Study Overview

Objective. To evaluate the association between intake of dietary fiber and type 2 diabetes.

Design. Case-cohort study (EPIC-InterAct Study), which is nested within the large prospective cohort study EPIC (European Prospective Investigation into Cancer & Nutrition) [1]. EPIC includes participants from 10 European countries and was designed to investigate the relationships between diet, nutritional status, lifestyle, and environmental factors and the incidence of cancer and other chronic disease [1].

Setting and participants. The EPIC-Interact study used data from 8 European countries (Denmark, France, Germany, Italy, the Netherlands, Spain, Sweden, and UK). The Interact sample includes 12,403 individuals who were identified as having developed type 2 diabetes, and a random subcohort of controls who were free of diabetes at baseline (n = 16,835, including 778 cases of incident diabetes) selected from 340,234 eligible EPIC participants. Of the 28,460 participants in the EPIC-InterAct study, excluded were those with prevalent diabetes, missing diabetes status information, post-censoring diabetes, extreme energy intake (top and bottom 1%), and missing values for education level, physical activity, smoking status, and BMI, leaving a final sample of 11,559 cases and 15,258 subcohort participants. No differences were observed in baseline characteristics between the included and excluded participants.

Analysis. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox proportional hazards models and were pooled using a random effects meta-analysis. Dietary intake over the previous 12 months before recruitment was assessed by country-specific or center-specific assessment methods (food-frequency questionnaire and dietary histories) that were developed and validated locally, and data were converted to nutrient intake.

Main outcome measure. Incident cases of diabetes.

Main results. During a median of 10.8 years of follow-up, total fiber intake was associated with a lower risk of diabetes after adjusting for lifestyle and dietary factors (hazard ratio for the highest quartile of fiber intake [> 26 g/day] vs the lowest [< 19 g/day], 0.82; 95% confidence interval, 0.69–0.97, P for trend = 0.02). When the researchers focused on specific types of fiber, they found that people who consumed the highest amounts of cereal and vegetable fiber were 19% and 16%, respectively, less likely to develop type 2 diabetes compared with those who consumed the lowest amounts (P < 0.001). Intake of fruit fiber was not associated with risk of diabetes. When the analyses were additionally adjusted for BMI, the inverse associations between intake of fiber and diabetes were attenuated and no longer statistically significant.

The researchers also conducted a meta-analysis that included 18 other cohorts in addition to the current EPIC-InterAct study. The summary relative risks per 10/g day increase in intake were 0.91 (95% CI, 0.87–0.96) for total fiber, 0.75 (95% CI, 0.65–0.86) for cereal fiber, 0.95 (95% CI, 0.87–1.03) for fruit fiber, and 0.93 (95% CI 0.82–1.05) for vegetable fiber.

Conclusion. Individuals with diets rich in fiber, in particular cereal fiber, may be at lower risk of type 2 diabetes.

Commentary

The current study by the European InterAct Consortium adds to the available evidence supporting the association of dietary fiber and risk of diabetes. Higher intake of dietary fiber, especially cereal fiber, has been consistently associated with a lower risk of diabetes [2,3].

This study showed that a high intake of total fiber (primarily cereal and vegetable fiber) was associated with an 18% lower risk of type 2 diabetes (adjusted for dietary and lifestyle factors). While there was no association after adjusting for BMI, their meta-analysis of 18 studies did support the an inverse association between total fiber and cereal fiber intake and risk of type 2 diabetes.

What is it about fiber that is protective? With regard to whole grains, a rich source of fiber, potential mechanisms have been identified [5], including the possible impact of improved postprandial glucose response. However, whole grains are rich in nutrients and phytochemicals, and new hypotheses for the health-protective mechanisms of whole grains beyond fiber are being proposed [6]. In addition, the beneficial effect of fiber seen in this and other studies may be partly mediated by a lower BMI. Dietary fiber may affect appetite and energy intake through a range of processes.

It should be noted that although the effect of whole-grain foods for the prevention of type 2 diabetes is strongly supported by numerous epidemiological studies, a 2008 systematic review by the Cochrane Collaboration [4], which included 1 low-quality RCT and 11 cohort studies, stated that the evidence is too weak to be able to draw a definite conclusion about the preventive effect of this dietary factor.

Strengths of the study included its prospective design and large sample size. Limitations of the study include that dietary intake was assessed only at baseline and measurement error through the use of a questionnaire may have occurred. Although food-frequency questionnaires are widely used, they are subjective estimates and subject to recall bias, and some researchers have questioned their value for use in epidemiologic studies [7]. In addition, the authors note that the inverse association for total fiber and cereal fiber intake in the meta-analysis could be due to residual confounding as fiber intake has been associated with healthier diet, lower BMI, and greater physical activity.

Applications for Clinical Practice

The prevalence of type 2 diabetes has increased rapidly during the past decades in the United States. Dietary guidelines recommend the consumption of whole grains to prevent chronic diseases. The results presented in the current study strengthen the evidence supporting cereal fiber as an important determinant of type 2 diabetes risk. Randomized controlled trials are needed and should elucidate this matter.

Study Overview

Objective. To evaluate the association between intake of dietary fiber and type 2 diabetes.

Design. Case-cohort study (EPIC-InterAct Study), which is nested within the large prospective cohort study EPIC (European Prospective Investigation into Cancer & Nutrition) [1]. EPIC includes participants from 10 European countries and was designed to investigate the relationships between diet, nutritional status, lifestyle, and environmental factors and the incidence of cancer and other chronic disease [1].

Setting and participants. The EPIC-Interact study used data from 8 European countries (Denmark, France, Germany, Italy, the Netherlands, Spain, Sweden, and UK). The Interact sample includes 12,403 individuals who were identified as having developed type 2 diabetes, and a random subcohort of controls who were free of diabetes at baseline (n = 16,835, including 778 cases of incident diabetes) selected from 340,234 eligible EPIC participants. Of the 28,460 participants in the EPIC-InterAct study, excluded were those with prevalent diabetes, missing diabetes status information, post-censoring diabetes, extreme energy intake (top and bottom 1%), and missing values for education level, physical activity, smoking status, and BMI, leaving a final sample of 11,559 cases and 15,258 subcohort participants. No differences were observed in baseline characteristics between the included and excluded participants.

Analysis. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox proportional hazards models and were pooled using a random effects meta-analysis. Dietary intake over the previous 12 months before recruitment was assessed by country-specific or center-specific assessment methods (food-frequency questionnaire and dietary histories) that were developed and validated locally, and data were converted to nutrient intake.

Main outcome measure. Incident cases of diabetes.

Main results. During a median of 10.8 years of follow-up, total fiber intake was associated with a lower risk of diabetes after adjusting for lifestyle and dietary factors (hazard ratio for the highest quartile of fiber intake [> 26 g/day] vs the lowest [< 19 g/day], 0.82; 95% confidence interval, 0.69–0.97, P for trend = 0.02). When the researchers focused on specific types of fiber, they found that people who consumed the highest amounts of cereal and vegetable fiber were 19% and 16%, respectively, less likely to develop type 2 diabetes compared with those who consumed the lowest amounts (P < 0.001). Intake of fruit fiber was not associated with risk of diabetes. When the analyses were additionally adjusted for BMI, the inverse associations between intake of fiber and diabetes were attenuated and no longer statistically significant.

The researchers also conducted a meta-analysis that included 18 other cohorts in addition to the current EPIC-InterAct study. The summary relative risks per 10/g day increase in intake were 0.91 (95% CI, 0.87–0.96) for total fiber, 0.75 (95% CI, 0.65–0.86) for cereal fiber, 0.95 (95% CI, 0.87–1.03) for fruit fiber, and 0.93 (95% CI 0.82–1.05) for vegetable fiber.

Conclusion. Individuals with diets rich in fiber, in particular cereal fiber, may be at lower risk of type 2 diabetes.

Commentary

The current study by the European InterAct Consortium adds to the available evidence supporting the association of dietary fiber and risk of diabetes. Higher intake of dietary fiber, especially cereal fiber, has been consistently associated with a lower risk of diabetes [2,3].

This study showed that a high intake of total fiber (primarily cereal and vegetable fiber) was associated with an 18% lower risk of type 2 diabetes (adjusted for dietary and lifestyle factors). While there was no association after adjusting for BMI, their meta-analysis of 18 studies did support the an inverse association between total fiber and cereal fiber intake and risk of type 2 diabetes.

What is it about fiber that is protective? With regard to whole grains, a rich source of fiber, potential mechanisms have been identified [5], including the possible impact of improved postprandial glucose response. However, whole grains are rich in nutrients and phytochemicals, and new hypotheses for the health-protective mechanisms of whole grains beyond fiber are being proposed [6]. In addition, the beneficial effect of fiber seen in this and other studies may be partly mediated by a lower BMI. Dietary fiber may affect appetite and energy intake through a range of processes.

It should be noted that although the effect of whole-grain foods for the prevention of type 2 diabetes is strongly supported by numerous epidemiological studies, a 2008 systematic review by the Cochrane Collaboration [4], which included 1 low-quality RCT and 11 cohort studies, stated that the evidence is too weak to be able to draw a definite conclusion about the preventive effect of this dietary factor.

Strengths of the study included its prospective design and large sample size. Limitations of the study include that dietary intake was assessed only at baseline and measurement error through the use of a questionnaire may have occurred. Although food-frequency questionnaires are widely used, they are subjective estimates and subject to recall bias, and some researchers have questioned their value for use in epidemiologic studies [7]. In addition, the authors note that the inverse association for total fiber and cereal fiber intake in the meta-analysis could be due to residual confounding as fiber intake has been associated with healthier diet, lower BMI, and greater physical activity.

Applications for Clinical Practice

The prevalence of type 2 diabetes has increased rapidly during the past decades in the United States. Dietary guidelines recommend the consumption of whole grains to prevent chronic diseases. The results presented in the current study strengthen the evidence supporting cereal fiber as an important determinant of type 2 diabetes risk. Randomized controlled trials are needed and should elucidate this matter.

Study Overview

Objective. To evaluate the association between intake of dietary fiber and type 2 diabetes.

Design. Case-cohort study (EPIC-InterAct Study), which is nested within the large prospective cohort study EPIC (European Prospective Investigation into Cancer & Nutrition) [1]. EPIC includes participants from 10 European countries and was designed to investigate the relationships between diet, nutritional status, lifestyle, and environmental factors and the incidence of cancer and other chronic disease [1].

Setting and participants. The EPIC-Interact study used data from 8 European countries (Denmark, France, Germany, Italy, the Netherlands, Spain, Sweden, and UK). The Interact sample includes 12,403 individuals who were identified as having developed type 2 diabetes, and a random subcohort of controls who were free of diabetes at baseline (n = 16,835, including 778 cases of incident diabetes) selected from 340,234 eligible EPIC participants. Of the 28,460 participants in the EPIC-InterAct study, excluded were those with prevalent diabetes, missing diabetes status information, post-censoring diabetes, extreme energy intake (top and bottom 1%), and missing values for education level, physical activity, smoking status, and BMI, leaving a final sample of 11,559 cases and 15,258 subcohort participants. No differences were observed in baseline characteristics between the included and excluded participants.

Analysis. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox proportional hazards models and were pooled using a random effects meta-analysis. Dietary intake over the previous 12 months before recruitment was assessed by country-specific or center-specific assessment methods (food-frequency questionnaire and dietary histories) that were developed and validated locally, and data were converted to nutrient intake.

Main outcome measure. Incident cases of diabetes.

Main results. During a median of 10.8 years of follow-up, total fiber intake was associated with a lower risk of diabetes after adjusting for lifestyle and dietary factors (hazard ratio for the highest quartile of fiber intake [> 26 g/day] vs the lowest [< 19 g/day], 0.82; 95% confidence interval, 0.69–0.97, P for trend = 0.02). When the researchers focused on specific types of fiber, they found that people who consumed the highest amounts of cereal and vegetable fiber were 19% and 16%, respectively, less likely to develop type 2 diabetes compared with those who consumed the lowest amounts (P < 0.001). Intake of fruit fiber was not associated with risk of diabetes. When the analyses were additionally adjusted for BMI, the inverse associations between intake of fiber and diabetes were attenuated and no longer statistically significant.

The researchers also conducted a meta-analysis that included 18 other cohorts in addition to the current EPIC-InterAct study. The summary relative risks per 10/g day increase in intake were 0.91 (95% CI, 0.87–0.96) for total fiber, 0.75 (95% CI, 0.65–0.86) for cereal fiber, 0.95 (95% CI, 0.87–1.03) for fruit fiber, and 0.93 (95% CI 0.82–1.05) for vegetable fiber.

Conclusion. Individuals with diets rich in fiber, in particular cereal fiber, may be at lower risk of type 2 diabetes.

Commentary

The current study by the European InterAct Consortium adds to the available evidence supporting the association of dietary fiber and risk of diabetes. Higher intake of dietary fiber, especially cereal fiber, has been consistently associated with a lower risk of diabetes [2,3].

This study showed that a high intake of total fiber (primarily cereal and vegetable fiber) was associated with an 18% lower risk of type 2 diabetes (adjusted for dietary and lifestyle factors). While there was no association after adjusting for BMI, their meta-analysis of 18 studies did support the an inverse association between total fiber and cereal fiber intake and risk of type 2 diabetes.

What is it about fiber that is protective? With regard to whole grains, a rich source of fiber, potential mechanisms have been identified [5], including the possible impact of improved postprandial glucose response. However, whole grains are rich in nutrients and phytochemicals, and new hypotheses for the health-protective mechanisms of whole grains beyond fiber are being proposed [6]. In addition, the beneficial effect of fiber seen in this and other studies may be partly mediated by a lower BMI. Dietary fiber may affect appetite and energy intake through a range of processes.

It should be noted that although the effect of whole-grain foods for the prevention of type 2 diabetes is strongly supported by numerous epidemiological studies, a 2008 systematic review by the Cochrane Collaboration [4], which included 1 low-quality RCT and 11 cohort studies, stated that the evidence is too weak to be able to draw a definite conclusion about the preventive effect of this dietary factor.

Strengths of the study included its prospective design and large sample size. Limitations of the study include that dietary intake was assessed only at baseline and measurement error through the use of a questionnaire may have occurred. Although food-frequency questionnaires are widely used, they are subjective estimates and subject to recall bias, and some researchers have questioned their value for use in epidemiologic studies [7]. In addition, the authors note that the inverse association for total fiber and cereal fiber intake in the meta-analysis could be due to residual confounding as fiber intake has been associated with healthier diet, lower BMI, and greater physical activity.

Applications for Clinical Practice

The prevalence of type 2 diabetes has increased rapidly during the past decades in the United States. Dietary guidelines recommend the consumption of whole grains to prevent chronic diseases. The results presented in the current study strengthen the evidence supporting cereal fiber as an important determinant of type 2 diabetes risk. Randomized controlled trials are needed and should elucidate this matter.

TORONTO – Idarucizumab is a promising agent that quickly and safely reverses the anticoagulant effects of dabigatran whether the goal is to control serious bleeding or to permit urgent surgery, according to interim results of a multicenter trial.

Idarucizumab is a monoclonal antibody that binds to dabigatran to reverse its activity. The data, presented by Dr. V. Charles Pollack Jr. at the International Society on Thrombosis and Haemostasis congress, involved the first 90 patients of an ongoing trial with a planned enrollment of 300. The data from this trial, called REVERSE-AD, were published online simultaneously with the June 22 presentation at the congress (N. Engl. J. Med 2015 [doi:10.1056/NEJMoa1502000]).

Courtesy International Society on Thrombosis and Haemostasis

“Non–vitamin K antagonist oral anticoagulants (NOACs) are generally safer than warfarin, and provide similar or improved efficacy in the prevention of stroke in patients with nonvalvular atrial fibrillation and in the prevention and treatment of venous thromboembolism,” Dr. Pollack said in an interview. “Nonetheless, serious bleeding events may occur with NOAC use, and patients taking one of these agents occasionally require urgent surgery or other intervention for which normal hemostasis is required,” added Dr. Pollack, chair of the department of emergency medicine at Pennsylvania Hospital in Philadelphia.

In RE-VERSE AD (a study of the reversal effects of idarucizumab on active dabigatran), the first 90 patients were divided into two distinct groups. Group A, with 51 patients, included those on dabigatran with serious bleeding. Group B, with 39 patients, required reversal of dabigatran for urgent or emergent procedures. In both, idarucizumab provided a median maximum reversal of 100% (95% confidence interval, 100-100) of the anticoagulation effect within 4 hours.

Clotting assays were normalized almost immediately in almost 90% of patients, and the effect was durable, with 80% having measured dabigatran levels reflecting no significant anticoagulation 24 hours later, Dr. Pollack said.

“Clinical outcomes were quite good in this multimorbid patient population, with restoration of hemostasis as reported by local investigators achieved in less than 12 hours when assessable, and with 92% of surgical patients being reported as having normal hemostasis at the time of the procedure,” he said.

Idarucizumab was generally well tolerated in the patient population. “There were no serious adverse events related to the reversal agent ... and only one patient experienced a thrombotic complication within 72 hours, and that patient had not been restarted on any antithrombotic medications,” Dr. Pollack said.

“The study is ongoing,” he added, “but these interim results show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes.”

In addition, Dr. Pollack said the availability of a specific reversal agent for dabigatran would enhance its safety margin, and thus alleviate the fears of providers who may hesitate to use a NOAC because of the lack of an “antidote.”

“In fact, most such cases can already be successfully and safely managed with general support and ‘tincture of time’ (the half-life of dabigatran is much shorter than that of warfarin), but having a specific ‘go-to’ option could streamline the care of the most significantly compromised patients,” he said.

Dr. Pollack emphasized, however, that idarucizumab is a specific reversal agent for dabigatran, not an antidote. “To me, the latter would imply that idarucizumab immediately stops bleeding associated with active use of dabigatran,” he said.

Providers should realize that while idarucizumab seems capable of removing dabigatran-induced coagulopathy from the list of concerns when managing a patient with serious bleeding or before a “sharp” procedure, bleeding is a multifaceted issue that also may be due to traumatized blood vessels, other causes of coagulopathy such as liver disease, or concurrent use of antiplatelet medications, he said.

“The patient with a serious or life-threatening bleed on dabigatran will likely need additional care to investigate and manage such concerns,” Dr. Pollack said. “But at least idarucizumab can specifically, safely, and rapidly address the primary consideration.

“The safety of anticoagulation therapy with dabigatran is further enhanced with idarucizumab, a specific reversal agent that won’t need to be used often, but the availability of which would be reassuring to prescribers,” he concluded.

Boehringer Ingelheim sponsored RE-VERSE AD. Idarucizumab was given a fast-track status by the Food and Drug Administration, and BI submitted a new drug application in March 2015, according to the company.

Dr. Pollack reported receiving personal fees from BI, Janssen, Daiichi-Sankyo, Bristol-Myers Squibb, and Pfizer. Disclosures for all the investigators are available at NEJM.org.

TORONTO – Idarucizumab is a promising agent that quickly and safely reverses the anticoagulant effects of dabigatran whether the goal is to control serious bleeding or to permit urgent surgery, according to interim results of a multicenter trial.

Idarucizumab is a monoclonal antibody that binds to dabigatran to reverse its activity. The data, presented by Dr. V. Charles Pollack Jr. at the International Society on Thrombosis and Haemostasis congress, involved the first 90 patients of an ongoing trial with a planned enrollment of 300. The data from this trial, called REVERSE-AD, were published online simultaneously with the June 22 presentation at the congress (N. Engl. J. Med 2015 [doi:10.1056/NEJMoa1502000]).

Courtesy International Society on Thrombosis and Haemostasis

“Non–vitamin K antagonist oral anticoagulants (NOACs) are generally safer than warfarin, and provide similar or improved efficacy in the prevention of stroke in patients with nonvalvular atrial fibrillation and in the prevention and treatment of venous thromboembolism,” Dr. Pollack said in an interview. “Nonetheless, serious bleeding events may occur with NOAC use, and patients taking one of these agents occasionally require urgent surgery or other intervention for which normal hemostasis is required,” added Dr. Pollack, chair of the department of emergency medicine at Pennsylvania Hospital in Philadelphia.

In RE-VERSE AD (a study of the reversal effects of idarucizumab on active dabigatran), the first 90 patients were divided into two distinct groups. Group A, with 51 patients, included those on dabigatran with serious bleeding. Group B, with 39 patients, required reversal of dabigatran for urgent or emergent procedures. In both, idarucizumab provided a median maximum reversal of 100% (95% confidence interval, 100-100) of the anticoagulation effect within 4 hours.

Clotting assays were normalized almost immediately in almost 90% of patients, and the effect was durable, with 80% having measured dabigatran levels reflecting no significant anticoagulation 24 hours later, Dr. Pollack said.

“Clinical outcomes were quite good in this multimorbid patient population, with restoration of hemostasis as reported by local investigators achieved in less than 12 hours when assessable, and with 92% of surgical patients being reported as having normal hemostasis at the time of the procedure,” he said.

Idarucizumab was generally well tolerated in the patient population. “There were no serious adverse events related to the reversal agent ... and only one patient experienced a thrombotic complication within 72 hours, and that patient had not been restarted on any antithrombotic medications,” Dr. Pollack said.

“The study is ongoing,” he added, “but these interim results show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes.”

In addition, Dr. Pollack said the availability of a specific reversal agent for dabigatran would enhance its safety margin, and thus alleviate the fears of providers who may hesitate to use a NOAC because of the lack of an “antidote.”

“In fact, most such cases can already be successfully and safely managed with general support and ‘tincture of time’ (the half-life of dabigatran is much shorter than that of warfarin), but having a specific ‘go-to’ option could streamline the care of the most significantly compromised patients,” he said.

Dr. Pollack emphasized, however, that idarucizumab is a specific reversal agent for dabigatran, not an antidote. “To me, the latter would imply that idarucizumab immediately stops bleeding associated with active use of dabigatran,” he said.

Providers should realize that while idarucizumab seems capable of removing dabigatran-induced coagulopathy from the list of concerns when managing a patient with serious bleeding or before a “sharp” procedure, bleeding is a multifaceted issue that also may be due to traumatized blood vessels, other causes of coagulopathy such as liver disease, or concurrent use of antiplatelet medications, he said.

“The patient with a serious or life-threatening bleed on dabigatran will likely need additional care to investigate and manage such concerns,” Dr. Pollack said. “But at least idarucizumab can specifically, safely, and rapidly address the primary consideration.

“The safety of anticoagulation therapy with dabigatran is further enhanced with idarucizumab, a specific reversal agent that won’t need to be used often, but the availability of which would be reassuring to prescribers,” he concluded.

Boehringer Ingelheim sponsored RE-VERSE AD. Idarucizumab was given a fast-track status by the Food and Drug Administration, and BI submitted a new drug application in March 2015, according to the company.

Dr. Pollack reported receiving personal fees from BI, Janssen, Daiichi-Sankyo, Bristol-Myers Squibb, and Pfizer. Disclosures for all the investigators are available at NEJM.org.

TORONTO – Idarucizumab is a promising agent that quickly and safely reverses the anticoagulant effects of dabigatran whether the goal is to control serious bleeding or to permit urgent surgery, according to interim results of a multicenter trial.

Idarucizumab is a monoclonal antibody that binds to dabigatran to reverse its activity. The data, presented by Dr. V. Charles Pollack Jr. at the International Society on Thrombosis and Haemostasis congress, involved the first 90 patients of an ongoing trial with a planned enrollment of 300. The data from this trial, called REVERSE-AD, were published online simultaneously with the June 22 presentation at the congress (N. Engl. J. Med 2015 [doi:10.1056/NEJMoa1502000]).

Courtesy International Society on Thrombosis and Haemostasis

“Non–vitamin K antagonist oral anticoagulants (NOACs) are generally safer than warfarin, and provide similar or improved efficacy in the prevention of stroke in patients with nonvalvular atrial fibrillation and in the prevention and treatment of venous thromboembolism,” Dr. Pollack said in an interview. “Nonetheless, serious bleeding events may occur with NOAC use, and patients taking one of these agents occasionally require urgent surgery or other intervention for which normal hemostasis is required,” added Dr. Pollack, chair of the department of emergency medicine at Pennsylvania Hospital in Philadelphia.

In RE-VERSE AD (a study of the reversal effects of idarucizumab on active dabigatran), the first 90 patients were divided into two distinct groups. Group A, with 51 patients, included those on dabigatran with serious bleeding. Group B, with 39 patients, required reversal of dabigatran for urgent or emergent procedures. In both, idarucizumab provided a median maximum reversal of 100% (95% confidence interval, 100-100) of the anticoagulation effect within 4 hours.

Clotting assays were normalized almost immediately in almost 90% of patients, and the effect was durable, with 80% having measured dabigatran levels reflecting no significant anticoagulation 24 hours later, Dr. Pollack said.

“Clinical outcomes were quite good in this multimorbid patient population, with restoration of hemostasis as reported by local investigators achieved in less than 12 hours when assessable, and with 92% of surgical patients being reported as having normal hemostasis at the time of the procedure,” he said.

Idarucizumab was generally well tolerated in the patient population. “There were no serious adverse events related to the reversal agent ... and only one patient experienced a thrombotic complication within 72 hours, and that patient had not been restarted on any antithrombotic medications,” Dr. Pollack said.

“The study is ongoing,” he added, “but these interim results show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes.”

In addition, Dr. Pollack said the availability of a specific reversal agent for dabigatran would enhance its safety margin, and thus alleviate the fears of providers who may hesitate to use a NOAC because of the lack of an “antidote.”

“In fact, most such cases can already be successfully and safely managed with general support and ‘tincture of time’ (the half-life of dabigatran is much shorter than that of warfarin), but having a specific ‘go-to’ option could streamline the care of the most significantly compromised patients,” he said.

Dr. Pollack emphasized, however, that idarucizumab is a specific reversal agent for dabigatran, not an antidote. “To me, the latter would imply that idarucizumab immediately stops bleeding associated with active use of dabigatran,” he said.

Providers should realize that while idarucizumab seems capable of removing dabigatran-induced coagulopathy from the list of concerns when managing a patient with serious bleeding or before a “sharp” procedure, bleeding is a multifaceted issue that also may be due to traumatized blood vessels, other causes of coagulopathy such as liver disease, or concurrent use of antiplatelet medications, he said.

“The patient with a serious or life-threatening bleed on dabigatran will likely need additional care to investigate and manage such concerns,” Dr. Pollack said. “But at least idarucizumab can specifically, safely, and rapidly address the primary consideration.

“The safety of anticoagulation therapy with dabigatran is further enhanced with idarucizumab, a specific reversal agent that won’t need to be used often, but the availability of which would be reassuring to prescribers,” he concluded.

Boehringer Ingelheim sponsored RE-VERSE AD. Idarucizumab was given a fast-track status by the Food and Drug Administration, and BI submitted a new drug application in March 2015, according to the company.

Dr. Pollack reported receiving personal fees from BI, Janssen, Daiichi-Sankyo, Bristol-Myers Squibb, and Pfizer. Disclosures for all the investigators are available at NEJM.org.

Cangrelor became the first intravenous antiplatelet agent acting on ADP receptors for adult patients undergoing percutaneous coronary intervention to receive marketing approval from the Food and Drug Administration, The Medicines Company announced on June 22.

While cangrelor’s unique delivery route and rapid onset and off-set of action set it apart and may give it certain clinical advantages over the three approved oral drugs that target the same platelet receptor – clopidogrel, prasugrel (Effient), and ticagrelor (Brilinta) – cangrelor will also be distinguished by its much higher price. The standard dosage to treat one patient undergoing percutaneous coronary intervention (PCI) with cangrelor (Kengreal) will have a wholesale acquisition cost of $749, Raymond Russo, senior vice president of The Medicines Company, said at a June 23 press briefing. That prices cangrelor substantially above its brand-name competition, which costs roughly $10 for similar treatment, as well as generic clopidogrel, which costs about $3 for the same indication.

“I believe in the strength of the data that showed that cangrelor was superior to the comparator drug [clopidogrel], and if cost were not an issue I’d use cangrelor routinely, but I am not naive; cost is an issue,” said Dr. Deepak L. Bhatt, professor of medicine at Harvard University and executive director of interventional cardiology programs at Brigham and Women’s Hospital in Boston, and co–lead investigator for the CHAMPION PHOENIX pivotal trial that led to cangrelor’s approval (N. Engl. J. Med. 2013;368:1303-13).

Whether or not interventional cardiologists and the centers where they work decide to use cangrelor or one of the oral antiplatelet drugs for coronary artery disease (CAD) patients undergoing PCI will likely depend on a series of considerations that will need to take into account not just drug cost but also practice strategies, a patient’s clinical state, and the potential for ancillary costs from following an entirely different management approach.

The first issue is whether the interventionalist decides to pretreat a patient scheduled for angioplasty and possible immediate PCI following angiography with an ADP-receptor antagonist (also known as a P2Y12-receptor inhibitor) prior to the start of angiography or opts to defer that treatment until the angiography results are available and a decision is made to proceed with PCI. Recent nationwide registry data suggest that roughly half of U.S. interventionalists treat their patients upfront with an ADP-receptor antagonist, usually clopidogrel for patients with stable angina or prasugrel or ticagrelor if they have either a non-ST-elevation MI or a ST-elevation MI, while the other 50% of interventionalists will wait to administer the ADP-receptor antagonist until angiography is complete, Dr. Bhatt explained in an interview.

The advantage to upfront treatment is that by the time the patient is ready for PCI an oral ADP-receptor antagonist is fully absorbed and on board. The disadvantage is that if the coronary anatomy demands a surgical approach to revascularization many surgeons would elect not to operate on a patient freshly dosed with an antiplatelet agent, and these patients often remain hospitalized for several days until the ADP-receptor antagonist clears and the patient’s platelet function returns to normal. Angiography generally identifies 10%-15% of these patients with a CAD distribution that necessitates surgical coronary bypass, and the potential hospitalization expense of waiting for their ADP-receptor antagonist to clear could be a major cost to counterbalance the price of cangrelor, which would obviate this expense if the quick-to-start-and-to-clear cangrelor were used instead of a more lumbering oral drug, he noted.

The other 50% of U.S. interventionalists, Dr. Bhatt included, take a different approach. Recognizing the potential downside of upfront oral antiplatelet therapy if the patient is pegged for bypass surgery following angiography, they elect to wait until the angiography results are in hand. If the angiography results show the patient is destined for surgery or for medical management, then the patient receives no ADP-receptor antagonist. The cardiologist administers an ADP-receptor antagonist only if the patient’s CAD is appropriate for PCI, the fate for most of these CAD patients following angiography. It’s under these circumstances that the advantages of cangrelor kick in, as shown in the results from CHAMPION PHOENIX.

This trial randomized patients to two different types of ADP-receptor antagonist treatment while they were in the coronary catheterization laboratory. The study results showed a statistically significant, 22% relative-risk reduction in the primary endpoint in favor of intravenous cangrelor compared with oral clopidogrel delivered while patients were “on the table” in the interval between angiography and PCI. That 22% relative improvement in outcomes, driven primarily by reductions in periprocedural MIs and stent thrombosis, improved to a 31% relative-risk reduction when The Medicines Company performed a new analysis of the study results at the FDA’s request using a more stringent and conventional definition of periprocedural MIs and stent thrombosis. The time needed to perform this and other FDA-requested analyses largely caused the greater than 2-year gap between the 2013 publication of the CHAMPION PHOENIX results and the FDA’s approval.

But the editorial that accompanied the 2013 publication highlighted what the editorialists perceived as flaws in the study’s design, such as an inadequate loading dose of clopidogrel delivered to a quarter of the patients randomized to that arm, inadequate time allowed for the clopidogrel to fully kick in before PCI began in a third of patients, and the use of clopidogrel as the comparator drug and not a more potent alternative drug, either prasugrel or ticagrelor (N. Engl. J. Med. 2013;368:1356-7).

“Cangrelor was never tested against prasugrel or ticagrelor, and it was compared with inadequate clopidogrel treatment. That was a problem,” reiterated Dr. Richard A. Lange, one of the 2013 editorialists, when interviewed following news of cangrelor’s FDA approval. CHAMPION PHOENIX “wasn’t really a comparison [of two drugs], it was a study of an intravenous strategy, and it’s not a strategy that is needed very often,” said Dr. Lange, an interventional cardiologist and president of the Texas Tech University Health Sciences Center in El Paso. In Dr. Lange’s opinion, the only real need for an intravenous ADP-receptor antagonist is for CAD patients undergoing PCI who are unable to take an oral agent, for example because they are on a ventilator, unable to hold down an oral pill, or unconscious, which collectively are “rare” situations, he said.

Dr. Bhatt noted that another clear indication for an intravenous agent is when MI patients receive morphine for their pain, a situation recently documented to interfere with absorption of oral ADP-receptor antagonists.

From Dr. Bhatt’s perspective, the major issue is practice patterns: “Do the interventionalists treat [with an ADP-receptor antagonist] upstream or not. If they do, then they should do the math,” and determine if the expense of holding a significant minority of patients in the hospital just to allow them to clear the ADP-receptor antagonist prior to coronary bypass surgery outweighs the cost for delaying this treatment and administering cangrelor later only to patients scheduled for PCI. At the center where he practices, Brigham and Women’s Hospital in Boston, he sees a roughly equal mix of interventionalists who prefer to treat patients with clopidogrel upfront, those who treat with ticagrelor upfront, and those who practice as he does and wait until the PCI is a go.

“For my personal practice, cangrelor will fit in quite nicely,” Dr. Bhatt said.

[email protected]

On Twitter@mitchelzoler

Cangrelor became the first intravenous antiplatelet agent acting on ADP receptors for adult patients undergoing percutaneous coronary intervention to receive marketing approval from the Food and Drug Administration, The Medicines Company announced on June 22.

While cangrelor’s unique delivery route and rapid onset and off-set of action set it apart and may give it certain clinical advantages over the three approved oral drugs that target the same platelet receptor – clopidogrel, prasugrel (Effient), and ticagrelor (Brilinta) – cangrelor will also be distinguished by its much higher price. The standard dosage to treat one patient undergoing percutaneous coronary intervention (PCI) with cangrelor (Kengreal) will have a wholesale acquisition cost of $749, Raymond Russo, senior vice president of The Medicines Company, said at a June 23 press briefing. That prices cangrelor substantially above its brand-name competition, which costs roughly $10 for similar treatment, as well as generic clopidogrel, which costs about $3 for the same indication.

“I believe in the strength of the data that showed that cangrelor was superior to the comparator drug [clopidogrel], and if cost were not an issue I’d use cangrelor routinely, but I am not naive; cost is an issue,” said Dr. Deepak L. Bhatt, professor of medicine at Harvard University and executive director of interventional cardiology programs at Brigham and Women’s Hospital in Boston, and co–lead investigator for the CHAMPION PHOENIX pivotal trial that led to cangrelor’s approval (N. Engl. J. Med. 2013;368:1303-13).

Whether or not interventional cardiologists and the centers where they work decide to use cangrelor or one of the oral antiplatelet drugs for coronary artery disease (CAD) patients undergoing PCI will likely depend on a series of considerations that will need to take into account not just drug cost but also practice strategies, a patient’s clinical state, and the potential for ancillary costs from following an entirely different management approach.

The first issue is whether the interventionalist decides to pretreat a patient scheduled for angioplasty and possible immediate PCI following angiography with an ADP-receptor antagonist (also known as a P2Y12-receptor inhibitor) prior to the start of angiography or opts to defer that treatment until the angiography results are available and a decision is made to proceed with PCI. Recent nationwide registry data suggest that roughly half of U.S. interventionalists treat their patients upfront with an ADP-receptor antagonist, usually clopidogrel for patients with stable angina or prasugrel or ticagrelor if they have either a non-ST-elevation MI or a ST-elevation MI, while the other 50% of interventionalists will wait to administer the ADP-receptor antagonist until angiography is complete, Dr. Bhatt explained in an interview.

The advantage to upfront treatment is that by the time the patient is ready for PCI an oral ADP-receptor antagonist is fully absorbed and on board. The disadvantage is that if the coronary anatomy demands a surgical approach to revascularization many surgeons would elect not to operate on a patient freshly dosed with an antiplatelet agent, and these patients often remain hospitalized for several days until the ADP-receptor antagonist clears and the patient’s platelet function returns to normal. Angiography generally identifies 10%-15% of these patients with a CAD distribution that necessitates surgical coronary bypass, and the potential hospitalization expense of waiting for their ADP-receptor antagonist to clear could be a major cost to counterbalance the price of cangrelor, which would obviate this expense if the quick-to-start-and-to-clear cangrelor were used instead of a more lumbering oral drug, he noted.

The other 50% of U.S. interventionalists, Dr. Bhatt included, take a different approach. Recognizing the potential downside of upfront oral antiplatelet therapy if the patient is pegged for bypass surgery following angiography, they elect to wait until the angiography results are in hand. If the angiography results show the patient is destined for surgery or for medical management, then the patient receives no ADP-receptor antagonist. The cardiologist administers an ADP-receptor antagonist only if the patient’s CAD is appropriate for PCI, the fate for most of these CAD patients following angiography. It’s under these circumstances that the advantages of cangrelor kick in, as shown in the results from CHAMPION PHOENIX.

This trial randomized patients to two different types of ADP-receptor antagonist treatment while they were in the coronary catheterization laboratory. The study results showed a statistically significant, 22% relative-risk reduction in the primary endpoint in favor of intravenous cangrelor compared with oral clopidogrel delivered while patients were “on the table” in the interval between angiography and PCI. That 22% relative improvement in outcomes, driven primarily by reductions in periprocedural MIs and stent thrombosis, improved to a 31% relative-risk reduction when The Medicines Company performed a new analysis of the study results at the FDA’s request using a more stringent and conventional definition of periprocedural MIs and stent thrombosis. The time needed to perform this and other FDA-requested analyses largely caused the greater than 2-year gap between the 2013 publication of the CHAMPION PHOENIX results and the FDA’s approval.

But the editorial that accompanied the 2013 publication highlighted what the editorialists perceived as flaws in the study’s design, such as an inadequate loading dose of clopidogrel delivered to a quarter of the patients randomized to that arm, inadequate time allowed for the clopidogrel to fully kick in before PCI began in a third of patients, and the use of clopidogrel as the comparator drug and not a more potent alternative drug, either prasugrel or ticagrelor (N. Engl. J. Med. 2013;368:1356-7).

“Cangrelor was never tested against prasugrel or ticagrelor, and it was compared with inadequate clopidogrel treatment. That was a problem,” reiterated Dr. Richard A. Lange, one of the 2013 editorialists, when interviewed following news of cangrelor’s FDA approval. CHAMPION PHOENIX “wasn’t really a comparison [of two drugs], it was a study of an intravenous strategy, and it’s not a strategy that is needed very often,” said Dr. Lange, an interventional cardiologist and president of the Texas Tech University Health Sciences Center in El Paso. In Dr. Lange’s opinion, the only real need for an intravenous ADP-receptor antagonist is for CAD patients undergoing PCI who are unable to take an oral agent, for example because they are on a ventilator, unable to hold down an oral pill, or unconscious, which collectively are “rare” situations, he said.

Dr. Bhatt noted that another clear indication for an intravenous agent is when MI patients receive morphine for their pain, a situation recently documented to interfere with absorption of oral ADP-receptor antagonists.

From Dr. Bhatt’s perspective, the major issue is practice patterns: “Do the interventionalists treat [with an ADP-receptor antagonist] upstream or not. If they do, then they should do the math,” and determine if the expense of holding a significant minority of patients in the hospital just to allow them to clear the ADP-receptor antagonist prior to coronary bypass surgery outweighs the cost for delaying this treatment and administering cangrelor later only to patients scheduled for PCI. At the center where he practices, Brigham and Women’s Hospital in Boston, he sees a roughly equal mix of interventionalists who prefer to treat patients with clopidogrel upfront, those who treat with ticagrelor upfront, and those who practice as he does and wait until the PCI is a go.

“For my personal practice, cangrelor will fit in quite nicely,” Dr. Bhatt said.

[email protected]

On Twitter@mitchelzoler

Cangrelor became the first intravenous antiplatelet agent acting on ADP receptors for adult patients undergoing percutaneous coronary intervention to receive marketing approval from the Food and Drug Administration, The Medicines Company announced on June 22.

While cangrelor’s unique delivery route and rapid onset and off-set of action set it apart and may give it certain clinical advantages over the three approved oral drugs that target the same platelet receptor – clopidogrel, prasugrel (Effient), and ticagrelor (Brilinta) – cangrelor will also be distinguished by its much higher price. The standard dosage to treat one patient undergoing percutaneous coronary intervention (PCI) with cangrelor (Kengreal) will have a wholesale acquisition cost of $749, Raymond Russo, senior vice president of The Medicines Company, said at a June 23 press briefing. That prices cangrelor substantially above its brand-name competition, which costs roughly $10 for similar treatment, as well as generic clopidogrel, which costs about $3 for the same indication.

“I believe in the strength of the data that showed that cangrelor was superior to the comparator drug [clopidogrel], and if cost were not an issue I’d use cangrelor routinely, but I am not naive; cost is an issue,” said Dr. Deepak L. Bhatt, professor of medicine at Harvard University and executive director of interventional cardiology programs at Brigham and Women’s Hospital in Boston, and co–lead investigator for the CHAMPION PHOENIX pivotal trial that led to cangrelor’s approval (N. Engl. J. Med. 2013;368:1303-13).

Whether or not interventional cardiologists and the centers where they work decide to use cangrelor or one of the oral antiplatelet drugs for coronary artery disease (CAD) patients undergoing PCI will likely depend on a series of considerations that will need to take into account not just drug cost but also practice strategies, a patient’s clinical state, and the potential for ancillary costs from following an entirely different management approach.

The first issue is whether the interventionalist decides to pretreat a patient scheduled for angioplasty and possible immediate PCI following angiography with an ADP-receptor antagonist (also known as a P2Y12-receptor inhibitor) prior to the start of angiography or opts to defer that treatment until the angiography results are available and a decision is made to proceed with PCI. Recent nationwide registry data suggest that roughly half of U.S. interventionalists treat their patients upfront with an ADP-receptor antagonist, usually clopidogrel for patients with stable angina or prasugrel or ticagrelor if they have either a non-ST-elevation MI or a ST-elevation MI, while the other 50% of interventionalists will wait to administer the ADP-receptor antagonist until angiography is complete, Dr. Bhatt explained in an interview.

The advantage to upfront treatment is that by the time the patient is ready for PCI an oral ADP-receptor antagonist is fully absorbed and on board. The disadvantage is that if the coronary anatomy demands a surgical approach to revascularization many surgeons would elect not to operate on a patient freshly dosed with an antiplatelet agent, and these patients often remain hospitalized for several days until the ADP-receptor antagonist clears and the patient’s platelet function returns to normal. Angiography generally identifies 10%-15% of these patients with a CAD distribution that necessitates surgical coronary bypass, and the potential hospitalization expense of waiting for their ADP-receptor antagonist to clear could be a major cost to counterbalance the price of cangrelor, which would obviate this expense if the quick-to-start-and-to-clear cangrelor were used instead of a more lumbering oral drug, he noted.

The other 50% of U.S. interventionalists, Dr. Bhatt included, take a different approach. Recognizing the potential downside of upfront oral antiplatelet therapy if the patient is pegged for bypass surgery following angiography, they elect to wait until the angiography results are in hand. If the angiography results show the patient is destined for surgery or for medical management, then the patient receives no ADP-receptor antagonist. The cardiologist administers an ADP-receptor antagonist only if the patient’s CAD is appropriate for PCI, the fate for most of these CAD patients following angiography. It’s under these circumstances that the advantages of cangrelor kick in, as shown in the results from CHAMPION PHOENIX.

This trial randomized patients to two different types of ADP-receptor antagonist treatment while they were in the coronary catheterization laboratory. The study results showed a statistically significant, 22% relative-risk reduction in the primary endpoint in favor of intravenous cangrelor compared with oral clopidogrel delivered while patients were “on the table” in the interval between angiography and PCI. That 22% relative improvement in outcomes, driven primarily by reductions in periprocedural MIs and stent thrombosis, improved to a 31% relative-risk reduction when The Medicines Company performed a new analysis of the study results at the FDA’s request using a more stringent and conventional definition of periprocedural MIs and stent thrombosis. The time needed to perform this and other FDA-requested analyses largely caused the greater than 2-year gap between the 2013 publication of the CHAMPION PHOENIX results and the FDA’s approval.

But the editorial that accompanied the 2013 publication highlighted what the editorialists perceived as flaws in the study’s design, such as an inadequate loading dose of clopidogrel delivered to a quarter of the patients randomized to that arm, inadequate time allowed for the clopidogrel to fully kick in before PCI began in a third of patients, and the use of clopidogrel as the comparator drug and not a more potent alternative drug, either prasugrel or ticagrelor (N. Engl. J. Med. 2013;368:1356-7).

“Cangrelor was never tested against prasugrel or ticagrelor, and it was compared with inadequate clopidogrel treatment. That was a problem,” reiterated Dr. Richard A. Lange, one of the 2013 editorialists, when interviewed following news of cangrelor’s FDA approval. CHAMPION PHOENIX “wasn’t really a comparison [of two drugs], it was a study of an intravenous strategy, and it’s not a strategy that is needed very often,” said Dr. Lange, an interventional cardiologist and president of the Texas Tech University Health Sciences Center in El Paso. In Dr. Lange’s opinion, the only real need for an intravenous ADP-receptor antagonist is for CAD patients undergoing PCI who are unable to take an oral agent, for example because they are on a ventilator, unable to hold down an oral pill, or unconscious, which collectively are “rare” situations, he said.

Dr. Bhatt noted that another clear indication for an intravenous agent is when MI patients receive morphine for their pain, a situation recently documented to interfere with absorption of oral ADP-receptor antagonists.

From Dr. Bhatt’s perspective, the major issue is practice patterns: “Do the interventionalists treat [with an ADP-receptor antagonist] upstream or not. If they do, then they should do the math,” and determine if the expense of holding a significant minority of patients in the hospital just to allow them to clear the ADP-receptor antagonist prior to coronary bypass surgery outweighs the cost for delaying this treatment and administering cangrelor later only to patients scheduled for PCI. At the center where he practices, Brigham and Women’s Hospital in Boston, he sees a roughly equal mix of interventionalists who prefer to treat patients with clopidogrel upfront, those who treat with ticagrelor upfront, and those who practice as he does and wait until the PCI is a go.

“For my personal practice, cangrelor will fit in quite nicely,” Dr. Bhatt said.

[email protected]

On Twitter@mitchelzoler

Recently, there have been several news stories about physicians committing suicide. This is across all levels of the profession, including medical students, residents, and attendings.

Historically, doctors have had a higher rate of suicide than most professions. I’m not sure if that number has crept up recently, or if events are garnering more attention than before. They’re certainly mentioned prominently on various medical blogs.

Why do you see this in medicine? There are probably a number of factors that overlap:

• A high pressure job, where mistakes aren’t allowed (which isn’t humanly possible).

• A culture of litigation, where even minor mistakes are taken to court.

• Declining financial reimbursement, making it harder to support a practice and family, especially when you’re already six figures in debt coming out of medical school.

• Pressure to work longer hours and see far more patients than is possible, which increases the potential for mistakes. This further reduces the amount of family and recreational time available to balance ourselves.

• An increase in “empowered patients” demanding unnecessary tests and treatments because it said so on the Internet.

• A general lack of respect for the profession, to where we’re now “providers” who are vilified for political reasons by insurance companies, consumer groups, and both major parties.

• The need for us not to admit or seek treatment for human vulnerabilities. Our own health (mental and physical) is neglected because we can’t take time off to address it and a fear that doing so may result in us having our licenses penalized.

Any of the above makes life unpleasant, but when you combine them … it can be a perfect storm that tips a person over the edge.

In medicine, seeking help is often seen as a weakness, and even the most rational person under difficult circumstances can snap. None of the physicians who’ve ended their lives started out saying that was how they wanted their medical career to wind up. But when stressors pile up, it may appear to them to be the only way out. In that frame of mind, you think doing something so drastic is better for everyone around you. It isn’t true, but at that point you don’t believe it.

A physician’s suicide, even outside of its effects on their family, is a loss. A physician is a community resource, leaving behind relationships with patients in various stages of work-ups and treatments. There’s always another doctor, but it’s not easy, or immediate, to find someone who’s a good fit for the area.

I don’t know if this is a peculiarly American phenomenon or if my colleagues in Canada, Europe, and elsewhere face similar challenges. If the suicide rate elsewhere is lower, what can we learn from them to make things better here? If it’s the same, what can we do collectively to find an answer? Every country needs doctors and can’t afford to lose them.

Is there an easy solution? Probably not. Too many factors to fix. But it’s a serious problem and needs attention.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Recently, there have been several news stories about physicians committing suicide. This is across all levels of the profession, including medical students, residents, and attendings.

Historically, doctors have had a higher rate of suicide than most professions. I’m not sure if that number has crept up recently, or if events are garnering more attention than before. They’re certainly mentioned prominently on various medical blogs.

Why do you see this in medicine? There are probably a number of factors that overlap:

• A high pressure job, where mistakes aren’t allowed (which isn’t humanly possible).

• A culture of litigation, where even minor mistakes are taken to court.

• Declining financial reimbursement, making it harder to support a practice and family, especially when you’re already six figures in debt coming out of medical school.

• Pressure to work longer hours and see far more patients than is possible, which increases the potential for mistakes. This further reduces the amount of family and recreational time available to balance ourselves.

• An increase in “empowered patients” demanding unnecessary tests and treatments because it said so on the Internet.

• A general lack of respect for the profession, to where we’re now “providers” who are vilified for political reasons by insurance companies, consumer groups, and both major parties.

• The need for us not to admit or seek treatment for human vulnerabilities. Our own health (mental and physical) is neglected because we can’t take time off to address it and a fear that doing so may result in us having our licenses penalized.

Any of the above makes life unpleasant, but when you combine them … it can be a perfect storm that tips a person over the edge.

In medicine, seeking help is often seen as a weakness, and even the most rational person under difficult circumstances can snap. None of the physicians who’ve ended their lives started out saying that was how they wanted their medical career to wind up. But when stressors pile up, it may appear to them to be the only way out. In that frame of mind, you think doing something so drastic is better for everyone around you. It isn’t true, but at that point you don’t believe it.

A physician’s suicide, even outside of its effects on their family, is a loss. A physician is a community resource, leaving behind relationships with patients in various stages of work-ups and treatments. There’s always another doctor, but it’s not easy, or immediate, to find someone who’s a good fit for the area.

I don’t know if this is a peculiarly American phenomenon or if my colleagues in Canada, Europe, and elsewhere face similar challenges. If the suicide rate elsewhere is lower, what can we learn from them to make things better here? If it’s the same, what can we do collectively to find an answer? Every country needs doctors and can’t afford to lose them.

Is there an easy solution? Probably not. Too many factors to fix. But it’s a serious problem and needs attention.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Recently, there have been several news stories about physicians committing suicide. This is across all levels of the profession, including medical students, residents, and attendings.

Historically, doctors have had a higher rate of suicide than most professions. I’m not sure if that number has crept up recently, or if events are garnering more attention than before. They’re certainly mentioned prominently on various medical blogs.

Why do you see this in medicine? There are probably a number of factors that overlap:

• A high pressure job, where mistakes aren’t allowed (which isn’t humanly possible).

• A culture of litigation, where even minor mistakes are taken to court.

• Declining financial reimbursement, making it harder to support a practice and family, especially when you’re already six figures in debt coming out of medical school.

• Pressure to work longer hours and see far more patients than is possible, which increases the potential for mistakes. This further reduces the amount of family and recreational time available to balance ourselves.

• An increase in “empowered patients” demanding unnecessary tests and treatments because it said so on the Internet.

• A general lack of respect for the profession, to where we’re now “providers” who are vilified for political reasons by insurance companies, consumer groups, and both major parties.

• The need for us not to admit or seek treatment for human vulnerabilities. Our own health (mental and physical) is neglected because we can’t take time off to address it and a fear that doing so may result in us having our licenses penalized.

Any of the above makes life unpleasant, but when you combine them … it can be a perfect storm that tips a person over the edge.

In medicine, seeking help is often seen as a weakness, and even the most rational person under difficult circumstances can snap. None of the physicians who’ve ended their lives started out saying that was how they wanted their medical career to wind up. But when stressors pile up, it may appear to them to be the only way out. In that frame of mind, you think doing something so drastic is better for everyone around you. It isn’t true, but at that point you don’t believe it.

A physician’s suicide, even outside of its effects on their family, is a loss. A physician is a community resource, leaving behind relationships with patients in various stages of work-ups and treatments. There’s always another doctor, but it’s not easy, or immediate, to find someone who’s a good fit for the area.

I don’t know if this is a peculiarly American phenomenon or if my colleagues in Canada, Europe, and elsewhere face similar challenges. If the suicide rate elsewhere is lower, what can we learn from them to make things better here? If it’s the same, what can we do collectively to find an answer? Every country needs doctors and can’t afford to lose them.

Is there an easy solution? Probably not. Too many factors to fix. But it’s a serious problem and needs attention.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

The recent endorsements by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee of the new genetically manufactured, subcutaneously administered cholesterol-lowering agents alirocumab (Sanofi-Regeneron) and evolocumab (Pfizer) have sent a jolt through the world of cholesterol therapy. Proposed for the treatment of patients with high-risk cardiovascular disease and homozygous familial hypercholesterolemia (HoFH), the decisions suggest that the committee has developed a severe case of scientific amnesia.

A case can be made for the approval for the very-high-risk and untreatable patients with HoFH, but the decision to treat millions of Americans based on the paucity of clinical data available would be disturbing, if not irresponsible.

It is clear that these proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide a powerful therapy for reducing LDL cholesterol, with a reported decrease of about 60% after only 12 or 52 weeks of treatment. Based on four small studies lasting 10-12 weeks and without any clinical outcome data, the committee recommended approving evolocumab for lifetime therapy without anything to support its clinical effectiveness or safety.

Dr. Robert J. Smith, who chaired the advisory committee meeting, faced with approving the drug or delaying a decision until a randomized clinical trial can be completed said, “I am unwilling to subject patients to the wait.” A publication of the American College of Cardiology suggested that these two monoclonal antibody drugs could replace generic statins in 70 million Americans at an estimated cost of $7,000-$12,000 a year. Talk about breaking the bank.

Only recently, we decided that the appropriate statin therapy for cholesterol control should use the dosing from the original clinical trials rather than chasing LDL levels to the lowest level possible. We now have a class of drugs that clearly can lower the cholesterol to a level never seen before, and we are about to discard that therapeutic advice.

We have experience in chasing blood levels with uncertain outcomes. Reducing blood sugar to a very low hemoglobin A_1c level led to adverse clinical events and increased mortality in type 2 diabetes. Raising HDL with the cholesterol ester transfer protein (CETP) inhibitor torcetrapib in a study of 15,000 patients in an outcome trial carried out over a number of years led to increased blood pressure and mortality by 58%, which was associated with a 25% decrease in LDL cholesterol and a 72% increase in HDL, both effects presumed to be remarkably beneficial (N. Engl. J. Med. 2007;357:2109-22).

It is quite possible that these new agents can further decrease coronary vascular mortality. A healthy controversy has raged for some time in regard to the “LDL hypothesis,” compared with therapy based upon the clinical trial outcome. The recent IMPROVE-IT report (N. Engl. J. Med. 2015;372:2387-97) provides some data to support the LDL hypothesis. In that study, the addition of 10 mg of ezetimibe to 40 mg of simvastatin in 18,144 patients followed for up to 6 years resulted in a 2% decrease in mortality associated with a 15.8-mg decrease in serum LDL.

Would it not be prudent to have similar data with the new drug on the street? If it is as potent as it appears to be, a trial of much shorter duration might demonstrate its potency and safety before it is offered to 70 million Americans. The FDA has been reluctant to use surrogate endpoints for approving drugs, but its position has not always been consistent. For some time the FDA has, on occasion, approved drugs that can lower cholesterol with limited outcome data as it did with ezetimibe. However, the decision in regard to the PCSK9 inhibitors will have a much larger impact on care than an add-on drug like ezetimibe. Let’s hope that the FDA shows better judgment than its advisory committee.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The recent endorsements by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee of the new genetically manufactured, subcutaneously administered cholesterol-lowering agents alirocumab (Sanofi-Regeneron) and evolocumab (Pfizer) have sent a jolt through the world of cholesterol therapy. Proposed for the treatment of patients with high-risk cardiovascular disease and homozygous familial hypercholesterolemia (HoFH), the decisions suggest that the committee has developed a severe case of scientific amnesia.

A case can be made for the approval for the very-high-risk and untreatable patients with HoFH, but the decision to treat millions of Americans based on the paucity of clinical data available would be disturbing, if not irresponsible.

It is clear that these proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide a powerful therapy for reducing LDL cholesterol, with a reported decrease of about 60% after only 12 or 52 weeks of treatment. Based on four small studies lasting 10-12 weeks and without any clinical outcome data, the committee recommended approving evolocumab for lifetime therapy without anything to support its clinical effectiveness or safety.

Dr. Robert J. Smith, who chaired the advisory committee meeting, faced with approving the drug or delaying a decision until a randomized clinical trial can be completed said, “I am unwilling to subject patients to the wait.” A publication of the American College of Cardiology suggested that these two monoclonal antibody drugs could replace generic statins in 70 million Americans at an estimated cost of $7,000-$12,000 a year. Talk about breaking the bank.

Only recently, we decided that the appropriate statin therapy for cholesterol control should use the dosing from the original clinical trials rather than chasing LDL levels to the lowest level possible. We now have a class of drugs that clearly can lower the cholesterol to a level never seen before, and we are about to discard that therapeutic advice.

We have experience in chasing blood levels with uncertain outcomes. Reducing blood sugar to a very low hemoglobin A_1c level led to adverse clinical events and increased mortality in type 2 diabetes. Raising HDL with the cholesterol ester transfer protein (CETP) inhibitor torcetrapib in a study of 15,000 patients in an outcome trial carried out over a number of years led to increased blood pressure and mortality by 58%, which was associated with a 25% decrease in LDL cholesterol and a 72% increase in HDL, both effects presumed to be remarkably beneficial (N. Engl. J. Med. 2007;357:2109-22).

It is quite possible that these new agents can further decrease coronary vascular mortality. A healthy controversy has raged for some time in regard to the “LDL hypothesis,” compared with therapy based upon the clinical trial outcome. The recent IMPROVE-IT report (N. Engl. J. Med. 2015;372:2387-97) provides some data to support the LDL hypothesis. In that study, the addition of 10 mg of ezetimibe to 40 mg of simvastatin in 18,144 patients followed for up to 6 years resulted in a 2% decrease in mortality associated with a 15.8-mg decrease in serum LDL.

Would it not be prudent to have similar data with the new drug on the street? If it is as potent as it appears to be, a trial of much shorter duration might demonstrate its potency and safety before it is offered to 70 million Americans. The FDA has been reluctant to use surrogate endpoints for approving drugs, but its position has not always been consistent. For some time the FDA has, on occasion, approved drugs that can lower cholesterol with limited outcome data as it did with ezetimibe. However, the decision in regard to the PCSK9 inhibitors will have a much larger impact on care than an add-on drug like ezetimibe. Let’s hope that the FDA shows better judgment than its advisory committee.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The recent endorsements by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee of the new genetically manufactured, subcutaneously administered cholesterol-lowering agents alirocumab (Sanofi-Regeneron) and evolocumab (Pfizer) have sent a jolt through the world of cholesterol therapy. Proposed for the treatment of patients with high-risk cardiovascular disease and homozygous familial hypercholesterolemia (HoFH), the decisions suggest that the committee has developed a severe case of scientific amnesia.

A case can be made for the approval for the very-high-risk and untreatable patients with HoFH, but the decision to treat millions of Americans based on the paucity of clinical data available would be disturbing, if not irresponsible.

It is clear that these proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide a powerful therapy for reducing LDL cholesterol, with a reported decrease of about 60% after only 12 or 52 weeks of treatment. Based on four small studies lasting 10-12 weeks and without any clinical outcome data, the committee recommended approving evolocumab for lifetime therapy without anything to support its clinical effectiveness or safety.

Dr. Robert J. Smith, who chaired the advisory committee meeting, faced with approving the drug or delaying a decision until a randomized clinical trial can be completed said, “I am unwilling to subject patients to the wait.” A publication of the American College of Cardiology suggested that these two monoclonal antibody drugs could replace generic statins in 70 million Americans at an estimated cost of $7,000-$12,000 a year. Talk about breaking the bank.

Only recently, we decided that the appropriate statin therapy for cholesterol control should use the dosing from the original clinical trials rather than chasing LDL levels to the lowest level possible. We now have a class of drugs that clearly can lower the cholesterol to a level never seen before, and we are about to discard that therapeutic advice.

We have experience in chasing blood levels with uncertain outcomes. Reducing blood sugar to a very low hemoglobin A_1c level led to adverse clinical events and increased mortality in type 2 diabetes. Raising HDL with the cholesterol ester transfer protein (CETP) inhibitor torcetrapib in a study of 15,000 patients in an outcome trial carried out over a number of years led to increased blood pressure and mortality by 58%, which was associated with a 25% decrease in LDL cholesterol and a 72% increase in HDL, both effects presumed to be remarkably beneficial (N. Engl. J. Med. 2007;357:2109-22).

It is quite possible that these new agents can further decrease coronary vascular mortality. A healthy controversy has raged for some time in regard to the “LDL hypothesis,” compared with therapy based upon the clinical trial outcome. The recent IMPROVE-IT report (N. Engl. J. Med. 2015;372:2387-97) provides some data to support the LDL hypothesis. In that study, the addition of 10 mg of ezetimibe to 40 mg of simvastatin in 18,144 patients followed for up to 6 years resulted in a 2% decrease in mortality associated with a 15.8-mg decrease in serum LDL.

Would it not be prudent to have similar data with the new drug on the street? If it is as potent as it appears to be, a trial of much shorter duration might demonstrate its potency and safety before it is offered to 70 million Americans. The FDA has been reluctant to use surrogate endpoints for approving drugs, but its position has not always been consistent. For some time the FDA has, on occasion, approved drugs that can lower cholesterol with limited outcome data as it did with ezetimibe. However, the decision in regard to the PCSK9 inhibitors will have a much larger impact on care than an add-on drug like ezetimibe. Let’s hope that the FDA shows better judgment than its advisory committee.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

Cognitive behavioral therapy for insomnia (CBT-I) is an effective treatment for adults with chronic insomnia, according to a review published online ahead of print June 9 in Annals of Internal Medicine. Researchers analyzed 20 randomized controlled trials that included 1,162 participants, of whom 64% were female, with a mean age of 56. Approaches to CBT-I incorporated techniques such as cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation. At the post-treatment time point, sleep onset latency improved by an average of 19.03 minutes, wake after sleep onset improved by 26.00 minutes, total sleep time improved by 7.61 minutes, and sleep efficiency improved by 9.91%. These changes seemed to be sustained at later time points. These findings provide evidence that the psychologic approach to chronic insomnia is safer and better tolerated than medication.

Lifelong cognitive activity may support better cognitive performance by a mechanism that is independent of brain β-amyloid burden, brain glucose metabolism, or hippocampal volume, according to a study published online ahead of print June 10 in Neurology. Researchers evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with an average age of 74. The researchers analyzed the data with backward elimination general linear models. Greater cognitive activity was correlated with greater estimated IQ and education and better neuropsychologic testing performance. Evidence did not support an association of Pittsburgh compound B retention, ¹⁸F-fluorodeoxyglucose uptake, or hippocampal volume with past or current levels of cognitive activity, nor with current physical activity.

Among people who have had organ transplants, taking calcineurin daily to prevent organ rejection may protect against Alzheimer’s disease, according to a study published online ahead of print June 8 in Journal of Alzheimer’s Disease. Researchers analyzed data from the medical records of 2,644 patients who received organ transplants and must take calcineurin inhibitor-based medications for the rest of their lives. The participants were separated into groups by age at the time of last visit or death, gender, and ethnicity. Eight participants showed evidence of dementia. Two of these participants were younger than 65, five were between ages 65 and 74, and one person was between ages 75 and 84. The prevalence of dementia and Alzheimer’s disease in the study population was significantly lower than that in the general population.

Academic performance may decline after pediatric epilepsy surgery, according to a study published in the June issue of Epilepsy & Behavior. Investigators examined 136 children with a mean age of 14.3 who underwent resective epilepsy surgery. Academic functioning was assessed before and after surgery using standardized tests of reading, reading comprehension, arithmetic, and spelling. At baseline, 65% of the children displayed low achievement, and 28% had underachievement in at least one academic domain. Performance in reading, numeral operations, and spelling significantly declined after surgery among all patients. Seizure freedom at follow-up did not influence this relationship. Reading comprehension and IQ remained unchanged after surgery. The researchers found similar results when examining patients with a baseline IQ of 70 or greater and when controlling for IQ.

Incident stroke does not explain racial differences in cognitive decline or affect cognition differently by race, according to a study published online ahead of print May 21 in Stroke. Included in this study were 4,908 black and white participants who were age 65 or older and free of stroke and cognitive impairment. Researchers examined longitudinal changes in global cognition by race, before and after adjusting the data. In all, 7.5% of blacks and 6.7% of whites had incident stroke during a mean of 4.1 years of follow-up. Blacks had greater cognitive decline than whites, and the difference persisted after adjustments for cumulative incidence of stroke. Stroke was associated with a decrease in global cognition similar to that associated with approximately 7.9 years of cognitive aging.

Type 2 diabetes may protect against amyotrophic lateral sclerosis (ALS), according to a study published online ahead of print June 1 in JAMA Neurology. The population-based, nested case–control study included 3,650 Danish residents who received a diagnosis of ALS between January 1, 1982, and December 31, 2009, and 365,000 age- and sex-matched controls. The estimated odds ratio for ALS among individuals with diabetes was 0.61. Researchers found a significant modification by age at ALS diagnosis and age at first mention of diabetes in the hospital registers. The protective association with diabetes was stronger with increasing age at ALS diagnosis, and the odds ratio for first mention of diabetes was 1.66 before age 40, but 0.52 for older ages.

The FDA has approved Qudexy XR (topiramate) extended-release capsules for use as initial monotherapy in patients age two and older with partial-onset seizures or primary generalized tonic–clonic seizures. The capsules are engineered to deliver a consistent pharmacokinetic profile. Qudexy XR is approved for administration by sprinkling the contents onto soft food, which may aid the treatment of young children who have difficulty swallowing whole capsules or tablets. Qudexy XR previously was approved for use as initial monotherapy in patients age 10 and older with partial-onset seizures or primary generalized tonic–clonic seizures. The drug is also approved as an adjunctive therapy in patients age two or older with partial-onset seizures, primary generalized tonic–clonic seizures, or seizures associated with Lennox-Gastaut syndrome.

—Kimberly Williams

Cognitive behavioral therapy for insomnia (CBT-I) is an effective treatment for adults with chronic insomnia, according to a review published online ahead of print June 9 in Annals of Internal Medicine. Researchers analyzed 20 randomized controlled trials that included 1,162 participants, of whom 64% were female, with a mean age of 56. Approaches to CBT-I incorporated techniques such as cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation. At the post-treatment time point, sleep onset latency improved by an average of 19.03 minutes, wake after sleep onset improved by 26.00 minutes, total sleep time improved by 7.61 minutes, and sleep efficiency improved by 9.91%. These changes seemed to be sustained at later time points. These findings provide evidence that the psychologic approach to chronic insomnia is safer and better tolerated than medication.

Lifelong cognitive activity may support better cognitive performance by a mechanism that is independent of brain β-amyloid burden, brain glucose metabolism, or hippocampal volume, according to a study published online ahead of print June 10 in Neurology. Researchers evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with an average age of 74. The researchers analyzed the data with backward elimination general linear models. Greater cognitive activity was correlated with greater estimated IQ and education and better neuropsychologic testing performance. Evidence did not support an association of Pittsburgh compound B retention, ¹⁸F-fluorodeoxyglucose uptake, or hippocampal volume with past or current levels of cognitive activity, nor with current physical activity.

Among people who have had organ transplants, taking calcineurin daily to prevent organ rejection may protect against Alzheimer’s disease, according to a study published online ahead of print June 8 in Journal of Alzheimer’s Disease. Researchers analyzed data from the medical records of 2,644 patients who received organ transplants and must take calcineurin inhibitor-based medications for the rest of their lives. The participants were separated into groups by age at the time of last visit or death, gender, and ethnicity. Eight participants showed evidence of dementia. Two of these participants were younger than 65, five were between ages 65 and 74, and one person was between ages 75 and 84. The prevalence of dementia and Alzheimer’s disease in the study population was significantly lower than that in the general population.

Academic performance may decline after pediatric epilepsy surgery, according to a study published in the June issue of Epilepsy & Behavior. Investigators examined 136 children with a mean age of 14.3 who underwent resective epilepsy surgery. Academic functioning was assessed before and after surgery using standardized tests of reading, reading comprehension, arithmetic, and spelling. At baseline, 65% of the children displayed low achievement, and 28% had underachievement in at least one academic domain. Performance in reading, numeral operations, and spelling significantly declined after surgery among all patients. Seizure freedom at follow-up did not influence this relationship. Reading comprehension and IQ remained unchanged after surgery. The researchers found similar results when examining patients with a baseline IQ of 70 or greater and when controlling for IQ.

Incident stroke does not explain racial differences in cognitive decline or affect cognition differently by race, according to a study published online ahead of print May 21 in Stroke. Included in this study were 4,908 black and white participants who were age 65 or older and free of stroke and cognitive impairment. Researchers examined longitudinal changes in global cognition by race, before and after adjusting the data. In all, 7.5% of blacks and 6.7% of whites had incident stroke during a mean of 4.1 years of follow-up. Blacks had greater cognitive decline than whites, and the difference persisted after adjustments for cumulative incidence of stroke. Stroke was associated with a decrease in global cognition similar to that associated with approximately 7.9 years of cognitive aging.

Type 2 diabetes may protect against amyotrophic lateral sclerosis (ALS), according to a study published online ahead of print June 1 in JAMA Neurology. The population-based, nested case–control study included 3,650 Danish residents who received a diagnosis of ALS between January 1, 1982, and December 31, 2009, and 365,000 age- and sex-matched controls. The estimated odds ratio for ALS among individuals with diabetes was 0.61. Researchers found a significant modification by age at ALS diagnosis and age at first mention of diabetes in the hospital registers. The protective association with diabetes was stronger with increasing age at ALS diagnosis, and the odds ratio for first mention of diabetes was 1.66 before age 40, but 0.52 for older ages.

The FDA has approved Qudexy XR (topiramate) extended-release capsules for use as initial monotherapy in patients age two and older with partial-onset seizures or primary generalized tonic–clonic seizures. The capsules are engineered to deliver a consistent pharmacokinetic profile. Qudexy XR is approved for administration by sprinkling the contents onto soft food, which may aid the treatment of young children who have difficulty swallowing whole capsules or tablets. Qudexy XR previously was approved for use as initial monotherapy in patients age 10 and older with partial-onset seizures or primary generalized tonic–clonic seizures. The drug is also approved as an adjunctive therapy in patients age two or older with partial-onset seizures, primary generalized tonic–clonic seizures, or seizures associated with Lennox-Gastaut syndrome.

—Kimberly Williams

Cognitive behavioral therapy for insomnia (CBT-I) is an effective treatment for adults with chronic insomnia, according to a review published online ahead of print June 9 in Annals of Internal Medicine. Researchers analyzed 20 randomized controlled trials that included 1,162 participants, of whom 64% were female, with a mean age of 56. Approaches to CBT-I incorporated techniques such as cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation. At the post-treatment time point, sleep onset latency improved by an average of 19.03 minutes, wake after sleep onset improved by 26.00 minutes, total sleep time improved by 7.61 minutes, and sleep efficiency improved by 9.91%. These changes seemed to be sustained at later time points. These findings provide evidence that the psychologic approach to chronic insomnia is safer and better tolerated than medication.

Lifelong cognitive activity may support better cognitive performance by a mechanism that is independent of brain β-amyloid burden, brain glucose metabolism, or hippocampal volume, according to a study published online ahead of print June 10 in Neurology. Researchers evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with an average age of 74. The researchers analyzed the data with backward elimination general linear models. Greater cognitive activity was correlated with greater estimated IQ and education and better neuropsychologic testing performance. Evidence did not support an association of Pittsburgh compound B retention, ¹⁸F-fluorodeoxyglucose uptake, or hippocampal volume with past or current levels of cognitive activity, nor with current physical activity.

Among people who have had organ transplants, taking calcineurin daily to prevent organ rejection may protect against Alzheimer’s disease, according to a study published online ahead of print June 8 in Journal of Alzheimer’s Disease. Researchers analyzed data from the medical records of 2,644 patients who received organ transplants and must take calcineurin inhibitor-based medications for the rest of their lives. The participants were separated into groups by age at the time of last visit or death, gender, and ethnicity. Eight participants showed evidence of dementia. Two of these participants were younger than 65, five were between ages 65 and 74, and one person was between ages 75 and 84. The prevalence of dementia and Alzheimer’s disease in the study population was significantly lower than that in the general population.

Academic performance may decline after pediatric epilepsy surgery, according to a study published in the June issue of Epilepsy & Behavior. Investigators examined 136 children with a mean age of 14.3 who underwent resective epilepsy surgery. Academic functioning was assessed before and after surgery using standardized tests of reading, reading comprehension, arithmetic, and spelling. At baseline, 65% of the children displayed low achievement, and 28% had underachievement in at least one academic domain. Performance in reading, numeral operations, and spelling significantly declined after surgery among all patients. Seizure freedom at follow-up did not influence this relationship. Reading comprehension and IQ remained unchanged after surgery. The researchers found similar results when examining patients with a baseline IQ of 70 or greater and when controlling for IQ.

Incident stroke does not explain racial differences in cognitive decline or affect cognition differently by race, according to a study published online ahead of print May 21 in Stroke. Included in this study were 4,908 black and white participants who were age 65 or older and free of stroke and cognitive impairment. Researchers examined longitudinal changes in global cognition by race, before and after adjusting the data. In all, 7.5% of blacks and 6.7% of whites had incident stroke during a mean of 4.1 years of follow-up. Blacks had greater cognitive decline than whites, and the difference persisted after adjustments for cumulative incidence of stroke. Stroke was associated with a decrease in global cognition similar to that associated with approximately 7.9 years of cognitive aging.

Type 2 diabetes may protect against amyotrophic lateral sclerosis (ALS), according to a study published online ahead of print June 1 in JAMA Neurology. The population-based, nested case–control study included 3,650 Danish residents who received a diagnosis of ALS between January 1, 1982, and December 31, 2009, and 365,000 age- and sex-matched controls. The estimated odds ratio for ALS among individuals with diabetes was 0.61. Researchers found a significant modification by age at ALS diagnosis and age at first mention of diabetes in the hospital registers. The protective association with diabetes was stronger with increasing age at ALS diagnosis, and the odds ratio for first mention of diabetes was 1.66 before age 40, but 0.52 for older ages.

The FDA has approved Qudexy XR (topiramate) extended-release capsules for use as initial monotherapy in patients age two and older with partial-onset seizures or primary generalized tonic–clonic seizures. The capsules are engineered to deliver a consistent pharmacokinetic profile. Qudexy XR is approved for administration by sprinkling the contents onto soft food, which may aid the treatment of young children who have difficulty swallowing whole capsules or tablets. Qudexy XR previously was approved for use as initial monotherapy in patients age 10 and older with partial-onset seizures or primary generalized tonic–clonic seizures. The drug is also approved as an adjunctive therapy in patients age two or older with partial-onset seizures, primary generalized tonic–clonic seizures, or seizures associated with Lennox-Gastaut syndrome.

—Kimberly Williams

A study published in JAMA Internal Medicine in December 2014 looked at decision fatigue in primary care providers. The researchers focused on antibiotic prescriptions for acute respiratory infections (including those for which antibiotics are never indicated) over a 16-month period covering 21,867 visits to 204 clinicians. They compared the rate of antibiotic prescription at the first, second, third, and fourth hour of clinic, with the premise being that over a period of repeated decision making the quality of the decisions declines (JAMA Intern. Med. 2014;174:2029-31).

If, like me, you think you have unrealistic expectations about physicians being unimpeachable, you might be disappointed to learn that antibiotic prescriptions were significantly higher for the third and fourth hour of clinic. It seems that as the clinic session wore on, physicians opted for the “safer,” “easier” option.

Another paper involving similarly weighty consequences was published in 2011 in Proceedings of the National Academy of Sciences (and cited as one of only six references in the JAMA paper). The researchers looked at parole decisions made by judges in four Israeli prisons. Data from 1,112 judicial rulings involving eight judges showed that “the percentage of favorable rulings drops gradually from ~65% to nearly zero within each decision session and returns abruptly to ~65% after a break” (Proc. Natl. Acad. Sci. U.S.A. 2011;108:6889-92). (Breaks lasted about 30 minutes and involved a meal.) That’s a pretty dramatic rate of change. It is sobering to think of lives being hugely affected by such seemingly irrelevant details. Talk about fate being fickle.

Decision fatigue suggests that when we make repeated decisions over a brief period of time there is an erosion of self-control and we are more likely to choose the “affectively pleasing” option. It has been written about in psychology journals for the past 2 decades, but for practical and ethical reasons, most studies on the subject involve minor decisions, such as what to choose at the grocery store or which items to add to one’s wedding registry. The concept has become quite popular in the fields of behavioral economic and advertising. It is the reason groceries display candy at the cash register.

Decision fatigue is part of a larger theory on our executive functions, proposed by Dr. Roy Baumeister, professor of social psychology at the University of Florida. His central idea is that self-control, volitional acts, responsibility, and self-regulatory efforts “draw upon a common resource and deplete it.” He calls it ego depletion. In one simple but powerful experiment, researchers conducted a study where students were asked to commit either two digits or seven digits to memory. When offered a choice of fruit salad or chocolate cake as compensation for participation in the study, those who had to remember seven digits were far more likely to choose the chocolate cake – certainly the more “affectively pleasing” option. So ego depletion is to blame for my constant kitchen-grazing behavior at the end of a trying clinic day. Apart from affecting my waistline, I’m sure it affects me in ways that I am unaware of, ways that may have an impact not just on patients but on society, too.

The JAMA Internal Medicine article seems to be the first of its kind in the medical literature. To me, it is hugely important because it reminds us of two major truths: that there are often bigger things at stake, and that doctors, being mere mortals, are not exempt from human frailty.

Dr. Chan practices rheumatology in Pawtucket, R.I.

A study published in JAMA Internal Medicine in December 2014 looked at decision fatigue in primary care providers. The researchers focused on antibiotic prescriptions for acute respiratory infections (including those for which antibiotics are never indicated) over a 16-month period covering 21,867 visits to 204 clinicians. They compared the rate of antibiotic prescription at the first, second, third, and fourth hour of clinic, with the premise being that over a period of repeated decision making the quality of the decisions declines (JAMA Intern. Med. 2014;174:2029-31).

If, like me, you think you have unrealistic expectations about physicians being unimpeachable, you might be disappointed to learn that antibiotic prescriptions were significantly higher for the third and fourth hour of clinic. It seems that as the clinic session wore on, physicians opted for the “safer,” “easier” option.

Another paper involving similarly weighty consequences was published in 2011 in Proceedings of the National Academy of Sciences (and cited as one of only six references in the JAMA paper). The researchers looked at parole decisions made by judges in four Israeli prisons. Data from 1,112 judicial rulings involving eight judges showed that “the percentage of favorable rulings drops gradually from ~65% to nearly zero within each decision session and returns abruptly to ~65% after a break” (Proc. Natl. Acad. Sci. U.S.A. 2011;108:6889-92). (Breaks lasted about 30 minutes and involved a meal.) That’s a pretty dramatic rate of change. It is sobering to think of lives being hugely affected by such seemingly irrelevant details. Talk about fate being fickle.

Decision fatigue suggests that when we make repeated decisions over a brief period of time there is an erosion of self-control and we are more likely to choose the “affectively pleasing” option. It has been written about in psychology journals for the past 2 decades, but for practical and ethical reasons, most studies on the subject involve minor decisions, such as what to choose at the grocery store or which items to add to one’s wedding registry. The concept has become quite popular in the fields of behavioral economic and advertising. It is the reason groceries display candy at the cash register.

Decision fatigue is part of a larger theory on our executive functions, proposed by Dr. Roy Baumeister, professor of social psychology at the University of Florida. His central idea is that self-control, volitional acts, responsibility, and self-regulatory efforts “draw upon a common resource and deplete it.” He calls it ego depletion. In one simple but powerful experiment, researchers conducted a study where students were asked to commit either two digits or seven digits to memory. When offered a choice of fruit salad or chocolate cake as compensation for participation in the study, those who had to remember seven digits were far more likely to choose the chocolate cake – certainly the more “affectively pleasing” option. So ego depletion is to blame for my constant kitchen-grazing behavior at the end of a trying clinic day. Apart from affecting my waistline, I’m sure it affects me in ways that I am unaware of, ways that may have an impact not just on patients but on society, too.

The JAMA Internal Medicine article seems to be the first of its kind in the medical literature. To me, it is hugely important because it reminds us of two major truths: that there are often bigger things at stake, and that doctors, being mere mortals, are not exempt from human frailty.

Dr. Chan practices rheumatology in Pawtucket, R.I.

A study published in JAMA Internal Medicine in December 2014 looked at decision fatigue in primary care providers. The researchers focused on antibiotic prescriptions for acute respiratory infections (including those for which antibiotics are never indicated) over a 16-month period covering 21,867 visits to 204 clinicians. They compared the rate of antibiotic prescription at the first, second, third, and fourth hour of clinic, with the premise being that over a period of repeated decision making the quality of the decisions declines (JAMA Intern. Med. 2014;174:2029-31).

If, like me, you think you have unrealistic expectations about physicians being unimpeachable, you might be disappointed to learn that antibiotic prescriptions were significantly higher for the third and fourth hour of clinic. It seems that as the clinic session wore on, physicians opted for the “safer,” “easier” option.

Another paper involving similarly weighty consequences was published in 2011 in Proceedings of the National Academy of Sciences (and cited as one of only six references in the JAMA paper). The researchers looked at parole decisions made by judges in four Israeli prisons. Data from 1,112 judicial rulings involving eight judges showed that “the percentage of favorable rulings drops gradually from ~65% to nearly zero within each decision session and returns abruptly to ~65% after a break” (Proc. Natl. Acad. Sci. U.S.A. 2011;108:6889-92). (Breaks lasted about 30 minutes and involved a meal.) That’s a pretty dramatic rate of change. It is sobering to think of lives being hugely affected by such seemingly irrelevant details. Talk about fate being fickle.

Decision fatigue suggests that when we make repeated decisions over a brief period of time there is an erosion of self-control and we are more likely to choose the “affectively pleasing” option. It has been written about in psychology journals for the past 2 decades, but for practical and ethical reasons, most studies on the subject involve minor decisions, such as what to choose at the grocery store or which items to add to one’s wedding registry. The concept has become quite popular in the fields of behavioral economic and advertising. It is the reason groceries display candy at the cash register.

Decision fatigue is part of a larger theory on our executive functions, proposed by Dr. Roy Baumeister, professor of social psychology at the University of Florida. His central idea is that self-control, volitional acts, responsibility, and self-regulatory efforts “draw upon a common resource and deplete it.” He calls it ego depletion. In one simple but powerful experiment, researchers conducted a study where students were asked to commit either two digits or seven digits to memory. When offered a choice of fruit salad or chocolate cake as compensation for participation in the study, those who had to remember seven digits were far more likely to choose the chocolate cake – certainly the more “affectively pleasing” option. So ego depletion is to blame for my constant kitchen-grazing behavior at the end of a trying clinic day. Apart from affecting my waistline, I’m sure it affects me in ways that I am unaware of, ways that may have an impact not just on patients but on society, too.

The JAMA Internal Medicine article seems to be the first of its kind in the medical literature. To me, it is hugely important because it reminds us of two major truths: that there are often bigger things at stake, and that doctors, being mere mortals, are not exempt from human frailty.

Dr. Chan practices rheumatology in Pawtucket, R.I.

TORONTO—Interim results of a phase 3 study suggest idarucizumab, a humanized antibody fragment, can reverse the anticoagulant effect of

dabigatran in real-world situations.

In the RE-VERSE AD trial, idarucizumab normalized diluted thrombin time (dTT) and ecarin clotting time (ECT) in a majority of patients with uncontrolled or life-threatening bleeding complications and most patients who required emergency surgery or an invasive procedure.

In addition, researchers said there were no safety concerns related to idarucizumab. However, 23% of patients in this trial experienced serious adverse events, 20% of patients died, and several patients had thrombotic or bleeding events.

These results have been published in NEJM and presented at the 2015 ISTH Congress (abstract LB005). The study was sponsored by Boehringer Ingelheim, the company developing idarucizumab and dabigatran.

“The interim analysis from RE-VERSE AD is important for healthcare professionals as it provides the first insights into the effect of a specific reversal agent to a non-vitamin K antagonist oral anticoagulant during real-world emergency situations,” said study investigator Charles Pollack, MD, of the University of Pennsylvania in Philadelphia.

Because RE-VERSE AD was designed to evaluate how idarucizumab would perform in real-world situations, severely ill or injured patients were eligible for enrollment. The interim analysis included data from 90 patients in emergency settings who were taking dabigatran and required reversal.

The patients were divided into 2 groups: those with uncontrolled or life-threatening bleeding complications, such as intracranial hemorrhage or severe trauma (group A, n=51), and patients requiring emergency surgery or an invasive procedure (group B, n=39).

The primary endpoint of the study is the degree to which 5 g of idarucizumab reversed the anticoagulant effect of dabigatran within 4 hours, measured by dTT and ECT.

The researchers were able to evaluate the percentage of reversal by dTT in 68 patients (40 in group A and 28 in group B) and the percentage of reversal by ECT in 81 patients (47 in group A and 34 in group B).

The dTT was normalized in 98% of evaluable patients in group A and 93% in group B. The ECT was normalized in 89% of evaluable patients in group A and 88% in group B.

At 12 hours and 24 hours, the dTT was below the upper limit of the normal range in 90% of evaluable patients in group A and 81% in group B. The ECT was below the upper limit of the normal range in 72% of evaluable group A patients and 54% of evaluable group B patients.

Among the 35 evaluable patients in group A, hemostasis was restored at a median of 11.4 hours. Among the 36 patients in group B who underwent a procedure, 33 had normal intraoperative hemostasis. Two patients had mildly abnormal hemostasis, and 1 patient had moderately abnormal hemostasis.

“As observed in earlier research in volunteers, idarucizumab reversed the anticoagulant effect of dabigatran in patients completely within minutes, even in those rare critical care situations studied in RE-VERSE AD,” Dr Pollack said.

“These data demonstrate that use of idarucizumab can help physicians focus on other vital aspects of emergency management beyond anticoagulant reversal in dabigatran-treated patients.”

Twenty-one patients (13 in group A and 8 in group B) experienced serious adverse events during the study.

This included 18 events that led to death, 5 thrombotic events, 2 cases of gastrointestinal hemorrhage, a postoperative wound infection, a case of delirium, a case of right ventricular failure, and a case of pulmonary edema. (Some patients had more than one serious adverse event.)

TORONTO—Interim results of a phase 3 study suggest idarucizumab, a humanized antibody fragment, can reverse the anticoagulant effect of

dabigatran in real-world situations.

In the RE-VERSE AD trial, idarucizumab normalized diluted thrombin time (dTT) and ecarin clotting time (ECT) in a majority of patients with uncontrolled or life-threatening bleeding complications and most patients who required emergency surgery or an invasive procedure.

In addition, researchers said there were no safety concerns related to idarucizumab. However, 23% of patients in this trial experienced serious adverse events, 20% of patients died, and several patients had thrombotic or bleeding events.

These results have been published in NEJM and presented at the 2015 ISTH Congress (abstract LB005). The study was sponsored by Boehringer Ingelheim, the company developing idarucizumab and dabigatran.

“The interim analysis from RE-VERSE AD is important for healthcare professionals as it provides the first insights into the effect of a specific reversal agent to a non-vitamin K antagonist oral anticoagulant during real-world emergency situations,” said study investigator Charles Pollack, MD, of the University of Pennsylvania in Philadelphia.

Because RE-VERSE AD was designed to evaluate how idarucizumab would perform in real-world situations, severely ill or injured patients were eligible for enrollment. The interim analysis included data from 90 patients in emergency settings who were taking dabigatran and required reversal.

The patients were divided into 2 groups: those with uncontrolled or life-threatening bleeding complications, such as intracranial hemorrhage or severe trauma (group A, n=51), and patients requiring emergency surgery or an invasive procedure (group B, n=39).

The primary endpoint of the study is the degree to which 5 g of idarucizumab reversed the anticoagulant effect of dabigatran within 4 hours, measured by dTT and ECT.

The researchers were able to evaluate the percentage of reversal by dTT in 68 patients (40 in group A and 28 in group B) and the percentage of reversal by ECT in 81 patients (47 in group A and 34 in group B).

The dTT was normalized in 98% of evaluable patients in group A and 93% in group B. The ECT was normalized in 89% of evaluable patients in group A and 88% in group B.

At 12 hours and 24 hours, the dTT was below the upper limit of the normal range in 90% of evaluable patients in group A and 81% in group B. The ECT was below the upper limit of the normal range in 72% of evaluable group A patients and 54% of evaluable group B patients.

Among the 35 evaluable patients in group A, hemostasis was restored at a median of 11.4 hours. Among the 36 patients in group B who underwent a procedure, 33 had normal intraoperative hemostasis. Two patients had mildly abnormal hemostasis, and 1 patient had moderately abnormal hemostasis.

“As observed in earlier research in volunteers, idarucizumab reversed the anticoagulant effect of dabigatran in patients completely within minutes, even in those rare critical care situations studied in RE-VERSE AD,” Dr Pollack said.

“These data demonstrate that use of idarucizumab can help physicians focus on other vital aspects of emergency management beyond anticoagulant reversal in dabigatran-treated patients.”

Twenty-one patients (13 in group A and 8 in group B) experienced serious adverse events during the study.

This included 18 events that led to death, 5 thrombotic events, 2 cases of gastrointestinal hemorrhage, a postoperative wound infection, a case of delirium, a case of right ventricular failure, and a case of pulmonary edema. (Some patients had more than one serious adverse event.)

TORONTO—Interim results of a phase 3 study suggest idarucizumab, a humanized antibody fragment, can reverse the anticoagulant effect of

dabigatran in real-world situations.

In the RE-VERSE AD trial, idarucizumab normalized diluted thrombin time (dTT) and ecarin clotting time (ECT) in a majority of patients with uncontrolled or life-threatening bleeding complications and most patients who required emergency surgery or an invasive procedure.

In addition, researchers said there were no safety concerns related to idarucizumab. However, 23% of patients in this trial experienced serious adverse events, 20% of patients died, and several patients had thrombotic or bleeding events.

These results have been published in NEJM and presented at the 2015 ISTH Congress (abstract LB005). The study was sponsored by Boehringer Ingelheim, the company developing idarucizumab and dabigatran.

“The interim analysis from RE-VERSE AD is important for healthcare professionals as it provides the first insights into the effect of a specific reversal agent to a non-vitamin K antagonist oral anticoagulant during real-world emergency situations,” said study investigator Charles Pollack, MD, of the University of Pennsylvania in Philadelphia.

Because RE-VERSE AD was designed to evaluate how idarucizumab would perform in real-world situations, severely ill or injured patients were eligible for enrollment. The interim analysis included data from 90 patients in emergency settings who were taking dabigatran and required reversal.

The patients were divided into 2 groups: those with uncontrolled or life-threatening bleeding complications, such as intracranial hemorrhage or severe trauma (group A, n=51), and patients requiring emergency surgery or an invasive procedure (group B, n=39).

The primary endpoint of the study is the degree to which 5 g of idarucizumab reversed the anticoagulant effect of dabigatran within 4 hours, measured by dTT and ECT.

The researchers were able to evaluate the percentage of reversal by dTT in 68 patients (40 in group A and 28 in group B) and the percentage of reversal by ECT in 81 patients (47 in group A and 34 in group B).

The dTT was normalized in 98% of evaluable patients in group A and 93% in group B. The ECT was normalized in 89% of evaluable patients in group A and 88% in group B.

At 12 hours and 24 hours, the dTT was below the upper limit of the normal range in 90% of evaluable patients in group A and 81% in group B. The ECT was below the upper limit of the normal range in 72% of evaluable group A patients and 54% of evaluable group B patients.

Among the 35 evaluable patients in group A, hemostasis was restored at a median of 11.4 hours. Among the 36 patients in group B who underwent a procedure, 33 had normal intraoperative hemostasis. Two patients had mildly abnormal hemostasis, and 1 patient had moderately abnormal hemostasis.

“As observed in earlier research in volunteers, idarucizumab reversed the anticoagulant effect of dabigatran in patients completely within minutes, even in those rare critical care situations studied in RE-VERSE AD,” Dr Pollack said.

“These data demonstrate that use of idarucizumab can help physicians focus on other vital aspects of emergency management beyond anticoagulant reversal in dabigatran-treated patients.”

Twenty-one patients (13 in group A and 8 in group B) experienced serious adverse events during the study.

This included 18 events that led to death, 5 thrombotic events, 2 cases of gastrointestinal hemorrhage, a postoperative wound infection, a case of delirium, a case of right ventricular failure, and a case of pulmonary edema. (Some patients had more than one serious adverse event.)

Palazzo Dei Congressi,

site of 13-ICML

LUGANO—Adding thiotepa and rituximab to the treatment of primary central nervous system (CNS) lymphoma is feasible from a safety perspective and has yielded promising results, according to new research.

An analysis of the IELSG 32 trial—in which patients received methotrexate and cytarabine alone, with rituximab, or with rituximab and thiotepa—has shown the 4-drug regimen improves responses and progression-free survival.

IELSG 32 builds on the foundation of the IELSG 20 trial to determine the best induction therapy for patients with primary CNS lymphoma. In IELSG 20, the complete response (CR) rate was higher among patients receiving high-dose methotrexate and cytarabine than in patients receiving methotrexate alone.

So the researchers decided to investigate whether rituximab and/or thiotepa added to the regimen would impact patient outcome. Rituximab has been associated with improved CR rates in primary CNS lymphoma, and thiotepa is active against aggressive lymphomas. Thiotepa is also able to cross the blood–brain barrier.

Andrés J.M. Ferreri, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, reported the results of this research on behalf of the International Extranodal Lymphoma Study Group (IELSG) at the 13th International Conference on Malignant Lymphoma (abstract 009).

Treatment and toxicity

The investigators randomized 227 patients from 53 centers in 5 countries to 4 cycles of treatment in 3 cohorts:

• Arm A consisted of 4 cycles of methotrexate (3.5 g/m²) on day 1 and cytarabine (2 g/m²) twice a day on days 2 and 3 every 3 weeks.
• Arm B added rituximab (375 mg/m²) on days 5 and 0 to the regimen.
• Arm C added rituximab and thiotepa (30 mg/m²) on day 4 to the regimen.

Eight patients were excluded for various reasons, including incorrect diagnosis. So 219 patients received therapy, 75 in arm A, 69 in arm B, and 75 in arm C.

Patients were a median age of 58 years in arm A and 57 in arms B and C, and the majority were male. More than 80% of patients in all arms were intermediate- or high-risk according to IELSG. And all patients had the diffuse large B-cell lymphoma histotype.

Patients in arm A received 74% of the planned courses, those in arm B received 86%, and those in arm C received 91%. The relative dose intensity across all arms of each drug administered was not significantly different among the arms.

“As expected, hematologic toxicity was common, with grade 4 neutropenia (P=0.01) and thrombocytopenia (P=0.0001) being significantly more common for arm C,” Dr Ferreri said. “However, this was not associated with an increasing array of severe infections, interruptions, toxicity, or toxic deaths.”

Peripheral blood stem cell collection was successful in 94% of patients in arms A and C and 96% of patients in arm B.

Response rates

The overall response rate (ORR) was 72% in IELSG 32, compared to 54% in IELSG 20. But the CR rate was not significantly higher in IELSG 32 than in IELSG 20, at 34% and 31%, respectively.

“There are many explanations for this,” Dr Ferreri said. “But I think it was because there were a significantly greater number of patients with higher IELSG risk [in IELSG 32], a higher proportion of poor-prognosis patients.”

Patients in arm C had significantly higher response rates than patients in the other 2 arms, with a CR rate of 49%, a partial response (PR) rate of 37%, and an ORR of 87%.

This compared to a CR rate of 23% in arm A and 30% in arm B, a PR rate of 31% in arm A and 30% in arm B, and an ORR of 53% in arm A and 74% in arm B.

The investigators also analyzed activity according to IELSG risk.

“Arm C was significantly more active in all the 3 subgroups,” Dr Ferreri observed, “and importantly, the overall response rate and complete remission rate were similar for each arm in the 3 different risk groups.”

Second randomization and survival

One hundred and eighteen patients went on to a second randomization, 35 from arm A, 35 from arm B, and 48 from arm C.

Fifty-nine patients were randomized to the whole-brain radiotherapy cohort, and 59 to the carmustine-thiotepa-autologous stem cell transplant cohort.

At a median follow-up of 21 months, 110 patients remain failure free, 32% from arm A, 54% from arm B, and 65% from arm C. Failure in 97% of the cases was due to primary site involvement, usually the brain.

Fifty-six percent of the patients are still alive, 39% in arm A, 59% in arm B, and 69% in arm C.

Ninety-seven patients died, 73 from lymphoma, 15 from toxicity of the first-line treatment, 2 from toxicity of the salvage regimen, 2 from neurotoxicity, and 5 from other causes.

Dr Ferreri concluded that the MATRIX regimen—the addition of rituximab and thiotepa to methotrexate and cytarabine—was associated with significant improvements in CR rate, ORR, and progression-free and overall survival.

The addition of rituximab and thiotepa did not increase toxicity, with the exception of greater hematologic adverse events, nor did the drugs increase the rates of severe complications. The agents also allowed for high rates of successful stem cell collection.

Palazzo Dei Congressi,

site of 13-ICML

LUGANO—Adding thiotepa and rituximab to the treatment of primary central nervous system (CNS) lymphoma is feasible from a safety perspective and has yielded promising results, according to new research.

An analysis of the IELSG 32 trial—in which patients received methotrexate and cytarabine alone, with rituximab, or with rituximab and thiotepa—has shown the 4-drug regimen improves responses and progression-free survival.

IELSG 32 builds on the foundation of the IELSG 20 trial to determine the best induction therapy for patients with primary CNS lymphoma. In IELSG 20, the complete response (CR) rate was higher among patients receiving high-dose methotrexate and cytarabine than in patients receiving methotrexate alone.

So the researchers decided to investigate whether rituximab and/or thiotepa added to the regimen would impact patient outcome. Rituximab has been associated with improved CR rates in primary CNS lymphoma, and thiotepa is active against aggressive lymphomas. Thiotepa is also able to cross the blood–brain barrier.

Andrés J.M. Ferreri, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, reported the results of this research on behalf of the International Extranodal Lymphoma Study Group (IELSG) at the 13th International Conference on Malignant Lymphoma (abstract 009).

Treatment and toxicity

The investigators randomized 227 patients from 53 centers in 5 countries to 4 cycles of treatment in 3 cohorts:

• Arm A consisted of 4 cycles of methotrexate (3.5 g/m²) on day 1 and cytarabine (2 g/m²) twice a day on days 2 and 3 every 3 weeks.
• Arm B added rituximab (375 mg/m²) on days 5 and 0 to the regimen.
• Arm C added rituximab and thiotepa (30 mg/m²) on day 4 to the regimen.

Eight patients were excluded for various reasons, including incorrect diagnosis. So 219 patients received therapy, 75 in arm A, 69 in arm B, and 75 in arm C.

Patients were a median age of 58 years in arm A and 57 in arms B and C, and the majority were male. More than 80% of patients in all arms were intermediate- or high-risk according to IELSG. And all patients had the diffuse large B-cell lymphoma histotype.

Patients in arm A received 74% of the planned courses, those in arm B received 86%, and those in arm C received 91%. The relative dose intensity across all arms of each drug administered was not significantly different among the arms.

“As expected, hematologic toxicity was common, with grade 4 neutropenia (P=0.01) and thrombocytopenia (P=0.0001) being significantly more common for arm C,” Dr Ferreri said. “However, this was not associated with an increasing array of severe infections, interruptions, toxicity, or toxic deaths.”

Peripheral blood stem cell collection was successful in 94% of patients in arms A and C and 96% of patients in arm B.

Response rates

The overall response rate (ORR) was 72% in IELSG 32, compared to 54% in IELSG 20. But the CR rate was not significantly higher in IELSG 32 than in IELSG 20, at 34% and 31%, respectively.

“There are many explanations for this,” Dr Ferreri said. “But I think it was because there were a significantly greater number of patients with higher IELSG risk [in IELSG 32], a higher proportion of poor-prognosis patients.”

Patients in arm C had significantly higher response rates than patients in the other 2 arms, with a CR rate of 49%, a partial response (PR) rate of 37%, and an ORR of 87%.

This compared to a CR rate of 23% in arm A and 30% in arm B, a PR rate of 31% in arm A and 30% in arm B, and an ORR of 53% in arm A and 74% in arm B.

The investigators also analyzed activity according to IELSG risk.

“Arm C was significantly more active in all the 3 subgroups,” Dr Ferreri observed, “and importantly, the overall response rate and complete remission rate were similar for each arm in the 3 different risk groups.”

Second randomization and survival

One hundred and eighteen patients went on to a second randomization, 35 from arm A, 35 from arm B, and 48 from arm C.

Fifty-nine patients were randomized to the whole-brain radiotherapy cohort, and 59 to the carmustine-thiotepa-autologous stem cell transplant cohort.

At a median follow-up of 21 months, 110 patients remain failure free, 32% from arm A, 54% from arm B, and 65% from arm C. Failure in 97% of the cases was due to primary site involvement, usually the brain.

Fifty-six percent of the patients are still alive, 39% in arm A, 59% in arm B, and 69% in arm C.

Ninety-seven patients died, 73 from lymphoma, 15 from toxicity of the first-line treatment, 2 from toxicity of the salvage regimen, 2 from neurotoxicity, and 5 from other causes.

Dr Ferreri concluded that the MATRIX regimen—the addition of rituximab and thiotepa to methotrexate and cytarabine—was associated with significant improvements in CR rate, ORR, and progression-free and overall survival.

The addition of rituximab and thiotepa did not increase toxicity, with the exception of greater hematologic adverse events, nor did the drugs increase the rates of severe complications. The agents also allowed for high rates of successful stem cell collection.

Palazzo Dei Congressi,

site of 13-ICML

LUGANO—Adding thiotepa and rituximab to the treatment of primary central nervous system (CNS) lymphoma is feasible from a safety perspective and has yielded promising results, according to new research.

An analysis of the IELSG 32 trial—in which patients received methotrexate and cytarabine alone, with rituximab, or with rituximab and thiotepa—has shown the 4-drug regimen improves responses and progression-free survival.

IELSG 32 builds on the foundation of the IELSG 20 trial to determine the best induction therapy for patients with primary CNS lymphoma. In IELSG 20, the complete response (CR) rate was higher among patients receiving high-dose methotrexate and cytarabine than in patients receiving methotrexate alone.

So the researchers decided to investigate whether rituximab and/or thiotepa added to the regimen would impact patient outcome. Rituximab has been associated with improved CR rates in primary CNS lymphoma, and thiotepa is active against aggressive lymphomas. Thiotepa is also able to cross the blood–brain barrier.

Andrés J.M. Ferreri, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, reported the results of this research on behalf of the International Extranodal Lymphoma Study Group (IELSG) at the 13th International Conference on Malignant Lymphoma (abstract 009).

Treatment and toxicity

The investigators randomized 227 patients from 53 centers in 5 countries to 4 cycles of treatment in 3 cohorts:

• Arm A consisted of 4 cycles of methotrexate (3.5 g/m²) on day 1 and cytarabine (2 g/m²) twice a day on days 2 and 3 every 3 weeks.
• Arm B added rituximab (375 mg/m²) on days 5 and 0 to the regimen.
• Arm C added rituximab and thiotepa (30 mg/m²) on day 4 to the regimen.

Eight patients were excluded for various reasons, including incorrect diagnosis. So 219 patients received therapy, 75 in arm A, 69 in arm B, and 75 in arm C.

Patients were a median age of 58 years in arm A and 57 in arms B and C, and the majority were male. More than 80% of patients in all arms were intermediate- or high-risk according to IELSG. And all patients had the diffuse large B-cell lymphoma histotype.

Patients in arm A received 74% of the planned courses, those in arm B received 86%, and those in arm C received 91%. The relative dose intensity across all arms of each drug administered was not significantly different among the arms.

“As expected, hematologic toxicity was common, with grade 4 neutropenia (P=0.01) and thrombocytopenia (P=0.0001) being significantly more common for arm C,” Dr Ferreri said. “However, this was not associated with an increasing array of severe infections, interruptions, toxicity, or toxic deaths.”

Peripheral blood stem cell collection was successful in 94% of patients in arms A and C and 96% of patients in arm B.

Response rates

The overall response rate (ORR) was 72% in IELSG 32, compared to 54% in IELSG 20. But the CR rate was not significantly higher in IELSG 32 than in IELSG 20, at 34% and 31%, respectively.

“There are many explanations for this,” Dr Ferreri said. “But I think it was because there were a significantly greater number of patients with higher IELSG risk [in IELSG 32], a higher proportion of poor-prognosis patients.”

Patients in arm C had significantly higher response rates than patients in the other 2 arms, with a CR rate of 49%, a partial response (PR) rate of 37%, and an ORR of 87%.

This compared to a CR rate of 23% in arm A and 30% in arm B, a PR rate of 31% in arm A and 30% in arm B, and an ORR of 53% in arm A and 74% in arm B.

The investigators also analyzed activity according to IELSG risk.

“Arm C was significantly more active in all the 3 subgroups,” Dr Ferreri observed, “and importantly, the overall response rate and complete remission rate were similar for each arm in the 3 different risk groups.”

Second randomization and survival

One hundred and eighteen patients went on to a second randomization, 35 from arm A, 35 from arm B, and 48 from arm C.

Fifty-nine patients were randomized to the whole-brain radiotherapy cohort, and 59 to the carmustine-thiotepa-autologous stem cell transplant cohort.

At a median follow-up of 21 months, 110 patients remain failure free, 32% from arm A, 54% from arm B, and 65% from arm C. Failure in 97% of the cases was due to primary site involvement, usually the brain.

Fifty-six percent of the patients are still alive, 39% in arm A, 59% in arm B, and 69% in arm C.

Ninety-seven patients died, 73 from lymphoma, 15 from toxicity of the first-line treatment, 2 from toxicity of the salvage regimen, 2 from neurotoxicity, and 5 from other causes.

Dr Ferreri concluded that the MATRIX regimen—the addition of rituximab and thiotepa to methotrexate and cytarabine—was associated with significant improvements in CR rate, ORR, and progression-free and overall survival.

The addition of rituximab and thiotepa did not increase toxicity, with the exception of greater hematologic adverse events, nor did the drugs increase the rates of severe complications. The agents also allowed for high rates of successful stem cell collection.

Warfarin tablets

TORONTO—Bridge anticoagulant therapy appears to be unnecessary in patients with atrial fibrillation (AFib) undergoing elective surgery, according to researchers.

In the BRIDGE study, AFib patients who stopped all anticoagulant therapy before elective surgery had no higher risk of thrombosis and a lower risk of major bleeding than patients who were given bridge therapy with low-molecular weight heparin after stopping warfarin.

This research was presented at the 2015 ISTH Congress (abstract LB002) and published in NEJM.

“Bridging has been controversial because there has been a lack of data demonstrating that it’s necessary, so people don’t know what to do,” said study author Thomas L. Ortel, MD, PhD, of Duke University Medical Center in Durham, North Carolina.

“You can go to 5 different doctors, and some will bridge, and others won’t. It just depends on what they feel they can safely do. This trial gives a firm answer to that question.”

The trial enrolled 1884 patients with AFib and atrial flutter. Roughly half received bridge therapy with dalteparin, and the other half received a placebo while halting their warfarin for up to 13 days around their elective surgeries. Patients were followed for up to 37 days after their procedures.

Among patients who stopped all anticoagulant therapy, the incidence of arterial thrombosis was 0.4%, compared to 0.3% for patients who received bridge therapy (P=0.01 for noninferiority).

Major bleeding events were significantly less common among the non-bridging group. They occurred in 1.3% of patients who were not on anticoagulant therapy and 3.2% of patients who received bridge therapy (P=0.005 for superiority).

“Bridging does not improve the outcome for stroke prevention but increases the risk of major bleeding complications,” Dr Ortel said. “That’s the counter balance. We’re not doing patients any good, and we are potentially hurting them.”

Dr Ortel noted that these findings are specific to AFib patients who take warfarin and should not be generalized to other types of patients or other anticoagulants. But the results will be taken into consideration by organizations that develop guidelines.

“This is the first study to provide high-quality clinical trial data demonstrating that, for patients with atrial fibrillation who need a procedure and who need to come off warfarin, they can simply stop and restart,” Dr Ortel said. “They do not need to be bridged.”

Warfarin tablets

TORONTO—Bridge anticoagulant therapy appears to be unnecessary in patients with atrial fibrillation (AFib) undergoing elective surgery, according to researchers.

In the BRIDGE study, AFib patients who stopped all anticoagulant therapy before elective surgery had no higher risk of thrombosis and a lower risk of major bleeding than patients who were given bridge therapy with low-molecular weight heparin after stopping warfarin.

This research was presented at the 2015 ISTH Congress (abstract LB002) and published in NEJM.

“Bridging has been controversial because there has been a lack of data demonstrating that it’s necessary, so people don’t know what to do,” said study author Thomas L. Ortel, MD, PhD, of Duke University Medical Center in Durham, North Carolina.

“You can go to 5 different doctors, and some will bridge, and others won’t. It just depends on what they feel they can safely do. This trial gives a firm answer to that question.”

The trial enrolled 1884 patients with AFib and atrial flutter. Roughly half received bridge therapy with dalteparin, and the other half received a placebo while halting their warfarin for up to 13 days around their elective surgeries. Patients were followed for up to 37 days after their procedures.

Among patients who stopped all anticoagulant therapy, the incidence of arterial thrombosis was 0.4%, compared to 0.3% for patients who received bridge therapy (P=0.01 for noninferiority).

Major bleeding events were significantly less common among the non-bridging group. They occurred in 1.3% of patients who were not on anticoagulant therapy and 3.2% of patients who received bridge therapy (P=0.005 for superiority).

“Bridging does not improve the outcome for stroke prevention but increases the risk of major bleeding complications,” Dr Ortel said. “That’s the counter balance. We’re not doing patients any good, and we are potentially hurting them.”

Dr Ortel noted that these findings are specific to AFib patients who take warfarin and should not be generalized to other types of patients or other anticoagulants. But the results will be taken into consideration by organizations that develop guidelines.

“This is the first study to provide high-quality clinical trial data demonstrating that, for patients with atrial fibrillation who need a procedure and who need to come off warfarin, they can simply stop and restart,” Dr Ortel said. “They do not need to be bridged.”

Warfarin tablets

TORONTO—Bridge anticoagulant therapy appears to be unnecessary in patients with atrial fibrillation (AFib) undergoing elective surgery, according to researchers.

In the BRIDGE study, AFib patients who stopped all anticoagulant therapy before elective surgery had no higher risk of thrombosis and a lower risk of major bleeding than patients who were given bridge therapy with low-molecular weight heparin after stopping warfarin.

This research was presented at the 2015 ISTH Congress (abstract LB002) and published in NEJM.

“Bridging has been controversial because there has been a lack of data demonstrating that it’s necessary, so people don’t know what to do,” said study author Thomas L. Ortel, MD, PhD, of Duke University Medical Center in Durham, North Carolina.

“You can go to 5 different doctors, and some will bridge, and others won’t. It just depends on what they feel they can safely do. This trial gives a firm answer to that question.”

The trial enrolled 1884 patients with AFib and atrial flutter. Roughly half received bridge therapy with dalteparin, and the other half received a placebo while halting their warfarin for up to 13 days around their elective surgeries. Patients were followed for up to 37 days after their procedures.

Among patients who stopped all anticoagulant therapy, the incidence of arterial thrombosis was 0.4%, compared to 0.3% for patients who received bridge therapy (P=0.01 for noninferiority).

Major bleeding events were significantly less common among the non-bridging group. They occurred in 1.3% of patients who were not on anticoagulant therapy and 3.2% of patients who received bridge therapy (P=0.005 for superiority).

“Bridging does not improve the outcome for stroke prevention but increases the risk of major bleeding complications,” Dr Ortel said. “That’s the counter balance. We’re not doing patients any good, and we are potentially hurting them.”

Dr Ortel noted that these findings are specific to AFib patients who take warfarin and should not be generalized to other types of patients or other anticoagulants. But the results will be taken into consideration by organizations that develop guidelines.

“This is the first study to provide high-quality clinical trial data demonstrating that, for patients with atrial fibrillation who need a procedure and who need to come off warfarin, they can simply stop and restart,” Dr Ortel said. “They do not need to be bridged.”