reverse antiplatelet affects of these drugs, which irreversibly block platelet function for the life of the platelet (8-10 days). Current recommendations for the management of severe GI bleeding in patients receiving antithrombotic therapy include platelet transfusion, including those with a normal platelet count. However, this comes with a price as reversal of platelet function may increase the rate of cardiovascular events.
Zakko et al. performed a retrospective case-control study evaluating the role of platelet transfusion in patients presenting with GI bleeding. Patients were matched by age, sex, and the location of the GI bleed. Most patients included in the study were on low-dose aspirin and almost a third of the patients were taking both aspirin and a thienopyridine. Patients receiving platelet transfusions appeared to have more severe GI bleeding compared with matched controls, as patients receiving transfusion were more likely to have been hypotensive, tachycardic, have a low hemoglobin level, and require treatment in the intensive care unit (72% vs. 28%, P less than .0001). Patients receiving platelet transfusions were also more likely than matched controls to have recurrent GI bleeding as well as major cardiovascular adverse events, including myocardial infarction and inpatient death. After adjusting for patient characteristics, patients receiving platelet transfusions were more likely to have an increased risk of death (adjusted OR, 5.57; 95% CI, 1.52-27.1). The authors conclude that “the use of platelet transfusions in patients with GI bleeding who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality.”
Currently, there is no convincing evidence to support platelet transfusion in patients with bleeding on aspirin and/or a thienopyridine. Because the majority of the deaths were due to GI bleeding and not cardiovascular events, the observed increase in adverse events in patients receiving platelet transfusions likely reflects more severe GI bleeding in patients receiving platelet transfusions than in controls. We should avoid platelet transfusions and focus our management on achieving adequate resuscitation, use of proton pump inhibitors for patients with high-risk ulcers, and early endoscopy with endoscopic therapy for high-risk lesions.
John R. Saltzman, MD, AGAF, is director of endoscopy, Brigham and Women’s Hospital, professor of medicine, Harvard Medical School, Boston. He has no conflicts of interest.
The management of patients with gastrointestinal bleeding on antithrombotic drugs is a major challenge for gastroenterologists. Unfortunately, the use of aspirin alone has been shown to increase the risk of GI bleed twofold, and the addition of a thienopyridine additionally increases the risk of bleeding twofold. Furthermore, there is no available agent to reverse antiplatelet affects of these drugs, which irreversibly block platelet function for the life of the platelet (8-10 days). Current recommendations for the management of severe GI bleeding in patients receiving antithrombotic therapy include platelet transfusion, including those with a normal platelet count. However, this comes with a price as reversal of platelet function may increase the rate of cardiovascular events.
Zakko et al. performed a retrospective case-control study evaluating the role of platelet transfusion in patients presenting with GI bleeding. Patients were matched by age, sex, and the location of the GI bleed. Most patients included in the study were on low-dose aspirin and almost a third of the patients were taking both aspirin and a thienopyridine. Patients receiving platelet transfusions appeared to have more severe GI bleeding compared with matched controls, as patients receiving transfusion were more likely to have been hypotensive, tachycardic, have a low hemoglobin level, and require treatment in the intensive care unit (72% vs. 28%, P less than .0001). Patients receiving platelet transfusions were also more likely than matched controls to have recurrent GI bleeding as well as major cardiovascular adverse events, including myocardial infarction and inpatient death. After adjusting for patient characteristics, patients receiving platelet transfusions were more likely to have an increased risk of death (adjusted OR, 5.57; 95% CI, 1.52-27.1). The authors conclude that “the use of platelet transfusions in patients with GI bleeding who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality.”
Currently, there is no convincing evidence to support platelet transfusion in patients with bleeding on aspirin and/or a thienopyridine. Because the majority of the deaths were due to GI bleeding and not cardiovascular events, the observed increase in adverse events in patients receiving platelet transfusions likely reflects more severe GI bleeding in patients receiving platelet transfusions than in controls. We should avoid platelet transfusions and focus our management on achieving adequate resuscitation, use of proton pump inhibitors for patients with high-risk ulcers, and early endoscopy with endoscopic therapy for high-risk lesions.
John R. Saltzman, MD, AGAF, is director of endoscopy, Brigham and Women’s Hospital, professor of medicine, Harvard Medical School, Boston. He has no conflicts of interest.
The management of patients with gastrointestinal bleeding on antithrombotic drugs is a major challenge for gastroenterologists. Unfortunately, the use of aspirin alone has been shown to increase the risk of GI bleed twofold, and the addition of a thienopyridine additionally increases the risk of bleeding twofold. Furthermore, there is no available agent to reverse antiplatelet affects of these drugs, which irreversibly block platelet function for the life of the platelet (8-10 days). Current recommendations for the management of severe GI bleeding in patients receiving antithrombotic therapy include platelet transfusion, including those with a normal platelet count. However, this comes with a price as reversal of platelet function may increase the rate of cardiovascular events.
Zakko et al. performed a retrospective case-control study evaluating the role of platelet transfusion in patients presenting with GI bleeding. Patients were matched by age, sex, and the location of the GI bleed. Most patients included in the study were on low-dose aspirin and almost a third of the patients were taking both aspirin and a thienopyridine. Patients receiving platelet transfusions appeared to have more severe GI bleeding compared with matched controls, as patients receiving transfusion were more likely to have been hypotensive, tachycardic, have a low hemoglobin level, and require treatment in the intensive care unit (72% vs. 28%, P less than .0001). Patients receiving platelet transfusions were also more likely than matched controls to have recurrent GI bleeding as well as major cardiovascular adverse events, including myocardial infarction and inpatient death. After adjusting for patient characteristics, patients receiving platelet transfusions were more likely to have an increased risk of death (adjusted OR, 5.57; 95% CI, 1.52-27.1). The authors conclude that “the use of platelet transfusions in patients with GI bleeding who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality.”
Currently, there is no convincing evidence to support platelet transfusion in patients with bleeding on aspirin and/or a thienopyridine. Because the majority of the deaths were due to GI bleeding and not cardiovascular events, the observed increase in adverse events in patients receiving platelet transfusions likely reflects more severe GI bleeding in patients receiving platelet transfusions than in controls. We should avoid platelet transfusions and focus our management on achieving adequate resuscitation, use of proton pump inhibitors for patients with high-risk ulcers, and early endoscopy with endoscopic therapy for high-risk lesions.
John R. Saltzman, MD, AGAF, is director of endoscopy, Brigham and Women’s Hospital, professor of medicine, Harvard Medical School, Boston. He has no conflicts of interest.
Patients with normal platelet counts who have a GI bleed while on antiplatelets were almost six times more likely to die in the hospital if they had a platelet transfusion in a retrospective cohort study from the Yale University in New Haven, Conn.
Ten of the 14 deaths in the 204 transfused patients – versus none of the 3 deaths in the 204 nontransfused patients - were due to bleeding, so it’s possible that the mortality difference was simply because patients with worse bleeding were more likely to get transfused. “On the other hand, the adjusted [odds ratios] for mortality (4.5-6.8 with different sensitivity analyses) [were] large, increasing the likelihood of a cause-and-effect relationship,” said investigators led by gastroenterologist Liam Zakko, MD, now at the Mayo Clinic in Rochester, Minn. (Clin Gastroenterol Hepatol. 2016 Jul 25. doi: 10.1016/j.cgh.2016.07.017).
Current guidelines suggest platelet transfusions are an option for antiplatelet patients with serious GI bleeds, but the Yale team found that they did not reduce rebleeding. “The observation of increased mortality without documentation of clinical benefit suggests a very cautious approach to the use of platelet transfusion. ... We do not support the use of platelet transfusions in patients with GI [bleeds] who are taking antiplatelet agents,” the investigators wrote.
Subjects in the two groups were matched for sex, age, and GI bleed location, and all had platelet counts above 100 × 109/L. Almost everyone was on aspirin for cardiovascular protection, and 30% were on also on clopidogrel.
Just over half in both groups had upper GI bleeds, and about 40% in each group had colonic bleeds. Transfused patients had more-severe bleeding, with overall lower blood pressure and lower hemoglobin; a larger proportion was admitted to the ICU.
On univariate analyses, platelet patients had more cardiovascular events (23% vs. 13%) while in the hospital. They were also more likely to stay in the hospital for more than 4 days (47% vs. 33%) and more likely to die while there (7% vs. 1%). On multivariable analysis, only the greater risk for death during admission remained statistically significant (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was not significant.
Four patients in the platelet group died from cardiovascular causes. One patient in the control group had a fatal cardiovascular event.
Although counterintuitive, the authors said that it’s possible that platelet transfusions might actually increase the risk of severe and fatal GI bleeding. “Mechanisms by which platelet transfusion would increase mortality or [GI bleeding]–related mortality are not clear,” but “platelet transfusions are reported to be proinflammatory and alter recipient immunity,” they said.
At least for now, “the most prudent way to manage patients on antiplatelet agents with [GI bleeding] is to follow current evidence-based recommendations,” including early endoscopy, endoscopic hemostatic therapy for high-risk lesions, and intensive proton pump inhibitor therapy in patients with ulcers and high-risk endoscopic features.
“Although not based on high-quality evidence, we believe that hemostatic techniques that do not cause significant tissue damage (e.g., clips rather than thermal devices or sclerosants) should be used in patients on antiplatelet agents, especially if patients are expected to remain on these agents in the future,” they said.
The mean age in the study was 74 years, and about two-thirds of the subjects were men.
The authors had no disclosures.
Patients with normal platelet counts who have a GI bleed while on antiplatelets were almost six times more likely to die in the hospital if they had a platelet transfusion in a retrospective cohort study from the Yale University in New Haven, Conn.
Ten of the 14 deaths in the 204 transfused patients – versus none of the 3 deaths in the 204 nontransfused patients - were due to bleeding, so it’s possible that the mortality difference was simply because patients with worse bleeding were more likely to get transfused. “On the other hand, the adjusted [odds ratios] for mortality (4.5-6.8 with different sensitivity analyses) [were] large, increasing the likelihood of a cause-and-effect relationship,” said investigators led by gastroenterologist Liam Zakko, MD, now at the Mayo Clinic in Rochester, Minn. (Clin Gastroenterol Hepatol. 2016 Jul 25. doi: 10.1016/j.cgh.2016.07.017).
Current guidelines suggest platelet transfusions are an option for antiplatelet patients with serious GI bleeds, but the Yale team found that they did not reduce rebleeding. “The observation of increased mortality without documentation of clinical benefit suggests a very cautious approach to the use of platelet transfusion. ... We do not support the use of platelet transfusions in patients with GI [bleeds] who are taking antiplatelet agents,” the investigators wrote.
Subjects in the two groups were matched for sex, age, and GI bleed location, and all had platelet counts above 100 × 109/L. Almost everyone was on aspirin for cardiovascular protection, and 30% were on also on clopidogrel.
Just over half in both groups had upper GI bleeds, and about 40% in each group had colonic bleeds. Transfused patients had more-severe bleeding, with overall lower blood pressure and lower hemoglobin; a larger proportion was admitted to the ICU.
On univariate analyses, platelet patients had more cardiovascular events (23% vs. 13%) while in the hospital. They were also more likely to stay in the hospital for more than 4 days (47% vs. 33%) and more likely to die while there (7% vs. 1%). On multivariable analysis, only the greater risk for death during admission remained statistically significant (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was not significant.
Four patients in the platelet group died from cardiovascular causes. One patient in the control group had a fatal cardiovascular event.
Although counterintuitive, the authors said that it’s possible that platelet transfusions might actually increase the risk of severe and fatal GI bleeding. “Mechanisms by which platelet transfusion would increase mortality or [GI bleeding]–related mortality are not clear,” but “platelet transfusions are reported to be proinflammatory and alter recipient immunity,” they said.
At least for now, “the most prudent way to manage patients on antiplatelet agents with [GI bleeding] is to follow current evidence-based recommendations,” including early endoscopy, endoscopic hemostatic therapy for high-risk lesions, and intensive proton pump inhibitor therapy in patients with ulcers and high-risk endoscopic features.
“Although not based on high-quality evidence, we believe that hemostatic techniques that do not cause significant tissue damage (e.g., clips rather than thermal devices or sclerosants) should be used in patients on antiplatelet agents, especially if patients are expected to remain on these agents in the future,” they said.
The mean age in the study was 74 years, and about two-thirds of the subjects were men.
The authors had no disclosures.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point:
Major finding: Compared with those not transfused, the risk for death during admission remained statistically significant on multivariate analysis (OR, 5.57; 95% CI, 1.52-27.1).
Data source: Retrospective cohort study of 408 GI bleed patients
Disclosures: The authors had no disclosures.
Mixed findings on iron repletion in HF
NEW ORLEANS – Oral iron supplementation was declared ineffective for the treatment of iron deficiency in patients with heart failure with reduced ejection fraction in one major randomized trial while intravenous ferric carboxymaltose improved exercise capacity and quality of life in another study presented at the American Heart Association scientific sessions.
Iron deficiency is present in roughly half of patients with heart failure with reduced ejection fraction (HFrEF). In affected patients it’s associated with diminished functional capacity and poor quality of life, and is an independent predictor of mortality. Thus, it has emerged as a potential therapeutic target in HFrEF.
The IRONOUT HF (Oral Iron Repletion Effects on Oxygen UpTake in Heart Failure) trial was a multicenter, randomized, double-blind, placebo-controlled clinical trial conducted by the National Heart, Lung, and Blood Institute’s Clinical Heart Failure Network investigators. It included 225 patients with HFrEF and iron deficiency who were randomized to 16 weeks of oral iron polysaccharide at 150 mg b.i.d. or matching placebo.
The primary endpoint was change from baseline to 16 weeks in exercise capacity, as measured via peak oxygen uptake during cardiopulmonary exercise testing. The results were no better in the iron-supplemented group than in placebo-treated controls. Nor was there any benefit for oral iron therapy in terms of quality of life, as assessed by the Kansas City Cardiomyopathy Questionnaire or any of numerous other secondary endpoints, according to Dr. Lewis, head of the heart failure section and director of the cardiopulmonary exercise testing laboratory at Massachusetts General Hospital, Boston.
Participants’ mean baseline hemoglobin level was 12.6 g/dL, but whether patients were anemic at baseline or not made no difference in terms of outcomes. Rates of venous congestion and bleeding were low during the trial.
The problem, the investigators found, was that high-dose oral iron only minimally repleted iron stores. Transferrin saturation increased by a paltry absolute 3% after 16 weeks of twice-daily therapy. Serum ferritin levels increased only 1/20th as much as after intravenous iron ferric carboxymaltose therapy in the earlier positive FAIR-HF (Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure) trial (N Engl J Med. 2009 Dec 17;361:2436-48).
Levels of hepcidin were elevated in study participants. And the higher the level of hepcidin – which Dr. Lewis called “a massive regulator of iron bioavailability and absorption” – the more refractory patients were to oral iron repletion.
“Hepcidin was invented by nature to protect against iron from stimulating growth of bacteria. And when it’s elevated, taking iron orally just has no chance of success,” explained Dr. Anker, professor of cardiology at the University of Gottingen (Germany).
Dr. Anker, who chaired the positive FAIR-HF trial of intravenous iron, said IRONOUT HF was a very well-conducted and definitive clinical trial of oral iron supplementation in HFrEF.
“It’s very simple: Oral iron does not work in patients with chronic heart failure. That’s the take home message. It’s true for peak VO2 [oxygen consumption], for 6-minute walk distance, for symptoms, for quality of life, and even for surrogate markers like NT-proBNP [N-terminal pro b-type natriuretic peptide]. If iron doesn’t get into the body, it’s really difficult to [imagine] that the iron that doesn’t get into the body can exert an effect,” he said.
The primary endpoint in EFFECT-HF was assessor-blinded change in peak VO2 from baseline to week 24. The control group experienced a decrease in peak VO2 over time such that there was a significant difference of 1.0 mL/kg per minute between the two groups.
The ferric carboxymaltose recipients also did significantly better in terms of secondary endpoints including improvement in New York Heart Association functional class, self-reported Patient Global Assessment score, and quality-of-life measures, reported Dr. van Veldhuisen, professor and chairman of cardiology at University Medical Center Groningen (the Netherlands).
Session moderator Clyde Yancy, MD, commented that intravenous iron is not ready for prime time use in clinical practice for several reasons. The open-label EFFECT-HF trial, like the earlier positive double-blind FAIR-HF and CONFIRM-HF IV ferric carboxymaltose trials, was too modest in size to be convincing, especially since this is an expensive and intrusive therapy.
“The endpoint of peak VO2, although a very powerful endpoint, is still one for which there may be some subjectivity, and so we need a more definitive endpoint to be absolutely certain about the potential benefit of the administration of ferric carboxymaltose,” said Dr. Yancy, professor of medicine and chief of cardiology at Northwestern University in Chicago.
Discussant Adrian Hernandez, MD, of the Duke Clinical Research Institute in Durham, N.C., said he considers peak VO2 an important endpoint.
“When you talk to patients, exercise capacity is an outcome that matters to them,” he said. “They often comment that what matters to them is living longer with a better quality of life, free of worsening heart failure, and having improvement in everyday functional status. So the cardiopulmonary exercise test is not just a surrogate endpoint; it’s a measure of functional outcome that matters to patients,” he said.
Still, like Dr. Yancy, Dr. Hernandez said he thinks it’s time to have larger, longer, definitive trials with clinical endpoints in order to understand the role of intravenous iron. Both cardiologists applauded Dr. Anker’s announcement that such a trial, known as FAIR-HF2, is now getting started.
The IRONOUT HF trial was funded by the National Institutes of Health. Dr. Lewis reported receiving research support from a handful of pharmaceutical and medical device companies. Dr. van Velduisen reported serving as a scientific adviser to Vifor Pharma, which sponsored the EFFECT-HF trial. Dr. Anker, who was an EFFECT-HF investigator, serves as a consultant to Vifor and several other companies. Dr. Hernandez was an IRONOUT HF investigator and reported receiving research grants from a handful of pharmaceutical companies.
NEW ORLEANS – Oral iron supplementation was declared ineffective for the treatment of iron deficiency in patients with heart failure with reduced ejection fraction in one major randomized trial while intravenous ferric carboxymaltose improved exercise capacity and quality of life in another study presented at the American Heart Association scientific sessions.
Iron deficiency is present in roughly half of patients with heart failure with reduced ejection fraction (HFrEF). In affected patients it’s associated with diminished functional capacity and poor quality of life, and is an independent predictor of mortality. Thus, it has emerged as a potential therapeutic target in HFrEF.
The IRONOUT HF (Oral Iron Repletion Effects on Oxygen UpTake in Heart Failure) trial was a multicenter, randomized, double-blind, placebo-controlled clinical trial conducted by the National Heart, Lung, and Blood Institute’s Clinical Heart Failure Network investigators. It included 225 patients with HFrEF and iron deficiency who were randomized to 16 weeks of oral iron polysaccharide at 150 mg b.i.d. or matching placebo.
The primary endpoint was change from baseline to 16 weeks in exercise capacity, as measured via peak oxygen uptake during cardiopulmonary exercise testing. The results were no better in the iron-supplemented group than in placebo-treated controls. Nor was there any benefit for oral iron therapy in terms of quality of life, as assessed by the Kansas City Cardiomyopathy Questionnaire or any of numerous other secondary endpoints, according to Dr. Lewis, head of the heart failure section and director of the cardiopulmonary exercise testing laboratory at Massachusetts General Hospital, Boston.
Participants’ mean baseline hemoglobin level was 12.6 g/dL, but whether patients were anemic at baseline or not made no difference in terms of outcomes. Rates of venous congestion and bleeding were low during the trial.
The problem, the investigators found, was that high-dose oral iron only minimally repleted iron stores. Transferrin saturation increased by a paltry absolute 3% after 16 weeks of twice-daily therapy. Serum ferritin levels increased only 1/20th as much as after intravenous iron ferric carboxymaltose therapy in the earlier positive FAIR-HF (Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure) trial (N Engl J Med. 2009 Dec 17;361:2436-48).
Levels of hepcidin were elevated in study participants. And the higher the level of hepcidin – which Dr. Lewis called “a massive regulator of iron bioavailability and absorption” – the more refractory patients were to oral iron repletion.
“Hepcidin was invented by nature to protect against iron from stimulating growth of bacteria. And when it’s elevated, taking iron orally just has no chance of success,” explained Dr. Anker, professor of cardiology at the University of Gottingen (Germany).
Dr. Anker, who chaired the positive FAIR-HF trial of intravenous iron, said IRONOUT HF was a very well-conducted and definitive clinical trial of oral iron supplementation in HFrEF.
“It’s very simple: Oral iron does not work in patients with chronic heart failure. That’s the take home message. It’s true for peak VO2 [oxygen consumption], for 6-minute walk distance, for symptoms, for quality of life, and even for surrogate markers like NT-proBNP [N-terminal pro b-type natriuretic peptide]. If iron doesn’t get into the body, it’s really difficult to [imagine] that the iron that doesn’t get into the body can exert an effect,” he said.
The primary endpoint in EFFECT-HF was assessor-blinded change in peak VO2 from baseline to week 24. The control group experienced a decrease in peak VO2 over time such that there was a significant difference of 1.0 mL/kg per minute between the two groups.
The ferric carboxymaltose recipients also did significantly better in terms of secondary endpoints including improvement in New York Heart Association functional class, self-reported Patient Global Assessment score, and quality-of-life measures, reported Dr. van Veldhuisen, professor and chairman of cardiology at University Medical Center Groningen (the Netherlands).
Session moderator Clyde Yancy, MD, commented that intravenous iron is not ready for prime time use in clinical practice for several reasons. The open-label EFFECT-HF trial, like the earlier positive double-blind FAIR-HF and CONFIRM-HF IV ferric carboxymaltose trials, was too modest in size to be convincing, especially since this is an expensive and intrusive therapy.
“The endpoint of peak VO2, although a very powerful endpoint, is still one for which there may be some subjectivity, and so we need a more definitive endpoint to be absolutely certain about the potential benefit of the administration of ferric carboxymaltose,” said Dr. Yancy, professor of medicine and chief of cardiology at Northwestern University in Chicago.
Discussant Adrian Hernandez, MD, of the Duke Clinical Research Institute in Durham, N.C., said he considers peak VO2 an important endpoint.
“When you talk to patients, exercise capacity is an outcome that matters to them,” he said. “They often comment that what matters to them is living longer with a better quality of life, free of worsening heart failure, and having improvement in everyday functional status. So the cardiopulmonary exercise test is not just a surrogate endpoint; it’s a measure of functional outcome that matters to patients,” he said.
Still, like Dr. Yancy, Dr. Hernandez said he thinks it’s time to have larger, longer, definitive trials with clinical endpoints in order to understand the role of intravenous iron. Both cardiologists applauded Dr. Anker’s announcement that such a trial, known as FAIR-HF2, is now getting started.
The IRONOUT HF trial was funded by the National Institutes of Health. Dr. Lewis reported receiving research support from a handful of pharmaceutical and medical device companies. Dr. van Velduisen reported serving as a scientific adviser to Vifor Pharma, which sponsored the EFFECT-HF trial. Dr. Anker, who was an EFFECT-HF investigator, serves as a consultant to Vifor and several other companies. Dr. Hernandez was an IRONOUT HF investigator and reported receiving research grants from a handful of pharmaceutical companies.
NEW ORLEANS – Oral iron supplementation was declared ineffective for the treatment of iron deficiency in patients with heart failure with reduced ejection fraction in one major randomized trial while intravenous ferric carboxymaltose improved exercise capacity and quality of life in another study presented at the American Heart Association scientific sessions.
Iron deficiency is present in roughly half of patients with heart failure with reduced ejection fraction (HFrEF). In affected patients it’s associated with diminished functional capacity and poor quality of life, and is an independent predictor of mortality. Thus, it has emerged as a potential therapeutic target in HFrEF.
The IRONOUT HF (Oral Iron Repletion Effects on Oxygen UpTake in Heart Failure) trial was a multicenter, randomized, double-blind, placebo-controlled clinical trial conducted by the National Heart, Lung, and Blood Institute’s Clinical Heart Failure Network investigators. It included 225 patients with HFrEF and iron deficiency who were randomized to 16 weeks of oral iron polysaccharide at 150 mg b.i.d. or matching placebo.
The primary endpoint was change from baseline to 16 weeks in exercise capacity, as measured via peak oxygen uptake during cardiopulmonary exercise testing. The results were no better in the iron-supplemented group than in placebo-treated controls. Nor was there any benefit for oral iron therapy in terms of quality of life, as assessed by the Kansas City Cardiomyopathy Questionnaire or any of numerous other secondary endpoints, according to Dr. Lewis, head of the heart failure section and director of the cardiopulmonary exercise testing laboratory at Massachusetts General Hospital, Boston.
Participants’ mean baseline hemoglobin level was 12.6 g/dL, but whether patients were anemic at baseline or not made no difference in terms of outcomes. Rates of venous congestion and bleeding were low during the trial.
The problem, the investigators found, was that high-dose oral iron only minimally repleted iron stores. Transferrin saturation increased by a paltry absolute 3% after 16 weeks of twice-daily therapy. Serum ferritin levels increased only 1/20th as much as after intravenous iron ferric carboxymaltose therapy in the earlier positive FAIR-HF (Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure) trial (N Engl J Med. 2009 Dec 17;361:2436-48).
Levels of hepcidin were elevated in study participants. And the higher the level of hepcidin – which Dr. Lewis called “a massive regulator of iron bioavailability and absorption” – the more refractory patients were to oral iron repletion.
“Hepcidin was invented by nature to protect against iron from stimulating growth of bacteria. And when it’s elevated, taking iron orally just has no chance of success,” explained Dr. Anker, professor of cardiology at the University of Gottingen (Germany).
Dr. Anker, who chaired the positive FAIR-HF trial of intravenous iron, said IRONOUT HF was a very well-conducted and definitive clinical trial of oral iron supplementation in HFrEF.
“It’s very simple: Oral iron does not work in patients with chronic heart failure. That’s the take home message. It’s true for peak VO2 [oxygen consumption], for 6-minute walk distance, for symptoms, for quality of life, and even for surrogate markers like NT-proBNP [N-terminal pro b-type natriuretic peptide]. If iron doesn’t get into the body, it’s really difficult to [imagine] that the iron that doesn’t get into the body can exert an effect,” he said.
The primary endpoint in EFFECT-HF was assessor-blinded change in peak VO2 from baseline to week 24. The control group experienced a decrease in peak VO2 over time such that there was a significant difference of 1.0 mL/kg per minute between the two groups.
The ferric carboxymaltose recipients also did significantly better in terms of secondary endpoints including improvement in New York Heart Association functional class, self-reported Patient Global Assessment score, and quality-of-life measures, reported Dr. van Veldhuisen, professor and chairman of cardiology at University Medical Center Groningen (the Netherlands).
Session moderator Clyde Yancy, MD, commented that intravenous iron is not ready for prime time use in clinical practice for several reasons. The open-label EFFECT-HF trial, like the earlier positive double-blind FAIR-HF and CONFIRM-HF IV ferric carboxymaltose trials, was too modest in size to be convincing, especially since this is an expensive and intrusive therapy.
“The endpoint of peak VO2, although a very powerful endpoint, is still one for which there may be some subjectivity, and so we need a more definitive endpoint to be absolutely certain about the potential benefit of the administration of ferric carboxymaltose,” said Dr. Yancy, professor of medicine and chief of cardiology at Northwestern University in Chicago.
Discussant Adrian Hernandez, MD, of the Duke Clinical Research Institute in Durham, N.C., said he considers peak VO2 an important endpoint.
“When you talk to patients, exercise capacity is an outcome that matters to them,” he said. “They often comment that what matters to them is living longer with a better quality of life, free of worsening heart failure, and having improvement in everyday functional status. So the cardiopulmonary exercise test is not just a surrogate endpoint; it’s a measure of functional outcome that matters to patients,” he said.
Still, like Dr. Yancy, Dr. Hernandez said he thinks it’s time to have larger, longer, definitive trials with clinical endpoints in order to understand the role of intravenous iron. Both cardiologists applauded Dr. Anker’s announcement that such a trial, known as FAIR-HF2, is now getting started.
The IRONOUT HF trial was funded by the National Institutes of Health. Dr. Lewis reported receiving research support from a handful of pharmaceutical and medical device companies. Dr. van Velduisen reported serving as a scientific adviser to Vifor Pharma, which sponsored the EFFECT-HF trial. Dr. Anker, who was an EFFECT-HF investigator, serves as a consultant to Vifor and several other companies. Dr. Hernandez was an IRONOUT HF investigator and reported receiving research grants from a handful of pharmaceutical companies.
EXPERT ANALYSIS FROM THE AHA SCIENTIFIC SESSIONS
HCT survivors experience high rates of late respiratory and infectious complications
Cancer survivors who underwent hematopoietic cell transplantation (HCT) face a greater risk for hospitalizations and mortality, compared with survivors who did not have HCT.
New findings show that disparities in infectious and respiratory complications were marked between the two groups, but differences in circulatory disease, mental health diagnoses, and second cancers were insignificant.
“Clinicians who care for long-term survivors of HCT should be aware of comprehensive surveillance guidelines available for this high-risk population,” wrote Eric J. Chow, MD, of the Fred Hutchinson Cancer Research Center, Seattle, and his colleagues (J Clin Oncol. 2016 Nov 21. doi: 10.1200/JCO.2016.68.8457).
There have only been a few comprehensive analyses that have compared HCT with non-HCT cancer survivors. Thus, the authors noted that it is unclear if HCT survivors are at a greater risk of late complications, compared with other cancer survivors.
To address this issue, Dr. Chow and his team matched 2-year cancer survivors who had undergone HCT (n = 1,792; 52% allogeneic and 90% hematologic malignancies) to non-HCT 2-year cancer survivors, using a state cancer registry (n = 5,455), and the general population (n = 16,340), using driver’s license files.
The investigators found that the 10-year cumulative incidence of any hospitalization or death related to all major organ-system outcomes was significantly different (P less than .05) between the HCT survivors and general population.
Patients with a history of HCT had a 30.6% cumulative incidence of infectious complications (difference vs. non-HCT: 8.7%) and a 26.8% incidence of any respiratory complications (difference vs. non-HCT: 6.9%), the investigators reported.
In contrast, the 10-year cumulative incidences of nervous system, circulatory, and genitourinary complications; mental health outcomes; and the development of new cancers did not differ between the HCT and non-HCT groups.
The incidence of pregnancy-related hospitalization among women of childbearing age was lower in the HCT group, compared with non-HCT patients (group difference, 24.4%).
At the 2-year endpoint, Dr. Chow and his associates noted that certain risks were “notably higher” in patients who had undergone HCT, including primary infections (hazard ratio, 1.4), respiratory complications (HR, 1.3), and death from any cause (HR, 1.1).
A significantly greater hospitalization rate also was observed in the HCT group versus the non-HCT group (280 episodes per 1,000 person-years vs. 173 episodes per 1,000 person years; P less than .001).
“Future work to identify more specific risk factors associated with late infections and respiratory complications may help to further refine these guidelines and identify new prevention strategies,” the authors concluded.
The study was funded by grants from the National Institutes of Health. Dr. Chow had no disclosures and several coauthors report relationships with industry.
Cancer survivors who underwent hematopoietic cell transplantation (HCT) face a greater risk for hospitalizations and mortality, compared with survivors who did not have HCT.
New findings show that disparities in infectious and respiratory complications were marked between the two groups, but differences in circulatory disease, mental health diagnoses, and second cancers were insignificant.
“Clinicians who care for long-term survivors of HCT should be aware of comprehensive surveillance guidelines available for this high-risk population,” wrote Eric J. Chow, MD, of the Fred Hutchinson Cancer Research Center, Seattle, and his colleagues (J Clin Oncol. 2016 Nov 21. doi: 10.1200/JCO.2016.68.8457).
There have only been a few comprehensive analyses that have compared HCT with non-HCT cancer survivors. Thus, the authors noted that it is unclear if HCT survivors are at a greater risk of late complications, compared with other cancer survivors.
To address this issue, Dr. Chow and his team matched 2-year cancer survivors who had undergone HCT (n = 1,792; 52% allogeneic and 90% hematologic malignancies) to non-HCT 2-year cancer survivors, using a state cancer registry (n = 5,455), and the general population (n = 16,340), using driver’s license files.
The investigators found that the 10-year cumulative incidence of any hospitalization or death related to all major organ-system outcomes was significantly different (P less than .05) between the HCT survivors and general population.
Patients with a history of HCT had a 30.6% cumulative incidence of infectious complications (difference vs. non-HCT: 8.7%) and a 26.8% incidence of any respiratory complications (difference vs. non-HCT: 6.9%), the investigators reported.
In contrast, the 10-year cumulative incidences of nervous system, circulatory, and genitourinary complications; mental health outcomes; and the development of new cancers did not differ between the HCT and non-HCT groups.
The incidence of pregnancy-related hospitalization among women of childbearing age was lower in the HCT group, compared with non-HCT patients (group difference, 24.4%).
At the 2-year endpoint, Dr. Chow and his associates noted that certain risks were “notably higher” in patients who had undergone HCT, including primary infections (hazard ratio, 1.4), respiratory complications (HR, 1.3), and death from any cause (HR, 1.1).
A significantly greater hospitalization rate also was observed in the HCT group versus the non-HCT group (280 episodes per 1,000 person-years vs. 173 episodes per 1,000 person years; P less than .001).
“Future work to identify more specific risk factors associated with late infections and respiratory complications may help to further refine these guidelines and identify new prevention strategies,” the authors concluded.
The study was funded by grants from the National Institutes of Health. Dr. Chow had no disclosures and several coauthors report relationships with industry.
Cancer survivors who underwent hematopoietic cell transplantation (HCT) face a greater risk for hospitalizations and mortality, compared with survivors who did not have HCT.
New findings show that disparities in infectious and respiratory complications were marked between the two groups, but differences in circulatory disease, mental health diagnoses, and second cancers were insignificant.
“Clinicians who care for long-term survivors of HCT should be aware of comprehensive surveillance guidelines available for this high-risk population,” wrote Eric J. Chow, MD, of the Fred Hutchinson Cancer Research Center, Seattle, and his colleagues (J Clin Oncol. 2016 Nov 21. doi: 10.1200/JCO.2016.68.8457).
There have only been a few comprehensive analyses that have compared HCT with non-HCT cancer survivors. Thus, the authors noted that it is unclear if HCT survivors are at a greater risk of late complications, compared with other cancer survivors.
To address this issue, Dr. Chow and his team matched 2-year cancer survivors who had undergone HCT (n = 1,792; 52% allogeneic and 90% hematologic malignancies) to non-HCT 2-year cancer survivors, using a state cancer registry (n = 5,455), and the general population (n = 16,340), using driver’s license files.
The investigators found that the 10-year cumulative incidence of any hospitalization or death related to all major organ-system outcomes was significantly different (P less than .05) between the HCT survivors and general population.
Patients with a history of HCT had a 30.6% cumulative incidence of infectious complications (difference vs. non-HCT: 8.7%) and a 26.8% incidence of any respiratory complications (difference vs. non-HCT: 6.9%), the investigators reported.
In contrast, the 10-year cumulative incidences of nervous system, circulatory, and genitourinary complications; mental health outcomes; and the development of new cancers did not differ between the HCT and non-HCT groups.
The incidence of pregnancy-related hospitalization among women of childbearing age was lower in the HCT group, compared with non-HCT patients (group difference, 24.4%).
At the 2-year endpoint, Dr. Chow and his associates noted that certain risks were “notably higher” in patients who had undergone HCT, including primary infections (hazard ratio, 1.4), respiratory complications (HR, 1.3), and death from any cause (HR, 1.1).
A significantly greater hospitalization rate also was observed in the HCT group versus the non-HCT group (280 episodes per 1,000 person-years vs. 173 episodes per 1,000 person years; P less than .001).
“Future work to identify more specific risk factors associated with late infections and respiratory complications may help to further refine these guidelines and identify new prevention strategies,” the authors concluded.
The study was funded by grants from the National Institutes of Health. Dr. Chow had no disclosures and several coauthors report relationships with industry.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Clinicians who care for HCT survivors should be aware of their high rates of late respiratory and infectious complications.
Major finding: Patients with a history of HCT had a 30.6% cumulative incidence of infectious complications (difference vs. non-HCT: 8.7%) and a 26.8% incidence of any respiratory complications (difference vs. non-HCT: 6.9%).
Data source: Retrospective population study using databases to match outcomes between two patient groups and the general population.
Disclosures: The study was funded by grants from the National Institutes of Health. Dr. Chow has no disclosures and several coauthors report relationships with industry.