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Precision CAD testing shows 70% cut in composite risk at 1 year
Benefits accrue on multiple endpoints
CHICAGO – A stepwise care pathway was associated with a substantial reduction in the number of invasive tests performed and a major improvement in outcomes, relative to usual management, in patients suspected of coronary artery disease (CAD), according to 1-year results of the multinational, randomized PRECISE trial.
The care pathway is appropriate for patients with nonacute chest pain or equivalent complaints that have raised suspicion of CAD, and it is extremely simple, according to the description from the principal investigator, Pamela S. Douglas, MD, given in her presentation at the annual scientific sessions of the American Heart Association.
Unlike the highly complex diagnostic algorithms shunting suspected CAD patients to the vast array of potential evaluations, the newly tested protocol, characterized as a “precision strategy,” divides patients into those who are immediate candidates for invasive testing and those who are not. The discriminator is the PROMISE minimal risk assessment score, a tool already validated.
Those deemed candidates for testing on the basis of an elevated score undergo computed coronary CT angiography (cCTA). In those who are not, testing is deferred.
Strategy is simple but effective
Although simple, this pathway is highly effective, judging by the results of the PRECISE trial, which tested the strategy in 2,103 patients at 65 sites in North America and Europe. The primary outcome was a composite of major adverse cardiovascular events (MACE) that included death, nonfatal MI, and catheterization without observed CAD.
After a median follow-up of 11.8 months, the primary MACE endpoint was reached in about 11.3% of those in the usual-care group, which was more than twofold higher than the 4.2% in the precision strategy group. The unadjusted risk reduction was 65% but rose to more than 70% (hazard ratio, 0.29; P < .001) after adjustment for gender and baseline characteristics.
In the arm randomized to the precision strategy, 16% were characterized as low risk and received no further testing. Almost all the others underwent cCTA alone (48%) or cCTA with fractional flow reserve (FFR) (31%). Stress echocardiography, treadmill electrocardiography, and other functional studies were performed in the small proportion of remaining patients.
cCTA performed in just 15% of usual care
In the usual-care arm, cCTA with or without FFR was only performed in 15%. More than 80% of patients underwent evaluations with one or more of an array of functional tests. For example, one-third were evaluated with single photon emission CT/PET and nearly as many underwent stress echocardiography testing. Only 7% in usual care underwent no testing after referral.
Within the MACE composite endpoint, almost all the relative benefit in the precision strategy arm was derived from the endpoint of angiography performed without evidence of obstructive CAD (2.6% vs. 10.2%). Rates of all-cause mortality and MI were not significantly different.
Important for the safety and utility of the precision strategy, there “were no deaths or MI events among those assigned deferred testing ” in that experimental arm, according to Dr. Douglas, professor of research in cardiovascular diseases at Duke University, Durham, N.C.
Instead, those in the precision strategy arm were far less likely to undergo catheterization without finding CAD (20% vs. 60%) and far less likely to undergo catheterization without revascularization (28% vs. 70%).
In addition, the group randomized to the precision strategy were more likely to be placed on risk reducing therapies following testing. Although the higher proportion of patients placed on antihypertensive therapy did not reach statistical significance (P = .1), the increased proportions placed on lipid therapy (P < .001) and antiplatelet therapy (P < .001) did.
Citing a study in JAMA Cardiology that found that more than 25% of patients presenting with stable chest pain have normal coronary arteries, Dr. Douglas said that the precision strategy as shown in the PRECISE trial addresses several agreed-upon goals in guidelines from the AHA, the European Society of Cardiology and the U.K.’s National Institute for Health and Care Excellence. These goals include reducing unnecessary testing by risk stratification, improving diagnostic yield of the testing that is performed, and avoiding the costs and complications of unneeded invasive testing.
New protocol called preferred approach
On the basis of these results, Dr. Douglas called the precision strategy “a preferred approach in evaluating patients with stable symptoms and suspected coronary disease.”
Julie Indik, MD, PhD, a professor of medicine at the University of Arizona, Tuscon, said that application of this approach in routine care could have “a major impact on care” by avoiding unnecessary tests with no apparent adverse effect on outcomes.
Although not demonstrated in this study, Dr. Indik suggested that the large number of patients tested for CAD each year – she estimated 4 million visits – means that less testing is likely to have a major impact on the costs of care, and she praised “the practical, efficient” approach of the precision strategy.
Ron Blankstein, MD, director of cardiac computed tomography, Brigham and Women’s Hospital, Boston, also said these data “have both economic and safety implications.” As an AHA-invited discussant of this study, he emphasized that this is a strategy that should only be applied to lower risk patients with no prior history of CAD, but, in this group, he believes these data “will inform future guidelines.”
Dr. Douglas declined to speculate on whether the precision strategy will be incorporated into future guidelines, but she did say that the PRECISE data demonstrate that this approach improves quality of care.
In an interview, Dr. Douglas suggested that this care pathway could provide a basis on which to demonstrate improved outcomes with more efficient use of resources, a common definition of quality care delivery.
Dr. Douglas reported financial relationships with Caption Health, Kowa, and Heartflow, which provided funding for the PRECISE trial. Dr. Indik reported no potential conflicts of interest. Dr. Blankstein reported financial relationships with Amgen, Caristo Diagnostics, and Novartis.
Benefits accrue on multiple endpoints
Benefits accrue on multiple endpoints
CHICAGO – A stepwise care pathway was associated with a substantial reduction in the number of invasive tests performed and a major improvement in outcomes, relative to usual management, in patients suspected of coronary artery disease (CAD), according to 1-year results of the multinational, randomized PRECISE trial.
The care pathway is appropriate for patients with nonacute chest pain or equivalent complaints that have raised suspicion of CAD, and it is extremely simple, according to the description from the principal investigator, Pamela S. Douglas, MD, given in her presentation at the annual scientific sessions of the American Heart Association.
Unlike the highly complex diagnostic algorithms shunting suspected CAD patients to the vast array of potential evaluations, the newly tested protocol, characterized as a “precision strategy,” divides patients into those who are immediate candidates for invasive testing and those who are not. The discriminator is the PROMISE minimal risk assessment score, a tool already validated.
Those deemed candidates for testing on the basis of an elevated score undergo computed coronary CT angiography (cCTA). In those who are not, testing is deferred.
Strategy is simple but effective
Although simple, this pathway is highly effective, judging by the results of the PRECISE trial, which tested the strategy in 2,103 patients at 65 sites in North America and Europe. The primary outcome was a composite of major adverse cardiovascular events (MACE) that included death, nonfatal MI, and catheterization without observed CAD.
After a median follow-up of 11.8 months, the primary MACE endpoint was reached in about 11.3% of those in the usual-care group, which was more than twofold higher than the 4.2% in the precision strategy group. The unadjusted risk reduction was 65% but rose to more than 70% (hazard ratio, 0.29; P < .001) after adjustment for gender and baseline characteristics.
In the arm randomized to the precision strategy, 16% were characterized as low risk and received no further testing. Almost all the others underwent cCTA alone (48%) or cCTA with fractional flow reserve (FFR) (31%). Stress echocardiography, treadmill electrocardiography, and other functional studies were performed in the small proportion of remaining patients.
cCTA performed in just 15% of usual care
In the usual-care arm, cCTA with or without FFR was only performed in 15%. More than 80% of patients underwent evaluations with one or more of an array of functional tests. For example, one-third were evaluated with single photon emission CT/PET and nearly as many underwent stress echocardiography testing. Only 7% in usual care underwent no testing after referral.
Within the MACE composite endpoint, almost all the relative benefit in the precision strategy arm was derived from the endpoint of angiography performed without evidence of obstructive CAD (2.6% vs. 10.2%). Rates of all-cause mortality and MI were not significantly different.
Important for the safety and utility of the precision strategy, there “were no deaths or MI events among those assigned deferred testing ” in that experimental arm, according to Dr. Douglas, professor of research in cardiovascular diseases at Duke University, Durham, N.C.
Instead, those in the precision strategy arm were far less likely to undergo catheterization without finding CAD (20% vs. 60%) and far less likely to undergo catheterization without revascularization (28% vs. 70%).
In addition, the group randomized to the precision strategy were more likely to be placed on risk reducing therapies following testing. Although the higher proportion of patients placed on antihypertensive therapy did not reach statistical significance (P = .1), the increased proportions placed on lipid therapy (P < .001) and antiplatelet therapy (P < .001) did.
Citing a study in JAMA Cardiology that found that more than 25% of patients presenting with stable chest pain have normal coronary arteries, Dr. Douglas said that the precision strategy as shown in the PRECISE trial addresses several agreed-upon goals in guidelines from the AHA, the European Society of Cardiology and the U.K.’s National Institute for Health and Care Excellence. These goals include reducing unnecessary testing by risk stratification, improving diagnostic yield of the testing that is performed, and avoiding the costs and complications of unneeded invasive testing.
New protocol called preferred approach
On the basis of these results, Dr. Douglas called the precision strategy “a preferred approach in evaluating patients with stable symptoms and suspected coronary disease.”
Julie Indik, MD, PhD, a professor of medicine at the University of Arizona, Tuscon, said that application of this approach in routine care could have “a major impact on care” by avoiding unnecessary tests with no apparent adverse effect on outcomes.
Although not demonstrated in this study, Dr. Indik suggested that the large number of patients tested for CAD each year – she estimated 4 million visits – means that less testing is likely to have a major impact on the costs of care, and she praised “the practical, efficient” approach of the precision strategy.
Ron Blankstein, MD, director of cardiac computed tomography, Brigham and Women’s Hospital, Boston, also said these data “have both economic and safety implications.” As an AHA-invited discussant of this study, he emphasized that this is a strategy that should only be applied to lower risk patients with no prior history of CAD, but, in this group, he believes these data “will inform future guidelines.”
Dr. Douglas declined to speculate on whether the precision strategy will be incorporated into future guidelines, but she did say that the PRECISE data demonstrate that this approach improves quality of care.
In an interview, Dr. Douglas suggested that this care pathway could provide a basis on which to demonstrate improved outcomes with more efficient use of resources, a common definition of quality care delivery.
Dr. Douglas reported financial relationships with Caption Health, Kowa, and Heartflow, which provided funding for the PRECISE trial. Dr. Indik reported no potential conflicts of interest. Dr. Blankstein reported financial relationships with Amgen, Caristo Diagnostics, and Novartis.
CHICAGO – A stepwise care pathway was associated with a substantial reduction in the number of invasive tests performed and a major improvement in outcomes, relative to usual management, in patients suspected of coronary artery disease (CAD), according to 1-year results of the multinational, randomized PRECISE trial.
The care pathway is appropriate for patients with nonacute chest pain or equivalent complaints that have raised suspicion of CAD, and it is extremely simple, according to the description from the principal investigator, Pamela S. Douglas, MD, given in her presentation at the annual scientific sessions of the American Heart Association.
Unlike the highly complex diagnostic algorithms shunting suspected CAD patients to the vast array of potential evaluations, the newly tested protocol, characterized as a “precision strategy,” divides patients into those who are immediate candidates for invasive testing and those who are not. The discriminator is the PROMISE minimal risk assessment score, a tool already validated.
Those deemed candidates for testing on the basis of an elevated score undergo computed coronary CT angiography (cCTA). In those who are not, testing is deferred.
Strategy is simple but effective
Although simple, this pathway is highly effective, judging by the results of the PRECISE trial, which tested the strategy in 2,103 patients at 65 sites in North America and Europe. The primary outcome was a composite of major adverse cardiovascular events (MACE) that included death, nonfatal MI, and catheterization without observed CAD.
After a median follow-up of 11.8 months, the primary MACE endpoint was reached in about 11.3% of those in the usual-care group, which was more than twofold higher than the 4.2% in the precision strategy group. The unadjusted risk reduction was 65% but rose to more than 70% (hazard ratio, 0.29; P < .001) after adjustment for gender and baseline characteristics.
In the arm randomized to the precision strategy, 16% were characterized as low risk and received no further testing. Almost all the others underwent cCTA alone (48%) or cCTA with fractional flow reserve (FFR) (31%). Stress echocardiography, treadmill electrocardiography, and other functional studies were performed in the small proportion of remaining patients.
cCTA performed in just 15% of usual care
In the usual-care arm, cCTA with or without FFR was only performed in 15%. More than 80% of patients underwent evaluations with one or more of an array of functional tests. For example, one-third were evaluated with single photon emission CT/PET and nearly as many underwent stress echocardiography testing. Only 7% in usual care underwent no testing after referral.
Within the MACE composite endpoint, almost all the relative benefit in the precision strategy arm was derived from the endpoint of angiography performed without evidence of obstructive CAD (2.6% vs. 10.2%). Rates of all-cause mortality and MI were not significantly different.
Important for the safety and utility of the precision strategy, there “were no deaths or MI events among those assigned deferred testing ” in that experimental arm, according to Dr. Douglas, professor of research in cardiovascular diseases at Duke University, Durham, N.C.
Instead, those in the precision strategy arm were far less likely to undergo catheterization without finding CAD (20% vs. 60%) and far less likely to undergo catheterization without revascularization (28% vs. 70%).
In addition, the group randomized to the precision strategy were more likely to be placed on risk reducing therapies following testing. Although the higher proportion of patients placed on antihypertensive therapy did not reach statistical significance (P = .1), the increased proportions placed on lipid therapy (P < .001) and antiplatelet therapy (P < .001) did.
Citing a study in JAMA Cardiology that found that more than 25% of patients presenting with stable chest pain have normal coronary arteries, Dr. Douglas said that the precision strategy as shown in the PRECISE trial addresses several agreed-upon goals in guidelines from the AHA, the European Society of Cardiology and the U.K.’s National Institute for Health and Care Excellence. These goals include reducing unnecessary testing by risk stratification, improving diagnostic yield of the testing that is performed, and avoiding the costs and complications of unneeded invasive testing.
New protocol called preferred approach
On the basis of these results, Dr. Douglas called the precision strategy “a preferred approach in evaluating patients with stable symptoms and suspected coronary disease.”
Julie Indik, MD, PhD, a professor of medicine at the University of Arizona, Tuscon, said that application of this approach in routine care could have “a major impact on care” by avoiding unnecessary tests with no apparent adverse effect on outcomes.
Although not demonstrated in this study, Dr. Indik suggested that the large number of patients tested for CAD each year – she estimated 4 million visits – means that less testing is likely to have a major impact on the costs of care, and she praised “the practical, efficient” approach of the precision strategy.
Ron Blankstein, MD, director of cardiac computed tomography, Brigham and Women’s Hospital, Boston, also said these data “have both economic and safety implications.” As an AHA-invited discussant of this study, he emphasized that this is a strategy that should only be applied to lower risk patients with no prior history of CAD, but, in this group, he believes these data “will inform future guidelines.”
Dr. Douglas declined to speculate on whether the precision strategy will be incorporated into future guidelines, but she did say that the PRECISE data demonstrate that this approach improves quality of care.
In an interview, Dr. Douglas suggested that this care pathway could provide a basis on which to demonstrate improved outcomes with more efficient use of resources, a common definition of quality care delivery.
Dr. Douglas reported financial relationships with Caption Health, Kowa, and Heartflow, which provided funding for the PRECISE trial. Dr. Indik reported no potential conflicts of interest. Dr. Blankstein reported financial relationships with Amgen, Caristo Diagnostics, and Novartis.
AT AHA 2022
In CABG, radial artery works best for second key graft: RAPCO at 15 years
Lower risk of MACE shown
CHICAGO – With more than 15 years of follow-up from two related trials, the best conduit for the second most important target vessel in coronary artery bypass grafting (CABG) appears to be resolved.
The radial artery (RA) graft is linked with a lower risk of major adverse cardiac events (MACE) relative to a saphenous vein (SV) or the free right internal thoracic artery (FRITA).
On the basis of these findings, “a radial artery graft should be considered in all isolated CABG operations unless there are contraindications,” reported David L. Hare, MBBS, director of research in the department of cardiology, University of Melbourne.
For the primary graft, there is general agreement that the left internal thoracic artery (LITA) is the first choice for the left anterior descending vessel, but the optimal graft for the second most important target has never been established, according to Dr. Hare.
Almost 25 years ago, two randomized controlled trials called RAPCO-RITA and RAPCO-SV were initiated to address the question. There is now 15 years of follow-up for both of the RAPCO (Radial Artery Patency and Clinical Outcomes) trials, which were presented together at the American Heart Association scientific sessions.
Two trials conducted simultaneously
The RAPCO-RITA trial randomized CABG patients less than 70 years of age (less than 60 years in those with diabetes) to grafting of the second target vessel with an RA or FRITA graft. The RAPCO-SV trial randomized those 70 years or older (60 years or older with diabetes) to an RA or SV graft.
The two primary endpoints were graft patency at 10 years and a composite MACE at 10 years. The assessment of the MACE endpoint, which consisted of cardiovascular mortality, acute myocardial infarction, and coronary revascularization, was later amended to include a comparison at 15 years.
Ten-year patency results, favoring the RA in both studies, were previously published in Circulation. In the new data presented at the meeting, the RA was associated with a significant reduction in MACE relative to the comparator graft in both studies.
“The main driver was a reduction in all-cause mortality,” Dr. Hare reported.
In RAPCO-RITA, 394 patients were randomized with follow-up data available for all but 1 patient at 15 years. Similarly, only 1 patient was lost to follow-up among the 225 randomized in RAPCO-SV. In both studies, baseline characteristics were well balanced.
MACE curves separate at 5 years
In RAPCO-RITA, the MACE survival curves began to separate at about 5 years and then gradually widened. By 15 years, the lower rate of MACE in the RA group (38% vs. 48%) translated into a 26% relative reduction (hazard ratio, 0.74; P = .04).
In RAPCO-SV, the pattern was similar, by 15 years, the rates of MACE were 60% and 73% for the RA and SV groups, respectively, translating into a 29% relative reduction (HR, 0.71; P = .04).
There was no heterogeneity in benefit across prespecified subgroups such as presence or absence of diabetes, gender, or age. In RAPCO-RITA, there was 8% absolute and 31% relative reduction in all-cause mortality. In RAPCO-SV, the absolute and relative reductions were 11% and 26%.
When the trial was initiated, Dr. Hare hypothesized that RITA would prove more durable than RA, so the outcome was not anticipated.
“This is the first randomized controlled trial program to address the question,” said Dr. Hare, who noted that there have been numerous retrospective and case control analyses that have produced mixed results in the past.
Discussant praises trial quality
The AHA-invited discussant, Marc Ruel, MD, chair of cardiac surgery, University of Ottawa (Ont.) Heart Institute, called these data “important,” and he congratulated Dr. Hare for conducting the first randomized trial to address the question about second graft durability.
However, he noted that, although the study was randomized, it was not blinded, and he questioned whether postoperative care, in particular, was similar. He also pointed out that the MACE rate seemed high, particularly among the older patients randomized in RAPCO-SV.
“All of the patients were referred to an independently run CABG rehab program that was quite separate from the trial but that provided identical mandated care,” Dr. Hare responded, indicating that there was no opportunity for differences in postprocedural management.
In the United States, the SV graft is often preferred on the basis of easy harvesting and handling characteristics, according to Dr. Hare, who estimated that fewer than 10% of the 200,000 CABG procedures performed in the United States employ the RA conduit for second target vessels. He believes the RAPCO trials data support a change.
“My personal view is [that, on the basis of] this data, given that it is from a controlled trial rather than from patient-level meta-analyses, all isolated CABG operations should be using a radial graft if it is suitable,” Dr. Hare said.
Dr. Hare reports financial relationships with Abbott, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, CSL-Biotherapies, Lundbeck, Menarini, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and Vifor. Dr. Ruel reports financial relationships with Cryolife, Edwards, and Medtronic.
Lower risk of MACE shown
Lower risk of MACE shown
CHICAGO – With more than 15 years of follow-up from two related trials, the best conduit for the second most important target vessel in coronary artery bypass grafting (CABG) appears to be resolved.
The radial artery (RA) graft is linked with a lower risk of major adverse cardiac events (MACE) relative to a saphenous vein (SV) or the free right internal thoracic artery (FRITA).
On the basis of these findings, “a radial artery graft should be considered in all isolated CABG operations unless there are contraindications,” reported David L. Hare, MBBS, director of research in the department of cardiology, University of Melbourne.
For the primary graft, there is general agreement that the left internal thoracic artery (LITA) is the first choice for the left anterior descending vessel, but the optimal graft for the second most important target has never been established, according to Dr. Hare.
Almost 25 years ago, two randomized controlled trials called RAPCO-RITA and RAPCO-SV were initiated to address the question. There is now 15 years of follow-up for both of the RAPCO (Radial Artery Patency and Clinical Outcomes) trials, which were presented together at the American Heart Association scientific sessions.
Two trials conducted simultaneously
The RAPCO-RITA trial randomized CABG patients less than 70 years of age (less than 60 years in those with diabetes) to grafting of the second target vessel with an RA or FRITA graft. The RAPCO-SV trial randomized those 70 years or older (60 years or older with diabetes) to an RA or SV graft.
The two primary endpoints were graft patency at 10 years and a composite MACE at 10 years. The assessment of the MACE endpoint, which consisted of cardiovascular mortality, acute myocardial infarction, and coronary revascularization, was later amended to include a comparison at 15 years.
Ten-year patency results, favoring the RA in both studies, were previously published in Circulation. In the new data presented at the meeting, the RA was associated with a significant reduction in MACE relative to the comparator graft in both studies.
“The main driver was a reduction in all-cause mortality,” Dr. Hare reported.
In RAPCO-RITA, 394 patients were randomized with follow-up data available for all but 1 patient at 15 years. Similarly, only 1 patient was lost to follow-up among the 225 randomized in RAPCO-SV. In both studies, baseline characteristics were well balanced.
MACE curves separate at 5 years
In RAPCO-RITA, the MACE survival curves began to separate at about 5 years and then gradually widened. By 15 years, the lower rate of MACE in the RA group (38% vs. 48%) translated into a 26% relative reduction (hazard ratio, 0.74; P = .04).
In RAPCO-SV, the pattern was similar, by 15 years, the rates of MACE were 60% and 73% for the RA and SV groups, respectively, translating into a 29% relative reduction (HR, 0.71; P = .04).
There was no heterogeneity in benefit across prespecified subgroups such as presence or absence of diabetes, gender, or age. In RAPCO-RITA, there was 8% absolute and 31% relative reduction in all-cause mortality. In RAPCO-SV, the absolute and relative reductions were 11% and 26%.
When the trial was initiated, Dr. Hare hypothesized that RITA would prove more durable than RA, so the outcome was not anticipated.
“This is the first randomized controlled trial program to address the question,” said Dr. Hare, who noted that there have been numerous retrospective and case control analyses that have produced mixed results in the past.
Discussant praises trial quality
The AHA-invited discussant, Marc Ruel, MD, chair of cardiac surgery, University of Ottawa (Ont.) Heart Institute, called these data “important,” and he congratulated Dr. Hare for conducting the first randomized trial to address the question about second graft durability.
However, he noted that, although the study was randomized, it was not blinded, and he questioned whether postoperative care, in particular, was similar. He also pointed out that the MACE rate seemed high, particularly among the older patients randomized in RAPCO-SV.
“All of the patients were referred to an independently run CABG rehab program that was quite separate from the trial but that provided identical mandated care,” Dr. Hare responded, indicating that there was no opportunity for differences in postprocedural management.
In the United States, the SV graft is often preferred on the basis of easy harvesting and handling characteristics, according to Dr. Hare, who estimated that fewer than 10% of the 200,000 CABG procedures performed in the United States employ the RA conduit for second target vessels. He believes the RAPCO trials data support a change.
“My personal view is [that, on the basis of] this data, given that it is from a controlled trial rather than from patient-level meta-analyses, all isolated CABG operations should be using a radial graft if it is suitable,” Dr. Hare said.
Dr. Hare reports financial relationships with Abbott, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, CSL-Biotherapies, Lundbeck, Menarini, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and Vifor. Dr. Ruel reports financial relationships with Cryolife, Edwards, and Medtronic.
CHICAGO – With more than 15 years of follow-up from two related trials, the best conduit for the second most important target vessel in coronary artery bypass grafting (CABG) appears to be resolved.
The radial artery (RA) graft is linked with a lower risk of major adverse cardiac events (MACE) relative to a saphenous vein (SV) or the free right internal thoracic artery (FRITA).
On the basis of these findings, “a radial artery graft should be considered in all isolated CABG operations unless there are contraindications,” reported David L. Hare, MBBS, director of research in the department of cardiology, University of Melbourne.
For the primary graft, there is general agreement that the left internal thoracic artery (LITA) is the first choice for the left anterior descending vessel, but the optimal graft for the second most important target has never been established, according to Dr. Hare.
Almost 25 years ago, two randomized controlled trials called RAPCO-RITA and RAPCO-SV were initiated to address the question. There is now 15 years of follow-up for both of the RAPCO (Radial Artery Patency and Clinical Outcomes) trials, which were presented together at the American Heart Association scientific sessions.
Two trials conducted simultaneously
The RAPCO-RITA trial randomized CABG patients less than 70 years of age (less than 60 years in those with diabetes) to grafting of the second target vessel with an RA or FRITA graft. The RAPCO-SV trial randomized those 70 years or older (60 years or older with diabetes) to an RA or SV graft.
The two primary endpoints were graft patency at 10 years and a composite MACE at 10 years. The assessment of the MACE endpoint, which consisted of cardiovascular mortality, acute myocardial infarction, and coronary revascularization, was later amended to include a comparison at 15 years.
Ten-year patency results, favoring the RA in both studies, were previously published in Circulation. In the new data presented at the meeting, the RA was associated with a significant reduction in MACE relative to the comparator graft in both studies.
“The main driver was a reduction in all-cause mortality,” Dr. Hare reported.
In RAPCO-RITA, 394 patients were randomized with follow-up data available for all but 1 patient at 15 years. Similarly, only 1 patient was lost to follow-up among the 225 randomized in RAPCO-SV. In both studies, baseline characteristics were well balanced.
MACE curves separate at 5 years
In RAPCO-RITA, the MACE survival curves began to separate at about 5 years and then gradually widened. By 15 years, the lower rate of MACE in the RA group (38% vs. 48%) translated into a 26% relative reduction (hazard ratio, 0.74; P = .04).
In RAPCO-SV, the pattern was similar, by 15 years, the rates of MACE were 60% and 73% for the RA and SV groups, respectively, translating into a 29% relative reduction (HR, 0.71; P = .04).
There was no heterogeneity in benefit across prespecified subgroups such as presence or absence of diabetes, gender, or age. In RAPCO-RITA, there was 8% absolute and 31% relative reduction in all-cause mortality. In RAPCO-SV, the absolute and relative reductions were 11% and 26%.
When the trial was initiated, Dr. Hare hypothesized that RITA would prove more durable than RA, so the outcome was not anticipated.
“This is the first randomized controlled trial program to address the question,” said Dr. Hare, who noted that there have been numerous retrospective and case control analyses that have produced mixed results in the past.
Discussant praises trial quality
The AHA-invited discussant, Marc Ruel, MD, chair of cardiac surgery, University of Ottawa (Ont.) Heart Institute, called these data “important,” and he congratulated Dr. Hare for conducting the first randomized trial to address the question about second graft durability.
However, he noted that, although the study was randomized, it was not blinded, and he questioned whether postoperative care, in particular, was similar. He also pointed out that the MACE rate seemed high, particularly among the older patients randomized in RAPCO-SV.
“All of the patients were referred to an independently run CABG rehab program that was quite separate from the trial but that provided identical mandated care,” Dr. Hare responded, indicating that there was no opportunity for differences in postprocedural management.
In the United States, the SV graft is often preferred on the basis of easy harvesting and handling characteristics, according to Dr. Hare, who estimated that fewer than 10% of the 200,000 CABG procedures performed in the United States employ the RA conduit for second target vessels. He believes the RAPCO trials data support a change.
“My personal view is [that, on the basis of] this data, given that it is from a controlled trial rather than from patient-level meta-analyses, all isolated CABG operations should be using a radial graft if it is suitable,” Dr. Hare said.
Dr. Hare reports financial relationships with Abbott, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, CSL-Biotherapies, Lundbeck, Menarini, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and Vifor. Dr. Ruel reports financial relationships with Cryolife, Edwards, and Medtronic.
AT AHA 2022
Triglyceride-lowering fails to show CV benefit in large fibrate trial
Twenty-five percent reduction has no effect
CHICAGO – Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.
“Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy,” reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.
It is the most recent in a series of trials that have failed to associate a meaningful reduction in TGs with protection from a composite MACE endpoint. This is a pattern that dates back 20 years, even though earlier trials did suggest that hypertriglyceridemia was a targetable risk factor.
No benefit from fibrates seen in statin era
“We have not seen a significant cardiovascular event reduction with a fibrate in the statin era,” according to Karol Watson, MD, PhD, director of the UCLA Women’s Cardiovascular Health Center, Los Angeles.
In the statin era, which began soon after the Helsinki Heart Study was published in 1987, Dr. Watson counted at least five studies with fibrates that had a null result.
In the setting of good control of LDL cholesterol, “fibrates have not been shown to further lower CV risk,” said Dr. Watson, who was invited by the AHA to discuss the PROMINENT trial.
In PROMINENT, 10,497 patients with type 2 diabetes were randomized to pemafibrate, a peroxisome proliferator-activated receptor a (PPAR-a) agonist, or placebo. Pemafibrate is not currently available in North America or Europe, but it is licensed in Japan for the treatment of hypertriglyceridemia.
The primary efficacy endpoint of the double-blind trial was a composite endpoint of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death.
The patients were eligible if they had TG levels from 200 to 400 mg/dL and HDL cholesterol levels of 40 mg/dL or below. Pemafibrate in a dose of 0.2 mg or placebo were taken twice daily. About two-thirds had a prior history of coronary heart disease. The goal was primary prevention in the remainder.
After a median follow-up of 3.4 years when the study was stopped for futility, the proportion of patients reaching a primary endpoint was slightly greater in the experimental arm (3.60 vs. 3.51 events per 100 patient-years). The hazard ratio, although not significant, was nominally in favor of placebo (hazard ratio, 1.03; P = .67).
When events within the composite endpoint were assessed individually, there was no signal of benefit for any outcome. The rates of death from any cause, although numerically higher in the pemafibrate group (2.44 vs. 2.34 per 100 patient years), were also comparable.
Lipid profile improved as predicted
Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.
Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.
The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation.
The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.
“I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level,” speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results.
He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.
“In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL,” Dr. Virani explained in an attempt to unravel the interplay of these variables.
Although this study enrolled patients “who would be predicted to have the most benefit from a TG-lowering strategy,” Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However, it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.
Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.
Twenty-five percent reduction has no effect
Twenty-five percent reduction has no effect
CHICAGO – Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.
“Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy,” reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.
It is the most recent in a series of trials that have failed to associate a meaningful reduction in TGs with protection from a composite MACE endpoint. This is a pattern that dates back 20 years, even though earlier trials did suggest that hypertriglyceridemia was a targetable risk factor.
No benefit from fibrates seen in statin era
“We have not seen a significant cardiovascular event reduction with a fibrate in the statin era,” according to Karol Watson, MD, PhD, director of the UCLA Women’s Cardiovascular Health Center, Los Angeles.
In the statin era, which began soon after the Helsinki Heart Study was published in 1987, Dr. Watson counted at least five studies with fibrates that had a null result.
In the setting of good control of LDL cholesterol, “fibrates have not been shown to further lower CV risk,” said Dr. Watson, who was invited by the AHA to discuss the PROMINENT trial.
In PROMINENT, 10,497 patients with type 2 diabetes were randomized to pemafibrate, a peroxisome proliferator-activated receptor a (PPAR-a) agonist, or placebo. Pemafibrate is not currently available in North America or Europe, but it is licensed in Japan for the treatment of hypertriglyceridemia.
The primary efficacy endpoint of the double-blind trial was a composite endpoint of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death.
The patients were eligible if they had TG levels from 200 to 400 mg/dL and HDL cholesterol levels of 40 mg/dL or below. Pemafibrate in a dose of 0.2 mg or placebo were taken twice daily. About two-thirds had a prior history of coronary heart disease. The goal was primary prevention in the remainder.
After a median follow-up of 3.4 years when the study was stopped for futility, the proportion of patients reaching a primary endpoint was slightly greater in the experimental arm (3.60 vs. 3.51 events per 100 patient-years). The hazard ratio, although not significant, was nominally in favor of placebo (hazard ratio, 1.03; P = .67).
When events within the composite endpoint were assessed individually, there was no signal of benefit for any outcome. The rates of death from any cause, although numerically higher in the pemafibrate group (2.44 vs. 2.34 per 100 patient years), were also comparable.
Lipid profile improved as predicted
Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.
Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.
The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation.
The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.
“I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level,” speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results.
He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.
“In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL,” Dr. Virani explained in an attempt to unravel the interplay of these variables.
Although this study enrolled patients “who would be predicted to have the most benefit from a TG-lowering strategy,” Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However, it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.
Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.
CHICAGO – Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.
“Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy,” reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.
It is the most recent in a series of trials that have failed to associate a meaningful reduction in TGs with protection from a composite MACE endpoint. This is a pattern that dates back 20 years, even though earlier trials did suggest that hypertriglyceridemia was a targetable risk factor.
No benefit from fibrates seen in statin era
“We have not seen a significant cardiovascular event reduction with a fibrate in the statin era,” according to Karol Watson, MD, PhD, director of the UCLA Women’s Cardiovascular Health Center, Los Angeles.
In the statin era, which began soon after the Helsinki Heart Study was published in 1987, Dr. Watson counted at least five studies with fibrates that had a null result.
In the setting of good control of LDL cholesterol, “fibrates have not been shown to further lower CV risk,” said Dr. Watson, who was invited by the AHA to discuss the PROMINENT trial.
In PROMINENT, 10,497 patients with type 2 diabetes were randomized to pemafibrate, a peroxisome proliferator-activated receptor a (PPAR-a) agonist, or placebo. Pemafibrate is not currently available in North America or Europe, but it is licensed in Japan for the treatment of hypertriglyceridemia.
The primary efficacy endpoint of the double-blind trial was a composite endpoint of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death.
The patients were eligible if they had TG levels from 200 to 400 mg/dL and HDL cholesterol levels of 40 mg/dL or below. Pemafibrate in a dose of 0.2 mg or placebo were taken twice daily. About two-thirds had a prior history of coronary heart disease. The goal was primary prevention in the remainder.
After a median follow-up of 3.4 years when the study was stopped for futility, the proportion of patients reaching a primary endpoint was slightly greater in the experimental arm (3.60 vs. 3.51 events per 100 patient-years). The hazard ratio, although not significant, was nominally in favor of placebo (hazard ratio, 1.03; P = .67).
When events within the composite endpoint were assessed individually, there was no signal of benefit for any outcome. The rates of death from any cause, although numerically higher in the pemafibrate group (2.44 vs. 2.34 per 100 patient years), were also comparable.
Lipid profile improved as predicted
Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.
Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.
The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation.
The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.
“I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level,” speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results.
He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.
“In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL,” Dr. Virani explained in an attempt to unravel the interplay of these variables.
Although this study enrolled patients “who would be predicted to have the most benefit from a TG-lowering strategy,” Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However, it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.
Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.
AT AHA 2022
Pulmonologist consult at COPD admission reduces risk of return
according to a retrospective cohort review presented at the annual meeting of the American College of Chest Physicians (CHEST).
“When stratified by severity of COPD at the time of admission, the difference in the readmission rate was even greater,” reported Nakisa Hekmat-Joo, MD, a third-year resident at Staten Island University Hospital, New York.
Just as protocols have been developed for prompt initiation of antibiotics in patients with septicemia or prompt revascularization in patients with ST-segment elevated myocardial infarction (STEMI), Dr. Hekmat-Joo said the data from this study warrant a larger trial to evaluate whether an AECOPD admission protocol is warranted to improve outcomes and lower costs.
In this study, all AECOPD admissions were included from a recent 2-year period at two Staten Island hospitals. Of these, 198 patients received a pulmonologist consult within 24 hours. The remaining 92 patients were not evaluated by pulmonologists but were admitted and then managed by residents, internists, or others.
The primary outcome was length of stay (LOS). Although the slightly lower LOS in pulmonologist-treated group did not approach significance (4.16 vs. 4.21 days; P = .88), the readmission rate at 90 days, which was a secondary outcome, was reduced by almost half (30.1% vs. 57.6%; P < .0001).
At admission, there was no significant difference between those receiving a pulmonologist consult and those who did not. The average O2 saturation was lower in the group seen by a pulmonologist (93% vs. 95.4%; P < .0001), but the most striking difference was the low relative readmission rate, which remained significant after controlling for severity and pulmonary function.
“When we stratified patients for baseline severity, the advantage of a pulmonologist consult was even greater for those with the most severe disease,” Dr. Hekmat-Joo said. Among those with the greatest severity, the 90-day readmission rate was nearly three times greater in the absence of a pulmonologist consult (72% vs. 28%).
Although the comparison of outcomes for those receiving a pulmonologist consult vs. those who did not was adjusted for COPD severity, the potential for pulmonologist consults to be ordered for those patients who looked the sickest would have likely worked against the study result.
“We speculate that pulmonologists were more likely than internists to treat beyond standard guidelines, particularly in the event of greater severity,” Dr. Hekmat-Joo explained. These steps might include earlier use of noninvasive positive pressure ventilation or earlier initiation of rehabilitation strategies.
There were several signals that a pulmonologist consult led to more rigorous care.
“The average time to follow-up after hospitalization was 23 days for the pulmonologist group and 66 days for the nonpulmonologist group,” said Dr. Hekmat-Joo, noting this difference was highly significant (P = .0052).
Based on these results, Dr. Hekmat-Joo and her co-investigators are now working on a protocol for COPD admissions that involves a pulmonologist consult within 24 hours of admission. She hopes to test this protocol in a prospective trial.
“COPD remains a major cause of death and consumes enormous health care resources. About 30% of the cost of COPD care is due to readmissions,” she said, noting that readmissions adversely impact quality of life.
Asked if there was sufficient staff at her institution to allow for a pulmonologist consult with every COPD admission, Dr. Hekmat-Joo acknowledged that this has to be demonstrated, but compelling evidence of a benefit might prompt a redistribution of resources.
“If we can show that readmissions are substantially reduced, adding staff to perform these consults would be a good investment,” said Dr. Hekmat-Joo, indicating that improved outcomes could also attract the attention of third-party payers and those tracking quality-of-care metrics.
There is a strong rationale for a randomized prospective trial to confirm the value of a pulmonologist consultation following admission for an acute exacerbation of COPD, according to Nicola A. Hanania, MD, director, Airways Clinical Research Center, Baylor College of Medicine, Houston.
The potential for benefit as seen in this retrospective study is a rational expectation and might be related to more appropriate therapy upon discharge as well as to earlier and more rigorous follow-up, according to Dr. Hanania. Although he cautioned that there is a meaningful risk of selection bias in a retrospective study, he thinks this study “is certainly probing an important issue.”
“Mortality from a hospitalized COPD exacerbation exceeds that of a myocardial infarction,” Dr. Hanania pointed out. Noting that all patients with an MI are evaluated by a cardiologist, he sees the logic of a pulmonologist consult – although he acknowledged that evidence is needed.
“I strongly believe that a prospective study is feasible and will answer the question in an unbiased manner if done properly,” he said in an interview. If a multicenter, well-controlled study was positive, it could change practice.
In the event of a study showing major clinical benefits, particularly a reduction in mortality, “I believe it is feasible to have a pulmonary consult to see every COPD exacerbation patient admitted to the hospital,” Dr. Hanania said.
Dr. Hekmat-Joo reports no relevant financial relationships. Dr. Hanania has financial relationships with AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan, Novartis, Regeneron, Sanofi, and Sunovion.
A version of this article first appeared on Medscape.com.
according to a retrospective cohort review presented at the annual meeting of the American College of Chest Physicians (CHEST).
“When stratified by severity of COPD at the time of admission, the difference in the readmission rate was even greater,” reported Nakisa Hekmat-Joo, MD, a third-year resident at Staten Island University Hospital, New York.
Just as protocols have been developed for prompt initiation of antibiotics in patients with septicemia or prompt revascularization in patients with ST-segment elevated myocardial infarction (STEMI), Dr. Hekmat-Joo said the data from this study warrant a larger trial to evaluate whether an AECOPD admission protocol is warranted to improve outcomes and lower costs.
In this study, all AECOPD admissions were included from a recent 2-year period at two Staten Island hospitals. Of these, 198 patients received a pulmonologist consult within 24 hours. The remaining 92 patients were not evaluated by pulmonologists but were admitted and then managed by residents, internists, or others.
The primary outcome was length of stay (LOS). Although the slightly lower LOS in pulmonologist-treated group did not approach significance (4.16 vs. 4.21 days; P = .88), the readmission rate at 90 days, which was a secondary outcome, was reduced by almost half (30.1% vs. 57.6%; P < .0001).
At admission, there was no significant difference between those receiving a pulmonologist consult and those who did not. The average O2 saturation was lower in the group seen by a pulmonologist (93% vs. 95.4%; P < .0001), but the most striking difference was the low relative readmission rate, which remained significant after controlling for severity and pulmonary function.
“When we stratified patients for baseline severity, the advantage of a pulmonologist consult was even greater for those with the most severe disease,” Dr. Hekmat-Joo said. Among those with the greatest severity, the 90-day readmission rate was nearly three times greater in the absence of a pulmonologist consult (72% vs. 28%).
Although the comparison of outcomes for those receiving a pulmonologist consult vs. those who did not was adjusted for COPD severity, the potential for pulmonologist consults to be ordered for those patients who looked the sickest would have likely worked against the study result.
“We speculate that pulmonologists were more likely than internists to treat beyond standard guidelines, particularly in the event of greater severity,” Dr. Hekmat-Joo explained. These steps might include earlier use of noninvasive positive pressure ventilation or earlier initiation of rehabilitation strategies.
There were several signals that a pulmonologist consult led to more rigorous care.
“The average time to follow-up after hospitalization was 23 days for the pulmonologist group and 66 days for the nonpulmonologist group,” said Dr. Hekmat-Joo, noting this difference was highly significant (P = .0052).
Based on these results, Dr. Hekmat-Joo and her co-investigators are now working on a protocol for COPD admissions that involves a pulmonologist consult within 24 hours of admission. She hopes to test this protocol in a prospective trial.
“COPD remains a major cause of death and consumes enormous health care resources. About 30% of the cost of COPD care is due to readmissions,” she said, noting that readmissions adversely impact quality of life.
Asked if there was sufficient staff at her institution to allow for a pulmonologist consult with every COPD admission, Dr. Hekmat-Joo acknowledged that this has to be demonstrated, but compelling evidence of a benefit might prompt a redistribution of resources.
“If we can show that readmissions are substantially reduced, adding staff to perform these consults would be a good investment,” said Dr. Hekmat-Joo, indicating that improved outcomes could also attract the attention of third-party payers and those tracking quality-of-care metrics.
There is a strong rationale for a randomized prospective trial to confirm the value of a pulmonologist consultation following admission for an acute exacerbation of COPD, according to Nicola A. Hanania, MD, director, Airways Clinical Research Center, Baylor College of Medicine, Houston.
The potential for benefit as seen in this retrospective study is a rational expectation and might be related to more appropriate therapy upon discharge as well as to earlier and more rigorous follow-up, according to Dr. Hanania. Although he cautioned that there is a meaningful risk of selection bias in a retrospective study, he thinks this study “is certainly probing an important issue.”
“Mortality from a hospitalized COPD exacerbation exceeds that of a myocardial infarction,” Dr. Hanania pointed out. Noting that all patients with an MI are evaluated by a cardiologist, he sees the logic of a pulmonologist consult – although he acknowledged that evidence is needed.
“I strongly believe that a prospective study is feasible and will answer the question in an unbiased manner if done properly,” he said in an interview. If a multicenter, well-controlled study was positive, it could change practice.
In the event of a study showing major clinical benefits, particularly a reduction in mortality, “I believe it is feasible to have a pulmonary consult to see every COPD exacerbation patient admitted to the hospital,” Dr. Hanania said.
Dr. Hekmat-Joo reports no relevant financial relationships. Dr. Hanania has financial relationships with AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan, Novartis, Regeneron, Sanofi, and Sunovion.
A version of this article first appeared on Medscape.com.
according to a retrospective cohort review presented at the annual meeting of the American College of Chest Physicians (CHEST).
“When stratified by severity of COPD at the time of admission, the difference in the readmission rate was even greater,” reported Nakisa Hekmat-Joo, MD, a third-year resident at Staten Island University Hospital, New York.
Just as protocols have been developed for prompt initiation of antibiotics in patients with septicemia or prompt revascularization in patients with ST-segment elevated myocardial infarction (STEMI), Dr. Hekmat-Joo said the data from this study warrant a larger trial to evaluate whether an AECOPD admission protocol is warranted to improve outcomes and lower costs.
In this study, all AECOPD admissions were included from a recent 2-year period at two Staten Island hospitals. Of these, 198 patients received a pulmonologist consult within 24 hours. The remaining 92 patients were not evaluated by pulmonologists but were admitted and then managed by residents, internists, or others.
The primary outcome was length of stay (LOS). Although the slightly lower LOS in pulmonologist-treated group did not approach significance (4.16 vs. 4.21 days; P = .88), the readmission rate at 90 days, which was a secondary outcome, was reduced by almost half (30.1% vs. 57.6%; P < .0001).
At admission, there was no significant difference between those receiving a pulmonologist consult and those who did not. The average O2 saturation was lower in the group seen by a pulmonologist (93% vs. 95.4%; P < .0001), but the most striking difference was the low relative readmission rate, which remained significant after controlling for severity and pulmonary function.
“When we stratified patients for baseline severity, the advantage of a pulmonologist consult was even greater for those with the most severe disease,” Dr. Hekmat-Joo said. Among those with the greatest severity, the 90-day readmission rate was nearly three times greater in the absence of a pulmonologist consult (72% vs. 28%).
Although the comparison of outcomes for those receiving a pulmonologist consult vs. those who did not was adjusted for COPD severity, the potential for pulmonologist consults to be ordered for those patients who looked the sickest would have likely worked against the study result.
“We speculate that pulmonologists were more likely than internists to treat beyond standard guidelines, particularly in the event of greater severity,” Dr. Hekmat-Joo explained. These steps might include earlier use of noninvasive positive pressure ventilation or earlier initiation of rehabilitation strategies.
There were several signals that a pulmonologist consult led to more rigorous care.
“The average time to follow-up after hospitalization was 23 days for the pulmonologist group and 66 days for the nonpulmonologist group,” said Dr. Hekmat-Joo, noting this difference was highly significant (P = .0052).
Based on these results, Dr. Hekmat-Joo and her co-investigators are now working on a protocol for COPD admissions that involves a pulmonologist consult within 24 hours of admission. She hopes to test this protocol in a prospective trial.
“COPD remains a major cause of death and consumes enormous health care resources. About 30% of the cost of COPD care is due to readmissions,” she said, noting that readmissions adversely impact quality of life.
Asked if there was sufficient staff at her institution to allow for a pulmonologist consult with every COPD admission, Dr. Hekmat-Joo acknowledged that this has to be demonstrated, but compelling evidence of a benefit might prompt a redistribution of resources.
“If we can show that readmissions are substantially reduced, adding staff to perform these consults would be a good investment,” said Dr. Hekmat-Joo, indicating that improved outcomes could also attract the attention of third-party payers and those tracking quality-of-care metrics.
There is a strong rationale for a randomized prospective trial to confirm the value of a pulmonologist consultation following admission for an acute exacerbation of COPD, according to Nicola A. Hanania, MD, director, Airways Clinical Research Center, Baylor College of Medicine, Houston.
The potential for benefit as seen in this retrospective study is a rational expectation and might be related to more appropriate therapy upon discharge as well as to earlier and more rigorous follow-up, according to Dr. Hanania. Although he cautioned that there is a meaningful risk of selection bias in a retrospective study, he thinks this study “is certainly probing an important issue.”
“Mortality from a hospitalized COPD exacerbation exceeds that of a myocardial infarction,” Dr. Hanania pointed out. Noting that all patients with an MI are evaluated by a cardiologist, he sees the logic of a pulmonologist consult – although he acknowledged that evidence is needed.
“I strongly believe that a prospective study is feasible and will answer the question in an unbiased manner if done properly,” he said in an interview. If a multicenter, well-controlled study was positive, it could change practice.
In the event of a study showing major clinical benefits, particularly a reduction in mortality, “I believe it is feasible to have a pulmonary consult to see every COPD exacerbation patient admitted to the hospital,” Dr. Hanania said.
Dr. Hekmat-Joo reports no relevant financial relationships. Dr. Hanania has financial relationships with AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan, Novartis, Regeneron, Sanofi, and Sunovion.
A version of this article first appeared on Medscape.com.
FROM CHEST 2022
Testosterone ranges for young men could help classify deficiency
Normative ranges of testosterone in young men have been identified on the basis of a nationally representative data in a new study, and these data are expected to provide guidance when evaluating younger individuals presenting with signs and symptoms of potential testosterone deficiency, according to the investigators.
It has long been known that the ranges of normal testosterone differ by age, but the authors of this study contend that this is the first large-scale, population-based analysis conducted in the United States of testosterone levels among in men aged 20-44 years.
“These findings will provide valuable information that clinicians can use in the evaluation and management of young men presenting with concerns about testosterone deficiency,” reported a team of investigators led by Alex Zhu, MD, a urology resident at the University of Michigan, Ann Arbor, in the Journal of Urology.
Outside experts, however, disagree, one saying that the conclusions are “far off and irrational.”
A normative range of testosterone is particularly important for the evaluation of hypogonadism because values vary markedly between individuals and within individuals on repeat measurements over a 24-hour period. At least partially because of this variability, many guidelines, including those issued in by the Endocrine Society and the American Urological Association, recommend testosterone assays only in symptomatic individuals in order to reduce risk of detecting low relative levels that are not clinically relevant.
NHANES data provide norms
The data for this study were drawn from the National Health and Nutrition Examination Surveys (NHANES), which sample representative United States residents. The analytic cohort included 1,486 men stratified in 5-year age intervals (20-24, 25-29, 30-34, 35-39, and 40-44).
Because of the known diurnal variation in endocrine levels, only morning total testosterone levels were considered, for consistency. Individuals at risk of disturbed testosterone levels, such as those on hormonal therapy or with a history of testicular cancer, were excluded. Unlike previous analyses that have limited measurements to nonobese individuals without major comorbidities, no such restrictions were imposed in this analysis, which included a sample balanced by race.
After dividing the testosterone levels collected in the NHANES data by tertiles, the cutoff for reduced testosterone were defined as the lowest tertile for each of the five age groups studied.
Consistent with previous reports that testosterone levels decline with age, the cutoff for low testosterone declined for each increase in 5-year age interval after the age of 29 years.
Specifically, these cutoffs were, in order of advancing age, 409 ng/dL (middle tertile range, 409-558), 413 ng/dL (range, 413-575), 359 ng/dL (range, 359-498), 352 ng/dL (range, 352-478), and 350 ng/dL (range, 350-473).
As in the AUA guidelines, which define a total testosterone level below 300 ng/dL “as a reasonable cutoff in support of the diagnosis of low testosterone,” these cutoffs were established without correlation with symptoms. In younger men, like older men, testosterone levels must be within a clinical context.
“Per the AUA guidelines, clinician should consider measuring testosterone levels in patients with certain medical conditions or signs or symptoms of testosterone deficiency, such as depression, reduced motivation, infertility, reduced sex drive, and changes in erectile function,” Dr. Zhu said in an interview, adding that it is appropriate to follow the AUA guidelines “regardless of age.”
Hormone levels and symptoms not correlated
These recommendations are based on the fact that the correlation between symptomatic hypogonadism and testosterone levels is poor, meaning that other factors should be considered when considering whether symptoms relate to deficiency. However, Dr. Zhu contended that objective evidence of a low level of testosterone is useful in considering the role of hormone deficiency.
“Even if one were to choose a different cutoff, our age-specific normative testosterone ranges still provide young men and their physicians a framework for counseling,” according to Dr. Zhu. Because of the risk of nonspecific symptoms, such as fatigue and diminished physical performance, he called for “a high index of suspicion for testosterone deficiency even when evaluating younger men.”
Considering the diurnal fluctuations, the single measurement employed to calculate normative ranges is a limitation of this study, the authors acknowledged. They cited data suggested that up to 35% of men classified as hypogonadal on the basis of a single testosterone assay will not meet the same criterion even if evaluated in the subsequent 24 hours. It is for this reason that guidelines typically recommend measuring testosterone at least twice or with more than one type of assay.
Up until now, decisions about testosterone deficiency have been with a one-size-fits-all approach, but it has long been known that patient age is a variable in determining average levels of this hormone, Dr. Zhu reported. For this reason, he predicted that these data will have clinical utility.
“We believe that our new cutoffs play an important role in evaluating younger men presenting with symptoms [of testosterone deficiency],” Dr. Zhu said. “However, clinicians should still remember that these symptoms have causes other than low testosterone, so we cannot only focus only on testing testosterone.”
However, given the lack of correlation between symptoms and testosterone levels, this area remains controversial.
Value of tertile cutoffs questioned
Two independent experts challenged the methodology and conclusions of this study.
Victor Adlin, MD, an associate professor emeritus at Temple University, Philadelphia, questioned tertile levels as an approach to defining normal.
“The authors propose unusually high cut-points for a definition of low testosterone in young men,” said Dr. Adlin, whose published a comment on age-related low testosterone in response to 2020 guidelines issued by the American College of Physicians. He is concerned that these data could lead to overtreatment.
The authors “imply that [these data] would justify treatment with testosterone in many young men with symptoms such as fatigue, depression, and lack of vigor, whose relation to low testosterone is controversial,” he said in an interview. “Trials in older men have failed to show a clear response of such symptoms to testosterone therapy.”
The first author of the 2018 Endocrine Society guidelines, Shalender Bhasin, MB, BS, director of a research program in aging and metabolism at the Brigham and Women’s Hospital in Boston, was even more skeptical.
“The whole premise of generating cutoffs for a disease or condition based on the middle tertile is just so far off and irrational,” he said. A coauthor of a 2017 study designed to define harmonized testosterone reference ranges by decade of age (that he described as providing “a much larger sample size and a wider age range” than this current study), Dr. Bhasin did not see any value in the NHANES-based analysis.
Rather, he called for an effort “to dispel this ill-conceived idea that could mislead young men to think they need testosterone treatment when they are healthy.”
Dr. Zhu and Dr. Adlin reported no potential conflicts of interest. Dr. Bhasin reported financial relationships with AbbVie, Eli Lilly, Novartis, Regeneron, and Takeda.
Normative ranges of testosterone in young men have been identified on the basis of a nationally representative data in a new study, and these data are expected to provide guidance when evaluating younger individuals presenting with signs and symptoms of potential testosterone deficiency, according to the investigators.
It has long been known that the ranges of normal testosterone differ by age, but the authors of this study contend that this is the first large-scale, population-based analysis conducted in the United States of testosterone levels among in men aged 20-44 years.
“These findings will provide valuable information that clinicians can use in the evaluation and management of young men presenting with concerns about testosterone deficiency,” reported a team of investigators led by Alex Zhu, MD, a urology resident at the University of Michigan, Ann Arbor, in the Journal of Urology.
Outside experts, however, disagree, one saying that the conclusions are “far off and irrational.”
A normative range of testosterone is particularly important for the evaluation of hypogonadism because values vary markedly between individuals and within individuals on repeat measurements over a 24-hour period. At least partially because of this variability, many guidelines, including those issued in by the Endocrine Society and the American Urological Association, recommend testosterone assays only in symptomatic individuals in order to reduce risk of detecting low relative levels that are not clinically relevant.
NHANES data provide norms
The data for this study were drawn from the National Health and Nutrition Examination Surveys (NHANES), which sample representative United States residents. The analytic cohort included 1,486 men stratified in 5-year age intervals (20-24, 25-29, 30-34, 35-39, and 40-44).
Because of the known diurnal variation in endocrine levels, only morning total testosterone levels were considered, for consistency. Individuals at risk of disturbed testosterone levels, such as those on hormonal therapy or with a history of testicular cancer, were excluded. Unlike previous analyses that have limited measurements to nonobese individuals without major comorbidities, no such restrictions were imposed in this analysis, which included a sample balanced by race.
After dividing the testosterone levels collected in the NHANES data by tertiles, the cutoff for reduced testosterone were defined as the lowest tertile for each of the five age groups studied.
Consistent with previous reports that testosterone levels decline with age, the cutoff for low testosterone declined for each increase in 5-year age interval after the age of 29 years.
Specifically, these cutoffs were, in order of advancing age, 409 ng/dL (middle tertile range, 409-558), 413 ng/dL (range, 413-575), 359 ng/dL (range, 359-498), 352 ng/dL (range, 352-478), and 350 ng/dL (range, 350-473).
As in the AUA guidelines, which define a total testosterone level below 300 ng/dL “as a reasonable cutoff in support of the diagnosis of low testosterone,” these cutoffs were established without correlation with symptoms. In younger men, like older men, testosterone levels must be within a clinical context.
“Per the AUA guidelines, clinician should consider measuring testosterone levels in patients with certain medical conditions or signs or symptoms of testosterone deficiency, such as depression, reduced motivation, infertility, reduced sex drive, and changes in erectile function,” Dr. Zhu said in an interview, adding that it is appropriate to follow the AUA guidelines “regardless of age.”
Hormone levels and symptoms not correlated
These recommendations are based on the fact that the correlation between symptomatic hypogonadism and testosterone levels is poor, meaning that other factors should be considered when considering whether symptoms relate to deficiency. However, Dr. Zhu contended that objective evidence of a low level of testosterone is useful in considering the role of hormone deficiency.
“Even if one were to choose a different cutoff, our age-specific normative testosterone ranges still provide young men and their physicians a framework for counseling,” according to Dr. Zhu. Because of the risk of nonspecific symptoms, such as fatigue and diminished physical performance, he called for “a high index of suspicion for testosterone deficiency even when evaluating younger men.”
Considering the diurnal fluctuations, the single measurement employed to calculate normative ranges is a limitation of this study, the authors acknowledged. They cited data suggested that up to 35% of men classified as hypogonadal on the basis of a single testosterone assay will not meet the same criterion even if evaluated in the subsequent 24 hours. It is for this reason that guidelines typically recommend measuring testosterone at least twice or with more than one type of assay.
Up until now, decisions about testosterone deficiency have been with a one-size-fits-all approach, but it has long been known that patient age is a variable in determining average levels of this hormone, Dr. Zhu reported. For this reason, he predicted that these data will have clinical utility.
“We believe that our new cutoffs play an important role in evaluating younger men presenting with symptoms [of testosterone deficiency],” Dr. Zhu said. “However, clinicians should still remember that these symptoms have causes other than low testosterone, so we cannot only focus only on testing testosterone.”
However, given the lack of correlation between symptoms and testosterone levels, this area remains controversial.
Value of tertile cutoffs questioned
Two independent experts challenged the methodology and conclusions of this study.
Victor Adlin, MD, an associate professor emeritus at Temple University, Philadelphia, questioned tertile levels as an approach to defining normal.
“The authors propose unusually high cut-points for a definition of low testosterone in young men,” said Dr. Adlin, whose published a comment on age-related low testosterone in response to 2020 guidelines issued by the American College of Physicians. He is concerned that these data could lead to overtreatment.
The authors “imply that [these data] would justify treatment with testosterone in many young men with symptoms such as fatigue, depression, and lack of vigor, whose relation to low testosterone is controversial,” he said in an interview. “Trials in older men have failed to show a clear response of such symptoms to testosterone therapy.”
The first author of the 2018 Endocrine Society guidelines, Shalender Bhasin, MB, BS, director of a research program in aging and metabolism at the Brigham and Women’s Hospital in Boston, was even more skeptical.
“The whole premise of generating cutoffs for a disease or condition based on the middle tertile is just so far off and irrational,” he said. A coauthor of a 2017 study designed to define harmonized testosterone reference ranges by decade of age (that he described as providing “a much larger sample size and a wider age range” than this current study), Dr. Bhasin did not see any value in the NHANES-based analysis.
Rather, he called for an effort “to dispel this ill-conceived idea that could mislead young men to think they need testosterone treatment when they are healthy.”
Dr. Zhu and Dr. Adlin reported no potential conflicts of interest. Dr. Bhasin reported financial relationships with AbbVie, Eli Lilly, Novartis, Regeneron, and Takeda.
Normative ranges of testosterone in young men have been identified on the basis of a nationally representative data in a new study, and these data are expected to provide guidance when evaluating younger individuals presenting with signs and symptoms of potential testosterone deficiency, according to the investigators.
It has long been known that the ranges of normal testosterone differ by age, but the authors of this study contend that this is the first large-scale, population-based analysis conducted in the United States of testosterone levels among in men aged 20-44 years.
“These findings will provide valuable information that clinicians can use in the evaluation and management of young men presenting with concerns about testosterone deficiency,” reported a team of investigators led by Alex Zhu, MD, a urology resident at the University of Michigan, Ann Arbor, in the Journal of Urology.
Outside experts, however, disagree, one saying that the conclusions are “far off and irrational.”
A normative range of testosterone is particularly important for the evaluation of hypogonadism because values vary markedly between individuals and within individuals on repeat measurements over a 24-hour period. At least partially because of this variability, many guidelines, including those issued in by the Endocrine Society and the American Urological Association, recommend testosterone assays only in symptomatic individuals in order to reduce risk of detecting low relative levels that are not clinically relevant.
NHANES data provide norms
The data for this study were drawn from the National Health and Nutrition Examination Surveys (NHANES), which sample representative United States residents. The analytic cohort included 1,486 men stratified in 5-year age intervals (20-24, 25-29, 30-34, 35-39, and 40-44).
Because of the known diurnal variation in endocrine levels, only morning total testosterone levels were considered, for consistency. Individuals at risk of disturbed testosterone levels, such as those on hormonal therapy or with a history of testicular cancer, were excluded. Unlike previous analyses that have limited measurements to nonobese individuals without major comorbidities, no such restrictions were imposed in this analysis, which included a sample balanced by race.
After dividing the testosterone levels collected in the NHANES data by tertiles, the cutoff for reduced testosterone were defined as the lowest tertile for each of the five age groups studied.
Consistent with previous reports that testosterone levels decline with age, the cutoff for low testosterone declined for each increase in 5-year age interval after the age of 29 years.
Specifically, these cutoffs were, in order of advancing age, 409 ng/dL (middle tertile range, 409-558), 413 ng/dL (range, 413-575), 359 ng/dL (range, 359-498), 352 ng/dL (range, 352-478), and 350 ng/dL (range, 350-473).
As in the AUA guidelines, which define a total testosterone level below 300 ng/dL “as a reasonable cutoff in support of the diagnosis of low testosterone,” these cutoffs were established without correlation with symptoms. In younger men, like older men, testosterone levels must be within a clinical context.
“Per the AUA guidelines, clinician should consider measuring testosterone levels in patients with certain medical conditions or signs or symptoms of testosterone deficiency, such as depression, reduced motivation, infertility, reduced sex drive, and changes in erectile function,” Dr. Zhu said in an interview, adding that it is appropriate to follow the AUA guidelines “regardless of age.”
Hormone levels and symptoms not correlated
These recommendations are based on the fact that the correlation between symptomatic hypogonadism and testosterone levels is poor, meaning that other factors should be considered when considering whether symptoms relate to deficiency. However, Dr. Zhu contended that objective evidence of a low level of testosterone is useful in considering the role of hormone deficiency.
“Even if one were to choose a different cutoff, our age-specific normative testosterone ranges still provide young men and their physicians a framework for counseling,” according to Dr. Zhu. Because of the risk of nonspecific symptoms, such as fatigue and diminished physical performance, he called for “a high index of suspicion for testosterone deficiency even when evaluating younger men.”
Considering the diurnal fluctuations, the single measurement employed to calculate normative ranges is a limitation of this study, the authors acknowledged. They cited data suggested that up to 35% of men classified as hypogonadal on the basis of a single testosterone assay will not meet the same criterion even if evaluated in the subsequent 24 hours. It is for this reason that guidelines typically recommend measuring testosterone at least twice or with more than one type of assay.
Up until now, decisions about testosterone deficiency have been with a one-size-fits-all approach, but it has long been known that patient age is a variable in determining average levels of this hormone, Dr. Zhu reported. For this reason, he predicted that these data will have clinical utility.
“We believe that our new cutoffs play an important role in evaluating younger men presenting with symptoms [of testosterone deficiency],” Dr. Zhu said. “However, clinicians should still remember that these symptoms have causes other than low testosterone, so we cannot only focus only on testing testosterone.”
However, given the lack of correlation between symptoms and testosterone levels, this area remains controversial.
Value of tertile cutoffs questioned
Two independent experts challenged the methodology and conclusions of this study.
Victor Adlin, MD, an associate professor emeritus at Temple University, Philadelphia, questioned tertile levels as an approach to defining normal.
“The authors propose unusually high cut-points for a definition of low testosterone in young men,” said Dr. Adlin, whose published a comment on age-related low testosterone in response to 2020 guidelines issued by the American College of Physicians. He is concerned that these data could lead to overtreatment.
The authors “imply that [these data] would justify treatment with testosterone in many young men with symptoms such as fatigue, depression, and lack of vigor, whose relation to low testosterone is controversial,” he said in an interview. “Trials in older men have failed to show a clear response of such symptoms to testosterone therapy.”
The first author of the 2018 Endocrine Society guidelines, Shalender Bhasin, MB, BS, director of a research program in aging and metabolism at the Brigham and Women’s Hospital in Boston, was even more skeptical.
“The whole premise of generating cutoffs for a disease or condition based on the middle tertile is just so far off and irrational,” he said. A coauthor of a 2017 study designed to define harmonized testosterone reference ranges by decade of age (that he described as providing “a much larger sample size and a wider age range” than this current study), Dr. Bhasin did not see any value in the NHANES-based analysis.
Rather, he called for an effort “to dispel this ill-conceived idea that could mislead young men to think they need testosterone treatment when they are healthy.”
Dr. Zhu and Dr. Adlin reported no potential conflicts of interest. Dr. Bhasin reported financial relationships with AbbVie, Eli Lilly, Novartis, Regeneron, and Takeda.
FROM THE JOURNAL OF UROLOGY
Two-year dupilumab data: Continued response for moderate to severe pediatric asthma
NASHVILLE, TENN. – For children with uncontrolled asthma on standard therapies and meeting criteria of a type 2 (T2) inflammatory phenotype, a prospective 1-year extension from a phase 3 trial supports the biologic dupilumab as a potential treatment standard, according to the investigator who presented the findings at the annual meeting of the American College of Chest Physicians (CHEST).
said Leonard B. Bacharier, MD, section chief, division of pediatric allergy, immunology, and pulmonary medicine, Vanderbilt University Medical Center, Nashville, Tenn.
By T2 inflammatory phenotype, Dr. Bacharier specified that key features include an eosinophil count of at least 150 cells/mL and a FENO level of at least 20 ppb. If children meet these and inadequate standard-therapy response criteria, Dr. Bacharier thinks the extension data support dupilumab as a routine therapy despite the cost.
“As a pediatrician, I think it is really important that children with asthma finish their childhood with the best bone health and the lowest risk of other steroid-associated adverse events,” Dr. Bacharier said.
Over the course of the 1-year extension, called EXCURSION, there was no evidence of diminished efficacy nor of any new safety signal. In other words, patients have remained well controlled for 2 years with a well-tolerated therapy. Dr. Bacharier pointed out, however, that one of the most compelling reasons to consider this as a potential standard was the very low rates at which patients required a course of steroids.
At the end of 1 year in the extension trial, called VOYAGE, the unadjusted annualized total number of steroid courses per patient was 0.414 in the dupilumab group vs. 0.816 in the placebo group. At the end of EXCURSION, following an additional year of therapy, the rate was 0.152.
“This means that fewer than 2 patients out of 10 required prednisone in the previous year,” Dr. Bacharier said.
The EXCURSION extension study did not capture data on steroid-related adverse events, but Dr. Bacharier said that these data are reassuring for both acute and long-term risks of steroid exposure.
“We know that the adverse effects associated with oral steroids are related to cumulative exposure. The more you receive, the greater the risk of adverse effects,” he said.
In patients who were randomly assigned to placebo in the VOYAGE trial and then switched to dupilumab in the EXCURSION extension, steroid exposure was also very low, but whether evaluated as annualized total courses (0.152 vs. 0.181) or by proportion of patients with any steroid intake (10.5% vs. 13.2%), there was a numerical advantage for starting and remaining on dupilumab over the 2-year follow-up.
In VOYAGE, which was published last year in the New England Journal of Medicine, 408 children from ages 6 to 11 years were randomly assigned in a 2:1 ratio to dupilumab or matching placebo. For children weighing less than 30 kg, the dose was 200 mg. For those who weighed less, the dose was 100 mg. Both doses were administered every 2 weeks.
As previously reported, the study met the primary endpoint of annualized rate of severe asthma exacerbations, which was 0.31 in the dupilumab group vs. 0.75 in the placebo group, a relative reduction of 59.3% (P < .001). Dupilumab was also superior on several secondary endpoints, including measures of lung function and asthma control.
The EXCURSION extension study enrolled 365 of the patients who participated in VOYAGE. This included 125 of the 135 randomly assigned to placebo and 240 of the 273 randomly assigned to dupilumab. Those initially randomly assigned to placebo were transitioned to dupilumab. The same weight-based dosing was employed.
At baseline, the children enrolled in VOYAGE had an annualized rate of 2.560 severe exacerbations. At the end of VOYAGE, this rate was 0.330. At the end of EXCURSION after 2 years on dupilumab, the rate was 0.118. In the group switched from placebo to dupilumab, the rate was 0.124.
During EXCURSION, treatment-emergent adverse events occurred in 2.5% of those who remained on dupilumab and 0.8% of those switched from placebo to dupilumab. Three patients (1.3%) permanently discontinued therapy because of a treatment-related event. The most common adverse events involved upper respiratory complaints, such as nasopharyngitis, pharyngitis, upper respiratory tract infections, and rhinitis influenza, but all were reported in fewer than 10% of patients. Other reported side effects, such as injection-site reactions and diarrhea, occurred in 5% or fewer of patients.
“Over the 2 years, dupilumab was well tolerated, and there was evidence of an increased risk of adverse events for longer exposure,” Dr. Bacharier reported.
It is for this reason that Dr. Bacharier concluded that children with repeated exacerbations requiring steroids despite standard therapies should be considered for dupilumab if they also meet criteria for the T2 inflammatory phenotype. This last point is important.
“In children with low levels of eosinophil and low phenol, we are not seeing these kinds of response,” Dr. Bacharier said. Rather, in the absence of eosinophilia, “there is probably no difference between dupilumab and placebo.”
An important steroid-sparing effect is “suggested” by the data, but Sally E. Wenzel, MD, director of the University of Pittsburgh Asthma and Environmental Lung Health Institute in Pittsburgh, characterized the idea that dupilumab is emerging to be a standard in uncontrolled asthma in children with the T2 phenotype as “a bit premature.”
She challenged the conclusion that the EXCURSION data associated dupilumab with a reduction in annualized steroid courses over time. While the number was lower after 2 years of treatment than after 1, Dr. Wenzel pointed out that all patients were on dupilumab in the second year, “so we don’t know what really happens without treatment.” She said there are other potential explanations, including the possibility that aging children have less active disease.
More importantly, Dr. Wenzel said in an interview that she would also hesitate to urge biologics in every child who meets the criteria that Dr. Bacharier outlined.
“The most important concern is that we do not know how long one should continue the dupilumab and if the long-term treatment adversely or positively affects a growing immune system,” she said.
There is reason to be concerned that blockage of an entire immune pathway with a biologic could adversely affect autoimmunity as well as susceptibility to cancer, according to Dr. Wenzel. She hopes this does not prove to be the case, but she encouraged prudence until there are more data to judge.
While extension data for dupilumab “sound good,” she thinks moving toward any type of standard of care with biologics in children “has to be done with caution and constant evaluation and reevaluation.”
Dr. Bacharier disclosed relationships with AstraZeneca, GlaxoSmithKline, Regeneron and Sanofi. The two latter companies collaborated on the development and marketing of dupilumab. Dr. Wenzel disclosed relationships with AstraZeneca, GlaxoSmithKline, Knopp Pharmaceuticals, Pieris, and Sanofi-Regeneron.
A version of this article first appeared on Medscape.com.
NASHVILLE, TENN. – For children with uncontrolled asthma on standard therapies and meeting criteria of a type 2 (T2) inflammatory phenotype, a prospective 1-year extension from a phase 3 trial supports the biologic dupilumab as a potential treatment standard, according to the investigator who presented the findings at the annual meeting of the American College of Chest Physicians (CHEST).
said Leonard B. Bacharier, MD, section chief, division of pediatric allergy, immunology, and pulmonary medicine, Vanderbilt University Medical Center, Nashville, Tenn.
By T2 inflammatory phenotype, Dr. Bacharier specified that key features include an eosinophil count of at least 150 cells/mL and a FENO level of at least 20 ppb. If children meet these and inadequate standard-therapy response criteria, Dr. Bacharier thinks the extension data support dupilumab as a routine therapy despite the cost.
“As a pediatrician, I think it is really important that children with asthma finish their childhood with the best bone health and the lowest risk of other steroid-associated adverse events,” Dr. Bacharier said.
Over the course of the 1-year extension, called EXCURSION, there was no evidence of diminished efficacy nor of any new safety signal. In other words, patients have remained well controlled for 2 years with a well-tolerated therapy. Dr. Bacharier pointed out, however, that one of the most compelling reasons to consider this as a potential standard was the very low rates at which patients required a course of steroids.
At the end of 1 year in the extension trial, called VOYAGE, the unadjusted annualized total number of steroid courses per patient was 0.414 in the dupilumab group vs. 0.816 in the placebo group. At the end of EXCURSION, following an additional year of therapy, the rate was 0.152.
“This means that fewer than 2 patients out of 10 required prednisone in the previous year,” Dr. Bacharier said.
The EXCURSION extension study did not capture data on steroid-related adverse events, but Dr. Bacharier said that these data are reassuring for both acute and long-term risks of steroid exposure.
“We know that the adverse effects associated with oral steroids are related to cumulative exposure. The more you receive, the greater the risk of adverse effects,” he said.
In patients who were randomly assigned to placebo in the VOYAGE trial and then switched to dupilumab in the EXCURSION extension, steroid exposure was also very low, but whether evaluated as annualized total courses (0.152 vs. 0.181) or by proportion of patients with any steroid intake (10.5% vs. 13.2%), there was a numerical advantage for starting and remaining on dupilumab over the 2-year follow-up.
In VOYAGE, which was published last year in the New England Journal of Medicine, 408 children from ages 6 to 11 years were randomly assigned in a 2:1 ratio to dupilumab or matching placebo. For children weighing less than 30 kg, the dose was 200 mg. For those who weighed less, the dose was 100 mg. Both doses were administered every 2 weeks.
As previously reported, the study met the primary endpoint of annualized rate of severe asthma exacerbations, which was 0.31 in the dupilumab group vs. 0.75 in the placebo group, a relative reduction of 59.3% (P < .001). Dupilumab was also superior on several secondary endpoints, including measures of lung function and asthma control.
The EXCURSION extension study enrolled 365 of the patients who participated in VOYAGE. This included 125 of the 135 randomly assigned to placebo and 240 of the 273 randomly assigned to dupilumab. Those initially randomly assigned to placebo were transitioned to dupilumab. The same weight-based dosing was employed.
At baseline, the children enrolled in VOYAGE had an annualized rate of 2.560 severe exacerbations. At the end of VOYAGE, this rate was 0.330. At the end of EXCURSION after 2 years on dupilumab, the rate was 0.118. In the group switched from placebo to dupilumab, the rate was 0.124.
During EXCURSION, treatment-emergent adverse events occurred in 2.5% of those who remained on dupilumab and 0.8% of those switched from placebo to dupilumab. Three patients (1.3%) permanently discontinued therapy because of a treatment-related event. The most common adverse events involved upper respiratory complaints, such as nasopharyngitis, pharyngitis, upper respiratory tract infections, and rhinitis influenza, but all were reported in fewer than 10% of patients. Other reported side effects, such as injection-site reactions and diarrhea, occurred in 5% or fewer of patients.
“Over the 2 years, dupilumab was well tolerated, and there was evidence of an increased risk of adverse events for longer exposure,” Dr. Bacharier reported.
It is for this reason that Dr. Bacharier concluded that children with repeated exacerbations requiring steroids despite standard therapies should be considered for dupilumab if they also meet criteria for the T2 inflammatory phenotype. This last point is important.
“In children with low levels of eosinophil and low phenol, we are not seeing these kinds of response,” Dr. Bacharier said. Rather, in the absence of eosinophilia, “there is probably no difference between dupilumab and placebo.”
An important steroid-sparing effect is “suggested” by the data, but Sally E. Wenzel, MD, director of the University of Pittsburgh Asthma and Environmental Lung Health Institute in Pittsburgh, characterized the idea that dupilumab is emerging to be a standard in uncontrolled asthma in children with the T2 phenotype as “a bit premature.”
She challenged the conclusion that the EXCURSION data associated dupilumab with a reduction in annualized steroid courses over time. While the number was lower after 2 years of treatment than after 1, Dr. Wenzel pointed out that all patients were on dupilumab in the second year, “so we don’t know what really happens without treatment.” She said there are other potential explanations, including the possibility that aging children have less active disease.
More importantly, Dr. Wenzel said in an interview that she would also hesitate to urge biologics in every child who meets the criteria that Dr. Bacharier outlined.
“The most important concern is that we do not know how long one should continue the dupilumab and if the long-term treatment adversely or positively affects a growing immune system,” she said.
There is reason to be concerned that blockage of an entire immune pathway with a biologic could adversely affect autoimmunity as well as susceptibility to cancer, according to Dr. Wenzel. She hopes this does not prove to be the case, but she encouraged prudence until there are more data to judge.
While extension data for dupilumab “sound good,” she thinks moving toward any type of standard of care with biologics in children “has to be done with caution and constant evaluation and reevaluation.”
Dr. Bacharier disclosed relationships with AstraZeneca, GlaxoSmithKline, Regeneron and Sanofi. The two latter companies collaborated on the development and marketing of dupilumab. Dr. Wenzel disclosed relationships with AstraZeneca, GlaxoSmithKline, Knopp Pharmaceuticals, Pieris, and Sanofi-Regeneron.
A version of this article first appeared on Medscape.com.
NASHVILLE, TENN. – For children with uncontrolled asthma on standard therapies and meeting criteria of a type 2 (T2) inflammatory phenotype, a prospective 1-year extension from a phase 3 trial supports the biologic dupilumab as a potential treatment standard, according to the investigator who presented the findings at the annual meeting of the American College of Chest Physicians (CHEST).
said Leonard B. Bacharier, MD, section chief, division of pediatric allergy, immunology, and pulmonary medicine, Vanderbilt University Medical Center, Nashville, Tenn.
By T2 inflammatory phenotype, Dr. Bacharier specified that key features include an eosinophil count of at least 150 cells/mL and a FENO level of at least 20 ppb. If children meet these and inadequate standard-therapy response criteria, Dr. Bacharier thinks the extension data support dupilumab as a routine therapy despite the cost.
“As a pediatrician, I think it is really important that children with asthma finish their childhood with the best bone health and the lowest risk of other steroid-associated adverse events,” Dr. Bacharier said.
Over the course of the 1-year extension, called EXCURSION, there was no evidence of diminished efficacy nor of any new safety signal. In other words, patients have remained well controlled for 2 years with a well-tolerated therapy. Dr. Bacharier pointed out, however, that one of the most compelling reasons to consider this as a potential standard was the very low rates at which patients required a course of steroids.
At the end of 1 year in the extension trial, called VOYAGE, the unadjusted annualized total number of steroid courses per patient was 0.414 in the dupilumab group vs. 0.816 in the placebo group. At the end of EXCURSION, following an additional year of therapy, the rate was 0.152.
“This means that fewer than 2 patients out of 10 required prednisone in the previous year,” Dr. Bacharier said.
The EXCURSION extension study did not capture data on steroid-related adverse events, but Dr. Bacharier said that these data are reassuring for both acute and long-term risks of steroid exposure.
“We know that the adverse effects associated with oral steroids are related to cumulative exposure. The more you receive, the greater the risk of adverse effects,” he said.
In patients who were randomly assigned to placebo in the VOYAGE trial and then switched to dupilumab in the EXCURSION extension, steroid exposure was also very low, but whether evaluated as annualized total courses (0.152 vs. 0.181) or by proportion of patients with any steroid intake (10.5% vs. 13.2%), there was a numerical advantage for starting and remaining on dupilumab over the 2-year follow-up.
In VOYAGE, which was published last year in the New England Journal of Medicine, 408 children from ages 6 to 11 years were randomly assigned in a 2:1 ratio to dupilumab or matching placebo. For children weighing less than 30 kg, the dose was 200 mg. For those who weighed less, the dose was 100 mg. Both doses were administered every 2 weeks.
As previously reported, the study met the primary endpoint of annualized rate of severe asthma exacerbations, which was 0.31 in the dupilumab group vs. 0.75 in the placebo group, a relative reduction of 59.3% (P < .001). Dupilumab was also superior on several secondary endpoints, including measures of lung function and asthma control.
The EXCURSION extension study enrolled 365 of the patients who participated in VOYAGE. This included 125 of the 135 randomly assigned to placebo and 240 of the 273 randomly assigned to dupilumab. Those initially randomly assigned to placebo were transitioned to dupilumab. The same weight-based dosing was employed.
At baseline, the children enrolled in VOYAGE had an annualized rate of 2.560 severe exacerbations. At the end of VOYAGE, this rate was 0.330. At the end of EXCURSION after 2 years on dupilumab, the rate was 0.118. In the group switched from placebo to dupilumab, the rate was 0.124.
During EXCURSION, treatment-emergent adverse events occurred in 2.5% of those who remained on dupilumab and 0.8% of those switched from placebo to dupilumab. Three patients (1.3%) permanently discontinued therapy because of a treatment-related event. The most common adverse events involved upper respiratory complaints, such as nasopharyngitis, pharyngitis, upper respiratory tract infections, and rhinitis influenza, but all were reported in fewer than 10% of patients. Other reported side effects, such as injection-site reactions and diarrhea, occurred in 5% or fewer of patients.
“Over the 2 years, dupilumab was well tolerated, and there was evidence of an increased risk of adverse events for longer exposure,” Dr. Bacharier reported.
It is for this reason that Dr. Bacharier concluded that children with repeated exacerbations requiring steroids despite standard therapies should be considered for dupilumab if they also meet criteria for the T2 inflammatory phenotype. This last point is important.
“In children with low levels of eosinophil and low phenol, we are not seeing these kinds of response,” Dr. Bacharier said. Rather, in the absence of eosinophilia, “there is probably no difference between dupilumab and placebo.”
An important steroid-sparing effect is “suggested” by the data, but Sally E. Wenzel, MD, director of the University of Pittsburgh Asthma and Environmental Lung Health Institute in Pittsburgh, characterized the idea that dupilumab is emerging to be a standard in uncontrolled asthma in children with the T2 phenotype as “a bit premature.”
She challenged the conclusion that the EXCURSION data associated dupilumab with a reduction in annualized steroid courses over time. While the number was lower after 2 years of treatment than after 1, Dr. Wenzel pointed out that all patients were on dupilumab in the second year, “so we don’t know what really happens without treatment.” She said there are other potential explanations, including the possibility that aging children have less active disease.
More importantly, Dr. Wenzel said in an interview that she would also hesitate to urge biologics in every child who meets the criteria that Dr. Bacharier outlined.
“The most important concern is that we do not know how long one should continue the dupilumab and if the long-term treatment adversely or positively affects a growing immune system,” she said.
There is reason to be concerned that blockage of an entire immune pathway with a biologic could adversely affect autoimmunity as well as susceptibility to cancer, according to Dr. Wenzel. She hopes this does not prove to be the case, but she encouraged prudence until there are more data to judge.
While extension data for dupilumab “sound good,” she thinks moving toward any type of standard of care with biologics in children “has to be done with caution and constant evaluation and reevaluation.”
Dr. Bacharier disclosed relationships with AstraZeneca, GlaxoSmithKline, Regeneron and Sanofi. The two latter companies collaborated on the development and marketing of dupilumab. Dr. Wenzel disclosed relationships with AstraZeneca, GlaxoSmithKline, Knopp Pharmaceuticals, Pieris, and Sanofi-Regeneron.
A version of this article first appeared on Medscape.com.
AT CHEST 2022
Pregnancy termination counseling for lung disease requires new caution
NASHVILLE, TENN. – In a growing number of states, , according to a panel of experts assembled for a special session at the annual meeting of the American College of Chest Physicians.
Following the June 24 decision by the U.S. Supreme Court to overturn Roe v. Wade, several states were swift to enact tight restrictions on abortion. These restrictions include bans on elective abortions for almost any reason. Worded in various ways, the new laws typically include exceptions when the health of the mother is threatened, but these exceptions must be navigated carefully.
As a general rule, “there is no clear and specific definition of when the mother’s life is at risk. These laws are vague on purpose,” said Rebecca Cohen, MD, division chief, Complex Family Planning, University of Colorado at Denver, Aurora.
The remarks were relevant to any clinician who advises women regarding pregnancy termination, but Dr. Cohen’s advice was tailored to pulmonologists. Advances have reduced the proportion of women with severe lung diseases, such as pulmonary arterial hypertension or interstitial lung disease, that make pregnancy untenable, but serious risks persist.
Clinicians need to assume a defensive posture, and the first step is to understand the laws, according to Dr. Cohen. For this, she recommended the nongovernmental Guttmacher Institute as a resource. With a focus on sexual and reproductive health, this research institute maintains a state-by-state summary of laws that govern pregnancy termination. The laws are being reconsidered across the country, and Dr. Cohen said the website updates its summaries accordingly.
In states with the most rigorous restrictions, the risks to physicians are substantial. Pulmonologists need to recognize that they might face legal consequences from merely advising a patient to terminate her pregnancy if the medical need is ambiguous or unclear, according to Dr. Cohen.
“If the advice is interpreted as aiding and abetting an elective abortion, it is a felony offense in some states,” Dr. Cohen said.
In states with restrictive laws, pregnancy prevention is the safest approach for women of childbearing age who face life-threatening complications in the event of pregnancy, according to Dr. Cohen. This might reasonably include a step beyond standard contraception. Dr. Cohen mentioned such approaches as period tracking to double down.
In addition, for women of childbearing age with health problems that might result in complications in the event of a pregnancy, it is appropriate to establish this fact in the medical record. This history could prove useful for maximizing options when making decisions in the best interest of the mother’s health in the event of contraception failure.
In addition, pulmonologists who counsel women about the potential for pregnancy termination should consider establishing a relationship with the legal department at the institution where they work, according to Dr. Cohen. In specific cases in which termination is recommended, she further advised building documentation with participation from additional medical specialists, such as an obstetrician who manages high-risk pregnancies.
“There is no guarantee that any given documentation is adequate,” Dr. Cohen warned. She indicated that consensus from multiple clinicians can strengthen the legal defense if one is necessary.
For some serious lung conditions that are incompatible with pregnancy, the threat to the mother’s life can occur early, according to Deborah Jo Levine, MD, a clinical instructor in the division of pulmonary, allergy, and critical care medicine, Stanford (Calif.) University.
As a result, “you need to identify at-risk patients early and develop a plan promptly,” said Dr. Levine, who joined Dr. Cohen on the special panel at the CHEST 2022 meeting. Even when termination is medically appropriate, restrictive laws are making these services harder to find.
In the case of a pregnancy likely to pose a high risk of complications owing to the patient’s having lung disease, “it is important to involve a high-risk ob quickly,” Dr. Levine warned. “In some cases, termination poses less risk if performed early.”
Sunjay R. Devarajan, MD, assistant professor of pulmonary medicine and critical care, Baylor College of Medicine, Houston, has faced this issue in a state that has some of the most restrictive laws. Even when there is no debate about the necessity of a medically indicated abortion, he cautioned that abortion services are becoming harder to find.
“A recent patient who had a complicated unintentional pregnancy on our service had to go out of state for pregnancy termination,” Dr. Devarajan said. He noted that this option is not available to all women, particularly in states such as his own in which most bordering states also now have highly restrictive abortion laws.
On the basis of this experience, he is thinking more defensively. Now that clinicians can be drawn into legal proceedings even when pregnancy termination is indicated, he agreed that clinicians must become familiar with the local laws.
“We are doing better in managing pregnancies in women with serious lung diseases, but termination is still the prudent approach in some cases,” Dr. Devarajan said. He indicated that he considered the advice offered by Dr. Cohen helpful in avoiding complications for the patient and the physician.
Dr. Cohen, Dr. Levine, and Dr. Devarajan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NASHVILLE, TENN. – In a growing number of states, , according to a panel of experts assembled for a special session at the annual meeting of the American College of Chest Physicians.
Following the June 24 decision by the U.S. Supreme Court to overturn Roe v. Wade, several states were swift to enact tight restrictions on abortion. These restrictions include bans on elective abortions for almost any reason. Worded in various ways, the new laws typically include exceptions when the health of the mother is threatened, but these exceptions must be navigated carefully.
As a general rule, “there is no clear and specific definition of when the mother’s life is at risk. These laws are vague on purpose,” said Rebecca Cohen, MD, division chief, Complex Family Planning, University of Colorado at Denver, Aurora.
The remarks were relevant to any clinician who advises women regarding pregnancy termination, but Dr. Cohen’s advice was tailored to pulmonologists. Advances have reduced the proportion of women with severe lung diseases, such as pulmonary arterial hypertension or interstitial lung disease, that make pregnancy untenable, but serious risks persist.
Clinicians need to assume a defensive posture, and the first step is to understand the laws, according to Dr. Cohen. For this, she recommended the nongovernmental Guttmacher Institute as a resource. With a focus on sexual and reproductive health, this research institute maintains a state-by-state summary of laws that govern pregnancy termination. The laws are being reconsidered across the country, and Dr. Cohen said the website updates its summaries accordingly.
In states with the most rigorous restrictions, the risks to physicians are substantial. Pulmonologists need to recognize that they might face legal consequences from merely advising a patient to terminate her pregnancy if the medical need is ambiguous or unclear, according to Dr. Cohen.
“If the advice is interpreted as aiding and abetting an elective abortion, it is a felony offense in some states,” Dr. Cohen said.
In states with restrictive laws, pregnancy prevention is the safest approach for women of childbearing age who face life-threatening complications in the event of pregnancy, according to Dr. Cohen. This might reasonably include a step beyond standard contraception. Dr. Cohen mentioned such approaches as period tracking to double down.
In addition, for women of childbearing age with health problems that might result in complications in the event of a pregnancy, it is appropriate to establish this fact in the medical record. This history could prove useful for maximizing options when making decisions in the best interest of the mother’s health in the event of contraception failure.
In addition, pulmonologists who counsel women about the potential for pregnancy termination should consider establishing a relationship with the legal department at the institution where they work, according to Dr. Cohen. In specific cases in which termination is recommended, she further advised building documentation with participation from additional medical specialists, such as an obstetrician who manages high-risk pregnancies.
“There is no guarantee that any given documentation is adequate,” Dr. Cohen warned. She indicated that consensus from multiple clinicians can strengthen the legal defense if one is necessary.
For some serious lung conditions that are incompatible with pregnancy, the threat to the mother’s life can occur early, according to Deborah Jo Levine, MD, a clinical instructor in the division of pulmonary, allergy, and critical care medicine, Stanford (Calif.) University.
As a result, “you need to identify at-risk patients early and develop a plan promptly,” said Dr. Levine, who joined Dr. Cohen on the special panel at the CHEST 2022 meeting. Even when termination is medically appropriate, restrictive laws are making these services harder to find.
In the case of a pregnancy likely to pose a high risk of complications owing to the patient’s having lung disease, “it is important to involve a high-risk ob quickly,” Dr. Levine warned. “In some cases, termination poses less risk if performed early.”
Sunjay R. Devarajan, MD, assistant professor of pulmonary medicine and critical care, Baylor College of Medicine, Houston, has faced this issue in a state that has some of the most restrictive laws. Even when there is no debate about the necessity of a medically indicated abortion, he cautioned that abortion services are becoming harder to find.
“A recent patient who had a complicated unintentional pregnancy on our service had to go out of state for pregnancy termination,” Dr. Devarajan said. He noted that this option is not available to all women, particularly in states such as his own in which most bordering states also now have highly restrictive abortion laws.
On the basis of this experience, he is thinking more defensively. Now that clinicians can be drawn into legal proceedings even when pregnancy termination is indicated, he agreed that clinicians must become familiar with the local laws.
“We are doing better in managing pregnancies in women with serious lung diseases, but termination is still the prudent approach in some cases,” Dr. Devarajan said. He indicated that he considered the advice offered by Dr. Cohen helpful in avoiding complications for the patient and the physician.
Dr. Cohen, Dr. Levine, and Dr. Devarajan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NASHVILLE, TENN. – In a growing number of states, , according to a panel of experts assembled for a special session at the annual meeting of the American College of Chest Physicians.
Following the June 24 decision by the U.S. Supreme Court to overturn Roe v. Wade, several states were swift to enact tight restrictions on abortion. These restrictions include bans on elective abortions for almost any reason. Worded in various ways, the new laws typically include exceptions when the health of the mother is threatened, but these exceptions must be navigated carefully.
As a general rule, “there is no clear and specific definition of when the mother’s life is at risk. These laws are vague on purpose,” said Rebecca Cohen, MD, division chief, Complex Family Planning, University of Colorado at Denver, Aurora.
The remarks were relevant to any clinician who advises women regarding pregnancy termination, but Dr. Cohen’s advice was tailored to pulmonologists. Advances have reduced the proportion of women with severe lung diseases, such as pulmonary arterial hypertension or interstitial lung disease, that make pregnancy untenable, but serious risks persist.
Clinicians need to assume a defensive posture, and the first step is to understand the laws, according to Dr. Cohen. For this, she recommended the nongovernmental Guttmacher Institute as a resource. With a focus on sexual and reproductive health, this research institute maintains a state-by-state summary of laws that govern pregnancy termination. The laws are being reconsidered across the country, and Dr. Cohen said the website updates its summaries accordingly.
In states with the most rigorous restrictions, the risks to physicians are substantial. Pulmonologists need to recognize that they might face legal consequences from merely advising a patient to terminate her pregnancy if the medical need is ambiguous or unclear, according to Dr. Cohen.
“If the advice is interpreted as aiding and abetting an elective abortion, it is a felony offense in some states,” Dr. Cohen said.
In states with restrictive laws, pregnancy prevention is the safest approach for women of childbearing age who face life-threatening complications in the event of pregnancy, according to Dr. Cohen. This might reasonably include a step beyond standard contraception. Dr. Cohen mentioned such approaches as period tracking to double down.
In addition, for women of childbearing age with health problems that might result in complications in the event of a pregnancy, it is appropriate to establish this fact in the medical record. This history could prove useful for maximizing options when making decisions in the best interest of the mother’s health in the event of contraception failure.
In addition, pulmonologists who counsel women about the potential for pregnancy termination should consider establishing a relationship with the legal department at the institution where they work, according to Dr. Cohen. In specific cases in which termination is recommended, she further advised building documentation with participation from additional medical specialists, such as an obstetrician who manages high-risk pregnancies.
“There is no guarantee that any given documentation is adequate,” Dr. Cohen warned. She indicated that consensus from multiple clinicians can strengthen the legal defense if one is necessary.
For some serious lung conditions that are incompatible with pregnancy, the threat to the mother’s life can occur early, according to Deborah Jo Levine, MD, a clinical instructor in the division of pulmonary, allergy, and critical care medicine, Stanford (Calif.) University.
As a result, “you need to identify at-risk patients early and develop a plan promptly,” said Dr. Levine, who joined Dr. Cohen on the special panel at the CHEST 2022 meeting. Even when termination is medically appropriate, restrictive laws are making these services harder to find.
In the case of a pregnancy likely to pose a high risk of complications owing to the patient’s having lung disease, “it is important to involve a high-risk ob quickly,” Dr. Levine warned. “In some cases, termination poses less risk if performed early.”
Sunjay R. Devarajan, MD, assistant professor of pulmonary medicine and critical care, Baylor College of Medicine, Houston, has faced this issue in a state that has some of the most restrictive laws. Even when there is no debate about the necessity of a medically indicated abortion, he cautioned that abortion services are becoming harder to find.
“A recent patient who had a complicated unintentional pregnancy on our service had to go out of state for pregnancy termination,” Dr. Devarajan said. He noted that this option is not available to all women, particularly in states such as his own in which most bordering states also now have highly restrictive abortion laws.
On the basis of this experience, he is thinking more defensively. Now that clinicians can be drawn into legal proceedings even when pregnancy termination is indicated, he agreed that clinicians must become familiar with the local laws.
“We are doing better in managing pregnancies in women with serious lung diseases, but termination is still the prudent approach in some cases,” Dr. Devarajan said. He indicated that he considered the advice offered by Dr. Cohen helpful in avoiding complications for the patient and the physician.
Dr. Cohen, Dr. Levine, and Dr. Devarajan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Large trial of home-based COPD rehab shows positive results
NASHVILLE – The first multicenter randomized controlled trial of a home-based rehabilitation program for patients with chronic obstructive pulmonary disease (COPD) showed highly positive results, according to findings presented at the annual meeting of the American College of Chest Physicians (CHEST).
At the end of 12 weeks, those randomly assigned to the intervention had a significant and clinically meaningful improvement in all domains of the Chronic Respiratory Questionnaire (CRQ), including activity levels and emotional well-being, reported Roberto P. Benzo, MD, a consultant in the division of pulmonary and critical care medicine, Mayo Clinic, Rochester, Minn.
Presenting soon-to-be-published data, Dr. Benzo said that the intervention is based on a tablet-based app. The tablet is programmed to upload data captured from an activity monitor and pulse oximeter. Along with documentation of app usage, this information can then be downloaded for the remote coach to review with the patient.
The primary outcome of the randomized study were the physical and emotional domains of the CRQ quality of life, but a long list of secondary outcomes – including physical activity, symptoms of depression, sleep quality, and health care utilization, such as emergency room visits – was also analyzed.
In addition to the significant benefit on the primary outcomes, the home-based rehabilitation program relative to a wait list for intervention was associated with benefit or a trend for benefit on essentially every outcome measured. Health care utilization was a possible exception, but even then, the absolute number of visits was lower in the treatment arm.
“With a study period of only 12 weeks, we were limited to our ability to show a difference in emergency room visits,” said Dr. Benzo, who also noted that the study was conducted during the COVID-19 pandemic, when hospital visits were already occurring at a lower than usual rate. Based on the other findings, he suspects that a reduction in health care utilization could also be shown in more typical circumstances, particularly with a longer follow-up.
In the study, 375 patients with COPD were randomly assigned to a home health care regimen delivered by an app with remote coaching or to a wait list and usual care. The median age was 69 years. Fifty-nine percent were women. The median FEV1 at enrollment was 45% of predicted.
The patients were able to access their own data to monitor their progress at any time, not just at the time of coaching, but contact with the remote coach occurred on a weekly basis. Patients rated their level of energy, how they felt generally, and their progress toward daily goals, which was also captured on the app and could be discussed with the coach during the review of the previous week’s activity.
At 12 weeks, the favorable 0.54-point change (P < .001) and 0.51 change (P < .001) in the physical and emotional summary scores, respectively, met the criteria for a clinically meaningful change, Dr. Benzo reported. There were also significantly favorable changes from baseline and relative to controls in CRQ domains of self-management, sleep quality, and depression (all P ≤ .01).
Other data collected are supportive. For example, Dr. Benzo reported that those in the rehabilitation group took 624 more steps on average per day than those in the control group. The experimental group also spent nearly an hour more performing moderate or greater levels of activity.
“The app promotes behavioral change,” said Dr. Benzo, who said that this “completely home-based model” of rehabilitation is likely to be cost-effective given the relatively low costs of remote coaching and reasonable costs of the activity monitor, tablet, and other equipment.
Importantly, home-based rehabilitation is a billable practice under currently available CPT codes, according to Dr. Benzo, who believes this approach is not only effective but “feasible and practical.”
Two clinicians active in the care of patients with COPD believe this approach could fulfill an unmet need if further validated. Andrew Berman, MD, professor of medicine, New Jersey Medical School, Newark, thinks the premise is sound.
“Digital competency is still a big issue as is access to adequate quality Internet, but this could be a very useful approach for many individuals, and it avoids visits to a center, which could be a big advantage for patients,” Dr. Berman said.
Abebaw M. Johannes, PhD, a professor of physical therapy at Azusa Pacific University, Azusa, Calif., agreed. He said that home-based remote coaching could be a way of overcoming the current hurdles of participating in institutional-based programs
“This is clearly an unmet need in COPD,” he said.
The development of more effective and patient-friendly programs is what was driving this research, according to Dr. Benzo. He cited data suggesting that only about 30% of patients with COPD are participating in rehabilitation programs once discharged from the hospital despite the evidence that they can improve quality of life. For many of these patients, a home-based program might be the answer.
Dr. Benzo, Dr. Berman, and Dr. Johannes reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NASHVILLE – The first multicenter randomized controlled trial of a home-based rehabilitation program for patients with chronic obstructive pulmonary disease (COPD) showed highly positive results, according to findings presented at the annual meeting of the American College of Chest Physicians (CHEST).
At the end of 12 weeks, those randomly assigned to the intervention had a significant and clinically meaningful improvement in all domains of the Chronic Respiratory Questionnaire (CRQ), including activity levels and emotional well-being, reported Roberto P. Benzo, MD, a consultant in the division of pulmonary and critical care medicine, Mayo Clinic, Rochester, Minn.
Presenting soon-to-be-published data, Dr. Benzo said that the intervention is based on a tablet-based app. The tablet is programmed to upload data captured from an activity monitor and pulse oximeter. Along with documentation of app usage, this information can then be downloaded for the remote coach to review with the patient.
The primary outcome of the randomized study were the physical and emotional domains of the CRQ quality of life, but a long list of secondary outcomes – including physical activity, symptoms of depression, sleep quality, and health care utilization, such as emergency room visits – was also analyzed.
In addition to the significant benefit on the primary outcomes, the home-based rehabilitation program relative to a wait list for intervention was associated with benefit or a trend for benefit on essentially every outcome measured. Health care utilization was a possible exception, but even then, the absolute number of visits was lower in the treatment arm.
“With a study period of only 12 weeks, we were limited to our ability to show a difference in emergency room visits,” said Dr. Benzo, who also noted that the study was conducted during the COVID-19 pandemic, when hospital visits were already occurring at a lower than usual rate. Based on the other findings, he suspects that a reduction in health care utilization could also be shown in more typical circumstances, particularly with a longer follow-up.
In the study, 375 patients with COPD were randomly assigned to a home health care regimen delivered by an app with remote coaching or to a wait list and usual care. The median age was 69 years. Fifty-nine percent were women. The median FEV1 at enrollment was 45% of predicted.
The patients were able to access their own data to monitor their progress at any time, not just at the time of coaching, but contact with the remote coach occurred on a weekly basis. Patients rated their level of energy, how they felt generally, and their progress toward daily goals, which was also captured on the app and could be discussed with the coach during the review of the previous week’s activity.
At 12 weeks, the favorable 0.54-point change (P < .001) and 0.51 change (P < .001) in the physical and emotional summary scores, respectively, met the criteria for a clinically meaningful change, Dr. Benzo reported. There were also significantly favorable changes from baseline and relative to controls in CRQ domains of self-management, sleep quality, and depression (all P ≤ .01).
Other data collected are supportive. For example, Dr. Benzo reported that those in the rehabilitation group took 624 more steps on average per day than those in the control group. The experimental group also spent nearly an hour more performing moderate or greater levels of activity.
“The app promotes behavioral change,” said Dr. Benzo, who said that this “completely home-based model” of rehabilitation is likely to be cost-effective given the relatively low costs of remote coaching and reasonable costs of the activity monitor, tablet, and other equipment.
Importantly, home-based rehabilitation is a billable practice under currently available CPT codes, according to Dr. Benzo, who believes this approach is not only effective but “feasible and practical.”
Two clinicians active in the care of patients with COPD believe this approach could fulfill an unmet need if further validated. Andrew Berman, MD, professor of medicine, New Jersey Medical School, Newark, thinks the premise is sound.
“Digital competency is still a big issue as is access to adequate quality Internet, but this could be a very useful approach for many individuals, and it avoids visits to a center, which could be a big advantage for patients,” Dr. Berman said.
Abebaw M. Johannes, PhD, a professor of physical therapy at Azusa Pacific University, Azusa, Calif., agreed. He said that home-based remote coaching could be a way of overcoming the current hurdles of participating in institutional-based programs
“This is clearly an unmet need in COPD,” he said.
The development of more effective and patient-friendly programs is what was driving this research, according to Dr. Benzo. He cited data suggesting that only about 30% of patients with COPD are participating in rehabilitation programs once discharged from the hospital despite the evidence that they can improve quality of life. For many of these patients, a home-based program might be the answer.
Dr. Benzo, Dr. Berman, and Dr. Johannes reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NASHVILLE – The first multicenter randomized controlled trial of a home-based rehabilitation program for patients with chronic obstructive pulmonary disease (COPD) showed highly positive results, according to findings presented at the annual meeting of the American College of Chest Physicians (CHEST).
At the end of 12 weeks, those randomly assigned to the intervention had a significant and clinically meaningful improvement in all domains of the Chronic Respiratory Questionnaire (CRQ), including activity levels and emotional well-being, reported Roberto P. Benzo, MD, a consultant in the division of pulmonary and critical care medicine, Mayo Clinic, Rochester, Minn.
Presenting soon-to-be-published data, Dr. Benzo said that the intervention is based on a tablet-based app. The tablet is programmed to upload data captured from an activity monitor and pulse oximeter. Along with documentation of app usage, this information can then be downloaded for the remote coach to review with the patient.
The primary outcome of the randomized study were the physical and emotional domains of the CRQ quality of life, but a long list of secondary outcomes – including physical activity, symptoms of depression, sleep quality, and health care utilization, such as emergency room visits – was also analyzed.
In addition to the significant benefit on the primary outcomes, the home-based rehabilitation program relative to a wait list for intervention was associated with benefit or a trend for benefit on essentially every outcome measured. Health care utilization was a possible exception, but even then, the absolute number of visits was lower in the treatment arm.
“With a study period of only 12 weeks, we were limited to our ability to show a difference in emergency room visits,” said Dr. Benzo, who also noted that the study was conducted during the COVID-19 pandemic, when hospital visits were already occurring at a lower than usual rate. Based on the other findings, he suspects that a reduction in health care utilization could also be shown in more typical circumstances, particularly with a longer follow-up.
In the study, 375 patients with COPD were randomly assigned to a home health care regimen delivered by an app with remote coaching or to a wait list and usual care. The median age was 69 years. Fifty-nine percent were women. The median FEV1 at enrollment was 45% of predicted.
The patients were able to access their own data to monitor their progress at any time, not just at the time of coaching, but contact with the remote coach occurred on a weekly basis. Patients rated their level of energy, how they felt generally, and their progress toward daily goals, which was also captured on the app and could be discussed with the coach during the review of the previous week’s activity.
At 12 weeks, the favorable 0.54-point change (P < .001) and 0.51 change (P < .001) in the physical and emotional summary scores, respectively, met the criteria for a clinically meaningful change, Dr. Benzo reported. There were also significantly favorable changes from baseline and relative to controls in CRQ domains of self-management, sleep quality, and depression (all P ≤ .01).
Other data collected are supportive. For example, Dr. Benzo reported that those in the rehabilitation group took 624 more steps on average per day than those in the control group. The experimental group also spent nearly an hour more performing moderate or greater levels of activity.
“The app promotes behavioral change,” said Dr. Benzo, who said that this “completely home-based model” of rehabilitation is likely to be cost-effective given the relatively low costs of remote coaching and reasonable costs of the activity monitor, tablet, and other equipment.
Importantly, home-based rehabilitation is a billable practice under currently available CPT codes, according to Dr. Benzo, who believes this approach is not only effective but “feasible and practical.”
Two clinicians active in the care of patients with COPD believe this approach could fulfill an unmet need if further validated. Andrew Berman, MD, professor of medicine, New Jersey Medical School, Newark, thinks the premise is sound.
“Digital competency is still a big issue as is access to adequate quality Internet, but this could be a very useful approach for many individuals, and it avoids visits to a center, which could be a big advantage for patients,” Dr. Berman said.
Abebaw M. Johannes, PhD, a professor of physical therapy at Azusa Pacific University, Azusa, Calif., agreed. He said that home-based remote coaching could be a way of overcoming the current hurdles of participating in institutional-based programs
“This is clearly an unmet need in COPD,” he said.
The development of more effective and patient-friendly programs is what was driving this research, according to Dr. Benzo. He cited data suggesting that only about 30% of patients with COPD are participating in rehabilitation programs once discharged from the hospital despite the evidence that they can improve quality of life. For many of these patients, a home-based program might be the answer.
Dr. Benzo, Dr. Berman, and Dr. Johannes reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM CHEST 2022
SPRINT’s intensive therapy benefit fades once BP creeps back up
The substantial reductions in cardiovascular disease (CVD) and all-cause mortality achieved with intensive blood pressure lowering in the landmark SPRINT trial were not sustained in a newly released long-term follow-up.
The loss of the mortality benefits corresponded with a steady climb in the average systolic blood pressures (SBP) in the intensive treatment group after the trial ended. The long-term benefit serves as a call to develop better strategies for sustained SBP control.
“We were disappointed but not surprised that the blood pressure levels in the intensive goal group were not sustained,” acknowledged William C. Cushman, MD, Medical Director, department of preventive medicine, University of Tennessee Health Science Center, Memphis. “There are many trials showing no residual or legacy effect once the intervention is stopped.”
Long-term results do not weaken SPRINT
One of the coinvestigators of this most recent analysis published in JAMA Cardiology and a member of the SPRINT writing committee at the time of its 2015 publication in the New England Journal of Medicine, Dr. Cushman pointed out that the long-term results do not weaken the main trial result. Long-term adherence was not part of the trial design.
“After the trial, we were no longer treating these participants, so it was up to them and their primary care providers to decide on blood pressure goals,” he noted in an interview. Based on the trajectory of benefit when the study was stopped, “it is possible longer intensive treatment may lead to more benefit and some long-term residual benefits.”
The senior author of this most recent analysis, Nicholas M. Pajewski, PhD, associate professor of biostatistics and data science, Wake Forest University, Winston-Salem, N.C., generally agreed. However, he pointed out that the most recent data do not rule out meaningful benefit after the study ended.
For one reason, the loss of the SBP advantage was gradual so that median SBP levels of the two groups did not meet for nearly 3 years. This likely explains why there was still an attenuation of CVD mortality for several years after the all-cause mortality benefit was lost, according to Dr. Pajewski.
“It is important to mention that we were not able to assess nonfatal cardiovascular events, so while the two groups do eventually come together, if one thinks about the distinction of healthspan versus lifespan, there was probably residual benefit in terms of delaying CVD morbidity and mortality,” Dr. Pajewski said.
In SPRINT, CVD mortality reduced 43%
In the 9,631-patient SPRINT trial, the intensive treatment group achieved a mean SBP of 121.4 mm Hg versus 136.2 mm Hg in the standard treatment group at the end of 1 year. The trial was stopped early after 3.26 years because of strength of the benefit in the intensive treatment arm. At that time, the reductions by hazard ratio were 25% (HR, 0.75; P < .001) for a composite major adverse cardiovascular event (MACE) endpoint, 43% for CVD mortality (P = .005), and 27% for all-cause mortality (P = .003).
In the new observational follow-up, mortality data were drawn from the National Death Index, and change in SBP from electronic health records in a subset of 2,944 SPRINT trial participants. Data were available and analyzed through 2020.
The newly published long-term observational analysis showed that the median SBP in the intensive treatment arm was already climbing by the end of the end of the trial. It reached 132.8 mm Hg at 5 years after randomization and then 140.4 mm Hg by 10 years.
This latter figure was essentially equivalent to the SBP among those who were initially randomized to the standard treatment arm.
Factors driving rising BP are unclear
There is limited information on what medications were taken by either group following the end of the trial, so the reason for the regression in the intensive treatment arm after leaving the trial is unknown. The authors speculated that this might have been due to therapeutic inertia among treating physicians, poor adherence among patients, the difficulty of keeping blood pressures low in patients with advancing pathology, or some combination of these.
“Perhaps the most important reason was that providers and patients were not aiming for the lower goals since guidelines did not recommend these targets until 2017,” Dr. Cushman pointed out. He noted that Healthcare Effectiveness Data and Information Set (HEDIS) “has still not adopted a performance measure goal of less than 140 mm Hg.”
In an accompanying editorial, the authors focused on what these data mean for population-based strategies to achieve sustained control of one of the most important risk factors for cardiovascular events. Led by Daniel W. Jones, MD, director of clinical and population science, University of Mississippi, Jackson, the authors of the editorial wrote that these data emphasized “the challenge of achieving sustained intensive BP reductions in the real-world setting.”
Basically, the editorial concluded that current approaches to achieving meaningful and sustained blood pressure control are not working.
This study “should be a wakeup call, but other previously published good data have also been ignored,” said Dr. Jones in an interview. Despite the compelling benefit from intensive blood pressure control the SPRINT trial, the observational follow-up emphasizes the difficulty of maintaining the rigorous reductions in blood pressure needed for sustained protection.
“Systemic change is necessary,” said Dr. Jones, reprising the major thrust of the editorial he wrote with Donald Clark III, MD, and Michael E. Hall, MD, who are both colleagues at the University of Mississippi.
“My view is that health care providers should be held responsible for motivating better compliance of their patients, just as a teacher is accountable for the outcomes of their students,” he said.
The solutions are not likely to be simple. Dr. Jones called for multiple strategies, such as employing telehealth and community health workers to monitor and reinforce blood pressure control, but he said that these and other data have convinced him that “simply trying harder at what we currently do” is not enough.
Dr. Pajewski and Dr. Jones report no potential conflicts of interest. Dr. Cushman reports a financial relationship with ReCor.
The substantial reductions in cardiovascular disease (CVD) and all-cause mortality achieved with intensive blood pressure lowering in the landmark SPRINT trial were not sustained in a newly released long-term follow-up.
The loss of the mortality benefits corresponded with a steady climb in the average systolic blood pressures (SBP) in the intensive treatment group after the trial ended. The long-term benefit serves as a call to develop better strategies for sustained SBP control.
“We were disappointed but not surprised that the blood pressure levels in the intensive goal group were not sustained,” acknowledged William C. Cushman, MD, Medical Director, department of preventive medicine, University of Tennessee Health Science Center, Memphis. “There are many trials showing no residual or legacy effect once the intervention is stopped.”
Long-term results do not weaken SPRINT
One of the coinvestigators of this most recent analysis published in JAMA Cardiology and a member of the SPRINT writing committee at the time of its 2015 publication in the New England Journal of Medicine, Dr. Cushman pointed out that the long-term results do not weaken the main trial result. Long-term adherence was not part of the trial design.
“After the trial, we were no longer treating these participants, so it was up to them and their primary care providers to decide on blood pressure goals,” he noted in an interview. Based on the trajectory of benefit when the study was stopped, “it is possible longer intensive treatment may lead to more benefit and some long-term residual benefits.”
The senior author of this most recent analysis, Nicholas M. Pajewski, PhD, associate professor of biostatistics and data science, Wake Forest University, Winston-Salem, N.C., generally agreed. However, he pointed out that the most recent data do not rule out meaningful benefit after the study ended.
For one reason, the loss of the SBP advantage was gradual so that median SBP levels of the two groups did not meet for nearly 3 years. This likely explains why there was still an attenuation of CVD mortality for several years after the all-cause mortality benefit was lost, according to Dr. Pajewski.
“It is important to mention that we were not able to assess nonfatal cardiovascular events, so while the two groups do eventually come together, if one thinks about the distinction of healthspan versus lifespan, there was probably residual benefit in terms of delaying CVD morbidity and mortality,” Dr. Pajewski said.
In SPRINT, CVD mortality reduced 43%
In the 9,631-patient SPRINT trial, the intensive treatment group achieved a mean SBP of 121.4 mm Hg versus 136.2 mm Hg in the standard treatment group at the end of 1 year. The trial was stopped early after 3.26 years because of strength of the benefit in the intensive treatment arm. At that time, the reductions by hazard ratio were 25% (HR, 0.75; P < .001) for a composite major adverse cardiovascular event (MACE) endpoint, 43% for CVD mortality (P = .005), and 27% for all-cause mortality (P = .003).
In the new observational follow-up, mortality data were drawn from the National Death Index, and change in SBP from electronic health records in a subset of 2,944 SPRINT trial participants. Data were available and analyzed through 2020.
The newly published long-term observational analysis showed that the median SBP in the intensive treatment arm was already climbing by the end of the end of the trial. It reached 132.8 mm Hg at 5 years after randomization and then 140.4 mm Hg by 10 years.
This latter figure was essentially equivalent to the SBP among those who were initially randomized to the standard treatment arm.
Factors driving rising BP are unclear
There is limited information on what medications were taken by either group following the end of the trial, so the reason for the regression in the intensive treatment arm after leaving the trial is unknown. The authors speculated that this might have been due to therapeutic inertia among treating physicians, poor adherence among patients, the difficulty of keeping blood pressures low in patients with advancing pathology, or some combination of these.
“Perhaps the most important reason was that providers and patients were not aiming for the lower goals since guidelines did not recommend these targets until 2017,” Dr. Cushman pointed out. He noted that Healthcare Effectiveness Data and Information Set (HEDIS) “has still not adopted a performance measure goal of less than 140 mm Hg.”
In an accompanying editorial, the authors focused on what these data mean for population-based strategies to achieve sustained control of one of the most important risk factors for cardiovascular events. Led by Daniel W. Jones, MD, director of clinical and population science, University of Mississippi, Jackson, the authors of the editorial wrote that these data emphasized “the challenge of achieving sustained intensive BP reductions in the real-world setting.”
Basically, the editorial concluded that current approaches to achieving meaningful and sustained blood pressure control are not working.
This study “should be a wakeup call, but other previously published good data have also been ignored,” said Dr. Jones in an interview. Despite the compelling benefit from intensive blood pressure control the SPRINT trial, the observational follow-up emphasizes the difficulty of maintaining the rigorous reductions in blood pressure needed for sustained protection.
“Systemic change is necessary,” said Dr. Jones, reprising the major thrust of the editorial he wrote with Donald Clark III, MD, and Michael E. Hall, MD, who are both colleagues at the University of Mississippi.
“My view is that health care providers should be held responsible for motivating better compliance of their patients, just as a teacher is accountable for the outcomes of their students,” he said.
The solutions are not likely to be simple. Dr. Jones called for multiple strategies, such as employing telehealth and community health workers to monitor and reinforce blood pressure control, but he said that these and other data have convinced him that “simply trying harder at what we currently do” is not enough.
Dr. Pajewski and Dr. Jones report no potential conflicts of interest. Dr. Cushman reports a financial relationship with ReCor.
The substantial reductions in cardiovascular disease (CVD) and all-cause mortality achieved with intensive blood pressure lowering in the landmark SPRINT trial were not sustained in a newly released long-term follow-up.
The loss of the mortality benefits corresponded with a steady climb in the average systolic blood pressures (SBP) in the intensive treatment group after the trial ended. The long-term benefit serves as a call to develop better strategies for sustained SBP control.
“We were disappointed but not surprised that the blood pressure levels in the intensive goal group were not sustained,” acknowledged William C. Cushman, MD, Medical Director, department of preventive medicine, University of Tennessee Health Science Center, Memphis. “There are many trials showing no residual or legacy effect once the intervention is stopped.”
Long-term results do not weaken SPRINT
One of the coinvestigators of this most recent analysis published in JAMA Cardiology and a member of the SPRINT writing committee at the time of its 2015 publication in the New England Journal of Medicine, Dr. Cushman pointed out that the long-term results do not weaken the main trial result. Long-term adherence was not part of the trial design.
“After the trial, we were no longer treating these participants, so it was up to them and their primary care providers to decide on blood pressure goals,” he noted in an interview. Based on the trajectory of benefit when the study was stopped, “it is possible longer intensive treatment may lead to more benefit and some long-term residual benefits.”
The senior author of this most recent analysis, Nicholas M. Pajewski, PhD, associate professor of biostatistics and data science, Wake Forest University, Winston-Salem, N.C., generally agreed. However, he pointed out that the most recent data do not rule out meaningful benefit after the study ended.
For one reason, the loss of the SBP advantage was gradual so that median SBP levels of the two groups did not meet for nearly 3 years. This likely explains why there was still an attenuation of CVD mortality for several years after the all-cause mortality benefit was lost, according to Dr. Pajewski.
“It is important to mention that we were not able to assess nonfatal cardiovascular events, so while the two groups do eventually come together, if one thinks about the distinction of healthspan versus lifespan, there was probably residual benefit in terms of delaying CVD morbidity and mortality,” Dr. Pajewski said.
In SPRINT, CVD mortality reduced 43%
In the 9,631-patient SPRINT trial, the intensive treatment group achieved a mean SBP of 121.4 mm Hg versus 136.2 mm Hg in the standard treatment group at the end of 1 year. The trial was stopped early after 3.26 years because of strength of the benefit in the intensive treatment arm. At that time, the reductions by hazard ratio were 25% (HR, 0.75; P < .001) for a composite major adverse cardiovascular event (MACE) endpoint, 43% for CVD mortality (P = .005), and 27% for all-cause mortality (P = .003).
In the new observational follow-up, mortality data were drawn from the National Death Index, and change in SBP from electronic health records in a subset of 2,944 SPRINT trial participants. Data were available and analyzed through 2020.
The newly published long-term observational analysis showed that the median SBP in the intensive treatment arm was already climbing by the end of the end of the trial. It reached 132.8 mm Hg at 5 years after randomization and then 140.4 mm Hg by 10 years.
This latter figure was essentially equivalent to the SBP among those who were initially randomized to the standard treatment arm.
Factors driving rising BP are unclear
There is limited information on what medications were taken by either group following the end of the trial, so the reason for the regression in the intensive treatment arm after leaving the trial is unknown. The authors speculated that this might have been due to therapeutic inertia among treating physicians, poor adherence among patients, the difficulty of keeping blood pressures low in patients with advancing pathology, or some combination of these.
“Perhaps the most important reason was that providers and patients were not aiming for the lower goals since guidelines did not recommend these targets until 2017,” Dr. Cushman pointed out. He noted that Healthcare Effectiveness Data and Information Set (HEDIS) “has still not adopted a performance measure goal of less than 140 mm Hg.”
In an accompanying editorial, the authors focused on what these data mean for population-based strategies to achieve sustained control of one of the most important risk factors for cardiovascular events. Led by Daniel W. Jones, MD, director of clinical and population science, University of Mississippi, Jackson, the authors of the editorial wrote that these data emphasized “the challenge of achieving sustained intensive BP reductions in the real-world setting.”
Basically, the editorial concluded that current approaches to achieving meaningful and sustained blood pressure control are not working.
This study “should be a wakeup call, but other previously published good data have also been ignored,” said Dr. Jones in an interview. Despite the compelling benefit from intensive blood pressure control the SPRINT trial, the observational follow-up emphasizes the difficulty of maintaining the rigorous reductions in blood pressure needed for sustained protection.
“Systemic change is necessary,” said Dr. Jones, reprising the major thrust of the editorial he wrote with Donald Clark III, MD, and Michael E. Hall, MD, who are both colleagues at the University of Mississippi.
“My view is that health care providers should be held responsible for motivating better compliance of their patients, just as a teacher is accountable for the outcomes of their students,” he said.
The solutions are not likely to be simple. Dr. Jones called for multiple strategies, such as employing telehealth and community health workers to monitor and reinforce blood pressure control, but he said that these and other data have convinced him that “simply trying harder at what we currently do” is not enough.
Dr. Pajewski and Dr. Jones report no potential conflicts of interest. Dr. Cushman reports a financial relationship with ReCor.
FROM JAMA CARDIOLOGY
Monkeypox features include mucocutaneous involvement in almost all cases
MILAN – In the current spread of monkeypox among countries outside of Africa, this zoonotic orthopox DNA virus is sexually transmitted in more than 90% of cases, mostly among men having sex with men (MSM), and can produce severe skin and systemic symptoms but is rarely fatal, according to a breaking news presentation at the annual congress of the European Academy of Dermatology and Venereology.
Synthesizing data from 185 cases in Spain with several sets of recently published data, Alba Català, MD, a dermatologist at Centro Médico Teknon, Barcelona, said at the meeting that there have been only two deaths in Spain in the current epidemic. (As of Sept. 30, after the EADV meeting had concluded, a total of three deaths related to monkeypox in Spain and one death in the United States had been reported, according to the Centers for Disease Control and Prevention).
Hospitalizations have been uncommon, and in Spain, there were only four hospitalizations, according to data collected from the beginning of May through early August, she said. Almost all cases in this Spanish series were from men having high-risk sex with men. Upon screening, 76% had another sexually transmitted disease, including 41% infected with human immunodeficiency virus.
More than 40% of patients with monkeypox have HIV
These data are consistent with several other recently published studies, such as one that evaluated 528 infections in 16 non-African countries, including those in North America, South America, Europe, the Mideast, as well as Australia. In that survey, published in the New England Journal of Medicine, and covering cases between late April and late June, 2022, 41% were HIV positive. Of those who were HIV negative, 57% were taking a pre-exposure prophylaxis regimen of antiretroviral drugs to prevent HIV infection.
However, these data do not preclude a significant risk of nonsexual transmission, according to Dr. Català, who noted that respiratory transmission and transmission through nonsexual skin contact is well documented in endemic areas.
“The virus has no preference for a sexual orientation,” Dr. Català cautioned. Despite the consistency of the data in regard to a largely MSM transmission in the epidemic so far, “these data may change with further spread of infection in the community.”
Typically, the incubation period of monkeypox lasts several days before the invasive period, which is commonly accompanied by systemic complaints, particularly fever, headache, and often lymphadenopathy. These systemic features usually but not always precede cutaneous involvement, which is seen in more than 90% of patients, according to Dr. Català. In the Spanish series, mucocutaneous involvement was recorded in 100% of patients.
Monkeypox and smallpox
“The differential diagnosis might include other vesicular eruptions, such as those caused by varicella or smallpox,” reported Dr. Català, who noted that monkeypox and smallpox are related.
Cutaneous lesions often appear first at the site of infection, such as the genitalia, but typically spread in a secondary eruption that is pruritic and may take days to resolve, according to Dr. Català. She reported that single lesions are less common but do occur. While hundreds of lesions have been reported among cases in endemic areas, most patients had 25 lesions or fewer in the Spanish epidemic and other recent series.
Even though there is a common progression in which lesions begin in a papular stage before the vesicular and pustular stages in a given area, new eruptions can occur before a prior eruption develops scabs.
“Frequently, not all the patient’s lesions are in the same stage of development,” said Dr. Català, who explained that disease activity and its complications, such as proctitis, pharyngitis, and penile edema, can take weeks to resolve. Because of the highly invasive nature of monkeypox, it is appropriate to be alert to less common manifestations, such as ocular involvement.
Many of these and other complications, such as secondary bacterial infections, will require targeted treatment, but the mainstay of therapy for the dermatologic manifestations of monkeypox is symptomatic treatment that includes nonsteroidal anti-inflammatory drugs and analgesics.
Re-epithelialization reduces transmission risk
“A clean, moist environment can mitigate transmission potential by covering infectious sores and promoting the re-epithelialization of the damaged exanthem,” Dr. Català advised. Tecovirimat (TPOXX, ST-246), an antiviral drug for smallpox, is approved for treating monkeypox in Europe but not in the United States (but it is approved for smallpox in the United States). Another antiviral drug, brincidofovir (CMX001 or Tembexa), is approved for smallpox in the United States, but not in Europe, according to Dr. Català. (In the United States, no treatment is specifically approved for treating monkeypox, but antivirals developed for smallpox “may prove beneficial against monkeypox,” according to the CDC.)
But she advised weighing the risks and benefits of using either drug in any individual patient.
The data suggest that the risk of viral shedding persists until the late stages of the disease trajectory. “A person is considered infectious from the onset of clinical manifestations until all skin lesions have scabbed over and re-epithelization has occurred,” Dr. Català said.
The prolonged period of contagion might be one reason to expect monkeypox to be transmitted more generally than it is now, according to Boghuma K. Titanji, MD, PhD, assistant professor of infectious diseases, Emory University, Atlanta.
“The longer the outbreak persists, the more likely we will see cases reported in groups other than MSM who have been most affected so far,” said Dr. Titanji, the first author of a recently published review article on monkeypox in Open Forum Infectious Diseases.
However, he acknowledged that a COVID-like spread is not expected. “The spread of monkeypox requires close and prolonged contact and is generally inefficient via fomites and droplet modes of transmission,” Dr. Titanji said in an interview. “Spread in heterosexual networks and congregate settings like crowded jails where close contact is unavoidable remains a concern that we need to educate the public about and maintain a high level of vigilance for.”
Dr. Català and Dr. Titanji report no potential conflicts of interest.
MILAN – In the current spread of monkeypox among countries outside of Africa, this zoonotic orthopox DNA virus is sexually transmitted in more than 90% of cases, mostly among men having sex with men (MSM), and can produce severe skin and systemic symptoms but is rarely fatal, according to a breaking news presentation at the annual congress of the European Academy of Dermatology and Venereology.
Synthesizing data from 185 cases in Spain with several sets of recently published data, Alba Català, MD, a dermatologist at Centro Médico Teknon, Barcelona, said at the meeting that there have been only two deaths in Spain in the current epidemic. (As of Sept. 30, after the EADV meeting had concluded, a total of three deaths related to monkeypox in Spain and one death in the United States had been reported, according to the Centers for Disease Control and Prevention).
Hospitalizations have been uncommon, and in Spain, there were only four hospitalizations, according to data collected from the beginning of May through early August, she said. Almost all cases in this Spanish series were from men having high-risk sex with men. Upon screening, 76% had another sexually transmitted disease, including 41% infected with human immunodeficiency virus.
More than 40% of patients with monkeypox have HIV
These data are consistent with several other recently published studies, such as one that evaluated 528 infections in 16 non-African countries, including those in North America, South America, Europe, the Mideast, as well as Australia. In that survey, published in the New England Journal of Medicine, and covering cases between late April and late June, 2022, 41% were HIV positive. Of those who were HIV negative, 57% were taking a pre-exposure prophylaxis regimen of antiretroviral drugs to prevent HIV infection.
However, these data do not preclude a significant risk of nonsexual transmission, according to Dr. Català, who noted that respiratory transmission and transmission through nonsexual skin contact is well documented in endemic areas.
“The virus has no preference for a sexual orientation,” Dr. Català cautioned. Despite the consistency of the data in regard to a largely MSM transmission in the epidemic so far, “these data may change with further spread of infection in the community.”
Typically, the incubation period of monkeypox lasts several days before the invasive period, which is commonly accompanied by systemic complaints, particularly fever, headache, and often lymphadenopathy. These systemic features usually but not always precede cutaneous involvement, which is seen in more than 90% of patients, according to Dr. Català. In the Spanish series, mucocutaneous involvement was recorded in 100% of patients.
Monkeypox and smallpox
“The differential diagnosis might include other vesicular eruptions, such as those caused by varicella or smallpox,” reported Dr. Català, who noted that monkeypox and smallpox are related.
Cutaneous lesions often appear first at the site of infection, such as the genitalia, but typically spread in a secondary eruption that is pruritic and may take days to resolve, according to Dr. Català. She reported that single lesions are less common but do occur. While hundreds of lesions have been reported among cases in endemic areas, most patients had 25 lesions or fewer in the Spanish epidemic and other recent series.
Even though there is a common progression in which lesions begin in a papular stage before the vesicular and pustular stages in a given area, new eruptions can occur before a prior eruption develops scabs.
“Frequently, not all the patient’s lesions are in the same stage of development,” said Dr. Català, who explained that disease activity and its complications, such as proctitis, pharyngitis, and penile edema, can take weeks to resolve. Because of the highly invasive nature of monkeypox, it is appropriate to be alert to less common manifestations, such as ocular involvement.
Many of these and other complications, such as secondary bacterial infections, will require targeted treatment, but the mainstay of therapy for the dermatologic manifestations of monkeypox is symptomatic treatment that includes nonsteroidal anti-inflammatory drugs and analgesics.
Re-epithelialization reduces transmission risk
“A clean, moist environment can mitigate transmission potential by covering infectious sores and promoting the re-epithelialization of the damaged exanthem,” Dr. Català advised. Tecovirimat (TPOXX, ST-246), an antiviral drug for smallpox, is approved for treating monkeypox in Europe but not in the United States (but it is approved for smallpox in the United States). Another antiviral drug, brincidofovir (CMX001 or Tembexa), is approved for smallpox in the United States, but not in Europe, according to Dr. Català. (In the United States, no treatment is specifically approved for treating monkeypox, but antivirals developed for smallpox “may prove beneficial against monkeypox,” according to the CDC.)
But she advised weighing the risks and benefits of using either drug in any individual patient.
The data suggest that the risk of viral shedding persists until the late stages of the disease trajectory. “A person is considered infectious from the onset of clinical manifestations until all skin lesions have scabbed over and re-epithelization has occurred,” Dr. Català said.
The prolonged period of contagion might be one reason to expect monkeypox to be transmitted more generally than it is now, according to Boghuma K. Titanji, MD, PhD, assistant professor of infectious diseases, Emory University, Atlanta.
“The longer the outbreak persists, the more likely we will see cases reported in groups other than MSM who have been most affected so far,” said Dr. Titanji, the first author of a recently published review article on monkeypox in Open Forum Infectious Diseases.
However, he acknowledged that a COVID-like spread is not expected. “The spread of monkeypox requires close and prolonged contact and is generally inefficient via fomites and droplet modes of transmission,” Dr. Titanji said in an interview. “Spread in heterosexual networks and congregate settings like crowded jails where close contact is unavoidable remains a concern that we need to educate the public about and maintain a high level of vigilance for.”
Dr. Català and Dr. Titanji report no potential conflicts of interest.
MILAN – In the current spread of monkeypox among countries outside of Africa, this zoonotic orthopox DNA virus is sexually transmitted in more than 90% of cases, mostly among men having sex with men (MSM), and can produce severe skin and systemic symptoms but is rarely fatal, according to a breaking news presentation at the annual congress of the European Academy of Dermatology and Venereology.
Synthesizing data from 185 cases in Spain with several sets of recently published data, Alba Català, MD, a dermatologist at Centro Médico Teknon, Barcelona, said at the meeting that there have been only two deaths in Spain in the current epidemic. (As of Sept. 30, after the EADV meeting had concluded, a total of three deaths related to monkeypox in Spain and one death in the United States had been reported, according to the Centers for Disease Control and Prevention).
Hospitalizations have been uncommon, and in Spain, there were only four hospitalizations, according to data collected from the beginning of May through early August, she said. Almost all cases in this Spanish series were from men having high-risk sex with men. Upon screening, 76% had another sexually transmitted disease, including 41% infected with human immunodeficiency virus.
More than 40% of patients with monkeypox have HIV
These data are consistent with several other recently published studies, such as one that evaluated 528 infections in 16 non-African countries, including those in North America, South America, Europe, the Mideast, as well as Australia. In that survey, published in the New England Journal of Medicine, and covering cases between late April and late June, 2022, 41% were HIV positive. Of those who were HIV negative, 57% were taking a pre-exposure prophylaxis regimen of antiretroviral drugs to prevent HIV infection.
However, these data do not preclude a significant risk of nonsexual transmission, according to Dr. Català, who noted that respiratory transmission and transmission through nonsexual skin contact is well documented in endemic areas.
“The virus has no preference for a sexual orientation,” Dr. Català cautioned. Despite the consistency of the data in regard to a largely MSM transmission in the epidemic so far, “these data may change with further spread of infection in the community.”
Typically, the incubation period of monkeypox lasts several days before the invasive period, which is commonly accompanied by systemic complaints, particularly fever, headache, and often lymphadenopathy. These systemic features usually but not always precede cutaneous involvement, which is seen in more than 90% of patients, according to Dr. Català. In the Spanish series, mucocutaneous involvement was recorded in 100% of patients.
Monkeypox and smallpox
“The differential diagnosis might include other vesicular eruptions, such as those caused by varicella or smallpox,” reported Dr. Català, who noted that monkeypox and smallpox are related.
Cutaneous lesions often appear first at the site of infection, such as the genitalia, but typically spread in a secondary eruption that is pruritic and may take days to resolve, according to Dr. Català. She reported that single lesions are less common but do occur. While hundreds of lesions have been reported among cases in endemic areas, most patients had 25 lesions or fewer in the Spanish epidemic and other recent series.
Even though there is a common progression in which lesions begin in a papular stage before the vesicular and pustular stages in a given area, new eruptions can occur before a prior eruption develops scabs.
“Frequently, not all the patient’s lesions are in the same stage of development,” said Dr. Català, who explained that disease activity and its complications, such as proctitis, pharyngitis, and penile edema, can take weeks to resolve. Because of the highly invasive nature of monkeypox, it is appropriate to be alert to less common manifestations, such as ocular involvement.
Many of these and other complications, such as secondary bacterial infections, will require targeted treatment, but the mainstay of therapy for the dermatologic manifestations of monkeypox is symptomatic treatment that includes nonsteroidal anti-inflammatory drugs and analgesics.
Re-epithelialization reduces transmission risk
“A clean, moist environment can mitigate transmission potential by covering infectious sores and promoting the re-epithelialization of the damaged exanthem,” Dr. Català advised. Tecovirimat (TPOXX, ST-246), an antiviral drug for smallpox, is approved for treating monkeypox in Europe but not in the United States (but it is approved for smallpox in the United States). Another antiviral drug, brincidofovir (CMX001 or Tembexa), is approved for smallpox in the United States, but not in Europe, according to Dr. Català. (In the United States, no treatment is specifically approved for treating monkeypox, but antivirals developed for smallpox “may prove beneficial against monkeypox,” according to the CDC.)
But she advised weighing the risks and benefits of using either drug in any individual patient.
The data suggest that the risk of viral shedding persists until the late stages of the disease trajectory. “A person is considered infectious from the onset of clinical manifestations until all skin lesions have scabbed over and re-epithelization has occurred,” Dr. Català said.
The prolonged period of contagion might be one reason to expect monkeypox to be transmitted more generally than it is now, according to Boghuma K. Titanji, MD, PhD, assistant professor of infectious diseases, Emory University, Atlanta.
“The longer the outbreak persists, the more likely we will see cases reported in groups other than MSM who have been most affected so far,” said Dr. Titanji, the first author of a recently published review article on monkeypox in Open Forum Infectious Diseases.
However, he acknowledged that a COVID-like spread is not expected. “The spread of monkeypox requires close and prolonged contact and is generally inefficient via fomites and droplet modes of transmission,” Dr. Titanji said in an interview. “Spread in heterosexual networks and congregate settings like crowded jails where close contact is unavoidable remains a concern that we need to educate the public about and maintain a high level of vigilance for.”
Dr. Català and Dr. Titanji report no potential conflicts of interest.
AT THE EADV CONGRESS