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Plan to ‘Learn by Doing’ at the CHEST Annual Meeting 2018
Don’t miss the CHEST Annual Meeting 2018 in San Antonio, Oct 6-10. Watch as CHEST 2018 Program Chair David A. Schulman, MD, MPH, FCCP, walks you through the vision of this year’s meeting. View complete details at chestmeeting.chestnet.org.
Don’t miss the CHEST Annual Meeting 2018 in San Antonio, Oct 6-10. Watch as CHEST 2018 Program Chair David A. Schulman, MD, MPH, FCCP, walks you through the vision of this year’s meeting. View complete details at chestmeeting.chestnet.org.
Don’t miss the CHEST Annual Meeting 2018 in San Antonio, Oct 6-10. Watch as CHEST 2018 Program Chair David A. Schulman, MD, MPH, FCCP, walks you through the vision of this year’s meeting. View complete details at chestmeeting.chestnet.org.
Avatrombopag cut procedure-related transfusions in patients with thrombocytopenia, chronic liver disease
Once-daily treatment with the oral second-generation thrombopoietin agonist avatrombopag (Doptelet) significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures, according to the results of two international, randomized, double-blind, phase III, placebo-controlled trials reported in the September issue of Gastroenterology.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia, versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group, versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).
These results led the Food and Drug Administration to approve avatrombopag in May 2018 under its priority review process. The novel therapy “may be a safe and effective alternative to platelet transfusions” that could simplify the clinical management of patients with chronic liver disease and thrombocytopenia, Norah Terrault, MD, MPH, and her associates wrote in Gastroenterology.
The ADAPT-1 study included 231 patients, while ADAPT-2 included 204 patients. In each trial, patients were randomized on a 2:1 basis to receive oral avatrombopag or placebo once daily for 5 consecutive days. Patients in the intervention arms received 60 mg avatrombopag if their baseline platelet count was less than 40 x 109 per liter, and 40 mg if their baseline platelet count was 40-50 x 109 per liter. Procedures were scheduled for 10-13 days after treatment initiation.
“Platelet counts increased by [treatment] day 4, peaked at days 10-13, and then returned to baseline levels by day 35,” the researchers reported. Among ADAPT-1 patients with low baseline counts, 69% of avatrombopag recipients reached a prespecified target of at least 50 x 109 platelets per liter on their procedure day, versus 4% of placebo recipients (P less than .0001). Corresponding proportions in ADAPT-2 were 67% and 7%, respectively (P less than .0001). Among patients with higher baseline counts, 88% and 20% achieved the target, respectively, in ADAPT-1 (P less than .0001), as did 93% versus 39%, respectively, in ADAPT-2 (P less than .0001).
Avatrombopag and placebo produced similar rates of treatment-emergent adverse events. These most often consisted of abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache. Only three avatrombopag patients developed platelet counts above 200 x 109 per liter, and they all remained asymptomatic, the investigators said.
Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.
SOURCE: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.
Thrombocytopenia in cirrhosis is frequent and multifactorial and includes sequestration in the spleen, reduced liver-derived thrombopoietin, bone marrow toxicity, and autoimmunity towards platelets. Severe thrombocytopenia (less than 50/nL) is rare in cirrhotic patients, but when it occurs may prevent required procedures from being performed or require platelet transfusions, which are associated with significant risks.
Previous attempts to increase platelets in cirrhotic patients with thrombopoietin agonists were halted because of increased frequency of portal vein thrombosis and hepatic decompensation.
Now avatrombopag has been specifically licensed with a 5-day regimen to increase platelets prior to elective interventions in severely thrombocytopenic (less than 50/nL) patients with chronic liver disease with a seemingly better safety profile than earlier treatments and good efficacy. The patient groups studied in the licensing trial had slightly milder but not significantly different liver disease, compared with those in the eltrombopag studies. The key difference was a pretreatment requirement of a portal vein flow of more than 10 cm/sec prior to enrollment, which likely reduced the risk of portal vein thrombosis. It is important that providers ready to use avatrombopag are aware of this.
Importantly, no data are currently available for patients with a Model for End-Stage Liver Disease score greater than 24, and very limited data are available for patients with Child B and Child C cirrhosis.
Given this limitation, careful judgment will be needed; a pretreatment portal vein flow may be advisable, though not a label requirement.
An observational study, NCT03554759, in patients with chronic liver disease and thrombocytopenia is ongoing and will further confirm the likely safety of avatrombopag.
Hans L. Tillmann, MD, is a clinical associate professor, East Carolina University, Greenville, and staff physician, Greenville (N.C.) VA Health Care Center. He has no relevant conflicts of interest.
Thrombocytopenia in cirrhosis is frequent and multifactorial and includes sequestration in the spleen, reduced liver-derived thrombopoietin, bone marrow toxicity, and autoimmunity towards platelets. Severe thrombocytopenia (less than 50/nL) is rare in cirrhotic patients, but when it occurs may prevent required procedures from being performed or require platelet transfusions, which are associated with significant risks.
Previous attempts to increase platelets in cirrhotic patients with thrombopoietin agonists were halted because of increased frequency of portal vein thrombosis and hepatic decompensation.
Now avatrombopag has been specifically licensed with a 5-day regimen to increase platelets prior to elective interventions in severely thrombocytopenic (less than 50/nL) patients with chronic liver disease with a seemingly better safety profile than earlier treatments and good efficacy. The patient groups studied in the licensing trial had slightly milder but not significantly different liver disease, compared with those in the eltrombopag studies. The key difference was a pretreatment requirement of a portal vein flow of more than 10 cm/sec prior to enrollment, which likely reduced the risk of portal vein thrombosis. It is important that providers ready to use avatrombopag are aware of this.
Importantly, no data are currently available for patients with a Model for End-Stage Liver Disease score greater than 24, and very limited data are available for patients with Child B and Child C cirrhosis.
Given this limitation, careful judgment will be needed; a pretreatment portal vein flow may be advisable, though not a label requirement.
An observational study, NCT03554759, in patients with chronic liver disease and thrombocytopenia is ongoing and will further confirm the likely safety of avatrombopag.
Hans L. Tillmann, MD, is a clinical associate professor, East Carolina University, Greenville, and staff physician, Greenville (N.C.) VA Health Care Center. He has no relevant conflicts of interest.
Thrombocytopenia in cirrhosis is frequent and multifactorial and includes sequestration in the spleen, reduced liver-derived thrombopoietin, bone marrow toxicity, and autoimmunity towards platelets. Severe thrombocytopenia (less than 50/nL) is rare in cirrhotic patients, but when it occurs may prevent required procedures from being performed or require platelet transfusions, which are associated with significant risks.
Previous attempts to increase platelets in cirrhotic patients with thrombopoietin agonists were halted because of increased frequency of portal vein thrombosis and hepatic decompensation.
Now avatrombopag has been specifically licensed with a 5-day regimen to increase platelets prior to elective interventions in severely thrombocytopenic (less than 50/nL) patients with chronic liver disease with a seemingly better safety profile than earlier treatments and good efficacy. The patient groups studied in the licensing trial had slightly milder but not significantly different liver disease, compared with those in the eltrombopag studies. The key difference was a pretreatment requirement of a portal vein flow of more than 10 cm/sec prior to enrollment, which likely reduced the risk of portal vein thrombosis. It is important that providers ready to use avatrombopag are aware of this.
Importantly, no data are currently available for patients with a Model for End-Stage Liver Disease score greater than 24, and very limited data are available for patients with Child B and Child C cirrhosis.
Given this limitation, careful judgment will be needed; a pretreatment portal vein flow may be advisable, though not a label requirement.
An observational study, NCT03554759, in patients with chronic liver disease and thrombocytopenia is ongoing and will further confirm the likely safety of avatrombopag.
Hans L. Tillmann, MD, is a clinical associate professor, East Carolina University, Greenville, and staff physician, Greenville (N.C.) VA Health Care Center. He has no relevant conflicts of interest.
Once-daily treatment with the oral second-generation thrombopoietin agonist avatrombopag (Doptelet) significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures, according to the results of two international, randomized, double-blind, phase III, placebo-controlled trials reported in the September issue of Gastroenterology.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia, versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group, versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).
These results led the Food and Drug Administration to approve avatrombopag in May 2018 under its priority review process. The novel therapy “may be a safe and effective alternative to platelet transfusions” that could simplify the clinical management of patients with chronic liver disease and thrombocytopenia, Norah Terrault, MD, MPH, and her associates wrote in Gastroenterology.
The ADAPT-1 study included 231 patients, while ADAPT-2 included 204 patients. In each trial, patients were randomized on a 2:1 basis to receive oral avatrombopag or placebo once daily for 5 consecutive days. Patients in the intervention arms received 60 mg avatrombopag if their baseline platelet count was less than 40 x 109 per liter, and 40 mg if their baseline platelet count was 40-50 x 109 per liter. Procedures were scheduled for 10-13 days after treatment initiation.
“Platelet counts increased by [treatment] day 4, peaked at days 10-13, and then returned to baseline levels by day 35,” the researchers reported. Among ADAPT-1 patients with low baseline counts, 69% of avatrombopag recipients reached a prespecified target of at least 50 x 109 platelets per liter on their procedure day, versus 4% of placebo recipients (P less than .0001). Corresponding proportions in ADAPT-2 were 67% and 7%, respectively (P less than .0001). Among patients with higher baseline counts, 88% and 20% achieved the target, respectively, in ADAPT-1 (P less than .0001), as did 93% versus 39%, respectively, in ADAPT-2 (P less than .0001).
Avatrombopag and placebo produced similar rates of treatment-emergent adverse events. These most often consisted of abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache. Only three avatrombopag patients developed platelet counts above 200 x 109 per liter, and they all remained asymptomatic, the investigators said.
Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.
SOURCE: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.
Once-daily treatment with the oral second-generation thrombopoietin agonist avatrombopag (Doptelet) significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures, according to the results of two international, randomized, double-blind, phase III, placebo-controlled trials reported in the September issue of Gastroenterology.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia, versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group, versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).
These results led the Food and Drug Administration to approve avatrombopag in May 2018 under its priority review process. The novel therapy “may be a safe and effective alternative to platelet transfusions” that could simplify the clinical management of patients with chronic liver disease and thrombocytopenia, Norah Terrault, MD, MPH, and her associates wrote in Gastroenterology.
The ADAPT-1 study included 231 patients, while ADAPT-2 included 204 patients. In each trial, patients were randomized on a 2:1 basis to receive oral avatrombopag or placebo once daily for 5 consecutive days. Patients in the intervention arms received 60 mg avatrombopag if their baseline platelet count was less than 40 x 109 per liter, and 40 mg if their baseline platelet count was 40-50 x 109 per liter. Procedures were scheduled for 10-13 days after treatment initiation.
“Platelet counts increased by [treatment] day 4, peaked at days 10-13, and then returned to baseline levels by day 35,” the researchers reported. Among ADAPT-1 patients with low baseline counts, 69% of avatrombopag recipients reached a prespecified target of at least 50 x 109 platelets per liter on their procedure day, versus 4% of placebo recipients (P less than .0001). Corresponding proportions in ADAPT-2 were 67% and 7%, respectively (P less than .0001). Among patients with higher baseline counts, 88% and 20% achieved the target, respectively, in ADAPT-1 (P less than .0001), as did 93% versus 39%, respectively, in ADAPT-2 (P less than .0001).
Avatrombopag and placebo produced similar rates of treatment-emergent adverse events. These most often consisted of abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache. Only three avatrombopag patients developed platelet counts above 200 x 109 per liter, and they all remained asymptomatic, the investigators said.
Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.
SOURCE: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.
FROM GASTROENTEROLOGY
Key clinical point: Once-daily treatment with oral avatrombopag significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures.
Major finding: In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).
Study details: ADAPT-1 and ADAPT-2, international, randomized, double-blind, placebo-controlled, phase III trials.
Disclosures: Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, BMS, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.
Source: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.
ASCEND: Aspirin, fish oil flop in diabetes
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.
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
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.
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.
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
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.
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.
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
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.
REPORTING FROM THE ESC CONGRESS 2018
Key clinical point:
Major finding: Low-dose aspirin reduced the risk of serious vascular events by 12% versus placebo, but boosted major bleeding events by 29%.
Study details: This prospective, randomized trial included 15,480 patients with diabetes without known cardiovascular disease who were randomized to 100 mg/day of enteric-coated aspirin or placebo and 1 g/day of omega-3 fatty acids or placebo and followed for a mean of 7.4 years.
Disclosures: The 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. The presenters reported receiving research grants from the Medicines Company, Bayer, and Mylan.
Lorcaserin shows CV safety in CAMELLIA-TIMI 61
MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.
In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.
In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”
“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.
MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.
In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.
In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”
“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.
MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.
In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.
In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”
“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.
Lorcaserin shows CV safety in CAMELLIA-TIMI 61
Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.
Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.
In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.
In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”
“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.
The AGA Obesity Practice Guide provides physicians with a comprehensive, multi-disciplinary process to guide and personalize innovative obesity care for safe and effective weight management. Learn more at https://www.gastro.org/practice-guidance/practice-updates/obesity-practice-guide.
Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.
Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.
In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.
In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”
“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.
The AGA Obesity Practice Guide provides physicians with a comprehensive, multi-disciplinary process to guide and personalize innovative obesity care for safe and effective weight management. Learn more at https://www.gastro.org/practice-guidance/practice-updates/obesity-practice-guide.
Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.
Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.
In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.
In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”
“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.
The AGA Obesity Practice Guide provides physicians with a comprehensive, multi-disciplinary process to guide and personalize innovative obesity care for safe and effective weight management. Learn more at https://www.gastro.org/practice-guidance/practice-updates/obesity-practice-guide.
REPORTING FROM THE ESC CONGRESS 2018
Neural-tube defect signal from dolutegravir HIV treatment raises concerns
AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.
The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.
“Dolutegravir has been a beacon of hope for treating HIV,” said Maggie Little, PhD, a professor of philosophy and medical ethicist at Georgetown University in Washington. “Dolutegravir offers substantial benefits to quality of life in addition to reducing women’s mortality.” The new finding of excess NTDs “appears to pit pregnant women against their children. But the numbers never tell us the answer; it’s not arithmetic.” The appropriate public health response should focus on “supporting meaningful choice by women,” Dr. Little said during a talk at the session. “Policies must be made in ongoing consultation with communities of women who live with HIV.”
Rise of the INSTIs
The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.
Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).
Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.
One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.
Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.
The NTD data
The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.
A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).
When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.
During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.
Modeling the risks and benefits
Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.
The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.
Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”
“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.
The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.
Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”
Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.
The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.
“Dolutegravir has been a beacon of hope for treating HIV,” said Maggie Little, PhD, a professor of philosophy and medical ethicist at Georgetown University in Washington. “Dolutegravir offers substantial benefits to quality of life in addition to reducing women’s mortality.” The new finding of excess NTDs “appears to pit pregnant women against their children. But the numbers never tell us the answer; it’s not arithmetic.” The appropriate public health response should focus on “supporting meaningful choice by women,” Dr. Little said during a talk at the session. “Policies must be made in ongoing consultation with communities of women who live with HIV.”
Rise of the INSTIs
The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.
Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).
Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.
One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.
Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.
The NTD data
The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.
A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).
When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.
During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.
Modeling the risks and benefits
Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.
The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.
Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”
“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.
The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.
Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”
Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.
The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.
“Dolutegravir has been a beacon of hope for treating HIV,” said Maggie Little, PhD, a professor of philosophy and medical ethicist at Georgetown University in Washington. “Dolutegravir offers substantial benefits to quality of life in addition to reducing women’s mortality.” The new finding of excess NTDs “appears to pit pregnant women against their children. But the numbers never tell us the answer; it’s not arithmetic.” The appropriate public health response should focus on “supporting meaningful choice by women,” Dr. Little said during a talk at the session. “Policies must be made in ongoing consultation with communities of women who live with HIV.”
Rise of the INSTIs
The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.
Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).
Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.
One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.
Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.
The NTD data
The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.
A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).
When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.
During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.
Modeling the risks and benefits
Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.
The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.
Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”
“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.
The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.
Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”
Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
REPORTING FROM AIDS 2018
Signal strength may limit potency of CAR T-cell therapy
Contrary to what might be expected, chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model, investigators reported.
Intracellular signaling strength was a key determinant of T cell fate in the study, which was published in the journal Science Signaling.
By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.
Based on those findings, tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center, Seattle, Wash.
In a press conference, Mr. Salter described results of the study, which used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.
While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T cell signaling pathways, Mr. Salter said.
That overlap was somewhat surprising, according to Mr. Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.
“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Mr. Salter said.
The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor, but the speed and strength of signaling, he added. In particular, the CARs that evoked stronger signals also had increased T cell dysfunction, decreasing their potency in the mouse lymphoma model.
The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model of lymphoma; by contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, he said.
Those findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.
As part of the study, Mr. Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense. “This is a modification that we think should be considered in future CAR design,” Mr. Salter said.
While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at the efficacy, noted Stanley Riddell, MD, scientific director of the Immunotherapy Integrated Research Center at Fred Hutchinson Cancer Research Center.
“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said during the press conference. “But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”
Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics, and together with Mr. Salter, he has filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.
SOURCE: Salter AI et al., Sci Signal. 2018 Aug 21;11. pii:eaat6753.
Contrary to what might be expected, chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model, investigators reported.
Intracellular signaling strength was a key determinant of T cell fate in the study, which was published in the journal Science Signaling.
By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.
Based on those findings, tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center, Seattle, Wash.
In a press conference, Mr. Salter described results of the study, which used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.
While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T cell signaling pathways, Mr. Salter said.
That overlap was somewhat surprising, according to Mr. Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.
“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Mr. Salter said.
The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor, but the speed and strength of signaling, he added. In particular, the CARs that evoked stronger signals also had increased T cell dysfunction, decreasing their potency in the mouse lymphoma model.
The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model of lymphoma; by contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, he said.
Those findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.
As part of the study, Mr. Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense. “This is a modification that we think should be considered in future CAR design,” Mr. Salter said.
While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at the efficacy, noted Stanley Riddell, MD, scientific director of the Immunotherapy Integrated Research Center at Fred Hutchinson Cancer Research Center.
“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said during the press conference. “But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”
Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics, and together with Mr. Salter, he has filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.
SOURCE: Salter AI et al., Sci Signal. 2018 Aug 21;11. pii:eaat6753.
Contrary to what might be expected, chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model, investigators reported.
Intracellular signaling strength was a key determinant of T cell fate in the study, which was published in the journal Science Signaling.
By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.
Based on those findings, tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center, Seattle, Wash.
In a press conference, Mr. Salter described results of the study, which used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.
While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T cell signaling pathways, Mr. Salter said.
That overlap was somewhat surprising, according to Mr. Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.
“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Mr. Salter said.
The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor, but the speed and strength of signaling, he added. In particular, the CARs that evoked stronger signals also had increased T cell dysfunction, decreasing their potency in the mouse lymphoma model.
The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model of lymphoma; by contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, he said.
Those findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.
As part of the study, Mr. Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense. “This is a modification that we think should be considered in future CAR design,” Mr. Salter said.
While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at the efficacy, noted Stanley Riddell, MD, scientific director of the Immunotherapy Integrated Research Center at Fred Hutchinson Cancer Research Center.
“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said during the press conference. “But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”
Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics, and together with Mr. Salter, he has filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.
SOURCE: Salter AI et al., Sci Signal. 2018 Aug 21;11. pii:eaat6753.
FROM SCIENCE SIGNALING
Key clinical point:
Major finding: T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in a mouse model of lymphoma, while the 4-1BB CAR signal led to T cells that better retained their function in vivo and had a longer median survival in the model.
Study details: Analysis of CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells using mass spectrometry, plus analysis of efficacy in a mouse model of lymphoma.
Disclosures: Study authors reported disclosures related to Juno therapeutics and a patent application related to use of mutant CD28 CARs for cellular therapy.
Source: Salter AI et al., Sci Signal. 2018 Aug 21;11. pii:eaat6753.
The second victim: More ob.gyn. organizations recognize need for support
When Patrice Weiss, MD, was a resident, a healthy, low-risk patient underwent what should have been an uncomplicated vaginal hysterectomy. But the patient developed a series of postoperative complications leading to multisystem organ failure and a lengthy stay in intensive care.
“None of us could really figure out how this happened. I still can’t figure out how this person who was relatively young developed all these complications,” said Dr. Weiss, now chief medical officer of Carilion Clinic and professor of obstetrics and gynecology at Virginia Tech Carilion School of Medicine and Research Institute, both in Roanoke, Va. “There are times when you don’t know why something happened or what you could have done differently – and the answer may be nothing – but that dramatic, potentially very complicated outcome can really weigh on people. You still harbor those feelings of a second victim.”
It’s the health care professional who is that “second victim,” a term coined in 2000 by Albert W. Wu, MD, professor of public health at Johns Hopkins University, Baltimore, to describe an increasingly recognized phenomenon following unexpected adverse patient events, medical errors, or patient injuries (BMJ. 2000 Mar 18;320[7237]:726-7). The patients and their loved ones are the first victims, but a health care professional’s feelings of guilt, shame, inadequacy, and other powerful, complicated emotions can have long-lasting effects on his or her psyche, clinical practice, and career, particularly if he or she does not receive validation, support, and access to resources to work through the experience.
“Second victims ... become victimized in the sense that the provider is traumatized by the event,” Susan D. Scott, PhD, of the University of Missouri Health System, Columbia, and her colleagues wrote in a 2009 paper about the phenomenon (Qual Saf Health Care. 2009;18[5]:325-30). “Frequently, these individuals feel personally responsible for the patient outcome. Many feel as though they have failed the patient, second-guessing their clinical skills and knowledge base,” they said.
It’s that latter part that can fester and potentially poison a health care professional’s ability to function, according to Charlie Jaynes, MD, senior director of medical operations for Ob Hospitalist Group in Greenville, S.C.
“ and therefore can have a direct effect on patient care and lead to poor outcomes,” Dr. Jaynes said. “It’s a very dangerous phenomenon because it can degrade the quality of medical care provided.”
Most physicians are trained to internalize and compartmentalize these experiences, to “suck it up and get on with it,” he said, but it’s now become clear that such a strategy can have disastrous professional and personal consequences.
“In the worst case scenario, people burn out, drop out or commit suicide, their marriage ends up in shambles, or they turn to drugs and alcohol,” Dr. Jaynes said. “What Dr. Wu did was open the box to allow some empathy and compassion to be introduced to the situation.”
Dangers of unaddressed second victim impact
Estimates vary widely on the prevalence of second victim phenomenon among physicians and nurses who have been involved in a medical error or unexpected serious outcome. Across the medical field, estimates range from 10% in a study among otolaryngologists (Laryngoscope. 2006 Jul;116[7]:1114-20) to up to 30% and 50% more broadly, although some fields may be more susceptible than others (Jt Comm J Qual Patient Saf. 2010;36[5]:233-40; BMJ Qual Saf. 2012;21[4]:267-70).
“In the world of obstetrics, we spend 99.9% of our time in a happy field of medicine filled with joy and new life,” Dr. Weiss said. “Whether consciously or unconsciously, those become the expectations of the patients and the providers, so when there is an outcome that is less than optimal, that’s when you’re even more affected because of what your expectations are going into it.”
Dr. Scott and her colleagues noted that the stages of being a second victim are similar to the Kübler-Ross stages:
- Stage 1: Chaos and event repair.
- Stage 2: Intrusive thoughts, “what if.”
- Stage 3: Restoring personal identity.
- Stage 4: Enduring the inquisition.
- Stage 5: Obtaining emotional first aid.
- Stage 6: Moving on or dropping out; surviving and/or thriving.”
“This can go on for years. Someone can spend years just surviving and not thriving,” Dr. Weiss said. “It can really happen along a continuum.”
Although studies have not looked specifically at second victims and patient care, research has shown that second victims have a higher risk of burnout, and that physicians with high burnout tend to order more tests, spend less time with patients, and have greater risk of making medical errors, Dr. Weiss said.
A study looking at the emotional impact of medical errors on physicians found that 61% had greater anxiety about making future medical errors, 44% had a loss of confidence, 42% had trouble sleeping, and 42% were less satisfied in their job (Jt Comm J Qual Patient Saf. 2007;33[8]:467-76).
“You have the risk of the provider leaving medicine altogether or significantly changing their practice patterns, or giving up obstetric care because of the emotional toll it takes on providers,” she said. “We already know that one of the crises facing medicine right now is burnout, so you have the risk of additional or worsening burnout.”
Recognizing the need for formal support programs
Research does clearly show a need for programs formally addressing these experiences. A 2007 survey found that only 10% of 3,171 of internal medicine doctors, pediatricians, family physicians, and surgeons felt their health care organizations provided adequate support in managing stress following a medical error, yet about 8 in 10 wanted support (Jt Comm J Qual Patient Saf. 2007;33[8]:467-76).
Organizations are responding. One of the first second-victim programs is the “forYOU” program implemented at the University of Missouri Health Care’s Office of Clinical Effectiveness in 2007. The free, 24-7 program provides a “safe zone” for expressing emotions and reactions confidentially.
Ob Hospitalist Group just launched the CARE (Clinician Assistance, Recovery & Encouragement) Program, the first national peer-support program for second victims. The first 25 volunteers who underwent training in September will serve the organization’s more than 700 health care professionals across 32 states.
Instead of psychological counseling or intervention, the program emphasizes active listening, nonjudgment, and compassion during confidential calls; peers don’t take notes or record the conversations.
“We will be quiet and listen and speak at the appropriate times to be compassionate and not make judgments,” Dr. Jaynes said. “I think its critical to realize that in order to do that you have to be one of us. If you haven’t been there yourself when a baby dies in utero or you have a mother almost die by hemorrhage or a complication of surgery ... it creates emotional turmoil. Everybody who’s worth their salt questions, ‘What did I do wrong?’ and we’re really harsh on ourselves. If I can say I realize it’s a horrible place to be because I’ve been there myself, I can be a useful peer.”
At Dr. Weiss’s institution, Carilion Clinic spent 5 years developing and implementing the TRUST second-victim program, emphasizing Treatment, Respect, Understanding/compassion, Supportive care, and Transparency. Dr. Weiss said the first step in developing such a program is talking about the problem.
“You need hospital leadership addressing the phenomenon of the second victim, recognizing it is real, that it’s not a sign of weakness for providers to have any of these signs,” she said. “It has to be done at an organizational level. There has to be a place where providers can talk freely about the emotional impact of the outcome, not just the clinical outcomes.”
Johns Hopkins Hospital in Baltimore published findings in September 2017 about its program RISE (Resilience In Stressful Events) (Jt Comm J Qual Patient Saf. 2017 Sep;43[9]:471-83 that was featured by the Joint Commission as a program that employs some of the tools the commission describes in its toolkit for health care organizations to develop second-victim support programs (Jt Comm J Qual Patient Saf. 2012 May;38[5]:235-40, 193).
It’s important that health care professionals are not expected or required to seek counseling or similar interventions, Dr. Weiss said, but they know of available resources.
“People need to be able to talk about it when they’re ready. It doesn’t necessarily matter how your peers judge your actions because these are feelings that come from within,” Dr. Weiss said, although colleagues can validate a second victim’s experience or feelings by sharing their own.
“It’s helpful when someone in a leadership role can acknowledge that this is real and say to a provider, ‘I’ve been there, and this is what helped me,’ or ‘I’ve been there, and there was no resource and I went without help for years,’ ” she said.
In fact, it’s her own past experiences that have made Dr. Weiss so passionate about raising awareness about second victims.
“I’ve been involved in cases of unanticipated outcomes and personally witnessed medical errors, and I’ve seen how very close colleagues can be affected,” she said. “This is a topic that really, really hits home for me.”
Signs and symptoms: How to recognize a possible second victim
Anyone can become a second victim, regardless of their training, experience, or years of practice, Dr. Weiss said. A health care professional may practice for years and witness many unanticipated poor outcomes before one suddenly drums up feelings they don’t expect.
“It’s almost inevitable that providers are going to have unanticipated outcomes or unexpected outcomes,” Dr. Weiss said. “The challenge with the second victim is no one can ever predict how someone is going to respond to an outcome, including ourselves. This may be the first time they have a response to something they never saw coming.”
Two aspects correlated with a higher risk of second victim are the severity of the morbidity or mortality of the patient and the degree of personal responsibility the health care professional feels. The signs and symptoms of being a second victim can be indistinguishable from those of depression, anxiety, or posttraumatic stress syndrome, but the biggest indicator is a change in a person’s normal behavior, Dr. Weiss said.
“The person who is never late to work is late to work. The person who is always mild-mannered is on edge,” she said. “A lot of it is subtle personality or behavior changes, or you begin to notice practice pattern differences, such as ordering a bunch of labs.”
Perhaps the providers are snapping at people when they’ve never snapped before, or they express more cynicism or sarcasm, she added. “A change in their sleeping or eating patterns or in their personal hygiene are all things that one could look for.”
According to Dr. Jaynes, emotional signs may include irritability, fear, anger, grief, remorse, frustration, desperation, numbness, guilt, loneliness, shock and feeling disconnected, feeling hopeless or out of control. Physical symptoms include headaches, muscle tension, chest pain, extreme fatigue, sleeping problems, appetite changes or gastrointestinal symptoms, dizziness, frequent illnesses, being easily startled, or increased heart rate, blood pressure, or breathing rate. Other possible signs include flashbacks, nightmares, social avoidance, difficulties concentrating, poor memory, avoiding patient care areas, fearing repercussions to their reputations, and decreased job satisfaction. Second victims also may experience a loss in confidence or spiritual connection, or loss of interest in work, usual activities, and connections with others.
Dr. Weiss and Dr. Jaynes said they had no relevant financial disclosures.
When Patrice Weiss, MD, was a resident, a healthy, low-risk patient underwent what should have been an uncomplicated vaginal hysterectomy. But the patient developed a series of postoperative complications leading to multisystem organ failure and a lengthy stay in intensive care.
“None of us could really figure out how this happened. I still can’t figure out how this person who was relatively young developed all these complications,” said Dr. Weiss, now chief medical officer of Carilion Clinic and professor of obstetrics and gynecology at Virginia Tech Carilion School of Medicine and Research Institute, both in Roanoke, Va. “There are times when you don’t know why something happened or what you could have done differently – and the answer may be nothing – but that dramatic, potentially very complicated outcome can really weigh on people. You still harbor those feelings of a second victim.”
It’s the health care professional who is that “second victim,” a term coined in 2000 by Albert W. Wu, MD, professor of public health at Johns Hopkins University, Baltimore, to describe an increasingly recognized phenomenon following unexpected adverse patient events, medical errors, or patient injuries (BMJ. 2000 Mar 18;320[7237]:726-7). The patients and their loved ones are the first victims, but a health care professional’s feelings of guilt, shame, inadequacy, and other powerful, complicated emotions can have long-lasting effects on his or her psyche, clinical practice, and career, particularly if he or she does not receive validation, support, and access to resources to work through the experience.
“Second victims ... become victimized in the sense that the provider is traumatized by the event,” Susan D. Scott, PhD, of the University of Missouri Health System, Columbia, and her colleagues wrote in a 2009 paper about the phenomenon (Qual Saf Health Care. 2009;18[5]:325-30). “Frequently, these individuals feel personally responsible for the patient outcome. Many feel as though they have failed the patient, second-guessing their clinical skills and knowledge base,” they said.
It’s that latter part that can fester and potentially poison a health care professional’s ability to function, according to Charlie Jaynes, MD, senior director of medical operations for Ob Hospitalist Group in Greenville, S.C.
“ and therefore can have a direct effect on patient care and lead to poor outcomes,” Dr. Jaynes said. “It’s a very dangerous phenomenon because it can degrade the quality of medical care provided.”
Most physicians are trained to internalize and compartmentalize these experiences, to “suck it up and get on with it,” he said, but it’s now become clear that such a strategy can have disastrous professional and personal consequences.
“In the worst case scenario, people burn out, drop out or commit suicide, their marriage ends up in shambles, or they turn to drugs and alcohol,” Dr. Jaynes said. “What Dr. Wu did was open the box to allow some empathy and compassion to be introduced to the situation.”
Dangers of unaddressed second victim impact
Estimates vary widely on the prevalence of second victim phenomenon among physicians and nurses who have been involved in a medical error or unexpected serious outcome. Across the medical field, estimates range from 10% in a study among otolaryngologists (Laryngoscope. 2006 Jul;116[7]:1114-20) to up to 30% and 50% more broadly, although some fields may be more susceptible than others (Jt Comm J Qual Patient Saf. 2010;36[5]:233-40; BMJ Qual Saf. 2012;21[4]:267-70).
“In the world of obstetrics, we spend 99.9% of our time in a happy field of medicine filled with joy and new life,” Dr. Weiss said. “Whether consciously or unconsciously, those become the expectations of the patients and the providers, so when there is an outcome that is less than optimal, that’s when you’re even more affected because of what your expectations are going into it.”
Dr. Scott and her colleagues noted that the stages of being a second victim are similar to the Kübler-Ross stages:
- Stage 1: Chaos and event repair.
- Stage 2: Intrusive thoughts, “what if.”
- Stage 3: Restoring personal identity.
- Stage 4: Enduring the inquisition.
- Stage 5: Obtaining emotional first aid.
- Stage 6: Moving on or dropping out; surviving and/or thriving.”
“This can go on for years. Someone can spend years just surviving and not thriving,” Dr. Weiss said. “It can really happen along a continuum.”
Although studies have not looked specifically at second victims and patient care, research has shown that second victims have a higher risk of burnout, and that physicians with high burnout tend to order more tests, spend less time with patients, and have greater risk of making medical errors, Dr. Weiss said.
A study looking at the emotional impact of medical errors on physicians found that 61% had greater anxiety about making future medical errors, 44% had a loss of confidence, 42% had trouble sleeping, and 42% were less satisfied in their job (Jt Comm J Qual Patient Saf. 2007;33[8]:467-76).
“You have the risk of the provider leaving medicine altogether or significantly changing their practice patterns, or giving up obstetric care because of the emotional toll it takes on providers,” she said. “We already know that one of the crises facing medicine right now is burnout, so you have the risk of additional or worsening burnout.”
Recognizing the need for formal support programs
Research does clearly show a need for programs formally addressing these experiences. A 2007 survey found that only 10% of 3,171 of internal medicine doctors, pediatricians, family physicians, and surgeons felt their health care organizations provided adequate support in managing stress following a medical error, yet about 8 in 10 wanted support (Jt Comm J Qual Patient Saf. 2007;33[8]:467-76).
Organizations are responding. One of the first second-victim programs is the “forYOU” program implemented at the University of Missouri Health Care’s Office of Clinical Effectiveness in 2007. The free, 24-7 program provides a “safe zone” for expressing emotions and reactions confidentially.
Ob Hospitalist Group just launched the CARE (Clinician Assistance, Recovery & Encouragement) Program, the first national peer-support program for second victims. The first 25 volunteers who underwent training in September will serve the organization’s more than 700 health care professionals across 32 states.
Instead of psychological counseling or intervention, the program emphasizes active listening, nonjudgment, and compassion during confidential calls; peers don’t take notes or record the conversations.
“We will be quiet and listen and speak at the appropriate times to be compassionate and not make judgments,” Dr. Jaynes said. “I think its critical to realize that in order to do that you have to be one of us. If you haven’t been there yourself when a baby dies in utero or you have a mother almost die by hemorrhage or a complication of surgery ... it creates emotional turmoil. Everybody who’s worth their salt questions, ‘What did I do wrong?’ and we’re really harsh on ourselves. If I can say I realize it’s a horrible place to be because I’ve been there myself, I can be a useful peer.”
At Dr. Weiss’s institution, Carilion Clinic spent 5 years developing and implementing the TRUST second-victim program, emphasizing Treatment, Respect, Understanding/compassion, Supportive care, and Transparency. Dr. Weiss said the first step in developing such a program is talking about the problem.
“You need hospital leadership addressing the phenomenon of the second victim, recognizing it is real, that it’s not a sign of weakness for providers to have any of these signs,” she said. “It has to be done at an organizational level. There has to be a place where providers can talk freely about the emotional impact of the outcome, not just the clinical outcomes.”
Johns Hopkins Hospital in Baltimore published findings in September 2017 about its program RISE (Resilience In Stressful Events) (Jt Comm J Qual Patient Saf. 2017 Sep;43[9]:471-83 that was featured by the Joint Commission as a program that employs some of the tools the commission describes in its toolkit for health care organizations to develop second-victim support programs (Jt Comm J Qual Patient Saf. 2012 May;38[5]:235-40, 193).
It’s important that health care professionals are not expected or required to seek counseling or similar interventions, Dr. Weiss said, but they know of available resources.
“People need to be able to talk about it when they’re ready. It doesn’t necessarily matter how your peers judge your actions because these are feelings that come from within,” Dr. Weiss said, although colleagues can validate a second victim’s experience or feelings by sharing their own.
“It’s helpful when someone in a leadership role can acknowledge that this is real and say to a provider, ‘I’ve been there, and this is what helped me,’ or ‘I’ve been there, and there was no resource and I went without help for years,’ ” she said.
In fact, it’s her own past experiences that have made Dr. Weiss so passionate about raising awareness about second victims.
“I’ve been involved in cases of unanticipated outcomes and personally witnessed medical errors, and I’ve seen how very close colleagues can be affected,” she said. “This is a topic that really, really hits home for me.”
Signs and symptoms: How to recognize a possible second victim
Anyone can become a second victim, regardless of their training, experience, or years of practice, Dr. Weiss said. A health care professional may practice for years and witness many unanticipated poor outcomes before one suddenly drums up feelings they don’t expect.
“It’s almost inevitable that providers are going to have unanticipated outcomes or unexpected outcomes,” Dr. Weiss said. “The challenge with the second victim is no one can ever predict how someone is going to respond to an outcome, including ourselves. This may be the first time they have a response to something they never saw coming.”
Two aspects correlated with a higher risk of second victim are the severity of the morbidity or mortality of the patient and the degree of personal responsibility the health care professional feels. The signs and symptoms of being a second victim can be indistinguishable from those of depression, anxiety, or posttraumatic stress syndrome, but the biggest indicator is a change in a person’s normal behavior, Dr. Weiss said.
“The person who is never late to work is late to work. The person who is always mild-mannered is on edge,” she said. “A lot of it is subtle personality or behavior changes, or you begin to notice practice pattern differences, such as ordering a bunch of labs.”
Perhaps the providers are snapping at people when they’ve never snapped before, or they express more cynicism or sarcasm, she added. “A change in their sleeping or eating patterns or in their personal hygiene are all things that one could look for.”
According to Dr. Jaynes, emotional signs may include irritability, fear, anger, grief, remorse, frustration, desperation, numbness, guilt, loneliness, shock and feeling disconnected, feeling hopeless or out of control. Physical symptoms include headaches, muscle tension, chest pain, extreme fatigue, sleeping problems, appetite changes or gastrointestinal symptoms, dizziness, frequent illnesses, being easily startled, or increased heart rate, blood pressure, or breathing rate. Other possible signs include flashbacks, nightmares, social avoidance, difficulties concentrating, poor memory, avoiding patient care areas, fearing repercussions to their reputations, and decreased job satisfaction. Second victims also may experience a loss in confidence or spiritual connection, or loss of interest in work, usual activities, and connections with others.
Dr. Weiss and Dr. Jaynes said they had no relevant financial disclosures.
When Patrice Weiss, MD, was a resident, a healthy, low-risk patient underwent what should have been an uncomplicated vaginal hysterectomy. But the patient developed a series of postoperative complications leading to multisystem organ failure and a lengthy stay in intensive care.
“None of us could really figure out how this happened. I still can’t figure out how this person who was relatively young developed all these complications,” said Dr. Weiss, now chief medical officer of Carilion Clinic and professor of obstetrics and gynecology at Virginia Tech Carilion School of Medicine and Research Institute, both in Roanoke, Va. “There are times when you don’t know why something happened or what you could have done differently – and the answer may be nothing – but that dramatic, potentially very complicated outcome can really weigh on people. You still harbor those feelings of a second victim.”
It’s the health care professional who is that “second victim,” a term coined in 2000 by Albert W. Wu, MD, professor of public health at Johns Hopkins University, Baltimore, to describe an increasingly recognized phenomenon following unexpected adverse patient events, medical errors, or patient injuries (BMJ. 2000 Mar 18;320[7237]:726-7). The patients and their loved ones are the first victims, but a health care professional’s feelings of guilt, shame, inadequacy, and other powerful, complicated emotions can have long-lasting effects on his or her psyche, clinical practice, and career, particularly if he or she does not receive validation, support, and access to resources to work through the experience.
“Second victims ... become victimized in the sense that the provider is traumatized by the event,” Susan D. Scott, PhD, of the University of Missouri Health System, Columbia, and her colleagues wrote in a 2009 paper about the phenomenon (Qual Saf Health Care. 2009;18[5]:325-30). “Frequently, these individuals feel personally responsible for the patient outcome. Many feel as though they have failed the patient, second-guessing their clinical skills and knowledge base,” they said.
It’s that latter part that can fester and potentially poison a health care professional’s ability to function, according to Charlie Jaynes, MD, senior director of medical operations for Ob Hospitalist Group in Greenville, S.C.
“ and therefore can have a direct effect on patient care and lead to poor outcomes,” Dr. Jaynes said. “It’s a very dangerous phenomenon because it can degrade the quality of medical care provided.”
Most physicians are trained to internalize and compartmentalize these experiences, to “suck it up and get on with it,” he said, but it’s now become clear that such a strategy can have disastrous professional and personal consequences.
“In the worst case scenario, people burn out, drop out or commit suicide, their marriage ends up in shambles, or they turn to drugs and alcohol,” Dr. Jaynes said. “What Dr. Wu did was open the box to allow some empathy and compassion to be introduced to the situation.”
Dangers of unaddressed second victim impact
Estimates vary widely on the prevalence of second victim phenomenon among physicians and nurses who have been involved in a medical error or unexpected serious outcome. Across the medical field, estimates range from 10% in a study among otolaryngologists (Laryngoscope. 2006 Jul;116[7]:1114-20) to up to 30% and 50% more broadly, although some fields may be more susceptible than others (Jt Comm J Qual Patient Saf. 2010;36[5]:233-40; BMJ Qual Saf. 2012;21[4]:267-70).
“In the world of obstetrics, we spend 99.9% of our time in a happy field of medicine filled with joy and new life,” Dr. Weiss said. “Whether consciously or unconsciously, those become the expectations of the patients and the providers, so when there is an outcome that is less than optimal, that’s when you’re even more affected because of what your expectations are going into it.”
Dr. Scott and her colleagues noted that the stages of being a second victim are similar to the Kübler-Ross stages:
- Stage 1: Chaos and event repair.
- Stage 2: Intrusive thoughts, “what if.”
- Stage 3: Restoring personal identity.
- Stage 4: Enduring the inquisition.
- Stage 5: Obtaining emotional first aid.
- Stage 6: Moving on or dropping out; surviving and/or thriving.”
“This can go on for years. Someone can spend years just surviving and not thriving,” Dr. Weiss said. “It can really happen along a continuum.”
Although studies have not looked specifically at second victims and patient care, research has shown that second victims have a higher risk of burnout, and that physicians with high burnout tend to order more tests, spend less time with patients, and have greater risk of making medical errors, Dr. Weiss said.
A study looking at the emotional impact of medical errors on physicians found that 61% had greater anxiety about making future medical errors, 44% had a loss of confidence, 42% had trouble sleeping, and 42% were less satisfied in their job (Jt Comm J Qual Patient Saf. 2007;33[8]:467-76).
“You have the risk of the provider leaving medicine altogether or significantly changing their practice patterns, or giving up obstetric care because of the emotional toll it takes on providers,” she said. “We already know that one of the crises facing medicine right now is burnout, so you have the risk of additional or worsening burnout.”
Recognizing the need for formal support programs
Research does clearly show a need for programs formally addressing these experiences. A 2007 survey found that only 10% of 3,171 of internal medicine doctors, pediatricians, family physicians, and surgeons felt their health care organizations provided adequate support in managing stress following a medical error, yet about 8 in 10 wanted support (Jt Comm J Qual Patient Saf. 2007;33[8]:467-76).
Organizations are responding. One of the first second-victim programs is the “forYOU” program implemented at the University of Missouri Health Care’s Office of Clinical Effectiveness in 2007. The free, 24-7 program provides a “safe zone” for expressing emotions and reactions confidentially.
Ob Hospitalist Group just launched the CARE (Clinician Assistance, Recovery & Encouragement) Program, the first national peer-support program for second victims. The first 25 volunteers who underwent training in September will serve the organization’s more than 700 health care professionals across 32 states.
Instead of psychological counseling or intervention, the program emphasizes active listening, nonjudgment, and compassion during confidential calls; peers don’t take notes or record the conversations.
“We will be quiet and listen and speak at the appropriate times to be compassionate and not make judgments,” Dr. Jaynes said. “I think its critical to realize that in order to do that you have to be one of us. If you haven’t been there yourself when a baby dies in utero or you have a mother almost die by hemorrhage or a complication of surgery ... it creates emotional turmoil. Everybody who’s worth their salt questions, ‘What did I do wrong?’ and we’re really harsh on ourselves. If I can say I realize it’s a horrible place to be because I’ve been there myself, I can be a useful peer.”
At Dr. Weiss’s institution, Carilion Clinic spent 5 years developing and implementing the TRUST second-victim program, emphasizing Treatment, Respect, Understanding/compassion, Supportive care, and Transparency. Dr. Weiss said the first step in developing such a program is talking about the problem.
“You need hospital leadership addressing the phenomenon of the second victim, recognizing it is real, that it’s not a sign of weakness for providers to have any of these signs,” she said. “It has to be done at an organizational level. There has to be a place where providers can talk freely about the emotional impact of the outcome, not just the clinical outcomes.”
Johns Hopkins Hospital in Baltimore published findings in September 2017 about its program RISE (Resilience In Stressful Events) (Jt Comm J Qual Patient Saf. 2017 Sep;43[9]:471-83 that was featured by the Joint Commission as a program that employs some of the tools the commission describes in its toolkit for health care organizations to develop second-victim support programs (Jt Comm J Qual Patient Saf. 2012 May;38[5]:235-40, 193).
It’s important that health care professionals are not expected or required to seek counseling or similar interventions, Dr. Weiss said, but they know of available resources.
“People need to be able to talk about it when they’re ready. It doesn’t necessarily matter how your peers judge your actions because these are feelings that come from within,” Dr. Weiss said, although colleagues can validate a second victim’s experience or feelings by sharing their own.
“It’s helpful when someone in a leadership role can acknowledge that this is real and say to a provider, ‘I’ve been there, and this is what helped me,’ or ‘I’ve been there, and there was no resource and I went without help for years,’ ” she said.
In fact, it’s her own past experiences that have made Dr. Weiss so passionate about raising awareness about second victims.
“I’ve been involved in cases of unanticipated outcomes and personally witnessed medical errors, and I’ve seen how very close colleagues can be affected,” she said. “This is a topic that really, really hits home for me.”
Signs and symptoms: How to recognize a possible second victim
Anyone can become a second victim, regardless of their training, experience, or years of practice, Dr. Weiss said. A health care professional may practice for years and witness many unanticipated poor outcomes before one suddenly drums up feelings they don’t expect.
“It’s almost inevitable that providers are going to have unanticipated outcomes or unexpected outcomes,” Dr. Weiss said. “The challenge with the second victim is no one can ever predict how someone is going to respond to an outcome, including ourselves. This may be the first time they have a response to something they never saw coming.”
Two aspects correlated with a higher risk of second victim are the severity of the morbidity or mortality of the patient and the degree of personal responsibility the health care professional feels. The signs and symptoms of being a second victim can be indistinguishable from those of depression, anxiety, or posttraumatic stress syndrome, but the biggest indicator is a change in a person’s normal behavior, Dr. Weiss said.
“The person who is never late to work is late to work. The person who is always mild-mannered is on edge,” she said. “A lot of it is subtle personality or behavior changes, or you begin to notice practice pattern differences, such as ordering a bunch of labs.”
Perhaps the providers are snapping at people when they’ve never snapped before, or they express more cynicism or sarcasm, she added. “A change in their sleeping or eating patterns or in their personal hygiene are all things that one could look for.”
According to Dr. Jaynes, emotional signs may include irritability, fear, anger, grief, remorse, frustration, desperation, numbness, guilt, loneliness, shock and feeling disconnected, feeling hopeless or out of control. Physical symptoms include headaches, muscle tension, chest pain, extreme fatigue, sleeping problems, appetite changes or gastrointestinal symptoms, dizziness, frequent illnesses, being easily startled, or increased heart rate, blood pressure, or breathing rate. Other possible signs include flashbacks, nightmares, social avoidance, difficulties concentrating, poor memory, avoiding patient care areas, fearing repercussions to their reputations, and decreased job satisfaction. Second victims also may experience a loss in confidence or spiritual connection, or loss of interest in work, usual activities, and connections with others.
Dr. Weiss and Dr. Jaynes said they had no relevant financial disclosures.
Climbing the therapeutic ladder in eczema-related itch
WASHINGTON – Currently available including antihistamines and an oral antiemetic approved for preventing chemotherapy-related nausea and vomiting, Peter Lio, MD, said at a symposium presented by the Coalition United for Better Eczema Care (CUBE-C).
There are four basic areas of treatment, which Dr. Lio, a dermatologist at Northwestern University, Chicago, referred to as the “itch therapeutic ladder.” In a video interview at the meeting, he reviewed the treatments, starting with topical therapies, which include camphor and menthol, strontium-containing topicals, as well as “dilute bleach-type products” that seem to have some anti-inflammatory and anti-itch effects.
The next levels: oral medications – antihistamines, followed by “more intense” options that may carry more risks, such as the antidepressant mirtazapine, and aprepitant, a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced and postoperative nausea and vomiting. Gabapentin and naltrexone can also be helpful for certain populations; all are used off-label, he pointed out.
Dr. Lio, formally trained in acupuncture, often uses alternative therapies as the fourth rung of the ladder. These include using a specific acupressure point, which he said “seems to give a little bit of relief.”
In the interview, he also discussed considerations in children with atopic dermatitis and exciting treatments in development, such as biologics that target “one of the master itch cytokines,” interleukin-31.
“Itch is such an important part of this disease because we know not only is it one of the key pieces that pushes the disease forward and keeps these cycles going, but also contributes a huge amount to the morbidity,” he said.
CUBE-C, established by the National Eczema Association (NEA), is a “network of cross-specialty leaders, patients and caregivers, constructing an educational curriculum based on standards of effective treatment and disease management,” according to the NEA.
The symposium was supported by an educational grant from Sanofi Genzyme, Regeneron Pharmaceuticals, and Pfizer. Dr. Lio reported serving as a speaker, consultant, and/or advisor for companies developing and marketing atopic dermatitis therapies and products.
WASHINGTON – Currently available including antihistamines and an oral antiemetic approved for preventing chemotherapy-related nausea and vomiting, Peter Lio, MD, said at a symposium presented by the Coalition United for Better Eczema Care (CUBE-C).
There are four basic areas of treatment, which Dr. Lio, a dermatologist at Northwestern University, Chicago, referred to as the “itch therapeutic ladder.” In a video interview at the meeting, he reviewed the treatments, starting with topical therapies, which include camphor and menthol, strontium-containing topicals, as well as “dilute bleach-type products” that seem to have some anti-inflammatory and anti-itch effects.
The next levels: oral medications – antihistamines, followed by “more intense” options that may carry more risks, such as the antidepressant mirtazapine, and aprepitant, a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced and postoperative nausea and vomiting. Gabapentin and naltrexone can also be helpful for certain populations; all are used off-label, he pointed out.
Dr. Lio, formally trained in acupuncture, often uses alternative therapies as the fourth rung of the ladder. These include using a specific acupressure point, which he said “seems to give a little bit of relief.”
In the interview, he also discussed considerations in children with atopic dermatitis and exciting treatments in development, such as biologics that target “one of the master itch cytokines,” interleukin-31.
“Itch is such an important part of this disease because we know not only is it one of the key pieces that pushes the disease forward and keeps these cycles going, but also contributes a huge amount to the morbidity,” he said.
CUBE-C, established by the National Eczema Association (NEA), is a “network of cross-specialty leaders, patients and caregivers, constructing an educational curriculum based on standards of effective treatment and disease management,” according to the NEA.
The symposium was supported by an educational grant from Sanofi Genzyme, Regeneron Pharmaceuticals, and Pfizer. Dr. Lio reported serving as a speaker, consultant, and/or advisor for companies developing and marketing atopic dermatitis therapies and products.
WASHINGTON – Currently available including antihistamines and an oral antiemetic approved for preventing chemotherapy-related nausea and vomiting, Peter Lio, MD, said at a symposium presented by the Coalition United for Better Eczema Care (CUBE-C).
There are four basic areas of treatment, which Dr. Lio, a dermatologist at Northwestern University, Chicago, referred to as the “itch therapeutic ladder.” In a video interview at the meeting, he reviewed the treatments, starting with topical therapies, which include camphor and menthol, strontium-containing topicals, as well as “dilute bleach-type products” that seem to have some anti-inflammatory and anti-itch effects.
The next levels: oral medications – antihistamines, followed by “more intense” options that may carry more risks, such as the antidepressant mirtazapine, and aprepitant, a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced and postoperative nausea and vomiting. Gabapentin and naltrexone can also be helpful for certain populations; all are used off-label, he pointed out.
Dr. Lio, formally trained in acupuncture, often uses alternative therapies as the fourth rung of the ladder. These include using a specific acupressure point, which he said “seems to give a little bit of relief.”
In the interview, he also discussed considerations in children with atopic dermatitis and exciting treatments in development, such as biologics that target “one of the master itch cytokines,” interleukin-31.
“Itch is such an important part of this disease because we know not only is it one of the key pieces that pushes the disease forward and keeps these cycles going, but also contributes a huge amount to the morbidity,” he said.
CUBE-C, established by the National Eczema Association (NEA), is a “network of cross-specialty leaders, patients and caregivers, constructing an educational curriculum based on standards of effective treatment and disease management,” according to the NEA.
The symposium was supported by an educational grant from Sanofi Genzyme, Regeneron Pharmaceuticals, and Pfizer. Dr. Lio reported serving as a speaker, consultant, and/or advisor for companies developing and marketing atopic dermatitis therapies and products.
CUBE-C initiative aims to educate about atopic dermatitis
WASHINGTON – The National Eczema Association (NEA) has established the Coalition United for Better Eczema Care (CUBE-C) to provide practitioners with a resource for “trustworthy, up-to-date, state of the art” information on atopic dermatitis, with the goal of improving health outcomes, according to Julie Block, president and chief executive officer of the NEA.
In an interview at a symposium presented by CUBE-C, Ms. Block provided more information on CUBE-C, including how and why it started and what it can offer to dermatologists, as well as primary care physicians, who care for patients with atopic dermatitis. She said that the NEA convened dermatologists, allergists, immunologists, psychologists, nurse practitioners, physician assistants, and patients “to design a curriculum that provided an entire picture of the patient experience, so that we could go out and educate not only on the basics of eczema and atopic dermatitis for a variety of practitioners ... but also for the specialists who are now going to be engaging in new innovations and new therapies for their patients.”
She was joined by Adam Friedman, MD, professor of dermatology and residency program director at George Washington University, Washington, where the symposium, a resident’s boot camp, was held. The boot camp was somewhat unique in that it was geared more towards trainees; typically, the CUBE-C program is a CME program for practitioners, but this reflects the flexibility of the program, which can be tailored to the audience, Dr. Friedman pointed out. “The hope is that programs like these pop up all over the place ... anywhere you have a critical mass of individuals who want to learn about this,” where planners can choose from a menu of topics provided by CUBE-C – which include therapeutics, infections, pathogenesis, and access to care – and “easily formulate a conference like we held here today for the right audience.”
Topics covered at the George Washington University symposium included the impact of climate on the prevalence of childhood eczema, the diagnosis and differential diagnosis in children, infections in atopic dermatitis patients, and itch treatment.
More information on CUBE-C is available on the NEA website.
The symposium was supported by an educational grant from Sanofi Genzyme, Regeneron Pharmaceuticals, and Pfizer. Dr. Friedman reported serving as a speaker for Regeneron, Pfizer, and other companies. He also consults and serves on the advisory board for Pfizer and multiple other companies developing and marketing atopic dermatitis therapies and products.
WASHINGTON – The National Eczema Association (NEA) has established the Coalition United for Better Eczema Care (CUBE-C) to provide practitioners with a resource for “trustworthy, up-to-date, state of the art” information on atopic dermatitis, with the goal of improving health outcomes, according to Julie Block, president and chief executive officer of the NEA.
In an interview at a symposium presented by CUBE-C, Ms. Block provided more information on CUBE-C, including how and why it started and what it can offer to dermatologists, as well as primary care physicians, who care for patients with atopic dermatitis. She said that the NEA convened dermatologists, allergists, immunologists, psychologists, nurse practitioners, physician assistants, and patients “to design a curriculum that provided an entire picture of the patient experience, so that we could go out and educate not only on the basics of eczema and atopic dermatitis for a variety of practitioners ... but also for the specialists who are now going to be engaging in new innovations and new therapies for their patients.”
She was joined by Adam Friedman, MD, professor of dermatology and residency program director at George Washington University, Washington, where the symposium, a resident’s boot camp, was held. The boot camp was somewhat unique in that it was geared more towards trainees; typically, the CUBE-C program is a CME program for practitioners, but this reflects the flexibility of the program, which can be tailored to the audience, Dr. Friedman pointed out. “The hope is that programs like these pop up all over the place ... anywhere you have a critical mass of individuals who want to learn about this,” where planners can choose from a menu of topics provided by CUBE-C – which include therapeutics, infections, pathogenesis, and access to care – and “easily formulate a conference like we held here today for the right audience.”
Topics covered at the George Washington University symposium included the impact of climate on the prevalence of childhood eczema, the diagnosis and differential diagnosis in children, infections in atopic dermatitis patients, and itch treatment.
More information on CUBE-C is available on the NEA website.
The symposium was supported by an educational grant from Sanofi Genzyme, Regeneron Pharmaceuticals, and Pfizer. Dr. Friedman reported serving as a speaker for Regeneron, Pfizer, and other companies. He also consults and serves on the advisory board for Pfizer and multiple other companies developing and marketing atopic dermatitis therapies and products.
WASHINGTON – The National Eczema Association (NEA) has established the Coalition United for Better Eczema Care (CUBE-C) to provide practitioners with a resource for “trustworthy, up-to-date, state of the art” information on atopic dermatitis, with the goal of improving health outcomes, according to Julie Block, president and chief executive officer of the NEA.
In an interview at a symposium presented by CUBE-C, Ms. Block provided more information on CUBE-C, including how and why it started and what it can offer to dermatologists, as well as primary care physicians, who care for patients with atopic dermatitis. She said that the NEA convened dermatologists, allergists, immunologists, psychologists, nurse practitioners, physician assistants, and patients “to design a curriculum that provided an entire picture of the patient experience, so that we could go out and educate not only on the basics of eczema and atopic dermatitis for a variety of practitioners ... but also for the specialists who are now going to be engaging in new innovations and new therapies for their patients.”
She was joined by Adam Friedman, MD, professor of dermatology and residency program director at George Washington University, Washington, where the symposium, a resident’s boot camp, was held. The boot camp was somewhat unique in that it was geared more towards trainees; typically, the CUBE-C program is a CME program for practitioners, but this reflects the flexibility of the program, which can be tailored to the audience, Dr. Friedman pointed out. “The hope is that programs like these pop up all over the place ... anywhere you have a critical mass of individuals who want to learn about this,” where planners can choose from a menu of topics provided by CUBE-C – which include therapeutics, infections, pathogenesis, and access to care – and “easily formulate a conference like we held here today for the right audience.”
Topics covered at the George Washington University symposium included the impact of climate on the prevalence of childhood eczema, the diagnosis and differential diagnosis in children, infections in atopic dermatitis patients, and itch treatment.
More information on CUBE-C is available on the NEA website.
The symposium was supported by an educational grant from Sanofi Genzyme, Regeneron Pharmaceuticals, and Pfizer. Dr. Friedman reported serving as a speaker for Regeneron, Pfizer, and other companies. He also consults and serves on the advisory board for Pfizer and multiple other companies developing and marketing atopic dermatitis therapies and products.
