User login
Bringing you the latest news, research and reviews, exclusive interviews, podcasts, quizzes, and more.
Powered by CHEST Physician, Clinician Reviews, MDedge Family Medicine, Internal Medicine News, and The Journal of Clinical Outcomes Management.
Severe Anaphylaxis in Children Predicts Biphasic Reactions
Children who present with a severe anaphylactic reaction are two to three times more likely to develop a second delayed, or late-phase, reaction, Dr. Waleed Alqurashi and his colleagues reported.
Their retrospective study found that of 484 children who came to the emergency department for anaphylaxis, 15% developed a biphasic reaction. Most of these (69%) were respiratory and/or cardiovascular; half required epinephrine (Ann. Allerg. Asth. Immunol. 2015 [doi.org/10.1016/j.anai.2015.05.013]).
Dr. Alqurashi of the pediatric department at the University of Ottawa and his associates identified five independent predictors of a biphasic reaction: age 6-9 years (odds ratio, 3.6); a delay in presentation of more than 90 minutes after the onset of the initial reaction (OR, 2.58); wide pulse pressure at triage (OR, 2.92); requiring more than one epinephrine dose for initial reaction (OR, 2.7); and needing inhaled beta-agonists at the ED (OR, 2.39).
Children with these characteristics should stay for observation, rather than being discharged when their initial reactions are stabilized, the authors wrote.
“This period should be individualized and based primarily on the degree of severity of the initial anaphylactic reaction. Given the relatively high sensitivity of the present predictors, children with mild anaphylaxis who do not match any of these predictors could be considered for early disposition from the ED (less than 6 hours timed from the onset of the anaphylactic reaction) as long as an appropriate counseling has been provided,” the investigators said. Nonetheless, Dr. Alqurashi and his associates think large-scale prospective pediatric studies are necessary to validate these predictors.
Dr Alqurashi and his associates have no financial disclosures.
Children who present with a severe anaphylactic reaction are two to three times more likely to develop a second delayed, or late-phase, reaction, Dr. Waleed Alqurashi and his colleagues reported.
Their retrospective study found that of 484 children who came to the emergency department for anaphylaxis, 15% developed a biphasic reaction. Most of these (69%) were respiratory and/or cardiovascular; half required epinephrine (Ann. Allerg. Asth. Immunol. 2015 [doi.org/10.1016/j.anai.2015.05.013]).
Dr. Alqurashi of the pediatric department at the University of Ottawa and his associates identified five independent predictors of a biphasic reaction: age 6-9 years (odds ratio, 3.6); a delay in presentation of more than 90 minutes after the onset of the initial reaction (OR, 2.58); wide pulse pressure at triage (OR, 2.92); requiring more than one epinephrine dose for initial reaction (OR, 2.7); and needing inhaled beta-agonists at the ED (OR, 2.39).
Children with these characteristics should stay for observation, rather than being discharged when their initial reactions are stabilized, the authors wrote.
“This period should be individualized and based primarily on the degree of severity of the initial anaphylactic reaction. Given the relatively high sensitivity of the present predictors, children with mild anaphylaxis who do not match any of these predictors could be considered for early disposition from the ED (less than 6 hours timed from the onset of the anaphylactic reaction) as long as an appropriate counseling has been provided,” the investigators said. Nonetheless, Dr. Alqurashi and his associates think large-scale prospective pediatric studies are necessary to validate these predictors.
Dr Alqurashi and his associates have no financial disclosures.
Children who present with a severe anaphylactic reaction are two to three times more likely to develop a second delayed, or late-phase, reaction, Dr. Waleed Alqurashi and his colleagues reported.
Their retrospective study found that of 484 children who came to the emergency department for anaphylaxis, 15% developed a biphasic reaction. Most of these (69%) were respiratory and/or cardiovascular; half required epinephrine (Ann. Allerg. Asth. Immunol. 2015 [doi.org/10.1016/j.anai.2015.05.013]).
Dr. Alqurashi of the pediatric department at the University of Ottawa and his associates identified five independent predictors of a biphasic reaction: age 6-9 years (odds ratio, 3.6); a delay in presentation of more than 90 minutes after the onset of the initial reaction (OR, 2.58); wide pulse pressure at triage (OR, 2.92); requiring more than one epinephrine dose for initial reaction (OR, 2.7); and needing inhaled beta-agonists at the ED (OR, 2.39).
Children with these characteristics should stay for observation, rather than being discharged when their initial reactions are stabilized, the authors wrote.
“This period should be individualized and based primarily on the degree of severity of the initial anaphylactic reaction. Given the relatively high sensitivity of the present predictors, children with mild anaphylaxis who do not match any of these predictors could be considered for early disposition from the ED (less than 6 hours timed from the onset of the anaphylactic reaction) as long as an appropriate counseling has been provided,” the investigators said. Nonetheless, Dr. Alqurashi and his associates think large-scale prospective pediatric studies are necessary to validate these predictors.
Dr Alqurashi and his associates have no financial disclosures.
FROM THE ANNALS OF ALLERGY, ASTHMA, AND IMMUNOLOGY
Severe anaphylaxis in children predicts biphasic reactions
Children who present with a severe anaphylactic reaction are two to three times more likely to develop a second delayed, or late-phase, reaction, Dr. Waleed Alqurashi and his colleagues reported.
Their retrospective study found that of 484 children who came to the emergency department for anaphylaxis, 15% developed a biphasic reaction. Most of these (69%) were respiratory and/or cardiovascular; half required epinephrine (Ann. Allerg. Asth. Immunol. 2015 [doi.org/10.1016/j.anai.2015.05.013]).
Dr. Alqurashi of the pediatric department at the University of Ottawa and his associates identified five independent predictors of a biphasic reaction: age 6-9 years (odds ratio, 3.6); a delay in presentation of more than 90 minutes after the onset of the initial reaction (OR, 2.58); wide pulse pressure at triage (OR, 2.92); requiring more than one epinephrine dose for initial reaction (OR, 2.7); and needing inhaled beta-agonists at the ED (OR, 2.39).
Children with these characteristics should stay for observation, rather than being discharged when their initial reactions are stabilized, the authors wrote.
“This period should be individualized and based primarily on the degree of severity of the initial anaphylactic reaction. Given the relatively high sensitivity of the present predictors, children with mild anaphylaxis who do not match any of these predictors could be considered for early disposition from the ED (less than 6 hours timed from the onset of the anaphylactic reaction) as long as an appropriate counseling has been provided,” the investigators said. Nonetheless, Dr. Alqurashi and his associates think large-scale prospective pediatric studies are necessary to validate these predictors.
Dr Alqurashi and his associates have no financial disclosures.
On Twitter @Alz_Gal
Children who present with a severe anaphylactic reaction are two to three times more likely to develop a second delayed, or late-phase, reaction, Dr. Waleed Alqurashi and his colleagues reported.
Their retrospective study found that of 484 children who came to the emergency department for anaphylaxis, 15% developed a biphasic reaction. Most of these (69%) were respiratory and/or cardiovascular; half required epinephrine (Ann. Allerg. Asth. Immunol. 2015 [doi.org/10.1016/j.anai.2015.05.013]).
Dr. Alqurashi of the pediatric department at the University of Ottawa and his associates identified five independent predictors of a biphasic reaction: age 6-9 years (odds ratio, 3.6); a delay in presentation of more than 90 minutes after the onset of the initial reaction (OR, 2.58); wide pulse pressure at triage (OR, 2.92); requiring more than one epinephrine dose for initial reaction (OR, 2.7); and needing inhaled beta-agonists at the ED (OR, 2.39).
Children with these characteristics should stay for observation, rather than being discharged when their initial reactions are stabilized, the authors wrote.
“This period should be individualized and based primarily on the degree of severity of the initial anaphylactic reaction. Given the relatively high sensitivity of the present predictors, children with mild anaphylaxis who do not match any of these predictors could be considered for early disposition from the ED (less than 6 hours timed from the onset of the anaphylactic reaction) as long as an appropriate counseling has been provided,” the investigators said. Nonetheless, Dr. Alqurashi and his associates think large-scale prospective pediatric studies are necessary to validate these predictors.
Dr Alqurashi and his associates have no financial disclosures.
On Twitter @Alz_Gal
Children who present with a severe anaphylactic reaction are two to three times more likely to develop a second delayed, or late-phase, reaction, Dr. Waleed Alqurashi and his colleagues reported.
Their retrospective study found that of 484 children who came to the emergency department for anaphylaxis, 15% developed a biphasic reaction. Most of these (69%) were respiratory and/or cardiovascular; half required epinephrine (Ann. Allerg. Asth. Immunol. 2015 [doi.org/10.1016/j.anai.2015.05.013]).
Dr. Alqurashi of the pediatric department at the University of Ottawa and his associates identified five independent predictors of a biphasic reaction: age 6-9 years (odds ratio, 3.6); a delay in presentation of more than 90 minutes after the onset of the initial reaction (OR, 2.58); wide pulse pressure at triage (OR, 2.92); requiring more than one epinephrine dose for initial reaction (OR, 2.7); and needing inhaled beta-agonists at the ED (OR, 2.39).
Children with these characteristics should stay for observation, rather than being discharged when their initial reactions are stabilized, the authors wrote.
“This period should be individualized and based primarily on the degree of severity of the initial anaphylactic reaction. Given the relatively high sensitivity of the present predictors, children with mild anaphylaxis who do not match any of these predictors could be considered for early disposition from the ED (less than 6 hours timed from the onset of the anaphylactic reaction) as long as an appropriate counseling has been provided,” the investigators said. Nonetheless, Dr. Alqurashi and his associates think large-scale prospective pediatric studies are necessary to validate these predictors.
Dr Alqurashi and his associates have no financial disclosures.
On Twitter @Alz_Gal
FROM THE ANNALS OF ALLERGY, ASTHMA, AND IMMUNOLOGY
Key clinical point: In children, severe anaphylactic reactions predict biphasic reactions.
Major finding: Children who present with a severe anaphylactic reaction, or delayed treatment, were two to three times times more likely to develop a secondary reaction.
Data source: The retrospective study comprised 484 children, 15% of whom had a biphasic reaction.
Disclosures: Dr. Alqurashi and his associates have no financial disclosures.
High VTE recurrence risk persists for at least 3 years
TORONTO – The risk of recurrence following an initial episode of venous thromboembolism is highest in the first 3 months, but remains high for up to 3 years, according to findings from a population-based study involving 2,989 adults.
Over a mean of 23 months (median, 30 months), there were 329 VTE recurrences in the study subjects. Cumulative incidence rates were 5.1% at 3 months, and 14.5% at 3 years. The corresponding rates were 8.7% and 24.8% among those with active cancer, 5.2% and 13.0% among those with provoked VTE, and 3.8% and 13.1% among those with unprovoked VTE, Dr. Wei Huang reported at the International Society on Thrombosis and Haemostasis congress.
Independent predictors of recurrence within 3 years after the index event were active cancer with chemotherapy (hazard ratio, 2.59), active cancer without chemotherapy (HR, 1.59), hypercoagulable state (HR, 2.53) superficial thrombophlebitis (HR, 1.62), varicose vein stripping (HR, 1.75), and inferior vena cava (IVC) filter placement (HR, 2.04), said Dr. Huang of the University of Massachusetts, Worcester.
Individuals included in the study were all residents of the Worcester Metropolitan Statistical Area (WMSA) who had a validated diagnosis of acute first-time deep vein thrombosis and/or pulmonary embolism in a hospital or ambulatory care center that provided short-term care for WMSA residents between 1999 and 2009. Medical records and national and local death registry data were reviewed to examine outcomes up to 3 years after the index event.
Subjects were adults with a mean age of 64 years; 44% were men, and 94% where white. Pulmonary embolism with or without deep vein thrombosis occurred in 42%, and 17% of cases were associated with cancer, 43% involved provoked VTE, and 40% involved unprovoked VTE.
Provoked VTE was defined as VTE occurring within 3 months of a prior surgery, pregnancy, trauma, fracture, or hospitalization in patients without presence of active cancer.
Though limited by the lack of information about variations in physician practices across regions, and by the high proportion of white resident in the WMSA, which both raise questions about whether the findings are generalizable to the U.S. population, the identification of these predictors could allow for improved estimation of risk for individual patients, and may aid in the design of new interventional studies, Dr. Huang concluded.
This study was supported by the National Institutes of Health.
TORONTO – The risk of recurrence following an initial episode of venous thromboembolism is highest in the first 3 months, but remains high for up to 3 years, according to findings from a population-based study involving 2,989 adults.
Over a mean of 23 months (median, 30 months), there were 329 VTE recurrences in the study subjects. Cumulative incidence rates were 5.1% at 3 months, and 14.5% at 3 years. The corresponding rates were 8.7% and 24.8% among those with active cancer, 5.2% and 13.0% among those with provoked VTE, and 3.8% and 13.1% among those with unprovoked VTE, Dr. Wei Huang reported at the International Society on Thrombosis and Haemostasis congress.
Independent predictors of recurrence within 3 years after the index event were active cancer with chemotherapy (hazard ratio, 2.59), active cancer without chemotherapy (HR, 1.59), hypercoagulable state (HR, 2.53) superficial thrombophlebitis (HR, 1.62), varicose vein stripping (HR, 1.75), and inferior vena cava (IVC) filter placement (HR, 2.04), said Dr. Huang of the University of Massachusetts, Worcester.
Individuals included in the study were all residents of the Worcester Metropolitan Statistical Area (WMSA) who had a validated diagnosis of acute first-time deep vein thrombosis and/or pulmonary embolism in a hospital or ambulatory care center that provided short-term care for WMSA residents between 1999 and 2009. Medical records and national and local death registry data were reviewed to examine outcomes up to 3 years after the index event.
Subjects were adults with a mean age of 64 years; 44% were men, and 94% where white. Pulmonary embolism with or without deep vein thrombosis occurred in 42%, and 17% of cases were associated with cancer, 43% involved provoked VTE, and 40% involved unprovoked VTE.
Provoked VTE was defined as VTE occurring within 3 months of a prior surgery, pregnancy, trauma, fracture, or hospitalization in patients without presence of active cancer.
Though limited by the lack of information about variations in physician practices across regions, and by the high proportion of white resident in the WMSA, which both raise questions about whether the findings are generalizable to the U.S. population, the identification of these predictors could allow for improved estimation of risk for individual patients, and may aid in the design of new interventional studies, Dr. Huang concluded.
This study was supported by the National Institutes of Health.
TORONTO – The risk of recurrence following an initial episode of venous thromboembolism is highest in the first 3 months, but remains high for up to 3 years, according to findings from a population-based study involving 2,989 adults.
Over a mean of 23 months (median, 30 months), there were 329 VTE recurrences in the study subjects. Cumulative incidence rates were 5.1% at 3 months, and 14.5% at 3 years. The corresponding rates were 8.7% and 24.8% among those with active cancer, 5.2% and 13.0% among those with provoked VTE, and 3.8% and 13.1% among those with unprovoked VTE, Dr. Wei Huang reported at the International Society on Thrombosis and Haemostasis congress.
Independent predictors of recurrence within 3 years after the index event were active cancer with chemotherapy (hazard ratio, 2.59), active cancer without chemotherapy (HR, 1.59), hypercoagulable state (HR, 2.53) superficial thrombophlebitis (HR, 1.62), varicose vein stripping (HR, 1.75), and inferior vena cava (IVC) filter placement (HR, 2.04), said Dr. Huang of the University of Massachusetts, Worcester.
Individuals included in the study were all residents of the Worcester Metropolitan Statistical Area (WMSA) who had a validated diagnosis of acute first-time deep vein thrombosis and/or pulmonary embolism in a hospital or ambulatory care center that provided short-term care for WMSA residents between 1999 and 2009. Medical records and national and local death registry data were reviewed to examine outcomes up to 3 years after the index event.
Subjects were adults with a mean age of 64 years; 44% were men, and 94% where white. Pulmonary embolism with or without deep vein thrombosis occurred in 42%, and 17% of cases were associated with cancer, 43% involved provoked VTE, and 40% involved unprovoked VTE.
Provoked VTE was defined as VTE occurring within 3 months of a prior surgery, pregnancy, trauma, fracture, or hospitalization in patients without presence of active cancer.
Though limited by the lack of information about variations in physician practices across regions, and by the high proportion of white resident in the WMSA, which both raise questions about whether the findings are generalizable to the U.S. population, the identification of these predictors could allow for improved estimation of risk for individual patients, and may aid in the design of new interventional studies, Dr. Huang concluded.
This study was supported by the National Institutes of Health.
AT THE 2015 ISTH CONGRESS
Key clinical point: The risk of recurrence following an initial episode of venous thromboembolism is highest in the first 3 months, but remains high for up to 3 years, according to findings from a population-based study involving 2,989 adults.
Major finding: Active cancer with chemotherapy was the strongest predictor of VTE recurrence (hazard ratio, 2.59).
Data source: Population-based surveillance of 2,989 adults patients.
Disclosures: The National Institutes of Health supported the study.
Statins showed no benefit in reducing risk of recurrent VTE
TORONTO – The use of statins showed no benefit in reducing the risk of recurrent venous thromboembolism in patients enrolled in phase III trials comparing direct oral anticoagulants with vitamin K antagonists, a large meta-analysis demonstrated.
Recurrence after an unprovoked VTE is 10%-15% in the first 6-12 months, and recurrence risk in the first 6 months is reduced by 80%-90% with anticoagulants, Dr. Mandy N. Lauw said at the International Society on Thrombosis and Haemostasis congress.
“However, the use of anticoagulants has the risk of bleeding, and therefore the long-term risk-benefit ratio is unclear,” said Dr. Lauw of the department of vascular medicine at Academic Medical Center, Amsterdam. “Therefore it’s interesting to look at modalities outside the coagulation cascade to treat patients for longer term and to prevent recurrent thrombosis. One of these modalities has been the use of statins, which are known to reduce arterial vascular events by lowering cholesterol levels. However, recent studies have also indicated that they may have an effect on VTE events.”
In an effort to evaluate the effects of statins on recurrent VTE, Dr. Lauw and her associates conducted a meta-analysis of statins in three randomized, phase III trials comparing non–vitamin K oral anticoagulant (NOAC) with vitamin K antagonist (VKA) therapy in patients with acute symptomatic VTE.
The trials included 5,153 patients enrolled in RE-COVER I and II (an analysis of dabigatran vs. standard therapy for acute VTE), 8,281 enrolled in the EINSTEIN clinical trials for DVT and pulmonary embolism (an analysis of rivaroxaban vs. standard therapy for symptomatic VTE), and 8,292 enrolled in a trial conducted by the Hokusai-DVT investigators (an analysis of edoxaban vs. standard therapy for symptomatic VTE). The researchers examined the effect of statin use on recurrent VTE or VTE-related death, recurrent DVT or PE, and major bleeding. To do this they conducted a pooled meta-analysis and an analysis per study, adjusted for age, gender, diabetes mellitus, creatinine clearance of less than 50 mL/min, hypertension, prior VTE, and use of aspirin.
Dr. Lauw reported results from 21,587 patients included in the analysis. Among all three studies, 2,754 patients (12.8%) used statins and 18,833 (87.2%) did not. In an unadjusted pooled analysis, the use of statins at baseline did not have an influence on the risk of recurrent VTE or VTE-related death, with an odds ratio of 0.91. There was also no effect of statins on the risk of recurrent PE or DVT (ORs of 0.84 and 1.05, respectively), while major bleeding seemed to be increased with the use of statins (OR, 1.65). A subanalysis in patients getting NOAC or VKA separately showed a non–statistically significant benefit of statins with NOACs, compared with VKAs on the risk of recurrent VTE or VTE-related death (ORs of 0.60 vs. OR 1.24, respectively). The results were similar for NOACs, compared with VKA, on the risk of recurrent DVT (ORs of 0.47 vs. OR 1.67) and the risk of recurrent PE (ORs of 0.73 vs. 1.02).
On adjusted analysis, the risk of recurrent VTE or VTE-related death between all three studies was similar and nonsignificant (hazard ratio of 0.99 in RE-COVER I and II, HR of 0.78 in the EINSTEIN clinical trials for DVT & PE, and HR of 0.99 in the trial conducted by the Hokusai-DVT Investigators). There also were no significant differences between the study groups in recurrent PE, recurrent DVT, or major bleeding. “So statins have no beneficial effect, but also no harmful effect,” Dr. Lauw said.
She acknowledged certain limitations of the study, including the fact that it was an on-treatment analysis, “so it could be that we had inadequate follow-up duration,” she said. “Also, we don’t have any assessment of statin effects without anticoagulation in these patients. Perhaps it would be interesting to use the extension trials to explore these results as well.”
For now, “there is no evidence that statins reduce the recurrence of VTE,” she concluded. “The only way to explore this is to do a randomized controlled trial properly designed and powered to estimate this effect prospectively.”
Dr. Lauw reported having no financial disclosures.
TORONTO – The use of statins showed no benefit in reducing the risk of recurrent venous thromboembolism in patients enrolled in phase III trials comparing direct oral anticoagulants with vitamin K antagonists, a large meta-analysis demonstrated.
Recurrence after an unprovoked VTE is 10%-15% in the first 6-12 months, and recurrence risk in the first 6 months is reduced by 80%-90% with anticoagulants, Dr. Mandy N. Lauw said at the International Society on Thrombosis and Haemostasis congress.
“However, the use of anticoagulants has the risk of bleeding, and therefore the long-term risk-benefit ratio is unclear,” said Dr. Lauw of the department of vascular medicine at Academic Medical Center, Amsterdam. “Therefore it’s interesting to look at modalities outside the coagulation cascade to treat patients for longer term and to prevent recurrent thrombosis. One of these modalities has been the use of statins, which are known to reduce arterial vascular events by lowering cholesterol levels. However, recent studies have also indicated that they may have an effect on VTE events.”
In an effort to evaluate the effects of statins on recurrent VTE, Dr. Lauw and her associates conducted a meta-analysis of statins in three randomized, phase III trials comparing non–vitamin K oral anticoagulant (NOAC) with vitamin K antagonist (VKA) therapy in patients with acute symptomatic VTE.
The trials included 5,153 patients enrolled in RE-COVER I and II (an analysis of dabigatran vs. standard therapy for acute VTE), 8,281 enrolled in the EINSTEIN clinical trials for DVT and pulmonary embolism (an analysis of rivaroxaban vs. standard therapy for symptomatic VTE), and 8,292 enrolled in a trial conducted by the Hokusai-DVT investigators (an analysis of edoxaban vs. standard therapy for symptomatic VTE). The researchers examined the effect of statin use on recurrent VTE or VTE-related death, recurrent DVT or PE, and major bleeding. To do this they conducted a pooled meta-analysis and an analysis per study, adjusted for age, gender, diabetes mellitus, creatinine clearance of less than 50 mL/min, hypertension, prior VTE, and use of aspirin.
Dr. Lauw reported results from 21,587 patients included in the analysis. Among all three studies, 2,754 patients (12.8%) used statins and 18,833 (87.2%) did not. In an unadjusted pooled analysis, the use of statins at baseline did not have an influence on the risk of recurrent VTE or VTE-related death, with an odds ratio of 0.91. There was also no effect of statins on the risk of recurrent PE or DVT (ORs of 0.84 and 1.05, respectively), while major bleeding seemed to be increased with the use of statins (OR, 1.65). A subanalysis in patients getting NOAC or VKA separately showed a non–statistically significant benefit of statins with NOACs, compared with VKAs on the risk of recurrent VTE or VTE-related death (ORs of 0.60 vs. OR 1.24, respectively). The results were similar for NOACs, compared with VKA, on the risk of recurrent DVT (ORs of 0.47 vs. OR 1.67) and the risk of recurrent PE (ORs of 0.73 vs. 1.02).
On adjusted analysis, the risk of recurrent VTE or VTE-related death between all three studies was similar and nonsignificant (hazard ratio of 0.99 in RE-COVER I and II, HR of 0.78 in the EINSTEIN clinical trials for DVT & PE, and HR of 0.99 in the trial conducted by the Hokusai-DVT Investigators). There also were no significant differences between the study groups in recurrent PE, recurrent DVT, or major bleeding. “So statins have no beneficial effect, but also no harmful effect,” Dr. Lauw said.
She acknowledged certain limitations of the study, including the fact that it was an on-treatment analysis, “so it could be that we had inadequate follow-up duration,” she said. “Also, we don’t have any assessment of statin effects without anticoagulation in these patients. Perhaps it would be interesting to use the extension trials to explore these results as well.”
For now, “there is no evidence that statins reduce the recurrence of VTE,” she concluded. “The only way to explore this is to do a randomized controlled trial properly designed and powered to estimate this effect prospectively.”
Dr. Lauw reported having no financial disclosures.
TORONTO – The use of statins showed no benefit in reducing the risk of recurrent venous thromboembolism in patients enrolled in phase III trials comparing direct oral anticoagulants with vitamin K antagonists, a large meta-analysis demonstrated.
Recurrence after an unprovoked VTE is 10%-15% in the first 6-12 months, and recurrence risk in the first 6 months is reduced by 80%-90% with anticoagulants, Dr. Mandy N. Lauw said at the International Society on Thrombosis and Haemostasis congress.
“However, the use of anticoagulants has the risk of bleeding, and therefore the long-term risk-benefit ratio is unclear,” said Dr. Lauw of the department of vascular medicine at Academic Medical Center, Amsterdam. “Therefore it’s interesting to look at modalities outside the coagulation cascade to treat patients for longer term and to prevent recurrent thrombosis. One of these modalities has been the use of statins, which are known to reduce arterial vascular events by lowering cholesterol levels. However, recent studies have also indicated that they may have an effect on VTE events.”
In an effort to evaluate the effects of statins on recurrent VTE, Dr. Lauw and her associates conducted a meta-analysis of statins in three randomized, phase III trials comparing non–vitamin K oral anticoagulant (NOAC) with vitamin K antagonist (VKA) therapy in patients with acute symptomatic VTE.
The trials included 5,153 patients enrolled in RE-COVER I and II (an analysis of dabigatran vs. standard therapy for acute VTE), 8,281 enrolled in the EINSTEIN clinical trials for DVT and pulmonary embolism (an analysis of rivaroxaban vs. standard therapy for symptomatic VTE), and 8,292 enrolled in a trial conducted by the Hokusai-DVT investigators (an analysis of edoxaban vs. standard therapy for symptomatic VTE). The researchers examined the effect of statin use on recurrent VTE or VTE-related death, recurrent DVT or PE, and major bleeding. To do this they conducted a pooled meta-analysis and an analysis per study, adjusted for age, gender, diabetes mellitus, creatinine clearance of less than 50 mL/min, hypertension, prior VTE, and use of aspirin.
Dr. Lauw reported results from 21,587 patients included in the analysis. Among all three studies, 2,754 patients (12.8%) used statins and 18,833 (87.2%) did not. In an unadjusted pooled analysis, the use of statins at baseline did not have an influence on the risk of recurrent VTE or VTE-related death, with an odds ratio of 0.91. There was also no effect of statins on the risk of recurrent PE or DVT (ORs of 0.84 and 1.05, respectively), while major bleeding seemed to be increased with the use of statins (OR, 1.65). A subanalysis in patients getting NOAC or VKA separately showed a non–statistically significant benefit of statins with NOACs, compared with VKAs on the risk of recurrent VTE or VTE-related death (ORs of 0.60 vs. OR 1.24, respectively). The results were similar for NOACs, compared with VKA, on the risk of recurrent DVT (ORs of 0.47 vs. OR 1.67) and the risk of recurrent PE (ORs of 0.73 vs. 1.02).
On adjusted analysis, the risk of recurrent VTE or VTE-related death between all three studies was similar and nonsignificant (hazard ratio of 0.99 in RE-COVER I and II, HR of 0.78 in the EINSTEIN clinical trials for DVT & PE, and HR of 0.99 in the trial conducted by the Hokusai-DVT Investigators). There also were no significant differences between the study groups in recurrent PE, recurrent DVT, or major bleeding. “So statins have no beneficial effect, but also no harmful effect,” Dr. Lauw said.
She acknowledged certain limitations of the study, including the fact that it was an on-treatment analysis, “so it could be that we had inadequate follow-up duration,” she said. “Also, we don’t have any assessment of statin effects without anticoagulation in these patients. Perhaps it would be interesting to use the extension trials to explore these results as well.”
For now, “there is no evidence that statins reduce the recurrence of VTE,” she concluded. “The only way to explore this is to do a randomized controlled trial properly designed and powered to estimate this effect prospectively.”
Dr. Lauw reported having no financial disclosures.
AT THE 2015 ISTH CONGRESS
Key clinical point: No beneficial effect of statins in reducing recurrent VTE was observed in patients threated in phase III acute VTE trials.
Major finding: On adjusted analysis, the risk of recurrent VTE or VTE-related death between all three studies was similar and nonsignificant (HR of 0.99 in RE-COVER I and II, HR of 0.78 in the EINSTEIN clinical trials for DVT and PE, and HR of 0.99 in the trial conducted by the Hokusai-DVT investigators).
Data source: A meta-analysis of 21,587 patients enrolled in three phase III trials comparing non–vitamin K oral anticoagulant (NOAC) with vitamin K antagonist (VKA) therapy in patients with acute symptomatic VTE.
Disclosures: Dr. Lauw reported having no financial disclosures.
COPD may start young with no rapid FEV1 decline
Approximately half of cases of COPD in older adults appear to stem from low forced expiratory volume in 1 second in early adulthood that declines at a normal rate, rather than the accelerated decline in normal FEV1 that has been considered “an obligate feature” of the disease, according to a report published online July 9 in the New England Journal of Medicine.
“Even though we cannot precisely estimate the contribution of the trajectory of low maximally attained lung function to COPD using our study design, our results suggest that this contribution may be substantial and that populations of patients with COPD comprise persons with different rates of decline in FEV1,” said Dr. Peter Lange of the Institute of Public Health, Copenhagen University, and his associates.
“This observation is in accord with previous studies and suggests that a substantial proportion of patients with COPD may not have had a rapid decline in FEV1, which for decades has been regarded as the hallmark of COPD,” the researchers added.
Previous authors have questioned the prevailing paradigm of COPD pathogenesis, but the possibility that low lung function in early adulthood can lead to later COPD has never been examined in a long-term, prospective study.
Dr. Lange and his colleagues explored that question using data from three large, independent longitudinal cohort studies: the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort. A total of 2,864 participants in the studies underwent serial spirometry beginning in early adulthood and continuing through approximately 22 years of follow-up. That allowed Dr. Lange and his associates to track their decline in lung function over time.
Overall, 332 participants (12% of the entire study population) had grade 2 or higher COPD at final follow-up when they were age 55 years or older, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) grading system.
A total of 48% of the COPD patients followed the typical trajectory of a normal FEV1 at baseline that declined an average of 53 mL per year. However, 52% followed a different trajectory, with a low FEV1 at baseline that declined only 27 mL per year, the investigators said (N. Engl. J. Med. 2015;373:111-22).
Compared with participants who had normal FEV1 at baseline, those with initially low FEV1 were significantly more likely to be hospitalized with respiratory disease (25% vs. 18%), to be admitted for COPD (9% vs. 4%), and to die (32% vs. 25%) during follow-up.
People with a low FEV1 at baseline “had a risk of COPD at midlife that was more than three times as high as the risk among those with a higher baseline FEV1 (26% vs 7%),” Dr. Lange and his associates added.
The three cohort studies that contributed data to this analysis were funded by the National Heart, Lung, and Blood Institute, GlaxoSmithKline, the Capital Region of Copenhagen, the Danish Heart Foundation, the Danish Lung Foundation, the Velux Foundation, the state of New Mexico, and the National Institutes of Health. Dr. Lange reported receiving grants and personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Norpharma, Novartis, Pfizer, Takeda, and TEVA. His associates reported ties to numerous industry sources.
To definitively sort out the FEV1 patterns that contribute to COPD risk would require large data sets with repeated spirometric measurements of a diverse population across the entire life course – an unrealistic proposition.
For the present, there are two clear implications from the study by Dr. Lange et al. First, spirometry, both in population studies and in clinical practice, still provides the best predictive measure of COPD risk and the best method of assessing disease progression. And second, smoking still remains the greatest risk factor for developing COPD and should continue to be our focus as the single major determinant of lung health.
Dr. Frank E. Speizer is in the Channing Division of Network Medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston. James H. Ware, Ph.D., is at Harvard School of Public Health, Boston, and is a statistical consultant to the New England Journal of Medicine. Dr. Speizer and Dr. Ware reported having no relevant financial conflicts of interest. They made these remarks in an editorial accompanying Dr. Lange’s report (N. Engl. J. Med. 2015;373:185-6).
To definitively sort out the FEV1 patterns that contribute to COPD risk would require large data sets with repeated spirometric measurements of a diverse population across the entire life course – an unrealistic proposition.
For the present, there are two clear implications from the study by Dr. Lange et al. First, spirometry, both in population studies and in clinical practice, still provides the best predictive measure of COPD risk and the best method of assessing disease progression. And second, smoking still remains the greatest risk factor for developing COPD and should continue to be our focus as the single major determinant of lung health.
Dr. Frank E. Speizer is in the Channing Division of Network Medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston. James H. Ware, Ph.D., is at Harvard School of Public Health, Boston, and is a statistical consultant to the New England Journal of Medicine. Dr. Speizer and Dr. Ware reported having no relevant financial conflicts of interest. They made these remarks in an editorial accompanying Dr. Lange’s report (N. Engl. J. Med. 2015;373:185-6).
To definitively sort out the FEV1 patterns that contribute to COPD risk would require large data sets with repeated spirometric measurements of a diverse population across the entire life course – an unrealistic proposition.
For the present, there are two clear implications from the study by Dr. Lange et al. First, spirometry, both in population studies and in clinical practice, still provides the best predictive measure of COPD risk and the best method of assessing disease progression. And second, smoking still remains the greatest risk factor for developing COPD and should continue to be our focus as the single major determinant of lung health.
Dr. Frank E. Speizer is in the Channing Division of Network Medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston. James H. Ware, Ph.D., is at Harvard School of Public Health, Boston, and is a statistical consultant to the New England Journal of Medicine. Dr. Speizer and Dr. Ware reported having no relevant financial conflicts of interest. They made these remarks in an editorial accompanying Dr. Lange’s report (N. Engl. J. Med. 2015;373:185-6).
Approximately half of cases of COPD in older adults appear to stem from low forced expiratory volume in 1 second in early adulthood that declines at a normal rate, rather than the accelerated decline in normal FEV1 that has been considered “an obligate feature” of the disease, according to a report published online July 9 in the New England Journal of Medicine.
“Even though we cannot precisely estimate the contribution of the trajectory of low maximally attained lung function to COPD using our study design, our results suggest that this contribution may be substantial and that populations of patients with COPD comprise persons with different rates of decline in FEV1,” said Dr. Peter Lange of the Institute of Public Health, Copenhagen University, and his associates.
“This observation is in accord with previous studies and suggests that a substantial proportion of patients with COPD may not have had a rapid decline in FEV1, which for decades has been regarded as the hallmark of COPD,” the researchers added.
Previous authors have questioned the prevailing paradigm of COPD pathogenesis, but the possibility that low lung function in early adulthood can lead to later COPD has never been examined in a long-term, prospective study.
Dr. Lange and his colleagues explored that question using data from three large, independent longitudinal cohort studies: the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort. A total of 2,864 participants in the studies underwent serial spirometry beginning in early adulthood and continuing through approximately 22 years of follow-up. That allowed Dr. Lange and his associates to track their decline in lung function over time.
Overall, 332 participants (12% of the entire study population) had grade 2 or higher COPD at final follow-up when they were age 55 years or older, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) grading system.
A total of 48% of the COPD patients followed the typical trajectory of a normal FEV1 at baseline that declined an average of 53 mL per year. However, 52% followed a different trajectory, with a low FEV1 at baseline that declined only 27 mL per year, the investigators said (N. Engl. J. Med. 2015;373:111-22).
Compared with participants who had normal FEV1 at baseline, those with initially low FEV1 were significantly more likely to be hospitalized with respiratory disease (25% vs. 18%), to be admitted for COPD (9% vs. 4%), and to die (32% vs. 25%) during follow-up.
People with a low FEV1 at baseline “had a risk of COPD at midlife that was more than three times as high as the risk among those with a higher baseline FEV1 (26% vs 7%),” Dr. Lange and his associates added.
The three cohort studies that contributed data to this analysis were funded by the National Heart, Lung, and Blood Institute, GlaxoSmithKline, the Capital Region of Copenhagen, the Danish Heart Foundation, the Danish Lung Foundation, the Velux Foundation, the state of New Mexico, and the National Institutes of Health. Dr. Lange reported receiving grants and personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Norpharma, Novartis, Pfizer, Takeda, and TEVA. His associates reported ties to numerous industry sources.
Approximately half of cases of COPD in older adults appear to stem from low forced expiratory volume in 1 second in early adulthood that declines at a normal rate, rather than the accelerated decline in normal FEV1 that has been considered “an obligate feature” of the disease, according to a report published online July 9 in the New England Journal of Medicine.
“Even though we cannot precisely estimate the contribution of the trajectory of low maximally attained lung function to COPD using our study design, our results suggest that this contribution may be substantial and that populations of patients with COPD comprise persons with different rates of decline in FEV1,” said Dr. Peter Lange of the Institute of Public Health, Copenhagen University, and his associates.
“This observation is in accord with previous studies and suggests that a substantial proportion of patients with COPD may not have had a rapid decline in FEV1, which for decades has been regarded as the hallmark of COPD,” the researchers added.
Previous authors have questioned the prevailing paradigm of COPD pathogenesis, but the possibility that low lung function in early adulthood can lead to later COPD has never been examined in a long-term, prospective study.
Dr. Lange and his colleagues explored that question using data from three large, independent longitudinal cohort studies: the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort. A total of 2,864 participants in the studies underwent serial spirometry beginning in early adulthood and continuing through approximately 22 years of follow-up. That allowed Dr. Lange and his associates to track their decline in lung function over time.
Overall, 332 participants (12% of the entire study population) had grade 2 or higher COPD at final follow-up when they were age 55 years or older, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) grading system.
A total of 48% of the COPD patients followed the typical trajectory of a normal FEV1 at baseline that declined an average of 53 mL per year. However, 52% followed a different trajectory, with a low FEV1 at baseline that declined only 27 mL per year, the investigators said (N. Engl. J. Med. 2015;373:111-22).
Compared with participants who had normal FEV1 at baseline, those with initially low FEV1 were significantly more likely to be hospitalized with respiratory disease (25% vs. 18%), to be admitted for COPD (9% vs. 4%), and to die (32% vs. 25%) during follow-up.
People with a low FEV1 at baseline “had a risk of COPD at midlife that was more than three times as high as the risk among those with a higher baseline FEV1 (26% vs 7%),” Dr. Lange and his associates added.
The three cohort studies that contributed data to this analysis were funded by the National Heart, Lung, and Blood Institute, GlaxoSmithKline, the Capital Region of Copenhagen, the Danish Heart Foundation, the Danish Lung Foundation, the Velux Foundation, the state of New Mexico, and the National Institutes of Health. Dr. Lange reported receiving grants and personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Norpharma, Novartis, Pfizer, Takeda, and TEVA. His associates reported ties to numerous industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Approximately half of COPD cases stem from a low FEV1 in early adulthood rather than an accelerated decline in FEV1.
Major finding: 52% of patients who eventually developed COPD followed an unexpected trajectory, with a low FEV1 at baseline that declined only 27 mL per year.
Data source: A secondary analysis of data from three longitudinal cohort studies of COPD in which 2,864 participants underwent repeated spirometry, allowing their decline in pulmonary function to be tracked over time.
Disclosures: The three cohort studies that contributed data to this analysis were funded by the National Heart, Lung, and Blood Institute, GlaxoSmithKline, the Capital Region of Copenhagen, the Danish Heart Foundation, the Danish Lung Foundation, the Velux Foundation, the state of New Mexico, and the National Institutes of Health. Dr. Lange reported receiving grants and personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Norpharma, Novartis, Pfizer, Takeda, and TEVA. His associates reported ties to numerous industry sources.
Extended warfarin delays return of unprovoked pulmonary embolism
Adding an extra 18 months of warfarin therapy to the standard 6 months of anticoagulation delays the recurrence of venous thrombosis in patients who have a first episode of unprovoked pulmonary embolism – but the risk of recurrence resumes as soon as the warfarin is discontinued, according to a report published online July 7 in JAMA.
“Our results suggest that patients such as those who participated in our study require long-term secondary prophylaxis measures. Whether these should include systematic treatment with vitamin K antagonists, new anticoagulants, or aspirin, or be tailored according to patient risk factors (including elevated D-dimer levels) needs further investigation,” said Dr. Francis Couturaud of the department of internal medicine and chest diseases, University of Brest (France) Hospital, and his associates (JAMA 2015;314:31-40).
Adults with a first episode of unprovoked VT are at much greater risk of recurrence when the standard 6 months of anticoagulation runs out, compared with those whose VT is provoked by a known, transient risk factor such as lengthy surgery, trauma with immobilization of the lower limbs, or bed rest extending longer than 72 hours.
Some experts have advocated extending anticoagulation further in such patients; but whether this is actually beneficial remains uncertain, the investigators said, because most studies have not pursued follow-up beyond the end of treatment.
The researchers performed a multicenter, double-blind trial in which 371 consecutive patients with a first episode of unprovoked PE completed 6 months of anticoagulation and then were randomly assigned to a further 18 months on either warfarin or matching placebo.
During this 18-month treatment period, the primary outcome – a composite of recurrent VT (including PE) and major bleeding – occurred in 3.3% of the warfarin group and 13.5% of the placebo group. That significant difference translated to a 78% reduction in favor of warfarin (hazard ratio, 0.22), Dr. Couturaud and his associates said.
However, after the treatment period ended, the composite outcome occurred in 17.7% of the warfarin group and 10.3% of the placebo group. Thus, the risk of recurrence returned to its normal high level once warfarin was discontinued, the study authors noted.
The study was supported by the Programme Hospitalier de Recherche Clinique (the French Department of Health) and the University Hospital of Brest (France). Dr. Couturaud reported receiving research grants, honoraria, and travel pay from Actelion, AstraZeneca, Bayer, Daiichi Sankyo, Intermune, Leo Pharma, and Pfizer, and his associates reported ties to numerous industry sources.
Related Information
- Computed tomographic pulmonary angiography (CTPA) may be useful in the diagnosis of suspected PE, wrote Dr. Gregoire Le Gal and co-authors from the University of Ottawa. Alternately, a V/Q scan may be performed. The complete accompanying article on diagnostic testing methods for suspected pulmonary embolism can be found here.
- The recently approved anticoagulant edoxaban is similar to warfarin in its ability to treat acute VTE, according to a report published in the Medical Letter on Drugs and Therapeutics in the same issue. However, further study is needed to evaluate its safety and efficacy compared with dabigatran, rivaroxaban, and apixaban, the three other oral anticoagulant drugs currently FDA-approved for acute VTE.
- A meta-analysis of 3,716 patients with VTE found that long-term treatment with Vitamin K antagonists was associated with lower rates of thromboembolic events (relative risk = 0.20) and higher rates of bleeding complications (RR = 3.44), compared with short-term therapy, Dr. Saskia Middeldorp and Dr. Barbara A. Hutten of the University of Amsterdam reported in the same issue. There was no difference in mortality between the two groups.
- Currently, recommended treatment duration for PE can range from three months to lifelong treatment, wrote Dr. Jill Jin in a clinical synopsis for patients published with the study.
- Read the full article and listen to the related podcast: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7046
Madhu Rajaraman contributed to this report.
Adding an extra 18 months of warfarin therapy to the standard 6 months of anticoagulation delays the recurrence of venous thrombosis in patients who have a first episode of unprovoked pulmonary embolism – but the risk of recurrence resumes as soon as the warfarin is discontinued, according to a report published online July 7 in JAMA.
“Our results suggest that patients such as those who participated in our study require long-term secondary prophylaxis measures. Whether these should include systematic treatment with vitamin K antagonists, new anticoagulants, or aspirin, or be tailored according to patient risk factors (including elevated D-dimer levels) needs further investigation,” said Dr. Francis Couturaud of the department of internal medicine and chest diseases, University of Brest (France) Hospital, and his associates (JAMA 2015;314:31-40).
Adults with a first episode of unprovoked VT are at much greater risk of recurrence when the standard 6 months of anticoagulation runs out, compared with those whose VT is provoked by a known, transient risk factor such as lengthy surgery, trauma with immobilization of the lower limbs, or bed rest extending longer than 72 hours.
Some experts have advocated extending anticoagulation further in such patients; but whether this is actually beneficial remains uncertain, the investigators said, because most studies have not pursued follow-up beyond the end of treatment.
The researchers performed a multicenter, double-blind trial in which 371 consecutive patients with a first episode of unprovoked PE completed 6 months of anticoagulation and then were randomly assigned to a further 18 months on either warfarin or matching placebo.
During this 18-month treatment period, the primary outcome – a composite of recurrent VT (including PE) and major bleeding – occurred in 3.3% of the warfarin group and 13.5% of the placebo group. That significant difference translated to a 78% reduction in favor of warfarin (hazard ratio, 0.22), Dr. Couturaud and his associates said.
However, after the treatment period ended, the composite outcome occurred in 17.7% of the warfarin group and 10.3% of the placebo group. Thus, the risk of recurrence returned to its normal high level once warfarin was discontinued, the study authors noted.
The study was supported by the Programme Hospitalier de Recherche Clinique (the French Department of Health) and the University Hospital of Brest (France). Dr. Couturaud reported receiving research grants, honoraria, and travel pay from Actelion, AstraZeneca, Bayer, Daiichi Sankyo, Intermune, Leo Pharma, and Pfizer, and his associates reported ties to numerous industry sources.
Related Information
- Computed tomographic pulmonary angiography (CTPA) may be useful in the diagnosis of suspected PE, wrote Dr. Gregoire Le Gal and co-authors from the University of Ottawa. Alternately, a V/Q scan may be performed. The complete accompanying article on diagnostic testing methods for suspected pulmonary embolism can be found here.
- The recently approved anticoagulant edoxaban is similar to warfarin in its ability to treat acute VTE, according to a report published in the Medical Letter on Drugs and Therapeutics in the same issue. However, further study is needed to evaluate its safety and efficacy compared with dabigatran, rivaroxaban, and apixaban, the three other oral anticoagulant drugs currently FDA-approved for acute VTE.
- A meta-analysis of 3,716 patients with VTE found that long-term treatment with Vitamin K antagonists was associated with lower rates of thromboembolic events (relative risk = 0.20) and higher rates of bleeding complications (RR = 3.44), compared with short-term therapy, Dr. Saskia Middeldorp and Dr. Barbara A. Hutten of the University of Amsterdam reported in the same issue. There was no difference in mortality between the two groups.
- Currently, recommended treatment duration for PE can range from three months to lifelong treatment, wrote Dr. Jill Jin in a clinical synopsis for patients published with the study.
- Read the full article and listen to the related podcast: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7046
Madhu Rajaraman contributed to this report.
Adding an extra 18 months of warfarin therapy to the standard 6 months of anticoagulation delays the recurrence of venous thrombosis in patients who have a first episode of unprovoked pulmonary embolism – but the risk of recurrence resumes as soon as the warfarin is discontinued, according to a report published online July 7 in JAMA.
“Our results suggest that patients such as those who participated in our study require long-term secondary prophylaxis measures. Whether these should include systematic treatment with vitamin K antagonists, new anticoagulants, or aspirin, or be tailored according to patient risk factors (including elevated D-dimer levels) needs further investigation,” said Dr. Francis Couturaud of the department of internal medicine and chest diseases, University of Brest (France) Hospital, and his associates (JAMA 2015;314:31-40).
Adults with a first episode of unprovoked VT are at much greater risk of recurrence when the standard 6 months of anticoagulation runs out, compared with those whose VT is provoked by a known, transient risk factor such as lengthy surgery, trauma with immobilization of the lower limbs, or bed rest extending longer than 72 hours.
Some experts have advocated extending anticoagulation further in such patients; but whether this is actually beneficial remains uncertain, the investigators said, because most studies have not pursued follow-up beyond the end of treatment.
The researchers performed a multicenter, double-blind trial in which 371 consecutive patients with a first episode of unprovoked PE completed 6 months of anticoagulation and then were randomly assigned to a further 18 months on either warfarin or matching placebo.
During this 18-month treatment period, the primary outcome – a composite of recurrent VT (including PE) and major bleeding – occurred in 3.3% of the warfarin group and 13.5% of the placebo group. That significant difference translated to a 78% reduction in favor of warfarin (hazard ratio, 0.22), Dr. Couturaud and his associates said.
However, after the treatment period ended, the composite outcome occurred in 17.7% of the warfarin group and 10.3% of the placebo group. Thus, the risk of recurrence returned to its normal high level once warfarin was discontinued, the study authors noted.
The study was supported by the Programme Hospitalier de Recherche Clinique (the French Department of Health) and the University Hospital of Brest (France). Dr. Couturaud reported receiving research grants, honoraria, and travel pay from Actelion, AstraZeneca, Bayer, Daiichi Sankyo, Intermune, Leo Pharma, and Pfizer, and his associates reported ties to numerous industry sources.
Related Information
- Computed tomographic pulmonary angiography (CTPA) may be useful in the diagnosis of suspected PE, wrote Dr. Gregoire Le Gal and co-authors from the University of Ottawa. Alternately, a V/Q scan may be performed. The complete accompanying article on diagnostic testing methods for suspected pulmonary embolism can be found here.
- The recently approved anticoagulant edoxaban is similar to warfarin in its ability to treat acute VTE, according to a report published in the Medical Letter on Drugs and Therapeutics in the same issue. However, further study is needed to evaluate its safety and efficacy compared with dabigatran, rivaroxaban, and apixaban, the three other oral anticoagulant drugs currently FDA-approved for acute VTE.
- A meta-analysis of 3,716 patients with VTE found that long-term treatment with Vitamin K antagonists was associated with lower rates of thromboembolic events (relative risk = 0.20) and higher rates of bleeding complications (RR = 3.44), compared with short-term therapy, Dr. Saskia Middeldorp and Dr. Barbara A. Hutten of the University of Amsterdam reported in the same issue. There was no difference in mortality between the two groups.
- Currently, recommended treatment duration for PE can range from three months to lifelong treatment, wrote Dr. Jill Jin in a clinical synopsis for patients published with the study.
- Read the full article and listen to the related podcast: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7046
Madhu Rajaraman contributed to this report.
FROM JAMA
Key clinical point: Eighteen additional months of warfarin therapy delays the recurrence of unprovoked pulmonary embolism.
Major finding: During treatment, the primary outcome – a composite of recurrent venous thromboembolism and major bleeding – occurred in 3.3% of the warfarin group and 13.5% of the placebo group, a significant difference that translated to a 78% reduction in favor of warfarin (hazard ratio, 0.22).
Data source: A multicenter, randomized, double-blind, placebo-controlled clinical trial involving 371 patients followed for a mean of 41 months.
Disclosures: This study was supported by the Programme Hospitalier de Recherche Clinique (the French Department of Health) and the University Hospital of Brest (France). Dr. Couturaud reported receiving research grants, honoraria, and travel pay from Actelion, AstraZeneca, Bayer, Daiichi Sankyo, Intermune, Leo Pharma, and Pfizer, and his associates reported ties to numerous industry sources.
Pediatric PH a growing burden, national study finds
Between 1997 and 2006, the proportion of hospitalizations in the United States for pediatric pulmonary hypertension doubled, from 1 in 1,000 discharges for the condition in 1997 to 1 in 500 in 2006, a national retrospective cohort study found.
“These results have practice and policy implications at the institutional, state, and national levels, particularly in the face of increasing pressure to restrain costs while caring for a population with increasingly complex medical needs,” researchers led by Dr. Bryan G. Maxwell reported online June 6, 2015 in Pediatrics (doi/10.1542/peds.2014-3834).
Dr. Maxwell of the departments of anesthesiology and critical care medicine at Johns Hopkins University, Baltimore, Md., and his associates examined data on pediatric pulmonary hypertension (PH) hospitalizations between 1997 and 2006 from the Kids’ Inpatient Database, which is part of the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality.
Of the estimated 43 million pediatric discharges that occurred between 1997 and 2006, 0.13% were for PH, and discharges for the condition increased over the study period, from 1 in 500 in 1997 to 1 in 1,000 in 2006 (P less than .0001). During the same time period, inflation-adjusted national hospital charges for PH hospitalizations increased from $926 million to 3.12 billion (P = .0003).
The researchers also found that the increase in PH discharges was most pronounced between 2006 and 2012, and that most PH hospitalizations did not occur in dedicated children’s hospitals. The overall mortality of patients discharged with PH was 5.9%, and steadily improved between 1997 and 2012 (P less than .0001).
Dr. Maxwell and his associates acknowledged certain limitations of the study, including the fact that the Kids’ Inpatient Database does not provide longitudinal data on patients with PH over time or on outpatient care, and that ICD-9-CM codes “do not permit accurate identification of subgroups of patients with PH in a way that is consistent with the most current schemata for categorizing PH.”
Despite such limitations, they concluded that the current study “is useful in demonstrating the burgeoning number and nature of pediatric PH hospitalizations and the implications of these trends for resource utilization and public policy.”
The researchers reported having no relevant financial disclosures.
It is likely that data from this report represent “the tip of the iceberg” regarding the true impact of PH on hospitalizations, resource utilization, costs, and clinical outcomes. The actual health care costs and resource needs of pediatric PH, as with other chronic diseases, are limited by a lack of data linking inpatient with outpatient care, in which frequent clinic appointments and diagnostic evaluations are essential for improving outcomes well beyond inpatient care alone. The impact of pediatric PH also may be underestimated in these data because the diagnosis of PH and its evaluation are complex, and the role of PH may not be recognized in some clinical settings by health care providers. Despite growing recognition and awareness of PH in many settings, such as prematurity, Down syndrome, obstructive sleep apnea, sickle cell disease, oncologic disorders, chronic lung diseases, liver disease, and others, PH is often a “hidden” contributor to morbidities and outcomes.
More research is needed to best define an optimal PH center for children, but it is likely that this goal will require creation of interdisciplinary teams of cardiologists, pulmonologists, intensivists, neonatologists, and other subspecialists, along with approaches that enhance collaboration between centers.
Dr. Steven H. Abman and Dr. D. Dunbar Ivy are with the pediatric heart lung center in the department of pediatrics at the University of Colorado at Denver Anschutz Medical Center and Children’s Hospital Colorado, Aurora. These remarks were excerpted from a commentary that appeared online in Pediatrics on July 6, 2015 (doi/10.1542/peds.2015-1697) that is supported in part by a grant from the National Heart, Lung, and Blood Institute and the National Institutes of Health. The authors reported having no relevant financial disclosures.
It is likely that data from this report represent “the tip of the iceberg” regarding the true impact of PH on hospitalizations, resource utilization, costs, and clinical outcomes. The actual health care costs and resource needs of pediatric PH, as with other chronic diseases, are limited by a lack of data linking inpatient with outpatient care, in which frequent clinic appointments and diagnostic evaluations are essential for improving outcomes well beyond inpatient care alone. The impact of pediatric PH also may be underestimated in these data because the diagnosis of PH and its evaluation are complex, and the role of PH may not be recognized in some clinical settings by health care providers. Despite growing recognition and awareness of PH in many settings, such as prematurity, Down syndrome, obstructive sleep apnea, sickle cell disease, oncologic disorders, chronic lung diseases, liver disease, and others, PH is often a “hidden” contributor to morbidities and outcomes.
More research is needed to best define an optimal PH center for children, but it is likely that this goal will require creation of interdisciplinary teams of cardiologists, pulmonologists, intensivists, neonatologists, and other subspecialists, along with approaches that enhance collaboration between centers.
Dr. Steven H. Abman and Dr. D. Dunbar Ivy are with the pediatric heart lung center in the department of pediatrics at the University of Colorado at Denver Anschutz Medical Center and Children’s Hospital Colorado, Aurora. These remarks were excerpted from a commentary that appeared online in Pediatrics on July 6, 2015 (doi/10.1542/peds.2015-1697) that is supported in part by a grant from the National Heart, Lung, and Blood Institute and the National Institutes of Health. The authors reported having no relevant financial disclosures.
It is likely that data from this report represent “the tip of the iceberg” regarding the true impact of PH on hospitalizations, resource utilization, costs, and clinical outcomes. The actual health care costs and resource needs of pediatric PH, as with other chronic diseases, are limited by a lack of data linking inpatient with outpatient care, in which frequent clinic appointments and diagnostic evaluations are essential for improving outcomes well beyond inpatient care alone. The impact of pediatric PH also may be underestimated in these data because the diagnosis of PH and its evaluation are complex, and the role of PH may not be recognized in some clinical settings by health care providers. Despite growing recognition and awareness of PH in many settings, such as prematurity, Down syndrome, obstructive sleep apnea, sickle cell disease, oncologic disorders, chronic lung diseases, liver disease, and others, PH is often a “hidden” contributor to morbidities and outcomes.
More research is needed to best define an optimal PH center for children, but it is likely that this goal will require creation of interdisciplinary teams of cardiologists, pulmonologists, intensivists, neonatologists, and other subspecialists, along with approaches that enhance collaboration between centers.
Dr. Steven H. Abman and Dr. D. Dunbar Ivy are with the pediatric heart lung center in the department of pediatrics at the University of Colorado at Denver Anschutz Medical Center and Children’s Hospital Colorado, Aurora. These remarks were excerpted from a commentary that appeared online in Pediatrics on July 6, 2015 (doi/10.1542/peds.2015-1697) that is supported in part by a grant from the National Heart, Lung, and Blood Institute and the National Institutes of Health. The authors reported having no relevant financial disclosures.
Between 1997 and 2006, the proportion of hospitalizations in the United States for pediatric pulmonary hypertension doubled, from 1 in 1,000 discharges for the condition in 1997 to 1 in 500 in 2006, a national retrospective cohort study found.
“These results have practice and policy implications at the institutional, state, and national levels, particularly in the face of increasing pressure to restrain costs while caring for a population with increasingly complex medical needs,” researchers led by Dr. Bryan G. Maxwell reported online June 6, 2015 in Pediatrics (doi/10.1542/peds.2014-3834).
Dr. Maxwell of the departments of anesthesiology and critical care medicine at Johns Hopkins University, Baltimore, Md., and his associates examined data on pediatric pulmonary hypertension (PH) hospitalizations between 1997 and 2006 from the Kids’ Inpatient Database, which is part of the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality.
Of the estimated 43 million pediatric discharges that occurred between 1997 and 2006, 0.13% were for PH, and discharges for the condition increased over the study period, from 1 in 500 in 1997 to 1 in 1,000 in 2006 (P less than .0001). During the same time period, inflation-adjusted national hospital charges for PH hospitalizations increased from $926 million to 3.12 billion (P = .0003).
The researchers also found that the increase in PH discharges was most pronounced between 2006 and 2012, and that most PH hospitalizations did not occur in dedicated children’s hospitals. The overall mortality of patients discharged with PH was 5.9%, and steadily improved between 1997 and 2012 (P less than .0001).
Dr. Maxwell and his associates acknowledged certain limitations of the study, including the fact that the Kids’ Inpatient Database does not provide longitudinal data on patients with PH over time or on outpatient care, and that ICD-9-CM codes “do not permit accurate identification of subgroups of patients with PH in a way that is consistent with the most current schemata for categorizing PH.”
Despite such limitations, they concluded that the current study “is useful in demonstrating the burgeoning number and nature of pediatric PH hospitalizations and the implications of these trends for resource utilization and public policy.”
The researchers reported having no relevant financial disclosures.
Between 1997 and 2006, the proportion of hospitalizations in the United States for pediatric pulmonary hypertension doubled, from 1 in 1,000 discharges for the condition in 1997 to 1 in 500 in 2006, a national retrospective cohort study found.
“These results have practice and policy implications at the institutional, state, and national levels, particularly in the face of increasing pressure to restrain costs while caring for a population with increasingly complex medical needs,” researchers led by Dr. Bryan G. Maxwell reported online June 6, 2015 in Pediatrics (doi/10.1542/peds.2014-3834).
Dr. Maxwell of the departments of anesthesiology and critical care medicine at Johns Hopkins University, Baltimore, Md., and his associates examined data on pediatric pulmonary hypertension (PH) hospitalizations between 1997 and 2006 from the Kids’ Inpatient Database, which is part of the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality.
Of the estimated 43 million pediatric discharges that occurred between 1997 and 2006, 0.13% were for PH, and discharges for the condition increased over the study period, from 1 in 500 in 1997 to 1 in 1,000 in 2006 (P less than .0001). During the same time period, inflation-adjusted national hospital charges for PH hospitalizations increased from $926 million to 3.12 billion (P = .0003).
The researchers also found that the increase in PH discharges was most pronounced between 2006 and 2012, and that most PH hospitalizations did not occur in dedicated children’s hospitals. The overall mortality of patients discharged with PH was 5.9%, and steadily improved between 1997 and 2012 (P less than .0001).
Dr. Maxwell and his associates acknowledged certain limitations of the study, including the fact that the Kids’ Inpatient Database does not provide longitudinal data on patients with PH over time or on outpatient care, and that ICD-9-CM codes “do not permit accurate identification of subgroups of patients with PH in a way that is consistent with the most current schemata for categorizing PH.”
Despite such limitations, they concluded that the current study “is useful in demonstrating the burgeoning number and nature of pediatric PH hospitalizations and the implications of these trends for resource utilization and public policy.”
The researchers reported having no relevant financial disclosures.
FROM PEDIATRICS
Key clinical point: Pediatric PH is associated with a rapidly increasing number of hospital discharges and magnitude of health care costs.
Major finding: Hospital discharges for pediatric PH increased from 1 in 1,000 in 1997 to 1 in 500 in 2012 (P less than .0001).
Data source: A retrospective analysis of pediatric PH hospitalizations in the Kids’ Inpatient Database between 1997 and 2012.
Disclosures: The researchers reported having no relevant financial disclosures.
FDA approves Orkambi for cystic fibrosis
The fixed-dose combination of ivacaftor and lumacaftor has been approved by the Food and Drug Administration for the treatment of cystic fibrosis in people aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. This is the first drug treatment approved for people who have two copies of this mutation, the most common type of cystic fibrosis.
“Today’s approval significantly broadens the availability of targeted treatments for the specific defects that cause cystic fibrosis,” Dr. John Jenkins, director of the Office of New Drugs in the FDA Center for Drug Evaluation and Research, said in a statement. About half of the approximately 30,000 people in the United States who have cystic fibrosis are homozygous for the F508del, the most common CF mutation, according to the FDA.
The combination contains 200 mg of lumacaftor and 125 mg of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator; it is taken twice a day. It will be marketed as Orkambi by Vertex Pharmaceuticals. Ivacaftor, marketed as Kalydeco by Vertex, was approved in January 2012 for treating patients with the G551D mutation (about 4% of patients with CF), and its indications have been expanded since that time to include other CFTR gene mutations.
Dr. Robert Giusti, director of the pediatric cystic fibrosis center at New York University Langone Medical Center, said in an interview that although new treatments have improved survival and patients with CF are now living longer, “we haven’t been able to reverse the downward trend in pulmonary function,” which is about 1%-2% a year in patients with CF. For a significant number of patients with CF, treatment with Orkambi “will reverse that trend and will allow them to maintain their lung function,” he added. Referring to the discovery of the CF gene in 1989, he pointed out that the availability of this treatment for half of all patients with CF is the culmination of more than 25 years of research,.
The approval is “very, very exciting,” said Dr. Susan Millard, director for clinical research for the pediatric cystic fibrosis care center at Helen DeVos Children’s Hospital, Grand Rapids, Mich. Ivacaftor alone was not effective in patients with two copies of the F08del mutation, and both drugs are needed for the beneficial effects, she said in an interview.
Lumacaftor “is designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the F508del CFTR protein, and ivacaftor... is designed to enhance the function of the CFTR protein once it reaches the cell surface,” according to a statement from Vertex.
According to the prescribing information for ivacaftor/lumacaftor, “if the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.” The indications and usage section also states that efficacy and safety “have not been established in patients with CF other than those homozygous for the F508del mutation.”
Approval was based on two double-blind, placebo-controlled studies of 1,108 patients with CF with the F508del mutation aged 12 years and older. In the studies, improvements in lung function among those treated with the combination drug were greater than those on placebo.
At 24 weeks, the absolute change in percent-predicted forced expiratory volume in 1 second (ppFEV1) over placebo, the primary efficacy endpoint, was a mean of 2.6% and 3.0% among those treated with the 400 mg/250 mg fixed dose (two pills) every 12 hours, which were statistically significant changes. In an extension study, the effect was sustained through 48 weeks. There also were reductions in pulmonary exacerbations, improvements in body mass index, and Cystic Fibrosis Questionnaire-Revised improvements – secondary endpoints that favored the treatment arms, according to company presentations at the FDA panel meeting where the drug was reviewed in May.
One of the issues raised by FDA advisers then was that there was no substantial evidence that the efficacy of the combination was greater than with ivacaftor alone. But despite the lack of monotherapy arms and the inability to determine the contribution of the individual components to the treatment effects, the panel agreed that the drug combination had been shown to be efficacious and voted 12-1 that the available safety and efficacy data supported approval for the proposed indication.
Dr. Millard said that one theory that may explain why BMI improves with treatment is that reduced bicarbonate production in CF patients increases the degradation of the pancreatic enzymes they take, and that the drug may result in more appropriate bicarbonate secretion. This possibility is being evaluated in studies comparing bicarbonate secretion in patients on and off the drug, she said.
The drug was reviewed under the FDA’s priority review program, which evaluates a drug “that may offer significant improvement in safety or effectiveness in treatment over available therapy in a serious disease or condition” in 6 months, instead of the usual 10 months, the FDA statement said. Orkambi has also been designated as an orphan drug, because it is used to treat a rare disease.
The wholesale acquisition cost of Orkambi is $259,000 per year. Vertex will offer a co-pay assistance program for patients with commercial insurance, and a free medicine program for uninsured patients who qualify, the company announced during a telephone briefing after the approval announcement. There are an estimated 8,500 patients aged 12 and older with CF with 2 copies of the F508del mutation in the United States; about 35%-40% are on Medicaid, and the majority of the remainder have commercial insurance, according to the company.
Dr. Giusti had no disclosures. Dr. Millard, an investigator in past and current trials of Orkambi, said she had no other disclosures.
This article was updated on 7/6/2015.
The fixed-dose combination of ivacaftor and lumacaftor has been approved by the Food and Drug Administration for the treatment of cystic fibrosis in people aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. This is the first drug treatment approved for people who have two copies of this mutation, the most common type of cystic fibrosis.
“Today’s approval significantly broadens the availability of targeted treatments for the specific defects that cause cystic fibrosis,” Dr. John Jenkins, director of the Office of New Drugs in the FDA Center for Drug Evaluation and Research, said in a statement. About half of the approximately 30,000 people in the United States who have cystic fibrosis are homozygous for the F508del, the most common CF mutation, according to the FDA.
The combination contains 200 mg of lumacaftor and 125 mg of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator; it is taken twice a day. It will be marketed as Orkambi by Vertex Pharmaceuticals. Ivacaftor, marketed as Kalydeco by Vertex, was approved in January 2012 for treating patients with the G551D mutation (about 4% of patients with CF), and its indications have been expanded since that time to include other CFTR gene mutations.
Dr. Robert Giusti, director of the pediatric cystic fibrosis center at New York University Langone Medical Center, said in an interview that although new treatments have improved survival and patients with CF are now living longer, “we haven’t been able to reverse the downward trend in pulmonary function,” which is about 1%-2% a year in patients with CF. For a significant number of patients with CF, treatment with Orkambi “will reverse that trend and will allow them to maintain their lung function,” he added. Referring to the discovery of the CF gene in 1989, he pointed out that the availability of this treatment for half of all patients with CF is the culmination of more than 25 years of research,.
The approval is “very, very exciting,” said Dr. Susan Millard, director for clinical research for the pediatric cystic fibrosis care center at Helen DeVos Children’s Hospital, Grand Rapids, Mich. Ivacaftor alone was not effective in patients with two copies of the F08del mutation, and both drugs are needed for the beneficial effects, she said in an interview.
Lumacaftor “is designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the F508del CFTR protein, and ivacaftor... is designed to enhance the function of the CFTR protein once it reaches the cell surface,” according to a statement from Vertex.
According to the prescribing information for ivacaftor/lumacaftor, “if the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.” The indications and usage section also states that efficacy and safety “have not been established in patients with CF other than those homozygous for the F508del mutation.”
Approval was based on two double-blind, placebo-controlled studies of 1,108 patients with CF with the F508del mutation aged 12 years and older. In the studies, improvements in lung function among those treated with the combination drug were greater than those on placebo.
At 24 weeks, the absolute change in percent-predicted forced expiratory volume in 1 second (ppFEV1) over placebo, the primary efficacy endpoint, was a mean of 2.6% and 3.0% among those treated with the 400 mg/250 mg fixed dose (two pills) every 12 hours, which were statistically significant changes. In an extension study, the effect was sustained through 48 weeks. There also were reductions in pulmonary exacerbations, improvements in body mass index, and Cystic Fibrosis Questionnaire-Revised improvements – secondary endpoints that favored the treatment arms, according to company presentations at the FDA panel meeting where the drug was reviewed in May.
One of the issues raised by FDA advisers then was that there was no substantial evidence that the efficacy of the combination was greater than with ivacaftor alone. But despite the lack of monotherapy arms and the inability to determine the contribution of the individual components to the treatment effects, the panel agreed that the drug combination had been shown to be efficacious and voted 12-1 that the available safety and efficacy data supported approval for the proposed indication.
Dr. Millard said that one theory that may explain why BMI improves with treatment is that reduced bicarbonate production in CF patients increases the degradation of the pancreatic enzymes they take, and that the drug may result in more appropriate bicarbonate secretion. This possibility is being evaluated in studies comparing bicarbonate secretion in patients on and off the drug, she said.
The drug was reviewed under the FDA’s priority review program, which evaluates a drug “that may offer significant improvement in safety or effectiveness in treatment over available therapy in a serious disease or condition” in 6 months, instead of the usual 10 months, the FDA statement said. Orkambi has also been designated as an orphan drug, because it is used to treat a rare disease.
The wholesale acquisition cost of Orkambi is $259,000 per year. Vertex will offer a co-pay assistance program for patients with commercial insurance, and a free medicine program for uninsured patients who qualify, the company announced during a telephone briefing after the approval announcement. There are an estimated 8,500 patients aged 12 and older with CF with 2 copies of the F508del mutation in the United States; about 35%-40% are on Medicaid, and the majority of the remainder have commercial insurance, according to the company.
Dr. Giusti had no disclosures. Dr. Millard, an investigator in past and current trials of Orkambi, said she had no other disclosures.
This article was updated on 7/6/2015.
The fixed-dose combination of ivacaftor and lumacaftor has been approved by the Food and Drug Administration for the treatment of cystic fibrosis in people aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. This is the first drug treatment approved for people who have two copies of this mutation, the most common type of cystic fibrosis.
“Today’s approval significantly broadens the availability of targeted treatments for the specific defects that cause cystic fibrosis,” Dr. John Jenkins, director of the Office of New Drugs in the FDA Center for Drug Evaluation and Research, said in a statement. About half of the approximately 30,000 people in the United States who have cystic fibrosis are homozygous for the F508del, the most common CF mutation, according to the FDA.
The combination contains 200 mg of lumacaftor and 125 mg of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator; it is taken twice a day. It will be marketed as Orkambi by Vertex Pharmaceuticals. Ivacaftor, marketed as Kalydeco by Vertex, was approved in January 2012 for treating patients with the G551D mutation (about 4% of patients with CF), and its indications have been expanded since that time to include other CFTR gene mutations.
Dr. Robert Giusti, director of the pediatric cystic fibrosis center at New York University Langone Medical Center, said in an interview that although new treatments have improved survival and patients with CF are now living longer, “we haven’t been able to reverse the downward trend in pulmonary function,” which is about 1%-2% a year in patients with CF. For a significant number of patients with CF, treatment with Orkambi “will reverse that trend and will allow them to maintain their lung function,” he added. Referring to the discovery of the CF gene in 1989, he pointed out that the availability of this treatment for half of all patients with CF is the culmination of more than 25 years of research,.
The approval is “very, very exciting,” said Dr. Susan Millard, director for clinical research for the pediatric cystic fibrosis care center at Helen DeVos Children’s Hospital, Grand Rapids, Mich. Ivacaftor alone was not effective in patients with two copies of the F08del mutation, and both drugs are needed for the beneficial effects, she said in an interview.
Lumacaftor “is designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the F508del CFTR protein, and ivacaftor... is designed to enhance the function of the CFTR protein once it reaches the cell surface,” according to a statement from Vertex.
According to the prescribing information for ivacaftor/lumacaftor, “if the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.” The indications and usage section also states that efficacy and safety “have not been established in patients with CF other than those homozygous for the F508del mutation.”
Approval was based on two double-blind, placebo-controlled studies of 1,108 patients with CF with the F508del mutation aged 12 years and older. In the studies, improvements in lung function among those treated with the combination drug were greater than those on placebo.
At 24 weeks, the absolute change in percent-predicted forced expiratory volume in 1 second (ppFEV1) over placebo, the primary efficacy endpoint, was a mean of 2.6% and 3.0% among those treated with the 400 mg/250 mg fixed dose (two pills) every 12 hours, which were statistically significant changes. In an extension study, the effect was sustained through 48 weeks. There also were reductions in pulmonary exacerbations, improvements in body mass index, and Cystic Fibrosis Questionnaire-Revised improvements – secondary endpoints that favored the treatment arms, according to company presentations at the FDA panel meeting where the drug was reviewed in May.
One of the issues raised by FDA advisers then was that there was no substantial evidence that the efficacy of the combination was greater than with ivacaftor alone. But despite the lack of monotherapy arms and the inability to determine the contribution of the individual components to the treatment effects, the panel agreed that the drug combination had been shown to be efficacious and voted 12-1 that the available safety and efficacy data supported approval for the proposed indication.
Dr. Millard said that one theory that may explain why BMI improves with treatment is that reduced bicarbonate production in CF patients increases the degradation of the pancreatic enzymes they take, and that the drug may result in more appropriate bicarbonate secretion. This possibility is being evaluated in studies comparing bicarbonate secretion in patients on and off the drug, she said.
The drug was reviewed under the FDA’s priority review program, which evaluates a drug “that may offer significant improvement in safety or effectiveness in treatment over available therapy in a serious disease or condition” in 6 months, instead of the usual 10 months, the FDA statement said. Orkambi has also been designated as an orphan drug, because it is used to treat a rare disease.
The wholesale acquisition cost of Orkambi is $259,000 per year. Vertex will offer a co-pay assistance program for patients with commercial insurance, and a free medicine program for uninsured patients who qualify, the company announced during a telephone briefing after the approval announcement. There are an estimated 8,500 patients aged 12 and older with CF with 2 copies of the F508del mutation in the United States; about 35%-40% are on Medicaid, and the majority of the remainder have commercial insurance, according to the company.
Dr. Giusti had no disclosures. Dr. Millard, an investigator in past and current trials of Orkambi, said she had no other disclosures.
This article was updated on 7/6/2015.
FDA probes safety of codeine-containing medicine in children
The Food and Drug Administration wants health care professionals and patients to report adverse events or side effects stemming from codeine-containing medicine use in people under age 18 years to assist it with a new investigation.
The agency is trying to determine if it is safe for people under 18 years of age to treat coughs and colds with codeine-containing medicines, according to a statement released today. These drugs’ potential for causing slowed or difficult breathing was the impetus for the investigation.
The investigation follows the European Medicine Agency’s announcement, in April 2015, that codeine must not be used to treat cough and cold in children under 12 years, and that codeine use is not recommended for people between the ages of 12 and 18 years who have breathing problems, including those with asthma and other chronic breathing problems. In 2013, the FDA issued a statement warning of the risks of codeine use by children who had recently had surgery to remove their tonsils and/or adenoids.
The FDA “will consider the EMA recommendations” and announce its final conclusions and recommendations after it completes the investigation, said the agency in its recent statement.
Reports on problems with codeine-containing medicines can be submitted online at www.fda.gov.MedWatch/report, by fax (1-800-FDA-0178), or by mail. The FDA’s official reporting forms can be obtained by download or by calling 1-800-332-1088 to request a form.
The Food and Drug Administration wants health care professionals and patients to report adverse events or side effects stemming from codeine-containing medicine use in people under age 18 years to assist it with a new investigation.
The agency is trying to determine if it is safe for people under 18 years of age to treat coughs and colds with codeine-containing medicines, according to a statement released today. These drugs’ potential for causing slowed or difficult breathing was the impetus for the investigation.
The investigation follows the European Medicine Agency’s announcement, in April 2015, that codeine must not be used to treat cough and cold in children under 12 years, and that codeine use is not recommended for people between the ages of 12 and 18 years who have breathing problems, including those with asthma and other chronic breathing problems. In 2013, the FDA issued a statement warning of the risks of codeine use by children who had recently had surgery to remove their tonsils and/or adenoids.
The FDA “will consider the EMA recommendations” and announce its final conclusions and recommendations after it completes the investigation, said the agency in its recent statement.
Reports on problems with codeine-containing medicines can be submitted online at www.fda.gov.MedWatch/report, by fax (1-800-FDA-0178), or by mail. The FDA’s official reporting forms can be obtained by download or by calling 1-800-332-1088 to request a form.
The Food and Drug Administration wants health care professionals and patients to report adverse events or side effects stemming from codeine-containing medicine use in people under age 18 years to assist it with a new investigation.
The agency is trying to determine if it is safe for people under 18 years of age to treat coughs and colds with codeine-containing medicines, according to a statement released today. These drugs’ potential for causing slowed or difficult breathing was the impetus for the investigation.
The investigation follows the European Medicine Agency’s announcement, in April 2015, that codeine must not be used to treat cough and cold in children under 12 years, and that codeine use is not recommended for people between the ages of 12 and 18 years who have breathing problems, including those with asthma and other chronic breathing problems. In 2013, the FDA issued a statement warning of the risks of codeine use by children who had recently had surgery to remove their tonsils and/or adenoids.
The FDA “will consider the EMA recommendations” and announce its final conclusions and recommendations after it completes the investigation, said the agency in its recent statement.
Reports on problems with codeine-containing medicines can be submitted online at www.fda.gov.MedWatch/report, by fax (1-800-FDA-0178), or by mail. The FDA’s official reporting forms can be obtained by download or by calling 1-800-332-1088 to request a form.
Researchers pin down possible cause, source for narcolepsy associated with flu vaccine
Patients with a history of vaccination with the pandemic influenza vaccine Pandemrix and narcolepsy were found to have antibodies to hypocretin receptor 2, possibly explaining this association after the 2009 (H1N1) pandemic.
The development of narcolepsy is associated with HLA-DQB1*0602 haplotype, loss of hypothalamic cells, and decrease production of hypocretin, a neuropeptide also known as orexin.
After the 2009 H1N1 influenza pandemic, there were increased reports of narcolepsy associated with the Pandemrix vaccine in Europe. Studies of this association found a 12.7-fold increased risk of narcolepsy within 8 months of Pandemrix vaccination. However, Focetria, the other H1N1 vaccine used in Europe in the 2009 pandemic, does not currently have a reported increased risk. Likewise, studies in China indicate an increased risk of narcolepsy after infection with the 2009 pandemic H1N1 influenza virus.
“We hypothesized that differences between the ‘adjuvanted’ A(H1N1)pdm09 vaccines Pandemrix and Focetria explain the association of narcolepsy with Pandemrix vaccinated subjects,” Dr. Syed Ahmed of Novartis Vaccines, Siena, Italy, and colleagues reported (Sci. Transl. Med. 2015;7:294ra105).
The researchers conducted a retrospective analysis of sera from narcoleptic individuals vaccinated with Pandemrix and a history of H1N1 infection as well as children from Finland without a history of narcolepsy and a history of Focetria vaccination. The samples were randomized and the investigators were blinded.
By aligning protein sequences of influenza strains, the researchers were able to identify an influenza nucleoprotein peptide similar to the hypocretin receptor. ELISA assays detected antibodies to hypocretin receptor 2 in a significantly higher percentage of sera samples from patients with a history of Pandemrix vaccination, HLA-DQB1*0602 haplotype, and narcolepsy (17 of 20), compared with patients with a history of Focetria vaccination (0 of 6; P < .001) or H1N1 infection (5 of 20; P < .001).
Furthermore, mass spectrometry indicated Focetria contained 72.7% less nucleoprotein than did Pandemrix. ELISA assays detected fewer nucleoprotein antibodies in individuals vaccinated with Focetria than in those infected with H1N1. Dr. Ahmed and his colleagues concluded that a possible mechanism for influenza and vaccine associated narcolepsy involves nucleoprotein antigen development after vaccination or infection and cross reaction with the hypocretin receptor 2. Furthermore, the difference in nucleoprotein content of the two vaccine types may further explain the association of Pandemrix vaccination with narcolepsy.
“The implications of the new work are important but specific. First of all, the findings show that in rare cases, vaccines can accidentally trigger autoimmunelike brain disease. The anti-H1N1 vaccine Pandemrix appears to make the case, stimulating in some individuals the production of hypocretin receptor cross-binding antibodies as a result of its high content of influenza [nucleoprotein].”
“Last, the work elegantly provides insight into vaccine-related narcolepsy but does not directly disclose whether similar mechanisms (autoimmune, parainfectious, etc.) contribute to sporadic narcolepsy. To settle this question definitively will require additional data from immune therapies, neuropathology, and much-needed narcolepsy animal models.”
Dr. Hartmut Wekerle is affiliated with the Max-Planck Institute of Neurobiology, Martinsried, Germany. These comments are taken from an editorial accompanying Dr. Ahmed and his colleagues’ report (Sci. Transl. Med. 2015;7:294fs27).
“The implications of the new work are important but specific. First of all, the findings show that in rare cases, vaccines can accidentally trigger autoimmunelike brain disease. The anti-H1N1 vaccine Pandemrix appears to make the case, stimulating in some individuals the production of hypocretin receptor cross-binding antibodies as a result of its high content of influenza [nucleoprotein].”
“Last, the work elegantly provides insight into vaccine-related narcolepsy but does not directly disclose whether similar mechanisms (autoimmune, parainfectious, etc.) contribute to sporadic narcolepsy. To settle this question definitively will require additional data from immune therapies, neuropathology, and much-needed narcolepsy animal models.”
Dr. Hartmut Wekerle is affiliated with the Max-Planck Institute of Neurobiology, Martinsried, Germany. These comments are taken from an editorial accompanying Dr. Ahmed and his colleagues’ report (Sci. Transl. Med. 2015;7:294fs27).
“The implications of the new work are important but specific. First of all, the findings show that in rare cases, vaccines can accidentally trigger autoimmunelike brain disease. The anti-H1N1 vaccine Pandemrix appears to make the case, stimulating in some individuals the production of hypocretin receptor cross-binding antibodies as a result of its high content of influenza [nucleoprotein].”
“Last, the work elegantly provides insight into vaccine-related narcolepsy but does not directly disclose whether similar mechanisms (autoimmune, parainfectious, etc.) contribute to sporadic narcolepsy. To settle this question definitively will require additional data from immune therapies, neuropathology, and much-needed narcolepsy animal models.”
Dr. Hartmut Wekerle is affiliated with the Max-Planck Institute of Neurobiology, Martinsried, Germany. These comments are taken from an editorial accompanying Dr. Ahmed and his colleagues’ report (Sci. Transl. Med. 2015;7:294fs27).
Patients with a history of vaccination with the pandemic influenza vaccine Pandemrix and narcolepsy were found to have antibodies to hypocretin receptor 2, possibly explaining this association after the 2009 (H1N1) pandemic.
The development of narcolepsy is associated with HLA-DQB1*0602 haplotype, loss of hypothalamic cells, and decrease production of hypocretin, a neuropeptide also known as orexin.
After the 2009 H1N1 influenza pandemic, there were increased reports of narcolepsy associated with the Pandemrix vaccine in Europe. Studies of this association found a 12.7-fold increased risk of narcolepsy within 8 months of Pandemrix vaccination. However, Focetria, the other H1N1 vaccine used in Europe in the 2009 pandemic, does not currently have a reported increased risk. Likewise, studies in China indicate an increased risk of narcolepsy after infection with the 2009 pandemic H1N1 influenza virus.
“We hypothesized that differences between the ‘adjuvanted’ A(H1N1)pdm09 vaccines Pandemrix and Focetria explain the association of narcolepsy with Pandemrix vaccinated subjects,” Dr. Syed Ahmed of Novartis Vaccines, Siena, Italy, and colleagues reported (Sci. Transl. Med. 2015;7:294ra105).
The researchers conducted a retrospective analysis of sera from narcoleptic individuals vaccinated with Pandemrix and a history of H1N1 infection as well as children from Finland without a history of narcolepsy and a history of Focetria vaccination. The samples were randomized and the investigators were blinded.
By aligning protein sequences of influenza strains, the researchers were able to identify an influenza nucleoprotein peptide similar to the hypocretin receptor. ELISA assays detected antibodies to hypocretin receptor 2 in a significantly higher percentage of sera samples from patients with a history of Pandemrix vaccination, HLA-DQB1*0602 haplotype, and narcolepsy (17 of 20), compared with patients with a history of Focetria vaccination (0 of 6; P < .001) or H1N1 infection (5 of 20; P < .001).
Furthermore, mass spectrometry indicated Focetria contained 72.7% less nucleoprotein than did Pandemrix. ELISA assays detected fewer nucleoprotein antibodies in individuals vaccinated with Focetria than in those infected with H1N1. Dr. Ahmed and his colleagues concluded that a possible mechanism for influenza and vaccine associated narcolepsy involves nucleoprotein antigen development after vaccination or infection and cross reaction with the hypocretin receptor 2. Furthermore, the difference in nucleoprotein content of the two vaccine types may further explain the association of Pandemrix vaccination with narcolepsy.
Patients with a history of vaccination with the pandemic influenza vaccine Pandemrix and narcolepsy were found to have antibodies to hypocretin receptor 2, possibly explaining this association after the 2009 (H1N1) pandemic.
The development of narcolepsy is associated with HLA-DQB1*0602 haplotype, loss of hypothalamic cells, and decrease production of hypocretin, a neuropeptide also known as orexin.
After the 2009 H1N1 influenza pandemic, there were increased reports of narcolepsy associated with the Pandemrix vaccine in Europe. Studies of this association found a 12.7-fold increased risk of narcolepsy within 8 months of Pandemrix vaccination. However, Focetria, the other H1N1 vaccine used in Europe in the 2009 pandemic, does not currently have a reported increased risk. Likewise, studies in China indicate an increased risk of narcolepsy after infection with the 2009 pandemic H1N1 influenza virus.
“We hypothesized that differences between the ‘adjuvanted’ A(H1N1)pdm09 vaccines Pandemrix and Focetria explain the association of narcolepsy with Pandemrix vaccinated subjects,” Dr. Syed Ahmed of Novartis Vaccines, Siena, Italy, and colleagues reported (Sci. Transl. Med. 2015;7:294ra105).
The researchers conducted a retrospective analysis of sera from narcoleptic individuals vaccinated with Pandemrix and a history of H1N1 infection as well as children from Finland without a history of narcolepsy and a history of Focetria vaccination. The samples were randomized and the investigators were blinded.
By aligning protein sequences of influenza strains, the researchers were able to identify an influenza nucleoprotein peptide similar to the hypocretin receptor. ELISA assays detected antibodies to hypocretin receptor 2 in a significantly higher percentage of sera samples from patients with a history of Pandemrix vaccination, HLA-DQB1*0602 haplotype, and narcolepsy (17 of 20), compared with patients with a history of Focetria vaccination (0 of 6; P < .001) or H1N1 infection (5 of 20; P < .001).
Furthermore, mass spectrometry indicated Focetria contained 72.7% less nucleoprotein than did Pandemrix. ELISA assays detected fewer nucleoprotein antibodies in individuals vaccinated with Focetria than in those infected with H1N1. Dr. Ahmed and his colleagues concluded that a possible mechanism for influenza and vaccine associated narcolepsy involves nucleoprotein antigen development after vaccination or infection and cross reaction with the hypocretin receptor 2. Furthermore, the difference in nucleoprotein content of the two vaccine types may further explain the association of Pandemrix vaccination with narcolepsy.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point:Nucleoprotein antibodies possibly explain influenza vaccine associated narcolepsy.
Major finding: Patients with a history of Pandemrix vaccination, HLA-DQB1*0602 haplotype, and narcolepsy had detectable antibodies to hypocretin receptor 2.
Data source: Retrospective analysis of sera from the 2009 H1N1 pandemic.
Disclosures: The authors note no funding sources for the study, but an award from the National Center for Research Resources helped provide the mass spectrometer used during the study. Multiple authors disclosed employment and stock holdings in Novartis and Atreca. There were also authors who reported receiving honoraria and holding patents.