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.”

[email protected]

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.”

[email protected]

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.”

[email protected]

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.

[email protected]

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.

[email protected]

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.

[email protected]

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 [email protected].

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 [email protected].

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 [email protected].

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.

MUNICH – For patients with heart disease, coronary artery disease, and normal sinus rhythm, giving rivaroxaban does not significantly reduce risks of death, myocardial infarction, or stroke, investigators in the COMMANDER trial said.

Rivaroxaban did not improve rehospitalization rates either, reported lead author Faiez Zannad, MD, PhD, from the University of Henri Poincaré in Nancy, France, and his co-investigators.

“After an episode of worsening chronic heart failure, rates of readmission to the hospital and of death are high, especially in the first few months,” they said in a presentation at the annual congress of the European Society of Cardiology. The report of the research was published simultaneously in the New England Journal of Medicine.

Findings from previous research have suggested that, for patients with coronary artery disease, a combination of antiplatelet agents and low-dose rivaroxaban (2.5 mg twice daily) reduced incidence of death, myocardial infarction, and stroke. The authors designed the COMMANDER trial to test a similar regimen in patients with chronic heart failure and coronary heart disease without an arrhythmia. Results were published simultaneously in the New England Journal of Medicine.

The COMMANDER trial involved 5,022 patients with coronary artery disease, reduced left ventricular ejection fraction (less than or equal to 40%), worsening chronic heart failure (index event within past 21 days), and normal splasma concentration of brain natriuretic peptide (BNP) of at least 200 ng per liter or N-terminal pro-brain natriuretic peptide (NT-proBNP) of at least 800 ng per liter.

Patients were randomly assigned to receive rivaroxaban 2.5 mg twice daily (n = 2,507) or placebo (n = 2,515). Treatment was given in addition to standard care for coronary disease or heart failure (single or dual antiplatelet therapy was allowed). Patients were assessed at week 4 and week 12, then every 12 weeks.

The primary efficacy outcome was a composite of stroke, myocardial infarction, or death from any cause. Secondary efficacy outcomes included death from cardiovascular disease, rehospitalization for heart failure, a composite of either, or rehospitalization for cardiovascular events. The principal safety outcome was a composite of bleeding into a critical space with potential for permanent disability or fatal bleeding.

Death, myocardial failure, or stroke occurred in 626 patients (25%) in the rivaroxaban group compared with 658 patients (26.2%) in the placebo group (P = .27). Secondary efficacy outcomes were also highly similar between groups, differing at most by 0.9%. The principal safety outcome (fatal bleeding or bleeding into a critical space) occurred in 18 patients (0.7%) in the rivaroxaban group and 23 patients (0.9%) in the placebo group (P = .25). Again, no significant difference was found between groups.

These results suggest that while low-dose rivaroxaban may be safe, it also offers no treatment benefit. “The most likely reason for the failure … is that thrombin-mediated events are not the major driver of heart failure-related events in patients with recent hospitalization for heart failure,” the authors wrote.

“Whether a higher dose of rivaroxaban could have led to a more favorable outcome remains unknown,” they concluded.

The COMMANDER trial was funded by Janssen Research and Development. Authors reported compensation from Bayer, Servier, Novartis, Impulse Dynamics, and others.

[email protected]

SOURCE: Zannad F et al. NEJM/ESC.

.

MUNICH – For patients with heart disease, coronary artery disease, and normal sinus rhythm, giving rivaroxaban does not significantly reduce risks of death, myocardial infarction, or stroke, investigators in the COMMANDER trial said.

Rivaroxaban did not improve rehospitalization rates either, reported lead author Faiez Zannad, MD, PhD, from the University of Henri Poincaré in Nancy, France, and his co-investigators.

“After an episode of worsening chronic heart failure, rates of readmission to the hospital and of death are high, especially in the first few months,” they said in a presentation at the annual congress of the European Society of Cardiology. The report of the research was published simultaneously in the New England Journal of Medicine.

Findings from previous research have suggested that, for patients with coronary artery disease, a combination of antiplatelet agents and low-dose rivaroxaban (2.5 mg twice daily) reduced incidence of death, myocardial infarction, and stroke. The authors designed the COMMANDER trial to test a similar regimen in patients with chronic heart failure and coronary heart disease without an arrhythmia. Results were published simultaneously in the New England Journal of Medicine.

The COMMANDER trial involved 5,022 patients with coronary artery disease, reduced left ventricular ejection fraction (less than or equal to 40%), worsening chronic heart failure (index event within past 21 days), and normal splasma concentration of brain natriuretic peptide (BNP) of at least 200 ng per liter or N-terminal pro-brain natriuretic peptide (NT-proBNP) of at least 800 ng per liter.

Patients were randomly assigned to receive rivaroxaban 2.5 mg twice daily (n = 2,507) or placebo (n = 2,515). Treatment was given in addition to standard care for coronary disease or heart failure (single or dual antiplatelet therapy was allowed). Patients were assessed at week 4 and week 12, then every 12 weeks.

The primary efficacy outcome was a composite of stroke, myocardial infarction, or death from any cause. Secondary efficacy outcomes included death from cardiovascular disease, rehospitalization for heart failure, a composite of either, or rehospitalization for cardiovascular events. The principal safety outcome was a composite of bleeding into a critical space with potential for permanent disability or fatal bleeding.

Death, myocardial failure, or stroke occurred in 626 patients (25%) in the rivaroxaban group compared with 658 patients (26.2%) in the placebo group (P = .27). Secondary efficacy outcomes were also highly similar between groups, differing at most by 0.9%. The principal safety outcome (fatal bleeding or bleeding into a critical space) occurred in 18 patients (0.7%) in the rivaroxaban group and 23 patients (0.9%) in the placebo group (P = .25). Again, no significant difference was found between groups.

These results suggest that while low-dose rivaroxaban may be safe, it also offers no treatment benefit. “The most likely reason for the failure … is that thrombin-mediated events are not the major driver of heart failure-related events in patients with recent hospitalization for heart failure,” the authors wrote.

“Whether a higher dose of rivaroxaban could have led to a more favorable outcome remains unknown,” they concluded.

The COMMANDER trial was funded by Janssen Research and Development. Authors reported compensation from Bayer, Servier, Novartis, Impulse Dynamics, and others.

[email protected]

SOURCE: Zannad F et al. NEJM/ESC.

.

MUNICH – For patients with heart disease, coronary artery disease, and normal sinus rhythm, giving rivaroxaban does not significantly reduce risks of death, myocardial infarction, or stroke, investigators in the COMMANDER trial said.

Rivaroxaban did not improve rehospitalization rates either, reported lead author Faiez Zannad, MD, PhD, from the University of Henri Poincaré in Nancy, France, and his co-investigators.

“After an episode of worsening chronic heart failure, rates of readmission to the hospital and of death are high, especially in the first few months,” they said in a presentation at the annual congress of the European Society of Cardiology. The report of the research was published simultaneously in the New England Journal of Medicine.

Findings from previous research have suggested that, for patients with coronary artery disease, a combination of antiplatelet agents and low-dose rivaroxaban (2.5 mg twice daily) reduced incidence of death, myocardial infarction, and stroke. The authors designed the COMMANDER trial to test a similar regimen in patients with chronic heart failure and coronary heart disease without an arrhythmia. Results were published simultaneously in the New England Journal of Medicine.

The COMMANDER trial involved 5,022 patients with coronary artery disease, reduced left ventricular ejection fraction (less than or equal to 40%), worsening chronic heart failure (index event within past 21 days), and normal splasma concentration of brain natriuretic peptide (BNP) of at least 200 ng per liter or N-terminal pro-brain natriuretic peptide (NT-proBNP) of at least 800 ng per liter.

Patients were randomly assigned to receive rivaroxaban 2.5 mg twice daily (n = 2,507) or placebo (n = 2,515). Treatment was given in addition to standard care for coronary disease or heart failure (single or dual antiplatelet therapy was allowed). Patients were assessed at week 4 and week 12, then every 12 weeks.

The primary efficacy outcome was a composite of stroke, myocardial infarction, or death from any cause. Secondary efficacy outcomes included death from cardiovascular disease, rehospitalization for heart failure, a composite of either, or rehospitalization for cardiovascular events. The principal safety outcome was a composite of bleeding into a critical space with potential for permanent disability or fatal bleeding.

Death, myocardial failure, or stroke occurred in 626 patients (25%) in the rivaroxaban group compared with 658 patients (26.2%) in the placebo group (P = .27). Secondary efficacy outcomes were also highly similar between groups, differing at most by 0.9%. The principal safety outcome (fatal bleeding or bleeding into a critical space) occurred in 18 patients (0.7%) in the rivaroxaban group and 23 patients (0.9%) in the placebo group (P = .25). Again, no significant difference was found between groups.

These results suggest that while low-dose rivaroxaban may be safe, it also offers no treatment benefit. “The most likely reason for the failure … is that thrombin-mediated events are not the major driver of heart failure-related events in patients with recent hospitalization for heart failure,” the authors wrote.

“Whether a higher dose of rivaroxaban could have led to a more favorable outcome remains unknown,” they concluded.

The COMMANDER trial was funded by Janssen Research and Development. Authors reported compensation from Bayer, Servier, Novartis, Impulse Dynamics, and others.

[email protected]

SOURCE: Zannad F et al. NEJM/ESC.

.

In 2014, 68% of male veterans and 41% of female veterans who committed suicide used a firearm. Research suggests that most suicidal crises pass within minutes to hours: Building in time and space between a suicidal impulse and access to a gun can be a safety valve.  

The VA Challenge Team launched an innovation contest for novel and effective approaches using gun-safety mechanisms to prevent suicide, injury, and accidents. One main criterion: the device or system must allow for 100% voluntary control (implementation, suspension, decommissioning) by the veteran.

The Challenge team was looking for solutions that would be inexpensive, applicable for at-home use, not impede responsible access to the weapon, and provide education about gun safety. The winners were:

• First place—Barret Schlegelmilch, for the DuoBox, a mechanical device that provides inexpensive, secure and reliable weapon storage and encourages responsible weapon access with 2 people present.
• Second place—Timothy Oh, Christine Tate, and Jorel Lalicki, for their “open environment” biometric safe that includes fingerprint authentication and other features to enhance control of access.
• Third place—Kathleen Gilligan and Leslie Bodi, for the Sentinel, a mobile application that helps veterans connect with peers in an innovative “buddy system” so they know they are not alone in a crisis. The app also controls Bluetooth-enabled gun-lock boxes and has unique features such as a time-lock and automated emergency calling.

The winners received cash awards, as well as access to VA resources, such as subject matter experts, for any potential follow-on design and development.

In 2014, 68% of male veterans and 41% of female veterans who committed suicide used a firearm. Research suggests that most suicidal crises pass within minutes to hours: Building in time and space between a suicidal impulse and access to a gun can be a safety valve.  

The VA Challenge Team launched an innovation contest for novel and effective approaches using gun-safety mechanisms to prevent suicide, injury, and accidents. One main criterion: the device or system must allow for 100% voluntary control (implementation, suspension, decommissioning) by the veteran.

The Challenge team was looking for solutions that would be inexpensive, applicable for at-home use, not impede responsible access to the weapon, and provide education about gun safety. The winners were:

• First place—Barret Schlegelmilch, for the DuoBox, a mechanical device that provides inexpensive, secure and reliable weapon storage and encourages responsible weapon access with 2 people present.
• Second place—Timothy Oh, Christine Tate, and Jorel Lalicki, for their “open environment” biometric safe that includes fingerprint authentication and other features to enhance control of access.
• Third place—Kathleen Gilligan and Leslie Bodi, for the Sentinel, a mobile application that helps veterans connect with peers in an innovative “buddy system” so they know they are not alone in a crisis. The app also controls Bluetooth-enabled gun-lock boxes and has unique features such as a time-lock and automated emergency calling.

The winners received cash awards, as well as access to VA resources, such as subject matter experts, for any potential follow-on design and development.

In 2014, 68% of male veterans and 41% of female veterans who committed suicide used a firearm. Research suggests that most suicidal crises pass within minutes to hours: Building in time and space between a suicidal impulse and access to a gun can be a safety valve.  

The VA Challenge Team launched an innovation contest for novel and effective approaches using gun-safety mechanisms to prevent suicide, injury, and accidents. One main criterion: the device or system must allow for 100% voluntary control (implementation, suspension, decommissioning) by the veteran.

The Challenge team was looking for solutions that would be inexpensive, applicable for at-home use, not impede responsible access to the weapon, and provide education about gun safety. The winners were:

• First place—Barret Schlegelmilch, for the DuoBox, a mechanical device that provides inexpensive, secure and reliable weapon storage and encourages responsible weapon access with 2 people present.
• Second place—Timothy Oh, Christine Tate, and Jorel Lalicki, for their “open environment” biometric safe that includes fingerprint authentication and other features to enhance control of access.
• Third place—Kathleen Gilligan and Leslie Bodi, for the Sentinel, a mobile application that helps veterans connect with peers in an innovative “buddy system” so they know they are not alone in a crisis. The app also controls Bluetooth-enabled gun-lock boxes and has unique features such as a time-lock and automated emergency calling.

The winners received cash awards, as well as access to VA resources, such as subject matter experts, for any potential follow-on design and development.