The United States loses 1.23 million working days and up to $411 billion per year because of insufficient sleep in workers, and the problem extends to a substantial economic toll and increased health-related costs in other countries worldwide, according to a cross-country comparative analysis.

Wavebreak Media/Thinkstockphotos

“Our study shows that the effects from a lack of sleep are massive. Sleep deprivation not only influences an individual’s health and well-being but has a significant impact on a nation’s economy, with lower productivity levels and a higher mortality risk among workers,” Marco Hafner, a research leader at RAND Europe and the report’s main author, stated in a press release.

Mr. Hafner and his colleagues analyzed data from 62,366 employees from the Britain’s Healthiest Workplace competition during 2015 and 2016 to determine factors affecting lack of sleep. Specifically, they found people who were overweight or obese slept an average of 2.5 minutes to 7 minutes less each day, compared with people at a healthy body mass index. Smoking was identified as a factor associated with insufficient sleep, and people who smoke slept 5 fewer minutes per day, compared with nonsmokers. People who had more than two sugary drinks per day slept an average of 3.4 minutes less per day, compared with those who consumed less or no sugary drinks. The authors noted people who performed 120 minutes of physical activity or less per day and people with a medium to high risk of mental health problems slept an average of 2.6 minutes and 17.2 minutes less each day, respectively.

Regarding workplace-associated factors for insufficient sleep, the authors found lack of choice in their work routine was associated with 2.3 minutes less sleep per day, and those who worked irregular hours slept 2.7 minutes less per day on average; people with workplace stress and unrealistic time pressures slept 8 minutes less per day on average. Commuters slept 9.3 minutes less per day if they had a 30- to 60-minute commute to work, while those who had a commute longer than 60 minutes slept 16.5 minutes less per day than people with shorter commutes.

The authors also found the following personal and sociodemographic factors were associated with insufficient sleep:

• People who had financial concerns slept 10 minutes less per day, compared with people who did not have financial concerns.
• Unpaid care was associated with an average of 5 minutes less sleep per day.
• People with dependent children under 18 years old in the same household slept an average of 4.2 minutes less daily.
• Men slept 9 minutes less per day, compared, with women.
• Never being married was associated with sleeping an average of 4.8 minutes less per day, while people who were separated from their partner slept an average of 6.5 minutes less per day.

“At first glance, the estimates of minutes of sleep lost due to the various factors outlined above may seem small,” the authors wrote in their report. “However, it is important to stress that the estimates represent the effect on sleep duration of each single factor, holding all other factors constant.”

That lost sleep can significantly affect a person’s health, the authors noted. Sleeping less than 6 hours per night was associated with a 13% increased risk in all-cause mortality and a person sleeping between 6 hours and 7 hours per night had a 7% increased risk of all-cause mortality, compared with people who slept between 7 hours and 9 hours per night.

Insufficient sleep can also affect workplace productivity, with factors such as absenteeism and presenteeism (working while tired) affecting performance at work because of loss of sleep. There was a 1.5% higher productivity loss among people sleeping between 6 hours and 7 hours of sleep per night, compared with people who slept between 7 hours and 9 hours a night, which the authors estimated would cost an employer 6 working days per year for a person sleeping less than 6 hours per night.

In the United States, the authors reported 1.23 million working days (9.9 million working hours) are lost per year because of lack of sleep. They studied four other member countries in the Organisation for Economic Co-operation and Development and found similar results: Japan loses 0.6 million working days (4.8 million working hours) per year, the United Kingdom loses 207,224 working days (1.6 million working hours), Germany loses 209,024 working days (1.6 million working hours), and Canada loses 78,861 working days (630,886 working hours) annually because of insufficient sleep among workers. In total, the report estimates lack of sleep costs approximately $680 billion for these countries.

The authors encouraged individuals, employers, and countries to adopt policies that would lessen the economic impact of insufficient sleep and improve sleep outcomes. For individuals, recommendations included setting a consistent wake-up time, limiting electronic devices before sleep, limiting intake of substances such as caffeine, alcohol, and nicotine prior to sleep, and increasing physical activity. Employers were encouraged to recognize the benefits that getting a full night’s sleep has for their employees, adopt routines that improve their employees’ sleep outcomes, and limit use of electronic devices outside office hours. Public health authorities were encouraged to create awareness campaigns and activities supporting sleep-related help and implementing more efficient public schedules such as delayed school starting times.

“Improving individual sleep habits and duration has huge implications, with our research showing that simple changes can make a big difference,” Mr. Hafner stated in a press release. “For example, if those who sleep under 6 hours a night increase their sleep to between 6 and 7 hours a night, this could add $226.4 billion to the U.S. economy.”

The authors report no relevant conflicts of interest.

SOURCE: Hafner M et al. RAND Corporation .

The United States loses 1.23 million working days and up to $411 billion per year because of insufficient sleep in workers, and the problem extends to a substantial economic toll and increased health-related costs in other countries worldwide, according to a cross-country comparative analysis.

Wavebreak Media/Thinkstockphotos

“Our study shows that the effects from a lack of sleep are massive. Sleep deprivation not only influences an individual’s health and well-being but has a significant impact on a nation’s economy, with lower productivity levels and a higher mortality risk among workers,” Marco Hafner, a research leader at RAND Europe and the report’s main author, stated in a press release.

Mr. Hafner and his colleagues analyzed data from 62,366 employees from the Britain’s Healthiest Workplace competition during 2015 and 2016 to determine factors affecting lack of sleep. Specifically, they found people who were overweight or obese slept an average of 2.5 minutes to 7 minutes less each day, compared with people at a healthy body mass index. Smoking was identified as a factor associated with insufficient sleep, and people who smoke slept 5 fewer minutes per day, compared with nonsmokers. People who had more than two sugary drinks per day slept an average of 3.4 minutes less per day, compared with those who consumed less or no sugary drinks. The authors noted people who performed 120 minutes of physical activity or less per day and people with a medium to high risk of mental health problems slept an average of 2.6 minutes and 17.2 minutes less each day, respectively.

Regarding workplace-associated factors for insufficient sleep, the authors found lack of choice in their work routine was associated with 2.3 minutes less sleep per day, and those who worked irregular hours slept 2.7 minutes less per day on average; people with workplace stress and unrealistic time pressures slept 8 minutes less per day on average. Commuters slept 9.3 minutes less per day if they had a 30- to 60-minute commute to work, while those who had a commute longer than 60 minutes slept 16.5 minutes less per day than people with shorter commutes.

The authors also found the following personal and sociodemographic factors were associated with insufficient sleep:

• People who had financial concerns slept 10 minutes less per day, compared with people who did not have financial concerns.
• Unpaid care was associated with an average of 5 minutes less sleep per day.
• People with dependent children under 18 years old in the same household slept an average of 4.2 minutes less daily.
• Men slept 9 minutes less per day, compared, with women.
• Never being married was associated with sleeping an average of 4.8 minutes less per day, while people who were separated from their partner slept an average of 6.5 minutes less per day.

“At first glance, the estimates of minutes of sleep lost due to the various factors outlined above may seem small,” the authors wrote in their report. “However, it is important to stress that the estimates represent the effect on sleep duration of each single factor, holding all other factors constant.”

That lost sleep can significantly affect a person’s health, the authors noted. Sleeping less than 6 hours per night was associated with a 13% increased risk in all-cause mortality and a person sleeping between 6 hours and 7 hours per night had a 7% increased risk of all-cause mortality, compared with people who slept between 7 hours and 9 hours per night.

Insufficient sleep can also affect workplace productivity, with factors such as absenteeism and presenteeism (working while tired) affecting performance at work because of loss of sleep. There was a 1.5% higher productivity loss among people sleeping between 6 hours and 7 hours of sleep per night, compared with people who slept between 7 hours and 9 hours a night, which the authors estimated would cost an employer 6 working days per year for a person sleeping less than 6 hours per night.

In the United States, the authors reported 1.23 million working days (9.9 million working hours) are lost per year because of lack of sleep. They studied four other member countries in the Organisation for Economic Co-operation and Development and found similar results: Japan loses 0.6 million working days (4.8 million working hours) per year, the United Kingdom loses 207,224 working days (1.6 million working hours), Germany loses 209,024 working days (1.6 million working hours), and Canada loses 78,861 working days (630,886 working hours) annually because of insufficient sleep among workers. In total, the report estimates lack of sleep costs approximately $680 billion for these countries.

The authors encouraged individuals, employers, and countries to adopt policies that would lessen the economic impact of insufficient sleep and improve sleep outcomes. For individuals, recommendations included setting a consistent wake-up time, limiting electronic devices before sleep, limiting intake of substances such as caffeine, alcohol, and nicotine prior to sleep, and increasing physical activity. Employers were encouraged to recognize the benefits that getting a full night’s sleep has for their employees, adopt routines that improve their employees’ sleep outcomes, and limit use of electronic devices outside office hours. Public health authorities were encouraged to create awareness campaigns and activities supporting sleep-related help and implementing more efficient public schedules such as delayed school starting times.

“Improving individual sleep habits and duration has huge implications, with our research showing that simple changes can make a big difference,” Mr. Hafner stated in a press release. “For example, if those who sleep under 6 hours a night increase their sleep to between 6 and 7 hours a night, this could add $226.4 billion to the U.S. economy.”

The authors report no relevant conflicts of interest.

SOURCE: Hafner M et al. RAND Corporation .

The United States loses 1.23 million working days and up to $411 billion per year because of insufficient sleep in workers, and the problem extends to a substantial economic toll and increased health-related costs in other countries worldwide, according to a cross-country comparative analysis.

Wavebreak Media/Thinkstockphotos

“Our study shows that the effects from a lack of sleep are massive. Sleep deprivation not only influences an individual’s health and well-being but has a significant impact on a nation’s economy, with lower productivity levels and a higher mortality risk among workers,” Marco Hafner, a research leader at RAND Europe and the report’s main author, stated in a press release.

Mr. Hafner and his colleagues analyzed data from 62,366 employees from the Britain’s Healthiest Workplace competition during 2015 and 2016 to determine factors affecting lack of sleep. Specifically, they found people who were overweight or obese slept an average of 2.5 minutes to 7 minutes less each day, compared with people at a healthy body mass index. Smoking was identified as a factor associated with insufficient sleep, and people who smoke slept 5 fewer minutes per day, compared with nonsmokers. People who had more than two sugary drinks per day slept an average of 3.4 minutes less per day, compared with those who consumed less or no sugary drinks. The authors noted people who performed 120 minutes of physical activity or less per day and people with a medium to high risk of mental health problems slept an average of 2.6 minutes and 17.2 minutes less each day, respectively.

Regarding workplace-associated factors for insufficient sleep, the authors found lack of choice in their work routine was associated with 2.3 minutes less sleep per day, and those who worked irregular hours slept 2.7 minutes less per day on average; people with workplace stress and unrealistic time pressures slept 8 minutes less per day on average. Commuters slept 9.3 minutes less per day if they had a 30- to 60-minute commute to work, while those who had a commute longer than 60 minutes slept 16.5 minutes less per day than people with shorter commutes.

The authors also found the following personal and sociodemographic factors were associated with insufficient sleep:

• People who had financial concerns slept 10 minutes less per day, compared with people who did not have financial concerns.
• Unpaid care was associated with an average of 5 minutes less sleep per day.
• People with dependent children under 18 years old in the same household slept an average of 4.2 minutes less daily.
• Men slept 9 minutes less per day, compared, with women.
• Never being married was associated with sleeping an average of 4.8 minutes less per day, while people who were separated from their partner slept an average of 6.5 minutes less per day.

“At first glance, the estimates of minutes of sleep lost due to the various factors outlined above may seem small,” the authors wrote in their report. “However, it is important to stress that the estimates represent the effect on sleep duration of each single factor, holding all other factors constant.”

That lost sleep can significantly affect a person’s health, the authors noted. Sleeping less than 6 hours per night was associated with a 13% increased risk in all-cause mortality and a person sleeping between 6 hours and 7 hours per night had a 7% increased risk of all-cause mortality, compared with people who slept between 7 hours and 9 hours per night.

Insufficient sleep can also affect workplace productivity, with factors such as absenteeism and presenteeism (working while tired) affecting performance at work because of loss of sleep. There was a 1.5% higher productivity loss among people sleeping between 6 hours and 7 hours of sleep per night, compared with people who slept between 7 hours and 9 hours a night, which the authors estimated would cost an employer 6 working days per year for a person sleeping less than 6 hours per night.

In the United States, the authors reported 1.23 million working days (9.9 million working hours) are lost per year because of lack of sleep. They studied four other member countries in the Organisation for Economic Co-operation and Development and found similar results: Japan loses 0.6 million working days (4.8 million working hours) per year, the United Kingdom loses 207,224 working days (1.6 million working hours), Germany loses 209,024 working days (1.6 million working hours), and Canada loses 78,861 working days (630,886 working hours) annually because of insufficient sleep among workers. In total, the report estimates lack of sleep costs approximately $680 billion for these countries.

The authors encouraged individuals, employers, and countries to adopt policies that would lessen the economic impact of insufficient sleep and improve sleep outcomes. For individuals, recommendations included setting a consistent wake-up time, limiting electronic devices before sleep, limiting intake of substances such as caffeine, alcohol, and nicotine prior to sleep, and increasing physical activity. Employers were encouraged to recognize the benefits that getting a full night’s sleep has for their employees, adopt routines that improve their employees’ sleep outcomes, and limit use of electronic devices outside office hours. Public health authorities were encouraged to create awareness campaigns and activities supporting sleep-related help and implementing more efficient public schedules such as delayed school starting times.

“Improving individual sleep habits and duration has huge implications, with our research showing that simple changes can make a big difference,” Mr. Hafner stated in a press release. “For example, if those who sleep under 6 hours a night increase their sleep to between 6 and 7 hours a night, this could add $226.4 billion to the U.S. economy.”

The authors report no relevant conflicts of interest.

SOURCE: Hafner M et al. RAND Corporation .

Photo from Novartis

The European Commission (EC) has granted approval for tisagenlecleucel (Kymriah®), a chimeric antigen receptor (CAR) T-cell therapy targeting CD19.

Tisagenlecleucel (formerly CTL019) is now approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.

Tisagenlecleucel is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.

The EC’s approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.

Novartis expects to launch tisagenlecleucel initially for pediatric ALL. The company said timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centers for the appropriate indications, as well as the completion of national reimbursement procedures.

The EC’s approval of tisagenlecleucel is based on results from the phase 2 JULIET and ELIANA trials.

JULIET trial

Updated results from JULIET were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).

The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).

Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.

The median time from infusion to data cutoff was 13.9 months.

The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached.

At the time of data cutoff, none of the responders had gone on to receive a stem cell transplant.

For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.

Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.

Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).

ELIANA trial

Updated results from ELIANA were published in NEJM in February.

The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).

All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.

The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.

The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.

All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.

Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

All patients experienced at least one AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.

AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).

Photo from Novartis

The European Commission (EC) has granted approval for tisagenlecleucel (Kymriah®), a chimeric antigen receptor (CAR) T-cell therapy targeting CD19.

Tisagenlecleucel (formerly CTL019) is now approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.

Tisagenlecleucel is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.

The EC’s approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.

Novartis expects to launch tisagenlecleucel initially for pediatric ALL. The company said timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centers for the appropriate indications, as well as the completion of national reimbursement procedures.

The EC’s approval of tisagenlecleucel is based on results from the phase 2 JULIET and ELIANA trials.

JULIET trial

Updated results from JULIET were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).

The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).

Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.

The median time from infusion to data cutoff was 13.9 months.

The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached.

At the time of data cutoff, none of the responders had gone on to receive a stem cell transplant.

For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.

Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.

Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).

ELIANA trial

Updated results from ELIANA were published in NEJM in February.

The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).

All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.

The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.

The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.

All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.

Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

All patients experienced at least one AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.

AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).

Photo from Novartis

The European Commission (EC) has granted approval for tisagenlecleucel (Kymriah®), a chimeric antigen receptor (CAR) T-cell therapy targeting CD19.

Tisagenlecleucel (formerly CTL019) is now approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.

Tisagenlecleucel is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.

The EC’s approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.

Novartis expects to launch tisagenlecleucel initially for pediatric ALL. The company said timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centers for the appropriate indications, as well as the completion of national reimbursement procedures.

The EC’s approval of tisagenlecleucel is based on results from the phase 2 JULIET and ELIANA trials.

JULIET trial

Updated results from JULIET were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).

The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).

Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.

The median time from infusion to data cutoff was 13.9 months.

The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached.

At the time of data cutoff, none of the responders had gone on to receive a stem cell transplant.

For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.

Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.

Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).

ELIANA trial

Updated results from ELIANA were published in NEJM in February.

The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).

All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.

The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.

The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.

All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.

Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

All patients experienced at least one AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.

AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica®) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).

This is the ninth FDA approval for ibrutinib and the second approval for the drug in WM.

The latest approval was supported by the phase 3 iNNOVATE trial, in which researchers compared ibrutinib plus rituximab to rituximab alone in patients with previously untreated or relapsed/refractory WM.

Results from iNNOVATE were presented at the 2018 ASCO Annual Meeting (abstract 8003) and simultaneously published in NEJM.

The trial enrolled 150 patients. They received rituximab at 375 mg/m² with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.

Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.

The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.

The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).

The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm. Serious AEs occurred in 43% and 33%, respectively.

There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.

Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).

AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).

About ibrutinib

Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA-approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), and WM.

In November 2013, ibrutinib was approved to treat adults with MCL who have received at least one prior therapy.

In February 2014, ibrutinib was approved to treat adults with CLL who have received at least one prior therapy. In July 2014, ibrutinib received approval for adult CLL patients with 17p deletion, and, in March 2016, ibrutinib was approved as a frontline CLL treatment.

Ibrutinib was approved for use as a single agent in adults with WM in January 2015.

In May 2016, ibrutinib was approved in combination with bendamustine and rituximab for adults with previously treated CLL/SLL.

In January 2017, ibrutinib was approved for adults with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.

In August 2017, ibrutinib was approved to treat adults with cGVHD that did not respond to one or more lines of systemic therapy.

Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica®) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).

This is the ninth FDA approval for ibrutinib and the second approval for the drug in WM.

The latest approval was supported by the phase 3 iNNOVATE trial, in which researchers compared ibrutinib plus rituximab to rituximab alone in patients with previously untreated or relapsed/refractory WM.

Results from iNNOVATE were presented at the 2018 ASCO Annual Meeting (abstract 8003) and simultaneously published in NEJM.

The trial enrolled 150 patients. They received rituximab at 375 mg/m² with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.

Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.

The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.

The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).

The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm. Serious AEs occurred in 43% and 33%, respectively.

There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.

Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).

AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).

About ibrutinib

Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA-approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), and WM.

In November 2013, ibrutinib was approved to treat adults with MCL who have received at least one prior therapy.

In February 2014, ibrutinib was approved to treat adults with CLL who have received at least one prior therapy. In July 2014, ibrutinib received approval for adult CLL patients with 17p deletion, and, in March 2016, ibrutinib was approved as a frontline CLL treatment.

Ibrutinib was approved for use as a single agent in adults with WM in January 2015.

In May 2016, ibrutinib was approved in combination with bendamustine and rituximab for adults with previously treated CLL/SLL.

In January 2017, ibrutinib was approved for adults with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.

In August 2017, ibrutinib was approved to treat adults with cGVHD that did not respond to one or more lines of systemic therapy.

Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica®) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).

This is the ninth FDA approval for ibrutinib and the second approval for the drug in WM.

The latest approval was supported by the phase 3 iNNOVATE trial, in which researchers compared ibrutinib plus rituximab to rituximab alone in patients with previously untreated or relapsed/refractory WM.

Results from iNNOVATE were presented at the 2018 ASCO Annual Meeting (abstract 8003) and simultaneously published in NEJM.

The trial enrolled 150 patients. They received rituximab at 375 mg/m² with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.

Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.

The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.

The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).

The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm. Serious AEs occurred in 43% and 33%, respectively.

There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.

Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).

AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).

About ibrutinib

Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA-approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), and WM.

In November 2013, ibrutinib was approved to treat adults with MCL who have received at least one prior therapy.

In February 2014, ibrutinib was approved to treat adults with CLL who have received at least one prior therapy. In July 2014, ibrutinib received approval for adult CLL patients with 17p deletion, and, in March 2016, ibrutinib was approved as a frontline CLL treatment.

Ibrutinib was approved for use as a single agent in adults with WM in January 2015.

In May 2016, ibrutinib was approved in combination with bendamustine and rituximab for adults with previously treated CLL/SLL.

In January 2017, ibrutinib was approved for adults with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.

In August 2017, ibrutinib was approved to treat adults with cGVHD that did not respond to one or more lines of systemic therapy.

Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

More than 5 million Medicare part D enrollees without low-income subsidies reached the coverage gap known as the “donut hole” in 2016, spending almost $1,600 out of pocket as a result, according to the Kaiser Family Foundation.

Those 5.2 million enrollees in 2016 represented a reversal from the rising number of those reaching the coverage-gap over the last 3 years and the potential start of a trend toward increasing out-of-pocket costs. The number of part D enrollees without low-income subsidies (the coverage gap does not apply to those who receive the subsidies) had risen from 2013 to 2015 after being fairly stable from 2007 to 2012. The average out-of-pocket cost for enrollees with low-income subsidies, on the other hand, dropped by 20% in 2011 – from $1,858 to $1,485 – with a smaller drop in 2013 before two consecutive years of increases in 2015 and 2016, Kaiser reported.

“As of 2019, there will no longer be a coverage gap for brand-name drugs, as a result of changes in the” Bipartisan Budget Act of 2018, which reduced enrollees’ share of costs and increased the manufacturer discount, Kaiser explained, but a proposal from the Trump administration “to exclude the manufacturer discount from the calculation of out-of-pocket spending would substantially increase part D enrollees’ out-of-pocket costs and would lead to fewer enrollees qualifying for catastrophic coverage.”

rfranki@mdedge.com

More than 5 million Medicare part D enrollees without low-income subsidies reached the coverage gap known as the “donut hole” in 2016, spending almost $1,600 out of pocket as a result, according to the Kaiser Family Foundation.

Those 5.2 million enrollees in 2016 represented a reversal from the rising number of those reaching the coverage-gap over the last 3 years and the potential start of a trend toward increasing out-of-pocket costs. The number of part D enrollees without low-income subsidies (the coverage gap does not apply to those who receive the subsidies) had risen from 2013 to 2015 after being fairly stable from 2007 to 2012. The average out-of-pocket cost for enrollees with low-income subsidies, on the other hand, dropped by 20% in 2011 – from $1,858 to $1,485 – with a smaller drop in 2013 before two consecutive years of increases in 2015 and 2016, Kaiser reported.

“As of 2019, there will no longer be a coverage gap for brand-name drugs, as a result of changes in the” Bipartisan Budget Act of 2018, which reduced enrollees’ share of costs and increased the manufacturer discount, Kaiser explained, but a proposal from the Trump administration “to exclude the manufacturer discount from the calculation of out-of-pocket spending would substantially increase part D enrollees’ out-of-pocket costs and would lead to fewer enrollees qualifying for catastrophic coverage.”

rfranki@mdedge.com

More than 5 million Medicare part D enrollees without low-income subsidies reached the coverage gap known as the “donut hole” in 2016, spending almost $1,600 out of pocket as a result, according to the Kaiser Family Foundation.

Those 5.2 million enrollees in 2016 represented a reversal from the rising number of those reaching the coverage-gap over the last 3 years and the potential start of a trend toward increasing out-of-pocket costs. The number of part D enrollees without low-income subsidies (the coverage gap does not apply to those who receive the subsidies) had risen from 2013 to 2015 after being fairly stable from 2007 to 2012. The average out-of-pocket cost for enrollees with low-income subsidies, on the other hand, dropped by 20% in 2011 – from $1,858 to $1,485 – with a smaller drop in 2013 before two consecutive years of increases in 2015 and 2016, Kaiser reported.

“As of 2019, there will no longer be a coverage gap for brand-name drugs, as a result of changes in the” Bipartisan Budget Act of 2018, which reduced enrollees’ share of costs and increased the manufacturer discount, Kaiser explained, but a proposal from the Trump administration “to exclude the manufacturer discount from the calculation of out-of-pocket spending would substantially increase part D enrollees’ out-of-pocket costs and would lead to fewer enrollees qualifying for catastrophic coverage.”

rfranki@mdedge.com

MUNICH – In a double blow to the current, widespread routine use of low-dose aspirin and fish oil supplements for primary cardiovascular prevention in patients with diabetes, neither treatment provided any net clinical benefit in the massive, long-term ASCEND study, investigators reported at the annual congress of the European Society of Cardiology.

And, in yet another bitter pill to swallow, low-dose aspirin failed to reduce the incidence of GI cancer or any other type of cancer, compared with placebo in the study. Earlier, nondefinitive meta-analyses of much smaller randomized trials had raised the possibility of a roughly 30% reduction in the incidence of colorectal cancer in long-time users, said Jane Armitage, MD, professor of clinical trials and epidemiology at the University of Oxford (England).

“We saw no suggestion of an anticancer effect emerging over time,” Dr. Armitage said. “We did see a significant reduction in the risk of vascular events but also an increase in major bleeding such that the absolute benefits from avoiding a serious vascular event were largely counterbalanced by increased risk of bleeding. And there was no subgroup in which we could clearly define that the benefit outweighs the risk,” she added in a video interview.

ASCEND (A Study of Cardiovascular Events in Diabetes) was a randomized, blinded trial in which 15,480 U.K. patients with diabetes and no known cardiovascular disease were placed on 100 mg/day of enteric-coated aspirin or placebo and 1 g/day of omega-3 fatty acids in capsule form or placebo in a 2 x 2 factorial design and followed prospectively for a mean of 7.4 years.

The study was undertaken because, even though the value of low-dose aspirin for secondary prevention is supported by strong evidence, the medication’s value for primary prevention in patients with diabetes has long been uncertain. American Diabetes Association guidelines give a Grade C recommendation to consideration of low-dose aspirin as a primary prevention strategy in patients with diabetes having a 10-year cardiovascular risk estimated at 10% or greater.

The primary efficacy endpoint in ASCEND was the occurrence of a first serious vascular event, defined as MI, stroke, transient ischemic attack, or death from any vascular cause other than intracranial hemorrhage. The rate was 8.5% in the aspirin group and 9.6% with placebo, for a statistically significant 12% relative risk reduction. However, the rate of the primary composite safety endpoint, comprising intracranial hemorrhage, GI bleeding, sight-threatening bleeding in the eye, or other bleeding serious enough to entail a trip to the hospital, was 4.1% in the aspirin group and 3.2% with placebo, a 29% increase in risk.

Aspirin reduced the absolute risk of a serious vascular event by 1.1%, compared with placebo, while boosting the risk of major bleeding by an absolute 0.9% – essentially a wash. The number needed to treat to avoid a serious vascular event was 91 patients, with 112 being the number needed to cause a major bleeding event. The risk of major bleeding rose with increasing baseline 5-year vascular event risk.

ASCEND provided no support for a recent report suggesting the benefit of low-dose aspirin for cardioprotection is largely confined to individuals weighing less than 70 kg (Lancet. 2018; 392:387-99); in fact, the opposite appeared to be true, according to Dr. Armitage.

The incidence of cancer of the GI tract was 2.0% in both study arms. The overall cancer rate was 11.6% in the aspirin arm and 11.5% with placebo. Additional follow-up focused on cancer is planned for 5 and 10 years after the end of ASCEND in order to examine the possibility of a delayed anticancer effect, she added.

Dr. Armitage said one reason aspirin may have failed to show a significant net benefit was the high rate of background cardioprotective medication usage, especially statins and antihypertensive drugs.

“I think if your diabetes is well managed and you’ve got your other risk factors under control, you have to consider very carefully whether or not, for you, the benefits of aspirin outweigh the risks,” she concluded.

Cardiologists respond

ASCEND’s two designated discussants, both cardiologists, took a more positive view of the results than Dr. Armitage, who isn’t a cardiologist.

Bruce Jancin/MDedge News

Sigrun Halvorsen, MD, professor of cardiology at the University of Oslo, noted that most ASCEND participants were at relatively low cardiovascular risk, with an event rate of about 1.3% per year. She indicated that she’d like to see more data on higher-risk individuals before excluding any role for aspirin in primary cardiovascular prevention in patients with diabetes.

“Serious vascular events and bleeding are not necessarily equally weighted,” she added. “Most major bleeds in ASCEND were GI bleeds, and these can be largely prevented by PPIs [proton pump inhibitors], in contrast to death and stroke, which are irreversible events.”

“I think this study could be interpreted more favorably,” agreed Christopher P. Cannon, MD, professor of medicine at Harvard Medical School, Boston. “Bleeds are reversible, but MIs and whatnot are not.”

Fish oil flounders in ASCEND

Bruce Jancin/MDedge News

Louise Bowman, MD, also at the University of Oxford, presented the ASCEND fish oil findings. Over an average of 7.4 years, omega-3 fatty acid supplementation had no effect on the rate of serious vascular events, no effect on cancer, no impact on all-cause or cause-specific mortality, and raised no safety issues in patients with diabetes. She argued that current guidelines recommending fish oil supplements for cardiovascular prevention should be reconsidered.

“Certainly there doesn’t seem to be any justification for the use of this dose of omega-3 fatty acids – 1 g/day – for the prevention of cardiovascular disease,” Dr. Bowman said.

However, Dr. Cannon saw a sliver of hope within the ASCEND findings. One component of the serious vascular event composite endpoint – vascular death – occurred in 2.4% of the fish oil group and 2.9% of placebo-treated controls, for a statistically significant 19% relative risk reduction. It could be a fluke, given that none of the other vascular endpoints followed suit. But physicians and patients won’t have to wait long to find out. Another randomized trial of low-dose fish oil supplements for primary cardiovascular prevention – the nearly 26,000-patient VITAL trial – is due to report later in 2018.

In addition, two major, randomized trials of higher-dose fish oil supplementation for secondary prevention are ongoing. The roughly 8,000-patient REDUCE-IT trial is expected to report results later this year, and the STRENGTH trial, featuring more than 13,000 patients, should be completed in 2020. Both studies are heavily loaded with diabetes patients, Dr. Cannon noted.

Simultaneous with presentation of the ASCEND results at the ESC congress, the study was published online at the New England Journal of Medicine website (doi: 10.1056/NEJMoa1804988 and doi: 10.1056/NEJMoa1804989).

The ASCEND study was funded by the British Heart Foundation and the U.K. Medical Research Council with support provided by Abbott Laboratories, Bayer, Mylan, and Solvay. Dr. Armitage and Dr. Bowman reported receiving research grants from the Medicines Company, Bayer, and Mylan. Dr. Halvorsen reported no financial conflicts. Dr. Cannon reported serving as a consultant to roughly a dozen pharmaceutical companies, including the Amarin Corporation, which markets a fish oil supplement and sponsored the REDUCE-IT trial.

bjancin@mdedge.com

MUNICH – In a double blow to the current, widespread routine use of low-dose aspirin and fish oil supplements for primary cardiovascular prevention in patients with diabetes, neither treatment provided any net clinical benefit in the massive, long-term ASCEND study, investigators reported at the annual congress of the European Society of Cardiology.

And, in yet another bitter pill to swallow, low-dose aspirin failed to reduce the incidence of GI cancer or any other type of cancer, compared with placebo in the study. Earlier, nondefinitive meta-analyses of much smaller randomized trials had raised the possibility of a roughly 30% reduction in the incidence of colorectal cancer in long-time users, said Jane Armitage, MD, professor of clinical trials and epidemiology at the University of Oxford (England).

“We saw no suggestion of an anticancer effect emerging over time,” Dr. Armitage said. “We did see a significant reduction in the risk of vascular events but also an increase in major bleeding such that the absolute benefits from avoiding a serious vascular event were largely counterbalanced by increased risk of bleeding. And there was no subgroup in which we could clearly define that the benefit outweighs the risk,” she added in a video interview.

ASCEND (A Study of Cardiovascular Events in Diabetes) was a randomized, blinded trial in which 15,480 U.K. patients with diabetes and no known cardiovascular disease were placed on 100 mg/day of enteric-coated aspirin or placebo and 1 g/day of omega-3 fatty acids in capsule form or placebo in a 2 x 2 factorial design and followed prospectively for a mean of 7.4 years.

The study was undertaken because, even though the value of low-dose aspirin for secondary prevention is supported by strong evidence, the medication’s value for primary prevention in patients with diabetes has long been uncertain. American Diabetes Association guidelines give a Grade C recommendation to consideration of low-dose aspirin as a primary prevention strategy in patients with diabetes having a 10-year cardiovascular risk estimated at 10% or greater.

The primary efficacy endpoint in ASCEND was the occurrence of a first serious vascular event, defined as MI, stroke, transient ischemic attack, or death from any vascular cause other than intracranial hemorrhage. The rate was 8.5% in the aspirin group and 9.6% with placebo, for a statistically significant 12% relative risk reduction. However, the rate of the primary composite safety endpoint, comprising intracranial hemorrhage, GI bleeding, sight-threatening bleeding in the eye, or other bleeding serious enough to entail a trip to the hospital, was 4.1% in the aspirin group and 3.2% with placebo, a 29% increase in risk.

Aspirin reduced the absolute risk of a serious vascular event by 1.1%, compared with placebo, while boosting the risk of major bleeding by an absolute 0.9% – essentially a wash. The number needed to treat to avoid a serious vascular event was 91 patients, with 112 being the number needed to cause a major bleeding event. The risk of major bleeding rose with increasing baseline 5-year vascular event risk.

ASCEND provided no support for a recent report suggesting the benefit of low-dose aspirin for cardioprotection is largely confined to individuals weighing less than 70 kg (Lancet. 2018; 392:387-99); in fact, the opposite appeared to be true, according to Dr. Armitage.

The incidence of cancer of the GI tract was 2.0% in both study arms. The overall cancer rate was 11.6% in the aspirin arm and 11.5% with placebo. Additional follow-up focused on cancer is planned for 5 and 10 years after the end of ASCEND in order to examine the possibility of a delayed anticancer effect, she added.

Dr. Armitage said one reason aspirin may have failed to show a significant net benefit was the high rate of background cardioprotective medication usage, especially statins and antihypertensive drugs.

“I think if your diabetes is well managed and you’ve got your other risk factors under control, you have to consider very carefully whether or not, for you, the benefits of aspirin outweigh the risks,” she concluded.

Cardiologists respond

ASCEND’s two designated discussants, both cardiologists, took a more positive view of the results than Dr. Armitage, who isn’t a cardiologist.

Bruce Jancin/MDedge News

Sigrun Halvorsen, MD, professor of cardiology at the University of Oslo, noted that most ASCEND participants were at relatively low cardiovascular risk, with an event rate of about 1.3% per year. She indicated that she’d like to see more data on higher-risk individuals before excluding any role for aspirin in primary cardiovascular prevention in patients with diabetes.

“Serious vascular events and bleeding are not necessarily equally weighted,” she added. “Most major bleeds in ASCEND were GI bleeds, and these can be largely prevented by PPIs [proton pump inhibitors], in contrast to death and stroke, which are irreversible events.”

“I think this study could be interpreted more favorably,” agreed Christopher P. Cannon, MD, professor of medicine at Harvard Medical School, Boston. “Bleeds are reversible, but MIs and whatnot are not.”

Fish oil flounders in ASCEND

Bruce Jancin/MDedge News

Louise Bowman, MD, also at the University of Oxford, presented the ASCEND fish oil findings. Over an average of 7.4 years, omega-3 fatty acid supplementation had no effect on the rate of serious vascular events, no effect on cancer, no impact on all-cause or cause-specific mortality, and raised no safety issues in patients with diabetes. She argued that current guidelines recommending fish oil supplements for cardiovascular prevention should be reconsidered.

“Certainly there doesn’t seem to be any justification for the use of this dose of omega-3 fatty acids – 1 g/day – for the prevention of cardiovascular disease,” Dr. Bowman said.

However, Dr. Cannon saw a sliver of hope within the ASCEND findings. One component of the serious vascular event composite endpoint – vascular death – occurred in 2.4% of the fish oil group and 2.9% of placebo-treated controls, for a statistically significant 19% relative risk reduction. It could be a fluke, given that none of the other vascular endpoints followed suit. But physicians and patients won’t have to wait long to find out. Another randomized trial of low-dose fish oil supplements for primary cardiovascular prevention – the nearly 26,000-patient VITAL trial – is due to report later in 2018.

In addition, two major, randomized trials of higher-dose fish oil supplementation for secondary prevention are ongoing. The roughly 8,000-patient REDUCE-IT trial is expected to report results later this year, and the STRENGTH trial, featuring more than 13,000 patients, should be completed in 2020. Both studies are heavily loaded with diabetes patients, Dr. Cannon noted.

Simultaneous with presentation of the ASCEND results at the ESC congress, the study was published online at the New England Journal of Medicine website (doi: 10.1056/NEJMoa1804988 and doi: 10.1056/NEJMoa1804989).

The ASCEND study was funded by the British Heart Foundation and the U.K. Medical Research Council with support provided by Abbott Laboratories, Bayer, Mylan, and Solvay. Dr. Armitage and Dr. Bowman reported receiving research grants from the Medicines Company, Bayer, and Mylan. Dr. Halvorsen reported no financial conflicts. Dr. Cannon reported serving as a consultant to roughly a dozen pharmaceutical companies, including the Amarin Corporation, which markets a fish oil supplement and sponsored the REDUCE-IT trial.

bjancin@mdedge.com

MUNICH – In a double blow to the current, widespread routine use of low-dose aspirin and fish oil supplements for primary cardiovascular prevention in patients with diabetes, neither treatment provided any net clinical benefit in the massive, long-term ASCEND study, investigators reported at the annual congress of the European Society of Cardiology.

And, in yet another bitter pill to swallow, low-dose aspirin failed to reduce the incidence of GI cancer or any other type of cancer, compared with placebo in the study. Earlier, nondefinitive meta-analyses of much smaller randomized trials had raised the possibility of a roughly 30% reduction in the incidence of colorectal cancer in long-time users, said Jane Armitage, MD, professor of clinical trials and epidemiology at the University of Oxford (England).

“We saw no suggestion of an anticancer effect emerging over time,” Dr. Armitage said. “We did see a significant reduction in the risk of vascular events but also an increase in major bleeding such that the absolute benefits from avoiding a serious vascular event were largely counterbalanced by increased risk of bleeding. And there was no subgroup in which we could clearly define that the benefit outweighs the risk,” she added in a video interview.

ASCEND (A Study of Cardiovascular Events in Diabetes) was a randomized, blinded trial in which 15,480 U.K. patients with diabetes and no known cardiovascular disease were placed on 100 mg/day of enteric-coated aspirin or placebo and 1 g/day of omega-3 fatty acids in capsule form or placebo in a 2 x 2 factorial design and followed prospectively for a mean of 7.4 years.

The study was undertaken because, even though the value of low-dose aspirin for secondary prevention is supported by strong evidence, the medication’s value for primary prevention in patients with diabetes has long been uncertain. American Diabetes Association guidelines give a Grade C recommendation to consideration of low-dose aspirin as a primary prevention strategy in patients with diabetes having a 10-year cardiovascular risk estimated at 10% or greater.

The primary efficacy endpoint in ASCEND was the occurrence of a first serious vascular event, defined as MI, stroke, transient ischemic attack, or death from any vascular cause other than intracranial hemorrhage. The rate was 8.5% in the aspirin group and 9.6% with placebo, for a statistically significant 12% relative risk reduction. However, the rate of the primary composite safety endpoint, comprising intracranial hemorrhage, GI bleeding, sight-threatening bleeding in the eye, or other bleeding serious enough to entail a trip to the hospital, was 4.1% in the aspirin group and 3.2% with placebo, a 29% increase in risk.

Aspirin reduced the absolute risk of a serious vascular event by 1.1%, compared with placebo, while boosting the risk of major bleeding by an absolute 0.9% – essentially a wash. The number needed to treat to avoid a serious vascular event was 91 patients, with 112 being the number needed to cause a major bleeding event. The risk of major bleeding rose with increasing baseline 5-year vascular event risk.

ASCEND provided no support for a recent report suggesting the benefit of low-dose aspirin for cardioprotection is largely confined to individuals weighing less than 70 kg (Lancet. 2018; 392:387-99); in fact, the opposite appeared to be true, according to Dr. Armitage.

The incidence of cancer of the GI tract was 2.0% in both study arms. The overall cancer rate was 11.6% in the aspirin arm and 11.5% with placebo. Additional follow-up focused on cancer is planned for 5 and 10 years after the end of ASCEND in order to examine the possibility of a delayed anticancer effect, she added.

Dr. Armitage said one reason aspirin may have failed to show a significant net benefit was the high rate of background cardioprotective medication usage, especially statins and antihypertensive drugs.

“I think if your diabetes is well managed and you’ve got your other risk factors under control, you have to consider very carefully whether or not, for you, the benefits of aspirin outweigh the risks,” she concluded.

Cardiologists respond

ASCEND’s two designated discussants, both cardiologists, took a more positive view of the results than Dr. Armitage, who isn’t a cardiologist.

Bruce Jancin/MDedge News

Sigrun Halvorsen, MD, professor of cardiology at the University of Oslo, noted that most ASCEND participants were at relatively low cardiovascular risk, with an event rate of about 1.3% per year. She indicated that she’d like to see more data on higher-risk individuals before excluding any role for aspirin in primary cardiovascular prevention in patients with diabetes.

“Serious vascular events and bleeding are not necessarily equally weighted,” she added. “Most major bleeds in ASCEND were GI bleeds, and these can be largely prevented by PPIs [proton pump inhibitors], in contrast to death and stroke, which are irreversible events.”

“I think this study could be interpreted more favorably,” agreed Christopher P. Cannon, MD, professor of medicine at Harvard Medical School, Boston. “Bleeds are reversible, but MIs and whatnot are not.”

Fish oil flounders in ASCEND

Bruce Jancin/MDedge News

Louise Bowman, MD, also at the University of Oxford, presented the ASCEND fish oil findings. Over an average of 7.4 years, omega-3 fatty acid supplementation had no effect on the rate of serious vascular events, no effect on cancer, no impact on all-cause or cause-specific mortality, and raised no safety issues in patients with diabetes. She argued that current guidelines recommending fish oil supplements for cardiovascular prevention should be reconsidered.

“Certainly there doesn’t seem to be any justification for the use of this dose of omega-3 fatty acids – 1 g/day – for the prevention of cardiovascular disease,” Dr. Bowman said.

However, Dr. Cannon saw a sliver of hope within the ASCEND findings. One component of the serious vascular event composite endpoint – vascular death – occurred in 2.4% of the fish oil group and 2.9% of placebo-treated controls, for a statistically significant 19% relative risk reduction. It could be a fluke, given that none of the other vascular endpoints followed suit. But physicians and patients won’t have to wait long to find out. Another randomized trial of low-dose fish oil supplements for primary cardiovascular prevention – the nearly 26,000-patient VITAL trial – is due to report later in 2018.

In addition, two major, randomized trials of higher-dose fish oil supplementation for secondary prevention are ongoing. The roughly 8,000-patient REDUCE-IT trial is expected to report results later this year, and the STRENGTH trial, featuring more than 13,000 patients, should be completed in 2020. Both studies are heavily loaded with diabetes patients, Dr. Cannon noted.

Simultaneous with presentation of the ASCEND results at the ESC congress, the study was published online at the New England Journal of Medicine website (doi: 10.1056/NEJMoa1804988 and doi: 10.1056/NEJMoa1804989).

The ASCEND study was funded by the British Heart Foundation and the U.K. Medical Research Council with support provided by Abbott Laboratories, Bayer, Mylan, and Solvay. Dr. Armitage and Dr. Bowman reported receiving research grants from the Medicines Company, Bayer, and Mylan. Dr. Halvorsen reported no financial conflicts. Dr. Cannon reported serving as a consultant to roughly a dozen pharmaceutical companies, including the Amarin Corporation, which markets a fish oil supplement and sponsored the REDUCE-IT trial.

bjancin@mdedge.com

The Society for Vascular Surgery is seeking applicants to serve as representative for the American College of Surgeons Advisory Council for Vascular Surgery. Please email letters of interest/nominations for the three-year term by Aug. 31. The nominee must be a Fellow of the ACS and be involved in SVS’ governing boards. 

The Society for Vascular Surgery is seeking applicants to serve as representative for the American College of Surgeons Advisory Council for Vascular Surgery. Please email letters of interest/nominations for the three-year term by Aug. 31. The nominee must be a Fellow of the ACS and be involved in SVS’ governing boards. 

The Society for Vascular Surgery is seeking applicants to serve as representative for the American College of Surgeons Advisory Council for Vascular Surgery. Please email letters of interest/nominations for the three-year term by Aug. 31. The nominee must be a Fellow of the ACS and be involved in SVS’ governing boards. 

VAM on Demand, a library of hundreds of presentations from the 2018 Vascular Annual Meeting is now available. Those who attended VAM can review sessions at their own pace and watch others that they missed. Those who did not attend now get the chance to learn from the sessions offered. Cost is $199 for VAM attendees and $499 for non-attendees. Access, including the ability to download materials, is good for one year. Learn more and purchase VAM on Demand here. Contact the SVS Education Department for more information at 312-334-2300, or at education@vascularsociety.org.

VAM on Demand, a library of hundreds of presentations from the 2018 Vascular Annual Meeting is now available. Those who attended VAM can review sessions at their own pace and watch others that they missed. Those who did not attend now get the chance to learn from the sessions offered. Cost is $199 for VAM attendees and $499 for non-attendees. Access, including the ability to download materials, is good for one year. Learn more and purchase VAM on Demand here. Contact the SVS Education Department for more information at 312-334-2300, or at education@vascularsociety.org.

VAM on Demand, a library of hundreds of presentations from the 2018 Vascular Annual Meeting is now available. Those who attended VAM can review sessions at their own pace and watch others that they missed. Those who did not attend now get the chance to learn from the sessions offered. Cost is $199 for VAM attendees and $499 for non-attendees. Access, including the ability to download materials, is good for one year. Learn more and purchase VAM on Demand here. Contact the SVS Education Department for more information at 312-334-2300, or at education@vascularsociety.org.

The Society for Vascular Surgery has set the date for the 2019 Vascular Research Initiatives Conference: May 13, 2019. Mark your calendars and plan to attend this conference, which focuses on emerging vascular science. VRIC will feature abstracts, the Alexander W. Clowes Distinguished Lecture, a Translational Panel, reception and posters. As in the past, VRIC will be held in conjunction with the American Heart Association's Scientific Sessions. Those take place May 14 to 16, 2019. 

The Society for Vascular Surgery has set the date for the 2019 Vascular Research Initiatives Conference: May 13, 2019. Mark your calendars and plan to attend this conference, which focuses on emerging vascular science. VRIC will feature abstracts, the Alexander W. Clowes Distinguished Lecture, a Translational Panel, reception and posters. As in the past, VRIC will be held in conjunction with the American Heart Association's Scientific Sessions. Those take place May 14 to 16, 2019. 

The Society for Vascular Surgery has set the date for the 2019 Vascular Research Initiatives Conference: May 13, 2019. Mark your calendars and plan to attend this conference, which focuses on emerging vascular science. VRIC will feature abstracts, the Alexander W. Clowes Distinguished Lecture, a Translational Panel, reception and posters. As in the past, VRIC will be held in conjunction with the American Heart Association's Scientific Sessions. Those take place May 14 to 16, 2019. 

Apply for the SVS International Scholars Program by Sept. 1. Up to four qualified vascular surgeons younger than 40, from countries other than the United States or Canada, will receive $5,000 each, to attend the 2019 Vascular Annual Meeting and to visit clinical, teaching and research facilities in the U.S. and Canada. Watch a past recipient discuss the impact on her career here.

Apply for the SVS International Scholars Program by Sept. 1. Up to four qualified vascular surgeons younger than 40, from countries other than the United States or Canada, will receive $5,000 each, to attend the 2019 Vascular Annual Meeting and to visit clinical, teaching and research facilities in the U.S. and Canada. Watch a past recipient discuss the impact on her career here.

Apply for the SVS International Scholars Program by Sept. 1. Up to four qualified vascular surgeons younger than 40, from countries other than the United States or Canada, will receive $5,000 each, to attend the 2019 Vascular Annual Meeting and to visit clinical, teaching and research facilities in the U.S. and Canada. Watch a past recipient discuss the impact on her career here.

Major depressive disorder (MDD) has a devastating impact on individuals and society because of its high prevalence, its recurrent nature, its frequent comorbidity with other disorders, and the functional impairment it causes. Compared with other chronic diseases, such as arthritis, asthma, and diabetes, MDD produces the greatest decrement in health worldwide.¹ The goals in treating MDD should be not just to reduce symptom severity but also to achieve continuing remission and lower the risk for relapse.²

Antidepressants are the most common treatment for depression.³ Among psychotherapies used to treat MDD, cognitive-behavioral therapy (CBT) has been identified as an effective treatment.⁴ Collaborative care models have been reported to manage MDD more effectively.⁵ In this article, we review the evidence supporting the use of CBT as monotherapy and in combination with antidepressants for acute and long-term treatment of MDD.

Acute treatment: Not too soon for CBT

Mild to moderate depression

Research has indicated that for the treatment of mild MDD, antidepressants are unlikely to be more effective than placebo.^6,7 Studies also have reported that response to anti­depressants begins to outpace response to placebo only when symptoms are no longer mild. Using antidepressants for patients with mild depression could therefore place them at risk of overtreatment.⁸ In keeping with these findings, the American Psychiatric Association (APA) has recommended the use of evidence-based psychotherapies, such as CBT, as an initial treatment choice for patients with mild to moderate MDD.⁹

Two recent studies have suggested that the combination of CBT plus antidepressants could boost improvement in psychosocial functioning for patients with mild MDD.^10,11 However, neither study included a group of patients who received only CBT to evaluate if CBT alone could have also produced similar effects. Other limitations include the lack of a control group in one study and small sample sizes in both studies. However, both studies had a long follow-up period and specifically studied the impact on psychosocial functioning.

Moderate to severe depression

Earlier depression treatment guidelines suggested that antidepressants should be used to treat more severe depression, while psychotherapy should be used mainly for mild depression.¹² This recommendation was influenced by the well-known National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program, a multicenter randomized controlled trial (RCT) that used a placebo control.¹³ In this study, CBT was compared with antidepressants and found to be no more effective than placebo for more severely depressed patients.¹³ However, this finding was not consistent across the 3 sites where the study was conducted; at the site where CBT was provided by more experienced CBT therapists, patients with more severe depression who received CBT fared as well as patients treated with antidepressants.¹⁴ A later double-blind RCT that used experienced therapists found that CBT was as effective as antidepressants (monoamine oxidase inhibitors), and both treatments were superior to placebo in reducing symptoms of atypical depression.¹⁵

Another placebo-controlled RCT conducted at 2 sites found that CBT was as effective as antidepressants in the treatment of moderately to severely depressed patients. As in the NIMH Treatment of Depression Collaborative Research Program trial,¹³ in this study, there were indications that the results were dependent on therapist experience.¹⁶ These findings suggest that the experience of the therapist is an important factor.

A recent meta-analysis of treatments of the acute phase of MDD compared 11 RCTs of CBT and second-generation antidepressants (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other medications with related mechanisms of action).¹⁷ It found that as a first-step treatment, CBT and antidepressants had a similar impact on symptom relief in patients with moderate to severe depression. Patients treated with antidepressants also had a higher risk of experiencing adverse events or discontinuing treatment because of adverse events. However, this meta-analysis included trials that had methodological shortcomings, which reduces the strength of these conclusions.

Continue to: Patients with MDD and comorbid personality disorders have been...

Patients with MDD and comorbid personality disorders have been reported to have poorer outcomes, regardless of the treatment used.¹⁸ Fournier et al¹⁹ examined the impact of antidepressants and CBT in moderately to severely depressed patients with and without a personality disorder. They found that a combination of antidepressants and CBT was suitable for patients with personality disorders because antidepressants would boost the initial response and CBT would help sustain improvement in the long term.

Presently, the APA suggests that the combination of psychotherapy and antidepressants may be used as an initial treatment for patients with moderate to severe MDD.⁹ As research brings to light other factors that affect treatment outcomes, these guidelines could change.

Table 1^10,11,15,16 summarizes the findings of select studies evaluating the use of CBT for the acute treatment of depression.

CBT’s role in long-term treatment

Recurrence and relapse are major problems associated with MDD. The large majority of individuals who experience an episode of depression go on to experience more episodes of depression,²⁰ and the risk of recurrence increases after each successive episode.²¹

To reduce the risk of relapse and the return of symptoms, it is recommended that patients treated with antidepressants continue pharmacotherapy for 4 to 9 months after remission.⁹ Maintenance pharmacotherapy, which involves keeping patients on antidepressants beyond the point of recovery, is intended to reduce the risk of recurrence, and is standard treatment for patients with chronic or recurrent MDD.²² However, this preventive effect exists only while the patient continues to take the medication. Rates of symptom recurrence following medication withdrawal are often high regardless of how long patients have taken medications.²³

Continue to: Studies examining CBT as a maintenance treatment...

Studies examining CBT as a maintenance treatment—provided alone or in combination with or sequentially with antidepressants—have found it has an enduring effect that extends beyond the end of treatment and equals the impact of continuing antidepressants.^24-27 A recent meta-analysis of 10 trials where CBT had been provided to patients after acute treatment found that the risk of relapse was reduced by 21% in the first year and by 28% in the first 2 years.²⁸

Studies have compared the prophylactic impact of maintenance CBT and antidepressants. In an early study, 40 patients who had been successfully treated with antidepressants but had residual symptoms were randomly assigned to 20 weeks of CBT or to clinical management.²⁹ By the end of 20 weeks, patients were tapered off their antidepressant. All patients were then followed for 2 years, during which time they received no treatment. At the 2-year follow-up, the CBT group had a relapse rate of 25%, compared with 80% in the antidepressant group.²⁹ Weaknesses of this study include a small sample size, and the fact that a single therapist provided the CBT.

This study was extended to a 6-year follow-up; antidepressants were prescribed only to patients who relapsed. The CBT group continued to have a significantly lower relapse rate (40%) compared with the antidepressant group (90%).³⁰

In another RCT, patients with depression who had recovered with CBT or medication continued with the same treatment during a maintenance phase.²⁶ The CBT group received 3 booster sessions during the next year and antidepressant group received medication. At the end of the second year (without CBT or medication) CBT patients were less likely to relapse compared with patients receiving antidepressants. The adjusted relapse rates were 17.3% for CBT and 53.6% for antidepressants.²⁶

An RCT that included 452 patients with severe depression used a long intervention period (up to 42 weeks) and a flexible treatment algorithm to more closely model the strategies used in clinical practice.³¹ Patients were randomly assigned to antidepressants only or in combination with CBT. At the end of 12 months, outcome assessment by blinded interviewers indicated that patients with more severe depression were more likely to benefit from the combination of antidepressants and CBT (76.9% vs 60.3%) and those with severe, non-chronic depression received the most benefit (79.5% vs 62.8%). The lack of a CBT-only group limits the generalizability of these findings. Neither patients nor clinicians were blinded to the treatment assignment, which is a common limitation in psychotherapy studies but could have contributed to the finding that combined treatment was more effective.

Continue to: Some evidence suggests...

Some evidence suggests that augmenting treatment as usual (TAU) with CBT can have a resilient protective impact that also intensifies with the number of depressive episodes experienced. In an RCT, 172 patients with depression in remission were randomly assigned to TAU or to TAU augmented with CBT.³² The time to recurrence was assessed over the course of 10 years. Augmenting TAU with CBT had a significant protective impact that was greater for patients who had >3 previous episodes.³²

Another long-term study assessed the longitudinal course of 158 patients who received CBT, medication, and clinical management, or medication and clinical management alone.³³ Patients were followed 6 years after randomization (4.5 years after completion of CBT). Researchers found the effects of CBT in preventing relapse and recurrence persisted for several years.³³

Table 2^24,26,29-32 summarizes the findings of select studies evaluating the use of CBT for the long-term treatment of depression.

Limitations of long-term studies

Studies that have examined the efficacy of adding CBT to antidepressants in the continuation and maintenance treatment of patients with MDD have had some limitations. The definitions of relapse and recurrence have not always been clearly delineated in all studies. This is important because recurrence rates tend to be lower, and long-term follow-up would be needed to detect multiple recurrences so that their incidence is not underestimated. In addition, the types of CBT interventions utilized has varied across studies. Some studies have employed standard interventions such as cognitive restructuring, while others have added strategies that focus on enhancing memories for positive experiences or interventions to encourage medication adherence. Despite these limitations, research has shown promising results and suggests that adding CBT to the maintenance treatment of patients with depression—with or without antidepressants—is likely to reduce the rate of relapse and recurrence.

Consider CBT for all depressed patients

Research indicates that CBT can be the preferred treatment for patients with mild to moderate MDD. Antidepressants significantly reduce depressive symptoms in patients with moderate to severe MDD. Some research suggests that CBT can be as effective as antidepressants for moderate and severe MDD. However, as the severity and chronicity of depression increase, other moderating factors need to be considered. The expertise of the CBT therapist has an impact on outcomes. Treatment protocols that utilize CBT plus antidepressants are likely to be more effective than CBT or antidepressants alone. Incorporating CBT in the acute phase of depression treatment, with or without antidepressants, can have a long-term impact. For maintenance treatment, CBT alone and CBT plus antidepressants have been found to help sustain remission.

Continue to: Bottom Line

 

 

Bottom Line

Cognitive-behavioral therapy (CBT) can be an effective treatment for patients with major depressive disorder, regardless of symptom severity. The expertise of the clinician who provides CBT has a substantial impact on outcomes. Combination treatment with CBT plus antidepressants is more likely to be effective than either treatment alone.

Related Resources

• Flynn HA, Warren R. Using CBT effectively for treating depression and anxiety. Current Psychiatry. 2014;13(6):45-53.
• Ijaz S, Davies P, Williams CJ, et al. Psychological therapies for treatment-resistant depression in adults. Cochrane Database Syst Rev. 2018;5:CD010558.

Major depressive disorder (MDD) has a devastating impact on individuals and society because of its high prevalence, its recurrent nature, its frequent comorbidity with other disorders, and the functional impairment it causes. Compared with other chronic diseases, such as arthritis, asthma, and diabetes, MDD produces the greatest decrement in health worldwide.¹ The goals in treating MDD should be not just to reduce symptom severity but also to achieve continuing remission and lower the risk for relapse.²

Antidepressants are the most common treatment for depression.³ Among psychotherapies used to treat MDD, cognitive-behavioral therapy (CBT) has been identified as an effective treatment.⁴ Collaborative care models have been reported to manage MDD more effectively.⁵ In this article, we review the evidence supporting the use of CBT as monotherapy and in combination with antidepressants for acute and long-term treatment of MDD.

Acute treatment: Not too soon for CBT

Mild to moderate depression

Research has indicated that for the treatment of mild MDD, antidepressants are unlikely to be more effective than placebo.^6,7 Studies also have reported that response to anti­depressants begins to outpace response to placebo only when symptoms are no longer mild. Using antidepressants for patients with mild depression could therefore place them at risk of overtreatment.⁸ In keeping with these findings, the American Psychiatric Association (APA) has recommended the use of evidence-based psychotherapies, such as CBT, as an initial treatment choice for patients with mild to moderate MDD.⁹

Two recent studies have suggested that the combination of CBT plus antidepressants could boost improvement in psychosocial functioning for patients with mild MDD.^10,11 However, neither study included a group of patients who received only CBT to evaluate if CBT alone could have also produced similar effects. Other limitations include the lack of a control group in one study and small sample sizes in both studies. However, both studies had a long follow-up period and specifically studied the impact on psychosocial functioning.

Moderate to severe depression

Earlier depression treatment guidelines suggested that antidepressants should be used to treat more severe depression, while psychotherapy should be used mainly for mild depression.¹² This recommendation was influenced by the well-known National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program, a multicenter randomized controlled trial (RCT) that used a placebo control.¹³ In this study, CBT was compared with antidepressants and found to be no more effective than placebo for more severely depressed patients.¹³ However, this finding was not consistent across the 3 sites where the study was conducted; at the site where CBT was provided by more experienced CBT therapists, patients with more severe depression who received CBT fared as well as patients treated with antidepressants.¹⁴ A later double-blind RCT that used experienced therapists found that CBT was as effective as antidepressants (monoamine oxidase inhibitors), and both treatments were superior to placebo in reducing symptoms of atypical depression.¹⁵

Another placebo-controlled RCT conducted at 2 sites found that CBT was as effective as antidepressants in the treatment of moderately to severely depressed patients. As in the NIMH Treatment of Depression Collaborative Research Program trial,¹³ in this study, there were indications that the results were dependent on therapist experience.¹⁶ These findings suggest that the experience of the therapist is an important factor.

A recent meta-analysis of treatments of the acute phase of MDD compared 11 RCTs of CBT and second-generation antidepressants (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other medications with related mechanisms of action).¹⁷ It found that as a first-step treatment, CBT and antidepressants had a similar impact on symptom relief in patients with moderate to severe depression. Patients treated with antidepressants also had a higher risk of experiencing adverse events or discontinuing treatment because of adverse events. However, this meta-analysis included trials that had methodological shortcomings, which reduces the strength of these conclusions.

Continue to: Patients with MDD and comorbid personality disorders have been...

Patients with MDD and comorbid personality disorders have been reported to have poorer outcomes, regardless of the treatment used.¹⁸ Fournier et al¹⁹ examined the impact of antidepressants and CBT in moderately to severely depressed patients with and without a personality disorder. They found that a combination of antidepressants and CBT was suitable for patients with personality disorders because antidepressants would boost the initial response and CBT would help sustain improvement in the long term.

Presently, the APA suggests that the combination of psychotherapy and antidepressants may be used as an initial treatment for patients with moderate to severe MDD.⁹ As research brings to light other factors that affect treatment outcomes, these guidelines could change.

Table 1^10,11,15,16 summarizes the findings of select studies evaluating the use of CBT for the acute treatment of depression.

CBT’s role in long-term treatment

Recurrence and relapse are major problems associated with MDD. The large majority of individuals who experience an episode of depression go on to experience more episodes of depression,²⁰ and the risk of recurrence increases after each successive episode.²¹

To reduce the risk of relapse and the return of symptoms, it is recommended that patients treated with antidepressants continue pharmacotherapy for 4 to 9 months after remission.⁹ Maintenance pharmacotherapy, which involves keeping patients on antidepressants beyond the point of recovery, is intended to reduce the risk of recurrence, and is standard treatment for patients with chronic or recurrent MDD.²² However, this preventive effect exists only while the patient continues to take the medication. Rates of symptom recurrence following medication withdrawal are often high regardless of how long patients have taken medications.²³

Continue to: Studies examining CBT as a maintenance treatment...

Studies examining CBT as a maintenance treatment—provided alone or in combination with or sequentially with antidepressants—have found it has an enduring effect that extends beyond the end of treatment and equals the impact of continuing antidepressants.^24-27 A recent meta-analysis of 10 trials where CBT had been provided to patients after acute treatment found that the risk of relapse was reduced by 21% in the first year and by 28% in the first 2 years.²⁸

Studies have compared the prophylactic impact of maintenance CBT and antidepressants. In an early study, 40 patients who had been successfully treated with antidepressants but had residual symptoms were randomly assigned to 20 weeks of CBT or to clinical management.²⁹ By the end of 20 weeks, patients were tapered off their antidepressant. All patients were then followed for 2 years, during which time they received no treatment. At the 2-year follow-up, the CBT group had a relapse rate of 25%, compared with 80% in the antidepressant group.²⁹ Weaknesses of this study include a small sample size, and the fact that a single therapist provided the CBT.

This study was extended to a 6-year follow-up; antidepressants were prescribed only to patients who relapsed. The CBT group continued to have a significantly lower relapse rate (40%) compared with the antidepressant group (90%).³⁰

In another RCT, patients with depression who had recovered with CBT or medication continued with the same treatment during a maintenance phase.²⁶ The CBT group received 3 booster sessions during the next year and antidepressant group received medication. At the end of the second year (without CBT or medication) CBT patients were less likely to relapse compared with patients receiving antidepressants. The adjusted relapse rates were 17.3% for CBT and 53.6% for antidepressants.²⁶

An RCT that included 452 patients with severe depression used a long intervention period (up to 42 weeks) and a flexible treatment algorithm to more closely model the strategies used in clinical practice.³¹ Patients were randomly assigned to antidepressants only or in combination with CBT. At the end of 12 months, outcome assessment by blinded interviewers indicated that patients with more severe depression were more likely to benefit from the combination of antidepressants and CBT (76.9% vs 60.3%) and those with severe, non-chronic depression received the most benefit (79.5% vs 62.8%). The lack of a CBT-only group limits the generalizability of these findings. Neither patients nor clinicians were blinded to the treatment assignment, which is a common limitation in psychotherapy studies but could have contributed to the finding that combined treatment was more effective.

Continue to: Some evidence suggests...

Some evidence suggests that augmenting treatment as usual (TAU) with CBT can have a resilient protective impact that also intensifies with the number of depressive episodes experienced. In an RCT, 172 patients with depression in remission were randomly assigned to TAU or to TAU augmented with CBT.³² The time to recurrence was assessed over the course of 10 years. Augmenting TAU with CBT had a significant protective impact that was greater for patients who had >3 previous episodes.³²

Another long-term study assessed the longitudinal course of 158 patients who received CBT, medication, and clinical management, or medication and clinical management alone.³³ Patients were followed 6 years after randomization (4.5 years after completion of CBT). Researchers found the effects of CBT in preventing relapse and recurrence persisted for several years.³³

Table 2^24,26,29-32 summarizes the findings of select studies evaluating the use of CBT for the long-term treatment of depression.

Limitations of long-term studies

Studies that have examined the efficacy of adding CBT to antidepressants in the continuation and maintenance treatment of patients with MDD have had some limitations. The definitions of relapse and recurrence have not always been clearly delineated in all studies. This is important because recurrence rates tend to be lower, and long-term follow-up would be needed to detect multiple recurrences so that their incidence is not underestimated. In addition, the types of CBT interventions utilized has varied across studies. Some studies have employed standard interventions such as cognitive restructuring, while others have added strategies that focus on enhancing memories for positive experiences or interventions to encourage medication adherence. Despite these limitations, research has shown promising results and suggests that adding CBT to the maintenance treatment of patients with depression—with or without antidepressants—is likely to reduce the rate of relapse and recurrence.

Consider CBT for all depressed patients

Research indicates that CBT can be the preferred treatment for patients with mild to moderate MDD. Antidepressants significantly reduce depressive symptoms in patients with moderate to severe MDD. Some research suggests that CBT can be as effective as antidepressants for moderate and severe MDD. However, as the severity and chronicity of depression increase, other moderating factors need to be considered. The expertise of the CBT therapist has an impact on outcomes. Treatment protocols that utilize CBT plus antidepressants are likely to be more effective than CBT or antidepressants alone. Incorporating CBT in the acute phase of depression treatment, with or without antidepressants, can have a long-term impact. For maintenance treatment, CBT alone and CBT plus antidepressants have been found to help sustain remission.

Continue to: Bottom Line

 

 

Bottom Line

Cognitive-behavioral therapy (CBT) can be an effective treatment for patients with major depressive disorder, regardless of symptom severity. The expertise of the clinician who provides CBT has a substantial impact on outcomes. Combination treatment with CBT plus antidepressants is more likely to be effective than either treatment alone.

Related Resources

• Flynn HA, Warren R. Using CBT effectively for treating depression and anxiety. Current Psychiatry. 2014;13(6):45-53.
• Ijaz S, Davies P, Williams CJ, et al. Psychological therapies for treatment-resistant depression in adults. Cochrane Database Syst Rev. 2018;5:CD010558.

Major depressive disorder (MDD) has a devastating impact on individuals and society because of its high prevalence, its recurrent nature, its frequent comorbidity with other disorders, and the functional impairment it causes. Compared with other chronic diseases, such as arthritis, asthma, and diabetes, MDD produces the greatest decrement in health worldwide.¹ The goals in treating MDD should be not just to reduce symptom severity but also to achieve continuing remission and lower the risk for relapse.²

Antidepressants are the most common treatment for depression.³ Among psychotherapies used to treat MDD, cognitive-behavioral therapy (CBT) has been identified as an effective treatment.⁴ Collaborative care models have been reported to manage MDD more effectively.⁵ In this article, we review the evidence supporting the use of CBT as monotherapy and in combination with antidepressants for acute and long-term treatment of MDD.

Acute treatment: Not too soon for CBT

Mild to moderate depression

Research has indicated that for the treatment of mild MDD, antidepressants are unlikely to be more effective than placebo.^6,7 Studies also have reported that response to anti­depressants begins to outpace response to placebo only when symptoms are no longer mild. Using antidepressants for patients with mild depression could therefore place them at risk of overtreatment.⁸ In keeping with these findings, the American Psychiatric Association (APA) has recommended the use of evidence-based psychotherapies, such as CBT, as an initial treatment choice for patients with mild to moderate MDD.⁹

Two recent studies have suggested that the combination of CBT plus antidepressants could boost improvement in psychosocial functioning for patients with mild MDD.^10,11 However, neither study included a group of patients who received only CBT to evaluate if CBT alone could have also produced similar effects. Other limitations include the lack of a control group in one study and small sample sizes in both studies. However, both studies had a long follow-up period and specifically studied the impact on psychosocial functioning.

Moderate to severe depression

Earlier depression treatment guidelines suggested that antidepressants should be used to treat more severe depression, while psychotherapy should be used mainly for mild depression.¹² This recommendation was influenced by the well-known National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program, a multicenter randomized controlled trial (RCT) that used a placebo control.¹³ In this study, CBT was compared with antidepressants and found to be no more effective than placebo for more severely depressed patients.¹³ However, this finding was not consistent across the 3 sites where the study was conducted; at the site where CBT was provided by more experienced CBT therapists, patients with more severe depression who received CBT fared as well as patients treated with antidepressants.¹⁴ A later double-blind RCT that used experienced therapists found that CBT was as effective as antidepressants (monoamine oxidase inhibitors), and both treatments were superior to placebo in reducing symptoms of atypical depression.¹⁵

Another placebo-controlled RCT conducted at 2 sites found that CBT was as effective as antidepressants in the treatment of moderately to severely depressed patients. As in the NIMH Treatment of Depression Collaborative Research Program trial,¹³ in this study, there were indications that the results were dependent on therapist experience.¹⁶ These findings suggest that the experience of the therapist is an important factor.

A recent meta-analysis of treatments of the acute phase of MDD compared 11 RCTs of CBT and second-generation antidepressants (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other medications with related mechanisms of action).¹⁷ It found that as a first-step treatment, CBT and antidepressants had a similar impact on symptom relief in patients with moderate to severe depression. Patients treated with antidepressants also had a higher risk of experiencing adverse events or discontinuing treatment because of adverse events. However, this meta-analysis included trials that had methodological shortcomings, which reduces the strength of these conclusions.

Continue to: Patients with MDD and comorbid personality disorders have been...

Patients with MDD and comorbid personality disorders have been reported to have poorer outcomes, regardless of the treatment used.¹⁸ Fournier et al¹⁹ examined the impact of antidepressants and CBT in moderately to severely depressed patients with and without a personality disorder. They found that a combination of antidepressants and CBT was suitable for patients with personality disorders because antidepressants would boost the initial response and CBT would help sustain improvement in the long term.

Presently, the APA suggests that the combination of psychotherapy and antidepressants may be used as an initial treatment for patients with moderate to severe MDD.⁹ As research brings to light other factors that affect treatment outcomes, these guidelines could change.

Table 1^10,11,15,16 summarizes the findings of select studies evaluating the use of CBT for the acute treatment of depression.

CBT’s role in long-term treatment

Recurrence and relapse are major problems associated with MDD. The large majority of individuals who experience an episode of depression go on to experience more episodes of depression,²⁰ and the risk of recurrence increases after each successive episode.²¹

To reduce the risk of relapse and the return of symptoms, it is recommended that patients treated with antidepressants continue pharmacotherapy for 4 to 9 months after remission.⁹ Maintenance pharmacotherapy, which involves keeping patients on antidepressants beyond the point of recovery, is intended to reduce the risk of recurrence, and is standard treatment for patients with chronic or recurrent MDD.²² However, this preventive effect exists only while the patient continues to take the medication. Rates of symptom recurrence following medication withdrawal are often high regardless of how long patients have taken medications.²³

Continue to: Studies examining CBT as a maintenance treatment...

Studies examining CBT as a maintenance treatment—provided alone or in combination with or sequentially with antidepressants—have found it has an enduring effect that extends beyond the end of treatment and equals the impact of continuing antidepressants.^24-27 A recent meta-analysis of 10 trials where CBT had been provided to patients after acute treatment found that the risk of relapse was reduced by 21% in the first year and by 28% in the first 2 years.²⁸

Studies have compared the prophylactic impact of maintenance CBT and antidepressants. In an early study, 40 patients who had been successfully treated with antidepressants but had residual symptoms were randomly assigned to 20 weeks of CBT or to clinical management.²⁹ By the end of 20 weeks, patients were tapered off their antidepressant. All patients were then followed for 2 years, during which time they received no treatment. At the 2-year follow-up, the CBT group had a relapse rate of 25%, compared with 80% in the antidepressant group.²⁹ Weaknesses of this study include a small sample size, and the fact that a single therapist provided the CBT.

This study was extended to a 6-year follow-up; antidepressants were prescribed only to patients who relapsed. The CBT group continued to have a significantly lower relapse rate (40%) compared with the antidepressant group (90%).³⁰

In another RCT, patients with depression who had recovered with CBT or medication continued with the same treatment during a maintenance phase.²⁶ The CBT group received 3 booster sessions during the next year and antidepressant group received medication. At the end of the second year (without CBT or medication) CBT patients were less likely to relapse compared with patients receiving antidepressants. The adjusted relapse rates were 17.3% for CBT and 53.6% for antidepressants.²⁶

An RCT that included 452 patients with severe depression used a long intervention period (up to 42 weeks) and a flexible treatment algorithm to more closely model the strategies used in clinical practice.³¹ Patients were randomly assigned to antidepressants only or in combination with CBT. At the end of 12 months, outcome assessment by blinded interviewers indicated that patients with more severe depression were more likely to benefit from the combination of antidepressants and CBT (76.9% vs 60.3%) and those with severe, non-chronic depression received the most benefit (79.5% vs 62.8%). The lack of a CBT-only group limits the generalizability of these findings. Neither patients nor clinicians were blinded to the treatment assignment, which is a common limitation in psychotherapy studies but could have contributed to the finding that combined treatment was more effective.

Continue to: Some evidence suggests...

Some evidence suggests that augmenting treatment as usual (TAU) with CBT can have a resilient protective impact that also intensifies with the number of depressive episodes experienced. In an RCT, 172 patients with depression in remission were randomly assigned to TAU or to TAU augmented with CBT.³² The time to recurrence was assessed over the course of 10 years. Augmenting TAU with CBT had a significant protective impact that was greater for patients who had >3 previous episodes.³²

Another long-term study assessed the longitudinal course of 158 patients who received CBT, medication, and clinical management, or medication and clinical management alone.³³ Patients were followed 6 years after randomization (4.5 years after completion of CBT). Researchers found the effects of CBT in preventing relapse and recurrence persisted for several years.³³

Table 2^24,26,29-32 summarizes the findings of select studies evaluating the use of CBT for the long-term treatment of depression.

Limitations of long-term studies

Studies that have examined the efficacy of adding CBT to antidepressants in the continuation and maintenance treatment of patients with MDD have had some limitations. The definitions of relapse and recurrence have not always been clearly delineated in all studies. This is important because recurrence rates tend to be lower, and long-term follow-up would be needed to detect multiple recurrences so that their incidence is not underestimated. In addition, the types of CBT interventions utilized has varied across studies. Some studies have employed standard interventions such as cognitive restructuring, while others have added strategies that focus on enhancing memories for positive experiences or interventions to encourage medication adherence. Despite these limitations, research has shown promising results and suggests that adding CBT to the maintenance treatment of patients with depression—with or without antidepressants—is likely to reduce the rate of relapse and recurrence.

Consider CBT for all depressed patients

Research indicates that CBT can be the preferred treatment for patients with mild to moderate MDD. Antidepressants significantly reduce depressive symptoms in patients with moderate to severe MDD. Some research suggests that CBT can be as effective as antidepressants for moderate and severe MDD. However, as the severity and chronicity of depression increase, other moderating factors need to be considered. The expertise of the CBT therapist has an impact on outcomes. Treatment protocols that utilize CBT plus antidepressants are likely to be more effective than CBT or antidepressants alone. Incorporating CBT in the acute phase of depression treatment, with or without antidepressants, can have a long-term impact. For maintenance treatment, CBT alone and CBT plus antidepressants have been found to help sustain remission.

Continue to: Bottom Line

 

 

Bottom Line

Cognitive-behavioral therapy (CBT) can be an effective treatment for patients with major depressive disorder, regardless of symptom severity. The expertise of the clinician who provides CBT has a substantial impact on outcomes. Combination treatment with CBT plus antidepressants is more likely to be effective than either treatment alone.

Related Resources

• Flynn HA, Warren R. Using CBT effectively for treating depression and anxiety. Current Psychiatry. 2014;13(6):45-53.
• Ijaz S, Davies P, Williams CJ, et al. Psychological therapies for treatment-resistant depression in adults. Cochrane Database Syst Rev. 2018;5:CD010558.