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Mitchel is a reporter for MDedge based in the Philadelphia area. He started with the company in 1992, when it was International Medical News Group (IMNG), and has since covered a range of medical specialties. Mitchel trained as a virologist at Roswell Park Memorial Institute in Buffalo, and then worked briefly as a researcher at Boston Children's Hospital before pivoting to journalism as a AAAS Mass Media Fellow in 1980. His first reporting job was with Science Digest magazine, and from the mid-1980s to early-1990s he was a reporter with Medical World News. @mitchelzoler
Revised CMS TAVR rules expected to widen access
The new National Coverage Determination by Medicare for transcatheter aortic valve replacement should produce a bump in the number of U.S. programs offering the procedure, especially with the Food and Drug Administration on the cusp of approving the procedure for low-risk patients.
In the revised National Coverage Determination (NCD) by the Centers for Medicare & Medicaid Services that went into effect on June 21, 2019, the agency allowed for Medicare coverage of transcatheter aortic valve (TAVR) procedures at hospitals that perform at least 20 of these procedures annually or at least 40 every 2 years, the same volume minimums that CMS first applied to TAVR in its prior 2012 NCD. Retention of this minimum ran against the 2018 proposal of the American College of Cardiology, the Society of Thoracic Surgeons, and two other collaborating societies that called for an annual TAVR volume minimum at a hospital program of 50 procedures annually or 100 every 2 years (J Am Coll Cardiol. 2019 Jan 29;73[3]:340-74).
That change, coupled with a cut in the minimum number of annual percutaneous coronary interventions a TAVR program needs to perform – newly revised to a minimum of 300 cases/year – will likely mean more U.S. sites performing TAVR, predicted James Vavricek, director of regulatory affairs for the ACC in Washington. TAVR volume is seen as a reasonable, approximate surrogate for a more rigorous, statistically adjusted assessment of program quality. The ACC and representatives from the other societies that collaborated on the 2018 statement used a 50 case/year minimum for a TAVR program because volume at that level generates enough outcomes data to allow for a meaningful, risk-adjusted measure of performance.
The ACC does not consider the minimum of 20 TAVR cases/year the “right decision,” Mr. Vavricek said in an interview, but the ACC sees it as a compromise that accommodated the interests of multiple TAVR stakeholders. “It will be interesting to see where new TAVR programs locate,” whether they will expand access in underserved regions or mostly cluster in regions already fairly replete with TAVR access, he added. Currently, over 600 U.S. TAVR programs are in operation.
In April 2019, the president of the ACC along with the presidents of three other U.S. societies with an interest in TAVR told the CMS in a comment letter that “we are extremely concerned that the proposed volume requirements will translate into a proliferation of low-volume TAVR programs at increased risk for having suboptimal outcomes.”
Another change to procedure volume requirements in the new NCD was setting a minimum of 100 total TAVR plus surgical aortic valve replacements in a 2-year period or 50 total procedures/year for each TAVR program. Setting a minimum that bundles TAVR plus surgical valve replacements is a “forward-looking” approach as wider application of TAVR gradually erodes the volume of surgical procedures, Mr. Vavricek said.
An additional notable change in the revised NCD was elimination of the “two-surgeon” rule, which the CMS had made mandatory for TAVR decisions until now, stipulating that a patient considered for TAVR needed independent assessment by two cardiac surgeons. The final 2019 NCD calls for the TAVR decision to come from one cardiac surgeon and one interventional cardiologist working together on a care team.
“The ACC is pleased to see CMS issue updated TAVR coverage criteria that emphasizes care by an interdisciplinary heart team for these complex patients, as well as continues to mandate the collection of TAVR patient data. With the new lowered minimum yearly volume criteria set by CMS in their efforts to improve patient access, the value of the STS/ACC TVT Registry, along with ACC’s Transcatheter Valve Certification, will be critical in assuring quality of care for our patients particularly in low-volume centers,” commented Richard J. Kovacs, MD, ACC’s president.
The new National Coverage Determination by Medicare for transcatheter aortic valve replacement should produce a bump in the number of U.S. programs offering the procedure, especially with the Food and Drug Administration on the cusp of approving the procedure for low-risk patients.
In the revised National Coverage Determination (NCD) by the Centers for Medicare & Medicaid Services that went into effect on June 21, 2019, the agency allowed for Medicare coverage of transcatheter aortic valve (TAVR) procedures at hospitals that perform at least 20 of these procedures annually or at least 40 every 2 years, the same volume minimums that CMS first applied to TAVR in its prior 2012 NCD. Retention of this minimum ran against the 2018 proposal of the American College of Cardiology, the Society of Thoracic Surgeons, and two other collaborating societies that called for an annual TAVR volume minimum at a hospital program of 50 procedures annually or 100 every 2 years (J Am Coll Cardiol. 2019 Jan 29;73[3]:340-74).
That change, coupled with a cut in the minimum number of annual percutaneous coronary interventions a TAVR program needs to perform – newly revised to a minimum of 300 cases/year – will likely mean more U.S. sites performing TAVR, predicted James Vavricek, director of regulatory affairs for the ACC in Washington. TAVR volume is seen as a reasonable, approximate surrogate for a more rigorous, statistically adjusted assessment of program quality. The ACC and representatives from the other societies that collaborated on the 2018 statement used a 50 case/year minimum for a TAVR program because volume at that level generates enough outcomes data to allow for a meaningful, risk-adjusted measure of performance.
The ACC does not consider the minimum of 20 TAVR cases/year the “right decision,” Mr. Vavricek said in an interview, but the ACC sees it as a compromise that accommodated the interests of multiple TAVR stakeholders. “It will be interesting to see where new TAVR programs locate,” whether they will expand access in underserved regions or mostly cluster in regions already fairly replete with TAVR access, he added. Currently, over 600 U.S. TAVR programs are in operation.
In April 2019, the president of the ACC along with the presidents of three other U.S. societies with an interest in TAVR told the CMS in a comment letter that “we are extremely concerned that the proposed volume requirements will translate into a proliferation of low-volume TAVR programs at increased risk for having suboptimal outcomes.”
Another change to procedure volume requirements in the new NCD was setting a minimum of 100 total TAVR plus surgical aortic valve replacements in a 2-year period or 50 total procedures/year for each TAVR program. Setting a minimum that bundles TAVR plus surgical valve replacements is a “forward-looking” approach as wider application of TAVR gradually erodes the volume of surgical procedures, Mr. Vavricek said.
An additional notable change in the revised NCD was elimination of the “two-surgeon” rule, which the CMS had made mandatory for TAVR decisions until now, stipulating that a patient considered for TAVR needed independent assessment by two cardiac surgeons. The final 2019 NCD calls for the TAVR decision to come from one cardiac surgeon and one interventional cardiologist working together on a care team.
“The ACC is pleased to see CMS issue updated TAVR coverage criteria that emphasizes care by an interdisciplinary heart team for these complex patients, as well as continues to mandate the collection of TAVR patient data. With the new lowered minimum yearly volume criteria set by CMS in their efforts to improve patient access, the value of the STS/ACC TVT Registry, along with ACC’s Transcatheter Valve Certification, will be critical in assuring quality of care for our patients particularly in low-volume centers,” commented Richard J. Kovacs, MD, ACC’s president.
The new National Coverage Determination by Medicare for transcatheter aortic valve replacement should produce a bump in the number of U.S. programs offering the procedure, especially with the Food and Drug Administration on the cusp of approving the procedure for low-risk patients.
In the revised National Coverage Determination (NCD) by the Centers for Medicare & Medicaid Services that went into effect on June 21, 2019, the agency allowed for Medicare coverage of transcatheter aortic valve (TAVR) procedures at hospitals that perform at least 20 of these procedures annually or at least 40 every 2 years, the same volume minimums that CMS first applied to TAVR in its prior 2012 NCD. Retention of this minimum ran against the 2018 proposal of the American College of Cardiology, the Society of Thoracic Surgeons, and two other collaborating societies that called for an annual TAVR volume minimum at a hospital program of 50 procedures annually or 100 every 2 years (J Am Coll Cardiol. 2019 Jan 29;73[3]:340-74).
That change, coupled with a cut in the minimum number of annual percutaneous coronary interventions a TAVR program needs to perform – newly revised to a minimum of 300 cases/year – will likely mean more U.S. sites performing TAVR, predicted James Vavricek, director of regulatory affairs for the ACC in Washington. TAVR volume is seen as a reasonable, approximate surrogate for a more rigorous, statistically adjusted assessment of program quality. The ACC and representatives from the other societies that collaborated on the 2018 statement used a 50 case/year minimum for a TAVR program because volume at that level generates enough outcomes data to allow for a meaningful, risk-adjusted measure of performance.
The ACC does not consider the minimum of 20 TAVR cases/year the “right decision,” Mr. Vavricek said in an interview, but the ACC sees it as a compromise that accommodated the interests of multiple TAVR stakeholders. “It will be interesting to see where new TAVR programs locate,” whether they will expand access in underserved regions or mostly cluster in regions already fairly replete with TAVR access, he added. Currently, over 600 U.S. TAVR programs are in operation.
In April 2019, the president of the ACC along with the presidents of three other U.S. societies with an interest in TAVR told the CMS in a comment letter that “we are extremely concerned that the proposed volume requirements will translate into a proliferation of low-volume TAVR programs at increased risk for having suboptimal outcomes.”
Another change to procedure volume requirements in the new NCD was setting a minimum of 100 total TAVR plus surgical aortic valve replacements in a 2-year period or 50 total procedures/year for each TAVR program. Setting a minimum that bundles TAVR plus surgical valve replacements is a “forward-looking” approach as wider application of TAVR gradually erodes the volume of surgical procedures, Mr. Vavricek said.
An additional notable change in the revised NCD was elimination of the “two-surgeon” rule, which the CMS had made mandatory for TAVR decisions until now, stipulating that a patient considered for TAVR needed independent assessment by two cardiac surgeons. The final 2019 NCD calls for the TAVR decision to come from one cardiac surgeon and one interventional cardiologist working together on a care team.
“The ACC is pleased to see CMS issue updated TAVR coverage criteria that emphasizes care by an interdisciplinary heart team for these complex patients, as well as continues to mandate the collection of TAVR patient data. With the new lowered minimum yearly volume criteria set by CMS in their efforts to improve patient access, the value of the STS/ACC TVT Registry, along with ACC’s Transcatheter Valve Certification, will be critical in assuring quality of care for our patients particularly in low-volume centers,” commented Richard J. Kovacs, MD, ACC’s president.
Imaging remission decried as ticket to RA overtreatment
MADRID – Defining remission in patients with rheumatoid arthritis depends on their clinical status, not on the presence or absence of inflammatory signals on ultrasound or MRI, many rheumatologists now agree.
The strong consensus that’s formed against using imaging as a criterion for RA remission was apparent at the European Congress of Rheumatology during presentation of a pending update to the EULAR recommendations for managing RA, as well as in at least two separate, invited lectures.
“Imaging is out,” proclaimed Josef S. Smolen, MD, as he spoke at the congress about the pending RA management revisions. This condemnation of imaging by ultrasound or MRI as an unsafe and misleading target for RA treatment by Dr. Smolen, professor of medicine at the Medical University of Vienna, was perhaps the most forceful statement he made while presenting the draft revision of EULAR’s RA recommendations.
The case for using ultrasound or MR to find inflammatory signatures in joints that can function as treatment targets collapsed earlier in 2019 with publication of results from IMAGINE-RA (An MRI-guided Treatment Strategy to Prevent Disease Progression in Patients With Rheumatoid Arthritis), a multicenter Danish study that randomized 200 RA patients in remission to either a conventional, disease activity–guided treatment target (in this case the DAS28-CRP [Disease Activity Score in 28 joints plus C-reactive protein]), or a treatment target that included the conventional clinical target plus treating to eliminate any bone marrow edema visualized by MRI. After 24 months of treatment, the prevalence of clinical remission and MRI remission was about the same in both arms, with no statistically significant differences. But serious adverse events in 6 patients managed by their clinical assessment compared favorably against 17 among those managed to an imaging remission endpoint, a difference that strongly hinted at dangerous overtreatment of the imaging-guided patients (JAMA. 2019 Feb 5;321[5]:461-72).
The failure of MRI assessment of inflammation to improve RA treatment in IMAGINE-RA came against the backdrop of two 2016 reports that documented the same limitation when using ultrasound to detect joint inflammation and guide treatment in RA patients. The TaSER (Targeting Synovitis in Early Rheumatoid Arthritis) study randomized 111 patients with newly diagnosed RA or undifferentiated arthritis to conventional disease activity assessment, DAS28–erythrocyte sedimentation rate, or to that plus assessment by musculoskeletal ultrasound, and found no difference in clinical or imaging outcomes (Ann Rheum Dis. 2016 Jun;75[6]:1043-50). The second report, ARCTIC (Aiming for Remission in Rheumatoid Arthritis), randomized 238 RA patients to either a tight RA control strategy based on DAS alone or based on DAS plus serial examination of joints with ultrasound. The results showed that, after 16-24 months on treatment, the two strategies produced no significant difference in the rates of sustained RA remission with no radiographic damage or swollen joints detected (BMJ. 2016 Aug 16;354:i4205).
The results from these three studies have shown that “not all inflammation seen by ultrasound or MR is pathological,” and that “no imaging technique or biomarker has shown superiority to clinical assessment as a treat-to-target” goal, Sofia Ramiro, MD, said in a talk at the congress during which she reviewed this evidence.
“Treat-to-target that takes imaging into account is high risk because it exposes patients to overtreatment, which has costs in the broad sense, safety included,” said Dr. Ramiro, a rheumatologist at Leiden (the Netherlands) University Medical Center. “I think that systematically evaluating a patient’s joint with imaging won’t have additional value, and is the wrong approach.”
A similar assessment came from Stefan Siebert, MD, during a separate lecture during the congress. He highlighted that use of ultrasound or MRI to guide treatment in these three studies consistently led to substantially higher rates of treatment escalation, treatment with biologics, and in two of the three studies a notable increase in serious adverse events. Treatment with a biologic drug was roughly twice as frequent in the imaging-guided arms of TaSER and ARCTIC, compared with the control arms in those studies, and in IMAGINE-RA, the use of a biologic drug occurred more than 20 times more often in the imaging arms, he noted. And in both TaSER and IMAGINE-RA the rate of serious adverse events was more than doubled in the imaging arms, compared with the controls.
“Just identifying inflammation [in a joint] is not enough to make a diagnosis. Inflammation is normal process, and finding it does not identify a pathological state,” noted Dr. Siebert, a rheumatologist at the University of Glasgow. “Imaging leads to overdiagnosis and overtreatment when physicians use imaging inappropriately,” he concluded.
Dr. Smolen has been a consultant to several drug companies. Dr. Ramiro has been a consultant to or speaker on behalf of AbbVie, Eli Lilly, Merck, Novartis, and Sanofi, and she has received research funding from Merck. Dr. Siebert has been a consultant to or speaker on behalf of AbbVie, Boehringer Ingelheim, Celgene, Janssen, Novartis, and UCB, and he has received research funding from Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.
MADRID – Defining remission in patients with rheumatoid arthritis depends on their clinical status, not on the presence or absence of inflammatory signals on ultrasound or MRI, many rheumatologists now agree.
The strong consensus that’s formed against using imaging as a criterion for RA remission was apparent at the European Congress of Rheumatology during presentation of a pending update to the EULAR recommendations for managing RA, as well as in at least two separate, invited lectures.
“Imaging is out,” proclaimed Josef S. Smolen, MD, as he spoke at the congress about the pending RA management revisions. This condemnation of imaging by ultrasound or MRI as an unsafe and misleading target for RA treatment by Dr. Smolen, professor of medicine at the Medical University of Vienna, was perhaps the most forceful statement he made while presenting the draft revision of EULAR’s RA recommendations.
The case for using ultrasound or MR to find inflammatory signatures in joints that can function as treatment targets collapsed earlier in 2019 with publication of results from IMAGINE-RA (An MRI-guided Treatment Strategy to Prevent Disease Progression in Patients With Rheumatoid Arthritis), a multicenter Danish study that randomized 200 RA patients in remission to either a conventional, disease activity–guided treatment target (in this case the DAS28-CRP [Disease Activity Score in 28 joints plus C-reactive protein]), or a treatment target that included the conventional clinical target plus treating to eliminate any bone marrow edema visualized by MRI. After 24 months of treatment, the prevalence of clinical remission and MRI remission was about the same in both arms, with no statistically significant differences. But serious adverse events in 6 patients managed by their clinical assessment compared favorably against 17 among those managed to an imaging remission endpoint, a difference that strongly hinted at dangerous overtreatment of the imaging-guided patients (JAMA. 2019 Feb 5;321[5]:461-72).
The failure of MRI assessment of inflammation to improve RA treatment in IMAGINE-RA came against the backdrop of two 2016 reports that documented the same limitation when using ultrasound to detect joint inflammation and guide treatment in RA patients. The TaSER (Targeting Synovitis in Early Rheumatoid Arthritis) study randomized 111 patients with newly diagnosed RA or undifferentiated arthritis to conventional disease activity assessment, DAS28–erythrocyte sedimentation rate, or to that plus assessment by musculoskeletal ultrasound, and found no difference in clinical or imaging outcomes (Ann Rheum Dis. 2016 Jun;75[6]:1043-50). The second report, ARCTIC (Aiming for Remission in Rheumatoid Arthritis), randomized 238 RA patients to either a tight RA control strategy based on DAS alone or based on DAS plus serial examination of joints with ultrasound. The results showed that, after 16-24 months on treatment, the two strategies produced no significant difference in the rates of sustained RA remission with no radiographic damage or swollen joints detected (BMJ. 2016 Aug 16;354:i4205).
The results from these three studies have shown that “not all inflammation seen by ultrasound or MR is pathological,” and that “no imaging technique or biomarker has shown superiority to clinical assessment as a treat-to-target” goal, Sofia Ramiro, MD, said in a talk at the congress during which she reviewed this evidence.
“Treat-to-target that takes imaging into account is high risk because it exposes patients to overtreatment, which has costs in the broad sense, safety included,” said Dr. Ramiro, a rheumatologist at Leiden (the Netherlands) University Medical Center. “I think that systematically evaluating a patient’s joint with imaging won’t have additional value, and is the wrong approach.”
A similar assessment came from Stefan Siebert, MD, during a separate lecture during the congress. He highlighted that use of ultrasound or MRI to guide treatment in these three studies consistently led to substantially higher rates of treatment escalation, treatment with biologics, and in two of the three studies a notable increase in serious adverse events. Treatment with a biologic drug was roughly twice as frequent in the imaging-guided arms of TaSER and ARCTIC, compared with the control arms in those studies, and in IMAGINE-RA, the use of a biologic drug occurred more than 20 times more often in the imaging arms, he noted. And in both TaSER and IMAGINE-RA the rate of serious adverse events was more than doubled in the imaging arms, compared with the controls.
“Just identifying inflammation [in a joint] is not enough to make a diagnosis. Inflammation is normal process, and finding it does not identify a pathological state,” noted Dr. Siebert, a rheumatologist at the University of Glasgow. “Imaging leads to overdiagnosis and overtreatment when physicians use imaging inappropriately,” he concluded.
Dr. Smolen has been a consultant to several drug companies. Dr. Ramiro has been a consultant to or speaker on behalf of AbbVie, Eli Lilly, Merck, Novartis, and Sanofi, and she has received research funding from Merck. Dr. Siebert has been a consultant to or speaker on behalf of AbbVie, Boehringer Ingelheim, Celgene, Janssen, Novartis, and UCB, and he has received research funding from Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.
MADRID – Defining remission in patients with rheumatoid arthritis depends on their clinical status, not on the presence or absence of inflammatory signals on ultrasound or MRI, many rheumatologists now agree.
The strong consensus that’s formed against using imaging as a criterion for RA remission was apparent at the European Congress of Rheumatology during presentation of a pending update to the EULAR recommendations for managing RA, as well as in at least two separate, invited lectures.
“Imaging is out,” proclaimed Josef S. Smolen, MD, as he spoke at the congress about the pending RA management revisions. This condemnation of imaging by ultrasound or MRI as an unsafe and misleading target for RA treatment by Dr. Smolen, professor of medicine at the Medical University of Vienna, was perhaps the most forceful statement he made while presenting the draft revision of EULAR’s RA recommendations.
The case for using ultrasound or MR to find inflammatory signatures in joints that can function as treatment targets collapsed earlier in 2019 with publication of results from IMAGINE-RA (An MRI-guided Treatment Strategy to Prevent Disease Progression in Patients With Rheumatoid Arthritis), a multicenter Danish study that randomized 200 RA patients in remission to either a conventional, disease activity–guided treatment target (in this case the DAS28-CRP [Disease Activity Score in 28 joints plus C-reactive protein]), or a treatment target that included the conventional clinical target plus treating to eliminate any bone marrow edema visualized by MRI. After 24 months of treatment, the prevalence of clinical remission and MRI remission was about the same in both arms, with no statistically significant differences. But serious adverse events in 6 patients managed by their clinical assessment compared favorably against 17 among those managed to an imaging remission endpoint, a difference that strongly hinted at dangerous overtreatment of the imaging-guided patients (JAMA. 2019 Feb 5;321[5]:461-72).
The failure of MRI assessment of inflammation to improve RA treatment in IMAGINE-RA came against the backdrop of two 2016 reports that documented the same limitation when using ultrasound to detect joint inflammation and guide treatment in RA patients. The TaSER (Targeting Synovitis in Early Rheumatoid Arthritis) study randomized 111 patients with newly diagnosed RA or undifferentiated arthritis to conventional disease activity assessment, DAS28–erythrocyte sedimentation rate, or to that plus assessment by musculoskeletal ultrasound, and found no difference in clinical or imaging outcomes (Ann Rheum Dis. 2016 Jun;75[6]:1043-50). The second report, ARCTIC (Aiming for Remission in Rheumatoid Arthritis), randomized 238 RA patients to either a tight RA control strategy based on DAS alone or based on DAS plus serial examination of joints with ultrasound. The results showed that, after 16-24 months on treatment, the two strategies produced no significant difference in the rates of sustained RA remission with no radiographic damage or swollen joints detected (BMJ. 2016 Aug 16;354:i4205).
The results from these three studies have shown that “not all inflammation seen by ultrasound or MR is pathological,” and that “no imaging technique or biomarker has shown superiority to clinical assessment as a treat-to-target” goal, Sofia Ramiro, MD, said in a talk at the congress during which she reviewed this evidence.
“Treat-to-target that takes imaging into account is high risk because it exposes patients to overtreatment, which has costs in the broad sense, safety included,” said Dr. Ramiro, a rheumatologist at Leiden (the Netherlands) University Medical Center. “I think that systematically evaluating a patient’s joint with imaging won’t have additional value, and is the wrong approach.”
A similar assessment came from Stefan Siebert, MD, during a separate lecture during the congress. He highlighted that use of ultrasound or MRI to guide treatment in these three studies consistently led to substantially higher rates of treatment escalation, treatment with biologics, and in two of the three studies a notable increase in serious adverse events. Treatment with a biologic drug was roughly twice as frequent in the imaging-guided arms of TaSER and ARCTIC, compared with the control arms in those studies, and in IMAGINE-RA, the use of a biologic drug occurred more than 20 times more often in the imaging arms, he noted. And in both TaSER and IMAGINE-RA the rate of serious adverse events was more than doubled in the imaging arms, compared with the controls.
“Just identifying inflammation [in a joint] is not enough to make a diagnosis. Inflammation is normal process, and finding it does not identify a pathological state,” noted Dr. Siebert, a rheumatologist at the University of Glasgow. “Imaging leads to overdiagnosis and overtreatment when physicians use imaging inappropriately,” he concluded.
Dr. Smolen has been a consultant to several drug companies. Dr. Ramiro has been a consultant to or speaker on behalf of AbbVie, Eli Lilly, Merck, Novartis, and Sanofi, and she has received research funding from Merck. Dr. Siebert has been a consultant to or speaker on behalf of AbbVie, Boehringer Ingelheim, Celgene, Janssen, Novartis, and UCB, and he has received research funding from Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.
REPORTING FROM EULAR 2019 CONGRESS
EULAR revises its RA management recommendations
MADRID – No change to designating methotrexate the first disease-modifying drug to prescribe, before any biologic drug, and no adoption of imaging criteria to determine whether a patient is in remission.
“Imaging with ultrasound or MRI is out” as a remission criterion. “It’s high risk and a waste of resources,” declared Josef S. Smolen, MD, head of the EULAR writing panel, in the most forceful declaration he made while presenting the pending recommendation revision at the European Congress of Rheumatology.
Dr. Smolen’s strong warning against an imaging parameter when treating RA patients toward a remission target was no surprise, as he had already voiced this opinion in an editorial he coauthored earlier this year (JAMA. 2019 Feb 5;321[5]:457-8). The editorial cited data from three independent studies that compared an RA treatment strategy that used an imaging measure of joint inflammation as a treatment target along with clinical assessment against clinical assessment alone. All three studies found no benefit from ultrasound or MRI for defining a treatment goal, and two of the studies showed evidence for harm. “Using imaging to guide therapy led to prescription of potentially harmful medicines without differences in the primary outcomes, but at high costs and potential burden of unnecessary treatment changes and risks for patients,” noted Dr. Smolen and his coauthor in the editorial.
The report that this editorial addressed (JAMA. 2019 Feb 5;321[5]:461-72) also provided some of the most recent evidence for the second omission from the new revision that Dr. Smolen called out: No change to the recommendation to use methotrexate as initial treatment for any RA patient. “We continue to say that methotrexate is the first treatment strategy. There is no new evidence that any biological treatment is better than methotrexate, so there is no change,” said Dr. Smolen, professor of medicine at the Medical University of Vienna, who also led the EULAR writing panel for the immediately preceding set of RA treatment recommendations first unveiled 3 years before (Ann Rheum Dis. 2017 Jun;76[6]:960-77).
Perhaps the most notable changes to the recommendations are the way they handle targeted-synthetic disease-modifying antirheumatic drugs (tsDMARDs), a class that currently is synonymous with the Janus kinase (JAK) inhibitors. “Because of new evidence we have lifted up the tsDMARDs” so that no preference is given to biologic DMARDs over the ts class as happened in the 2016 version, Dr. Smolen said. Another revision to this recommendation was to change the addition of either a biologic or tsDMARD to a patient not fully responsive to a conventional-synthetic (cs) DMARD and with poor prognostic factors from a “should be considered” to a “should be added” recommendation.
Another way in which the pending revision uplifted tsDMARDs was in the wording for the recommendation that deals with patients who do not respond to a first tumor necrosis factor (TNF) inhibitor plus methotrexate or another csDMARD, and now lists as the first option switching to a biologic or tsDMARD with a different mode of action followed by a different TNF inhibitor, a reversal of order from before when a different TNF inhibitor got first mention. This order change was a modest revision that reflected observational evidence that was modestly persuasive that switching to an agent with a different mechanism of action is often the most effective approach, Dr. Smolen said.
The new recommendations also reaffirmed the eleventh recommendation from the 2016 version, which called for tapering of the biologic or tsDMARD from a patient in remission while retaining the csDMARD, usually methotrexate. Dr. Smolen cited new evidence in favor of this approach (Ann Rheum Dis. 2019 Jun;78[6]:746-53), which allowed the writing panel to upgrade the evidence supporting this recommendation to the A level. The concept of tapering down the biologic or tsDMARD for a patient in sustained remission while maintaining the csDMARD was “fully confirmed” in a recent report, he added. The writing panel also upticked its rating of the evidence in favor of cautiously tapering the csDMARD in patients who maintain remission on just a csDMARD.
One final element in the pending revision called out a newly identified safety signal, an increased risk for venous thromboembolism among patients on certain high dosages of JAK inhibitors, especially in patients with increased risk for venous thromboembolism. This new safety concern adds to the already-described increased risk for herpes zoster from JAK inhibitors, especially in Japanese and Korean populations, Dr. Smolen said. In general, more long-term safety data for JAK inhibitors are needed.
The draft update also added one new overarching principle: “Patients require access to multiple drugs with different modes of action to address the heterogeneity of RA, and patients may require multiple, successive treatments throughout life.” Overall, pending changes to the RA recommendations were limited because “the EULAR recommendations have achieved a steady state of the art” for defining whom to treat, treatment targets, and appropriate treatment strategies, Dr. Smolen said.
Dr. Smolen had been a consultant to or a speaker on behalf of several drug companies.
MADRID – No change to designating methotrexate the first disease-modifying drug to prescribe, before any biologic drug, and no adoption of imaging criteria to determine whether a patient is in remission.
“Imaging with ultrasound or MRI is out” as a remission criterion. “It’s high risk and a waste of resources,” declared Josef S. Smolen, MD, head of the EULAR writing panel, in the most forceful declaration he made while presenting the pending recommendation revision at the European Congress of Rheumatology.
Dr. Smolen’s strong warning against an imaging parameter when treating RA patients toward a remission target was no surprise, as he had already voiced this opinion in an editorial he coauthored earlier this year (JAMA. 2019 Feb 5;321[5]:457-8). The editorial cited data from three independent studies that compared an RA treatment strategy that used an imaging measure of joint inflammation as a treatment target along with clinical assessment against clinical assessment alone. All three studies found no benefit from ultrasound or MRI for defining a treatment goal, and two of the studies showed evidence for harm. “Using imaging to guide therapy led to prescription of potentially harmful medicines without differences in the primary outcomes, but at high costs and potential burden of unnecessary treatment changes and risks for patients,” noted Dr. Smolen and his coauthor in the editorial.
The report that this editorial addressed (JAMA. 2019 Feb 5;321[5]:461-72) also provided some of the most recent evidence for the second omission from the new revision that Dr. Smolen called out: No change to the recommendation to use methotrexate as initial treatment for any RA patient. “We continue to say that methotrexate is the first treatment strategy. There is no new evidence that any biological treatment is better than methotrexate, so there is no change,” said Dr. Smolen, professor of medicine at the Medical University of Vienna, who also led the EULAR writing panel for the immediately preceding set of RA treatment recommendations first unveiled 3 years before (Ann Rheum Dis. 2017 Jun;76[6]:960-77).
Perhaps the most notable changes to the recommendations are the way they handle targeted-synthetic disease-modifying antirheumatic drugs (tsDMARDs), a class that currently is synonymous with the Janus kinase (JAK) inhibitors. “Because of new evidence we have lifted up the tsDMARDs” so that no preference is given to biologic DMARDs over the ts class as happened in the 2016 version, Dr. Smolen said. Another revision to this recommendation was to change the addition of either a biologic or tsDMARD to a patient not fully responsive to a conventional-synthetic (cs) DMARD and with poor prognostic factors from a “should be considered” to a “should be added” recommendation.
Another way in which the pending revision uplifted tsDMARDs was in the wording for the recommendation that deals with patients who do not respond to a first tumor necrosis factor (TNF) inhibitor plus methotrexate or another csDMARD, and now lists as the first option switching to a biologic or tsDMARD with a different mode of action followed by a different TNF inhibitor, a reversal of order from before when a different TNF inhibitor got first mention. This order change was a modest revision that reflected observational evidence that was modestly persuasive that switching to an agent with a different mechanism of action is often the most effective approach, Dr. Smolen said.
The new recommendations also reaffirmed the eleventh recommendation from the 2016 version, which called for tapering of the biologic or tsDMARD from a patient in remission while retaining the csDMARD, usually methotrexate. Dr. Smolen cited new evidence in favor of this approach (Ann Rheum Dis. 2019 Jun;78[6]:746-53), which allowed the writing panel to upgrade the evidence supporting this recommendation to the A level. The concept of tapering down the biologic or tsDMARD for a patient in sustained remission while maintaining the csDMARD was “fully confirmed” in a recent report, he added. The writing panel also upticked its rating of the evidence in favor of cautiously tapering the csDMARD in patients who maintain remission on just a csDMARD.
One final element in the pending revision called out a newly identified safety signal, an increased risk for venous thromboembolism among patients on certain high dosages of JAK inhibitors, especially in patients with increased risk for venous thromboembolism. This new safety concern adds to the already-described increased risk for herpes zoster from JAK inhibitors, especially in Japanese and Korean populations, Dr. Smolen said. In general, more long-term safety data for JAK inhibitors are needed.
The draft update also added one new overarching principle: “Patients require access to multiple drugs with different modes of action to address the heterogeneity of RA, and patients may require multiple, successive treatments throughout life.” Overall, pending changes to the RA recommendations were limited because “the EULAR recommendations have achieved a steady state of the art” for defining whom to treat, treatment targets, and appropriate treatment strategies, Dr. Smolen said.
Dr. Smolen had been a consultant to or a speaker on behalf of several drug companies.
MADRID – No change to designating methotrexate the first disease-modifying drug to prescribe, before any biologic drug, and no adoption of imaging criteria to determine whether a patient is in remission.
“Imaging with ultrasound or MRI is out” as a remission criterion. “It’s high risk and a waste of resources,” declared Josef S. Smolen, MD, head of the EULAR writing panel, in the most forceful declaration he made while presenting the pending recommendation revision at the European Congress of Rheumatology.
Dr. Smolen’s strong warning against an imaging parameter when treating RA patients toward a remission target was no surprise, as he had already voiced this opinion in an editorial he coauthored earlier this year (JAMA. 2019 Feb 5;321[5]:457-8). The editorial cited data from three independent studies that compared an RA treatment strategy that used an imaging measure of joint inflammation as a treatment target along with clinical assessment against clinical assessment alone. All three studies found no benefit from ultrasound or MRI for defining a treatment goal, and two of the studies showed evidence for harm. “Using imaging to guide therapy led to prescription of potentially harmful medicines without differences in the primary outcomes, but at high costs and potential burden of unnecessary treatment changes and risks for patients,” noted Dr. Smolen and his coauthor in the editorial.
The report that this editorial addressed (JAMA. 2019 Feb 5;321[5]:461-72) also provided some of the most recent evidence for the second omission from the new revision that Dr. Smolen called out: No change to the recommendation to use methotrexate as initial treatment for any RA patient. “We continue to say that methotrexate is the first treatment strategy. There is no new evidence that any biological treatment is better than methotrexate, so there is no change,” said Dr. Smolen, professor of medicine at the Medical University of Vienna, who also led the EULAR writing panel for the immediately preceding set of RA treatment recommendations first unveiled 3 years before (Ann Rheum Dis. 2017 Jun;76[6]:960-77).
Perhaps the most notable changes to the recommendations are the way they handle targeted-synthetic disease-modifying antirheumatic drugs (tsDMARDs), a class that currently is synonymous with the Janus kinase (JAK) inhibitors. “Because of new evidence we have lifted up the tsDMARDs” so that no preference is given to biologic DMARDs over the ts class as happened in the 2016 version, Dr. Smolen said. Another revision to this recommendation was to change the addition of either a biologic or tsDMARD to a patient not fully responsive to a conventional-synthetic (cs) DMARD and with poor prognostic factors from a “should be considered” to a “should be added” recommendation.
Another way in which the pending revision uplifted tsDMARDs was in the wording for the recommendation that deals with patients who do not respond to a first tumor necrosis factor (TNF) inhibitor plus methotrexate or another csDMARD, and now lists as the first option switching to a biologic or tsDMARD with a different mode of action followed by a different TNF inhibitor, a reversal of order from before when a different TNF inhibitor got first mention. This order change was a modest revision that reflected observational evidence that was modestly persuasive that switching to an agent with a different mechanism of action is often the most effective approach, Dr. Smolen said.
The new recommendations also reaffirmed the eleventh recommendation from the 2016 version, which called for tapering of the biologic or tsDMARD from a patient in remission while retaining the csDMARD, usually methotrexate. Dr. Smolen cited new evidence in favor of this approach (Ann Rheum Dis. 2019 Jun;78[6]:746-53), which allowed the writing panel to upgrade the evidence supporting this recommendation to the A level. The concept of tapering down the biologic or tsDMARD for a patient in sustained remission while maintaining the csDMARD was “fully confirmed” in a recent report, he added. The writing panel also upticked its rating of the evidence in favor of cautiously tapering the csDMARD in patients who maintain remission on just a csDMARD.
One final element in the pending revision called out a newly identified safety signal, an increased risk for venous thromboembolism among patients on certain high dosages of JAK inhibitors, especially in patients with increased risk for venous thromboembolism. This new safety concern adds to the already-described increased risk for herpes zoster from JAK inhibitors, especially in Japanese and Korean populations, Dr. Smolen said. In general, more long-term safety data for JAK inhibitors are needed.
The draft update also added one new overarching principle: “Patients require access to multiple drugs with different modes of action to address the heterogeneity of RA, and patients may require multiple, successive treatments throughout life.” Overall, pending changes to the RA recommendations were limited because “the EULAR recommendations have achieved a steady state of the art” for defining whom to treat, treatment targets, and appropriate treatment strategies, Dr. Smolen said.
Dr. Smolen had been a consultant to or a speaker on behalf of several drug companies.
EXPERT ANALYSIS FROM EULAR 2019 CONGRESS
Ixekizumab surpasses adalimumab in PsA head-to-head study
MADRID – The interleukin-17A inhibitor ixekizumab surpassed the tumor necrosis factor inhibitor adalimumab for treatment of patients with psoriatic arthritis in a multicenter, randomized study with 566 enrolled patients, the first reported results from a head-to-head comparison for this disease of two different classes of biological drugs.
The results showed that a standard, 24-week regimen with each of these agents, both of which already have regulatory approval for treating psoriatic arthritis (PsA), led to achievement of the primary endpoint in 36% of patients treated with ixekizumab (Taltz) and 28% of patients treated with adalimumab (Humira), a statistically significant difference, Philip J. Mease, MD, said at the European Congress of Rheumatology.
“Ixekizumab was superior to adalimumab for improving signs and symptoms of active PsA, as measured by simultaneous achievement of ACR50 [American College of Rheumatology] and PASI 100 [Psoriasis Area and Severity Index],” the study’s primary endpoint that combined a measure of joint disease activity with a measure of skin involvement, said Dr. Mease, a rheumatologist at Swedish Medical Center in Seattle.
This unconventional primary endpoint for testing drugs that treat PsA was called out during discussion of the report for having an inherent bias favoring ixekizumab by its inclusion of a skin outcome that received equal weight with an assessment tool that focused on joint responses. “This was a very unusual primary endpoint that favored ixekizumab,” Roy M. Fleischmann, MD, a Dallas rheumatologist, commented during the discussion.
Dr. Mease readily admitted that the study’s design stacked the deck in favor of ixekizumab, but he added that this decision reflected a desire by the researchers who ran the study to choose a primary endpoint that represented both of the prominent pathologies seen in patients with PsA.
The primary endpoint used in the study “looks at PsA more holistically,” Dr. Mease said in an interview. “It forced clinicians to look beyond just the joints,” in PsA patients. “That has been a limitation of prior PsA treatment assessments,” which until this study have uniformly used single primary outcomes that focus on joint responses, most commonly the ACR20 measure of joint disease activity.
The SPIRIT-H2H (A Study of Ixekizumab [LY2439821] Versus Adalimumab in Participants With Psoriatic Arthritis) study enrolled adults with active PsA who had never before received treatment with a biological drug. Enrolled patients had to have both active disease in their joints and active plaque psoriasis, with an inadequate response to at least one conventional synthetic disease-modifying antirheumatic drug. The 566 patients randomized in the study averaged about 48 years old, a bit more than half were men, and patients averaged about 6 years with diagnosed PsA and about 15 years diagnosed with psoriasis. Just over two-thirds of the patients were on concurrent treatment with a conventional synthetic agent, most often methotrexate.
The two components of the primary endpoint each showed the anticipated result. Among the 269 patients treated with adalimumab for the full 24 weeks, 47% had an ACR50 response, as did 51% of the 262 patients who completed their full course of ixekizumab, a between-group difference that was not statistically significant. In contrast, the PASI 100 measure of complete skin resolution occurred in 47% of the adalimumab-treated patients and 60% of those on ixekizumab, a statistically significant difference.
Dr. Mease reported results for several other efficacy measures, and what was notable was statistically significant superiority for ixekizumab in a measure of entheses disease activity, the SPARCC [Spondyloarthritis Research Consortium of Canada] Enthesitis Index, which fell to zero in 57% of the ixekizumab patients and 45% of those on adalimumab. “It makes you wonder whether there is something special about interleukin-17 in enthesitis,” Dr. Mease said.
The safety results of the study were consistent with the known adverse effect profiles of both drugs.
The impact of these findings on practice remains to be seen, and will likely depend on both cost considerations as well as clinicians trying to tailor drug choices to individual patients. The relatively new drug, ixekizumab, is consequentially more expensive than the older adalimumab, which has had its price depressed by the recent introduction of a biosimilar agent as well as long-standing competition from multiple TNF inhibitors.
“I think in the United States insurers will continue to steer patients toward whichever drug is cheapest among the highly-effective options,” but this result should lead to more use of interleukin-17 inhibitors as second-line agents for PsA, and it might push some clinicians to prescribe it as the first-line treatment, Dr. Mease said. He was confident that the efficacy profile shown by ixekizumab in SPIRIT-H2H was likely a class effect. Economics aside, the impetus to prescribe ixekizumab or another interleukin-17 inhibitor will be greatest when a patient has more extensive skin involvement, while for patients with little or no skin symptoms clinicians will likely stick with the more established TNF inhibitors as the first drug class to prescribe for PsA.
SPIRIT-H2H was sponsored by Eli Lilly, the company that markets ixekizumab (Taltz). Dr. Mease has been a consultant to, speaker for, and received research funding from Eli Lilly and from several other companies. Dr. Fleischmann has been a consultant to and has received research funding from several companies including Eli Lilly.
SOURCE: Mease PJ et al. Ann Rheum Dis. 2019 Jun. doi: 10.1136/annrheumdis-2019-eular.8709.
The results from SPIRIT-H2H confirm with rigorously-collected, prospective data what we had already seen during our routine use of ixekizumab for treating patients with psoriatic arthritis: it does a better job of resolving skin manifestations than any tumor necrosis factor (TNF) inhibitor. For joint symptoms, the two drugs are similar, but for skin ixekizumab has substantial superiority.
I had been hopeful that inhibition of interleukin-17 would surpass TNF inhibition for resolution of joint symptoms, but it looks like they are similar. That’s a little below expectations. But working well for improving skin symptoms is important because it’s something that many patients care about, especially those with more substantial skin symptoms. When matching the best drug to each PsA patient other considerations also exist, such as ease of use. These drugs are delivered by different devices, and ease of administration also matters to patients.
I think it would be premature to presume that the effects shown by ixekizumab extrapolate to all the other interleukin-17 inhibitors. Some of these drugs act via different mechanisms, and so the SPIRIT-H2H results may very well not reflect a class effect.
Thomas Dörner, MD, is professor of rheumatology at Charité University Hospital in Berlin. He has been a consultant to Eli Lilly, as well as to AbbVie, Celgene, Novartis, Pfizer, and Roche, he has been a speaker on behalf of Amgen, Biogen, and Celgene, and he has received research funding from Chugai, Janssen, Roche, and Sanofi. He made these comments in an interview.
The results from SPIRIT-H2H confirm with rigorously-collected, prospective data what we had already seen during our routine use of ixekizumab for treating patients with psoriatic arthritis: it does a better job of resolving skin manifestations than any tumor necrosis factor (TNF) inhibitor. For joint symptoms, the two drugs are similar, but for skin ixekizumab has substantial superiority.
I had been hopeful that inhibition of interleukin-17 would surpass TNF inhibition for resolution of joint symptoms, but it looks like they are similar. That’s a little below expectations. But working well for improving skin symptoms is important because it’s something that many patients care about, especially those with more substantial skin symptoms. When matching the best drug to each PsA patient other considerations also exist, such as ease of use. These drugs are delivered by different devices, and ease of administration also matters to patients.
I think it would be premature to presume that the effects shown by ixekizumab extrapolate to all the other interleukin-17 inhibitors. Some of these drugs act via different mechanisms, and so the SPIRIT-H2H results may very well not reflect a class effect.
Thomas Dörner, MD, is professor of rheumatology at Charité University Hospital in Berlin. He has been a consultant to Eli Lilly, as well as to AbbVie, Celgene, Novartis, Pfizer, and Roche, he has been a speaker on behalf of Amgen, Biogen, and Celgene, and he has received research funding from Chugai, Janssen, Roche, and Sanofi. He made these comments in an interview.
The results from SPIRIT-H2H confirm with rigorously-collected, prospective data what we had already seen during our routine use of ixekizumab for treating patients with psoriatic arthritis: it does a better job of resolving skin manifestations than any tumor necrosis factor (TNF) inhibitor. For joint symptoms, the two drugs are similar, but for skin ixekizumab has substantial superiority.
I had been hopeful that inhibition of interleukin-17 would surpass TNF inhibition for resolution of joint symptoms, but it looks like they are similar. That’s a little below expectations. But working well for improving skin symptoms is important because it’s something that many patients care about, especially those with more substantial skin symptoms. When matching the best drug to each PsA patient other considerations also exist, such as ease of use. These drugs are delivered by different devices, and ease of administration also matters to patients.
I think it would be premature to presume that the effects shown by ixekizumab extrapolate to all the other interleukin-17 inhibitors. Some of these drugs act via different mechanisms, and so the SPIRIT-H2H results may very well not reflect a class effect.
Thomas Dörner, MD, is professor of rheumatology at Charité University Hospital in Berlin. He has been a consultant to Eli Lilly, as well as to AbbVie, Celgene, Novartis, Pfizer, and Roche, he has been a speaker on behalf of Amgen, Biogen, and Celgene, and he has received research funding from Chugai, Janssen, Roche, and Sanofi. He made these comments in an interview.
MADRID – The interleukin-17A inhibitor ixekizumab surpassed the tumor necrosis factor inhibitor adalimumab for treatment of patients with psoriatic arthritis in a multicenter, randomized study with 566 enrolled patients, the first reported results from a head-to-head comparison for this disease of two different classes of biological drugs.
The results showed that a standard, 24-week regimen with each of these agents, both of which already have regulatory approval for treating psoriatic arthritis (PsA), led to achievement of the primary endpoint in 36% of patients treated with ixekizumab (Taltz) and 28% of patients treated with adalimumab (Humira), a statistically significant difference, Philip J. Mease, MD, said at the European Congress of Rheumatology.
“Ixekizumab was superior to adalimumab for improving signs and symptoms of active PsA, as measured by simultaneous achievement of ACR50 [American College of Rheumatology] and PASI 100 [Psoriasis Area and Severity Index],” the study’s primary endpoint that combined a measure of joint disease activity with a measure of skin involvement, said Dr. Mease, a rheumatologist at Swedish Medical Center in Seattle.
This unconventional primary endpoint for testing drugs that treat PsA was called out during discussion of the report for having an inherent bias favoring ixekizumab by its inclusion of a skin outcome that received equal weight with an assessment tool that focused on joint responses. “This was a very unusual primary endpoint that favored ixekizumab,” Roy M. Fleischmann, MD, a Dallas rheumatologist, commented during the discussion.
Dr. Mease readily admitted that the study’s design stacked the deck in favor of ixekizumab, but he added that this decision reflected a desire by the researchers who ran the study to choose a primary endpoint that represented both of the prominent pathologies seen in patients with PsA.
The primary endpoint used in the study “looks at PsA more holistically,” Dr. Mease said in an interview. “It forced clinicians to look beyond just the joints,” in PsA patients. “That has been a limitation of prior PsA treatment assessments,” which until this study have uniformly used single primary outcomes that focus on joint responses, most commonly the ACR20 measure of joint disease activity.
The SPIRIT-H2H (A Study of Ixekizumab [LY2439821] Versus Adalimumab in Participants With Psoriatic Arthritis) study enrolled adults with active PsA who had never before received treatment with a biological drug. Enrolled patients had to have both active disease in their joints and active plaque psoriasis, with an inadequate response to at least one conventional synthetic disease-modifying antirheumatic drug. The 566 patients randomized in the study averaged about 48 years old, a bit more than half were men, and patients averaged about 6 years with diagnosed PsA and about 15 years diagnosed with psoriasis. Just over two-thirds of the patients were on concurrent treatment with a conventional synthetic agent, most often methotrexate.
The two components of the primary endpoint each showed the anticipated result. Among the 269 patients treated with adalimumab for the full 24 weeks, 47% had an ACR50 response, as did 51% of the 262 patients who completed their full course of ixekizumab, a between-group difference that was not statistically significant. In contrast, the PASI 100 measure of complete skin resolution occurred in 47% of the adalimumab-treated patients and 60% of those on ixekizumab, a statistically significant difference.
Dr. Mease reported results for several other efficacy measures, and what was notable was statistically significant superiority for ixekizumab in a measure of entheses disease activity, the SPARCC [Spondyloarthritis Research Consortium of Canada] Enthesitis Index, which fell to zero in 57% of the ixekizumab patients and 45% of those on adalimumab. “It makes you wonder whether there is something special about interleukin-17 in enthesitis,” Dr. Mease said.
The safety results of the study were consistent with the known adverse effect profiles of both drugs.
The impact of these findings on practice remains to be seen, and will likely depend on both cost considerations as well as clinicians trying to tailor drug choices to individual patients. The relatively new drug, ixekizumab, is consequentially more expensive than the older adalimumab, which has had its price depressed by the recent introduction of a biosimilar agent as well as long-standing competition from multiple TNF inhibitors.
“I think in the United States insurers will continue to steer patients toward whichever drug is cheapest among the highly-effective options,” but this result should lead to more use of interleukin-17 inhibitors as second-line agents for PsA, and it might push some clinicians to prescribe it as the first-line treatment, Dr. Mease said. He was confident that the efficacy profile shown by ixekizumab in SPIRIT-H2H was likely a class effect. Economics aside, the impetus to prescribe ixekizumab or another interleukin-17 inhibitor will be greatest when a patient has more extensive skin involvement, while for patients with little or no skin symptoms clinicians will likely stick with the more established TNF inhibitors as the first drug class to prescribe for PsA.
SPIRIT-H2H was sponsored by Eli Lilly, the company that markets ixekizumab (Taltz). Dr. Mease has been a consultant to, speaker for, and received research funding from Eli Lilly and from several other companies. Dr. Fleischmann has been a consultant to and has received research funding from several companies including Eli Lilly.
SOURCE: Mease PJ et al. Ann Rheum Dis. 2019 Jun. doi: 10.1136/annrheumdis-2019-eular.8709.
MADRID – The interleukin-17A inhibitor ixekizumab surpassed the tumor necrosis factor inhibitor adalimumab for treatment of patients with psoriatic arthritis in a multicenter, randomized study with 566 enrolled patients, the first reported results from a head-to-head comparison for this disease of two different classes of biological drugs.
The results showed that a standard, 24-week regimen with each of these agents, both of which already have regulatory approval for treating psoriatic arthritis (PsA), led to achievement of the primary endpoint in 36% of patients treated with ixekizumab (Taltz) and 28% of patients treated with adalimumab (Humira), a statistically significant difference, Philip J. Mease, MD, said at the European Congress of Rheumatology.
“Ixekizumab was superior to adalimumab for improving signs and symptoms of active PsA, as measured by simultaneous achievement of ACR50 [American College of Rheumatology] and PASI 100 [Psoriasis Area and Severity Index],” the study’s primary endpoint that combined a measure of joint disease activity with a measure of skin involvement, said Dr. Mease, a rheumatologist at Swedish Medical Center in Seattle.
This unconventional primary endpoint for testing drugs that treat PsA was called out during discussion of the report for having an inherent bias favoring ixekizumab by its inclusion of a skin outcome that received equal weight with an assessment tool that focused on joint responses. “This was a very unusual primary endpoint that favored ixekizumab,” Roy M. Fleischmann, MD, a Dallas rheumatologist, commented during the discussion.
Dr. Mease readily admitted that the study’s design stacked the deck in favor of ixekizumab, but he added that this decision reflected a desire by the researchers who ran the study to choose a primary endpoint that represented both of the prominent pathologies seen in patients with PsA.
The primary endpoint used in the study “looks at PsA more holistically,” Dr. Mease said in an interview. “It forced clinicians to look beyond just the joints,” in PsA patients. “That has been a limitation of prior PsA treatment assessments,” which until this study have uniformly used single primary outcomes that focus on joint responses, most commonly the ACR20 measure of joint disease activity.
The SPIRIT-H2H (A Study of Ixekizumab [LY2439821] Versus Adalimumab in Participants With Psoriatic Arthritis) study enrolled adults with active PsA who had never before received treatment with a biological drug. Enrolled patients had to have both active disease in their joints and active plaque psoriasis, with an inadequate response to at least one conventional synthetic disease-modifying antirheumatic drug. The 566 patients randomized in the study averaged about 48 years old, a bit more than half were men, and patients averaged about 6 years with diagnosed PsA and about 15 years diagnosed with psoriasis. Just over two-thirds of the patients were on concurrent treatment with a conventional synthetic agent, most often methotrexate.
The two components of the primary endpoint each showed the anticipated result. Among the 269 patients treated with adalimumab for the full 24 weeks, 47% had an ACR50 response, as did 51% of the 262 patients who completed their full course of ixekizumab, a between-group difference that was not statistically significant. In contrast, the PASI 100 measure of complete skin resolution occurred in 47% of the adalimumab-treated patients and 60% of those on ixekizumab, a statistically significant difference.
Dr. Mease reported results for several other efficacy measures, and what was notable was statistically significant superiority for ixekizumab in a measure of entheses disease activity, the SPARCC [Spondyloarthritis Research Consortium of Canada] Enthesitis Index, which fell to zero in 57% of the ixekizumab patients and 45% of those on adalimumab. “It makes you wonder whether there is something special about interleukin-17 in enthesitis,” Dr. Mease said.
The safety results of the study were consistent with the known adverse effect profiles of both drugs.
The impact of these findings on practice remains to be seen, and will likely depend on both cost considerations as well as clinicians trying to tailor drug choices to individual patients. The relatively new drug, ixekizumab, is consequentially more expensive than the older adalimumab, which has had its price depressed by the recent introduction of a biosimilar agent as well as long-standing competition from multiple TNF inhibitors.
“I think in the United States insurers will continue to steer patients toward whichever drug is cheapest among the highly-effective options,” but this result should lead to more use of interleukin-17 inhibitors as second-line agents for PsA, and it might push some clinicians to prescribe it as the first-line treatment, Dr. Mease said. He was confident that the efficacy profile shown by ixekizumab in SPIRIT-H2H was likely a class effect. Economics aside, the impetus to prescribe ixekizumab or another interleukin-17 inhibitor will be greatest when a patient has more extensive skin involvement, while for patients with little or no skin symptoms clinicians will likely stick with the more established TNF inhibitors as the first drug class to prescribe for PsA.
SPIRIT-H2H was sponsored by Eli Lilly, the company that markets ixekizumab (Taltz). Dr. Mease has been a consultant to, speaker for, and received research funding from Eli Lilly and from several other companies. Dr. Fleischmann has been a consultant to and has received research funding from several companies including Eli Lilly.
SOURCE: Mease PJ et al. Ann Rheum Dis. 2019 Jun. doi: 10.1136/annrheumdis-2019-eular.8709.
REPORTING FROM THE EULAR 2019 CONGRESS
Cardiovascular events in U.S. RA patients fall to non-RA level
MADRID – U.S. patients with rheumatoid arthritis stopped having an excess of cardiovascular disease events during the 2000s.
During both the 1980s and 1990s, patients with rheumatoid arthritis (RA) residing in a 27-county region in southeastern Minnesota and northwestern Wisconsin had cardiovascular disease event rates that were more than twice the rates in similar adults without RA, but that changed during the 2000s, Elena Myasoedova, MD, said in a poster she presented at the European Congress of Rheumatology. During 2000-2009, RA patients enrolled in the Rochester (Minn.) Epidemiology Project had an incidence of cardiovascular disease events at a rate that was 12% lower, compared with matched adults without RA who were also enrolled in the same regional database, reported Dr. Myasoedova, a rheumatologist at the Mayo Clinic in Rochester, and her associates.
“We hypothesize that improved management of RA, including implementation of a treat-to-target strategy and the introduction of biological drugs could have influenced this, as well as increased awareness of and improved prevention of cardiovascular disease,” Dr. Myasoedova said in an interview. The findings “give us a hint that tight control of RA disease activity is also likely to help cardiovascular disease burden.”
She and her associates identified 906 people enrolled in the Rochester Epidemiology Project who had incident RA based on the 1987 criteria of the American College of Rheumatology and matched them by age, sex, and index year with 905 people in the registry without RA. These cohorts included roughly 200 people from each subgroup tracked during the 1980s, 300 from each subgroup tracked during the 1990s, and about 400 in each subgroup tracked during the 2000s. They averaged about 56 years old, and about two-thirds were women.
During the 1980s, the cumulative incidence of nonfatal MI, nonfatal stroke, or cardiovascular disease (CVD) death was 2.11-fold more common among the RA patients than in the matched controls without RA, and during the 1990s this ratio showed a 2.13-fold excess of CVD events among the RA patients. The between-group differences in both decades were statistically significant. During the 2000s, the RA patients actually had a nominally lower rate of CVD events, at 0.88 times the rate of the controls, a difference that was not statistically significant.
Dr. Myasoedova and her associates had previously reported a similar finding in an analysis that used a smaller number of people and focused exclusively on rates of CVD (J Rheumatol. 2017 Jun;44[6]:732-9).
A few factors limit the generalizability of the finding, Dr. Myasoedova cautioned. First, the population studied was about 90% white. Also, people in the Rochester Epidemiology Project receive their medical care from clinicians at the Mayo Clinic or an affiliated hospital in the region covered by the Project.
“These data are from a large, tertiary care center,” and so the findings are most directly applicable to patients who receive medical care in a similar setting that provides guideline-directed management of both RA and CVD risk.
A long-standing hypothesis is that CVD has an inflammatory component. These data support that concept by suggesting that when inflammatory disease is well controlled in RA patients, their CVD risk drops, Dr. Myasoedova said. “CVD has been seen as the number one comorbidity for RA patients, and it remains that way, but it’s very reassuring that the CVD rate has improved. It shows we’re doing something right.”
The study received no commercial funding. Dr. Myasoedova had no relevant disclosures.
SOURCE: Myasoedova E et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):1024-5. Abstract FRI0654. DOI: 10.1136/annrheumdis-2019-eular.4996.
MADRID – U.S. patients with rheumatoid arthritis stopped having an excess of cardiovascular disease events during the 2000s.
During both the 1980s and 1990s, patients with rheumatoid arthritis (RA) residing in a 27-county region in southeastern Minnesota and northwestern Wisconsin had cardiovascular disease event rates that were more than twice the rates in similar adults without RA, but that changed during the 2000s, Elena Myasoedova, MD, said in a poster she presented at the European Congress of Rheumatology. During 2000-2009, RA patients enrolled in the Rochester (Minn.) Epidemiology Project had an incidence of cardiovascular disease events at a rate that was 12% lower, compared with matched adults without RA who were also enrolled in the same regional database, reported Dr. Myasoedova, a rheumatologist at the Mayo Clinic in Rochester, and her associates.
“We hypothesize that improved management of RA, including implementation of a treat-to-target strategy and the introduction of biological drugs could have influenced this, as well as increased awareness of and improved prevention of cardiovascular disease,” Dr. Myasoedova said in an interview. The findings “give us a hint that tight control of RA disease activity is also likely to help cardiovascular disease burden.”
She and her associates identified 906 people enrolled in the Rochester Epidemiology Project who had incident RA based on the 1987 criteria of the American College of Rheumatology and matched them by age, sex, and index year with 905 people in the registry without RA. These cohorts included roughly 200 people from each subgroup tracked during the 1980s, 300 from each subgroup tracked during the 1990s, and about 400 in each subgroup tracked during the 2000s. They averaged about 56 years old, and about two-thirds were women.
During the 1980s, the cumulative incidence of nonfatal MI, nonfatal stroke, or cardiovascular disease (CVD) death was 2.11-fold more common among the RA patients than in the matched controls without RA, and during the 1990s this ratio showed a 2.13-fold excess of CVD events among the RA patients. The between-group differences in both decades were statistically significant. During the 2000s, the RA patients actually had a nominally lower rate of CVD events, at 0.88 times the rate of the controls, a difference that was not statistically significant.
Dr. Myasoedova and her associates had previously reported a similar finding in an analysis that used a smaller number of people and focused exclusively on rates of CVD (J Rheumatol. 2017 Jun;44[6]:732-9).
A few factors limit the generalizability of the finding, Dr. Myasoedova cautioned. First, the population studied was about 90% white. Also, people in the Rochester Epidemiology Project receive their medical care from clinicians at the Mayo Clinic or an affiliated hospital in the region covered by the Project.
“These data are from a large, tertiary care center,” and so the findings are most directly applicable to patients who receive medical care in a similar setting that provides guideline-directed management of both RA and CVD risk.
A long-standing hypothesis is that CVD has an inflammatory component. These data support that concept by suggesting that when inflammatory disease is well controlled in RA patients, their CVD risk drops, Dr. Myasoedova said. “CVD has been seen as the number one comorbidity for RA patients, and it remains that way, but it’s very reassuring that the CVD rate has improved. It shows we’re doing something right.”
The study received no commercial funding. Dr. Myasoedova had no relevant disclosures.
SOURCE: Myasoedova E et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):1024-5. Abstract FRI0654. DOI: 10.1136/annrheumdis-2019-eular.4996.
MADRID – U.S. patients with rheumatoid arthritis stopped having an excess of cardiovascular disease events during the 2000s.
During both the 1980s and 1990s, patients with rheumatoid arthritis (RA) residing in a 27-county region in southeastern Minnesota and northwestern Wisconsin had cardiovascular disease event rates that were more than twice the rates in similar adults without RA, but that changed during the 2000s, Elena Myasoedova, MD, said in a poster she presented at the European Congress of Rheumatology. During 2000-2009, RA patients enrolled in the Rochester (Minn.) Epidemiology Project had an incidence of cardiovascular disease events at a rate that was 12% lower, compared with matched adults without RA who were also enrolled in the same regional database, reported Dr. Myasoedova, a rheumatologist at the Mayo Clinic in Rochester, and her associates.
“We hypothesize that improved management of RA, including implementation of a treat-to-target strategy and the introduction of biological drugs could have influenced this, as well as increased awareness of and improved prevention of cardiovascular disease,” Dr. Myasoedova said in an interview. The findings “give us a hint that tight control of RA disease activity is also likely to help cardiovascular disease burden.”
She and her associates identified 906 people enrolled in the Rochester Epidemiology Project who had incident RA based on the 1987 criteria of the American College of Rheumatology and matched them by age, sex, and index year with 905 people in the registry without RA. These cohorts included roughly 200 people from each subgroup tracked during the 1980s, 300 from each subgroup tracked during the 1990s, and about 400 in each subgroup tracked during the 2000s. They averaged about 56 years old, and about two-thirds were women.
During the 1980s, the cumulative incidence of nonfatal MI, nonfatal stroke, or cardiovascular disease (CVD) death was 2.11-fold more common among the RA patients than in the matched controls without RA, and during the 1990s this ratio showed a 2.13-fold excess of CVD events among the RA patients. The between-group differences in both decades were statistically significant. During the 2000s, the RA patients actually had a nominally lower rate of CVD events, at 0.88 times the rate of the controls, a difference that was not statistically significant.
Dr. Myasoedova and her associates had previously reported a similar finding in an analysis that used a smaller number of people and focused exclusively on rates of CVD (J Rheumatol. 2017 Jun;44[6]:732-9).
A few factors limit the generalizability of the finding, Dr. Myasoedova cautioned. First, the population studied was about 90% white. Also, people in the Rochester Epidemiology Project receive their medical care from clinicians at the Mayo Clinic or an affiliated hospital in the region covered by the Project.
“These data are from a large, tertiary care center,” and so the findings are most directly applicable to patients who receive medical care in a similar setting that provides guideline-directed management of both RA and CVD risk.
A long-standing hypothesis is that CVD has an inflammatory component. These data support that concept by suggesting that when inflammatory disease is well controlled in RA patients, their CVD risk drops, Dr. Myasoedova said. “CVD has been seen as the number one comorbidity for RA patients, and it remains that way, but it’s very reassuring that the CVD rate has improved. It shows we’re doing something right.”
The study received no commercial funding. Dr. Myasoedova had no relevant disclosures.
SOURCE: Myasoedova E et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):1024-5. Abstract FRI0654. DOI: 10.1136/annrheumdis-2019-eular.4996.
REPORTING FROM EULAR 2019 CONGRESS
Lowering hyperuricemia improved endothelial function but failed as an antihypertensive
MADRID – Using allopurinol to reduce hyperuricemia in young adults with prehypertension or stage 1 hypertension failed to significantly lower blood pressure but succeeded in significantly improving endothelial function as measured by increased flow-mediated arterial dilation in a single-center crossover study with 82 participants.
The finding of improved endothelial function suggests that reducing hyperuricemia may be a new way to manage hypertension or prevent progression to stage 1 hypertension, improve cardiovascular health, and ultimately cut cardiovascular events, Angelo L. Gaffo, MD, said at the European Congress of Rheumatology. The results indicated that the BP-lowering effect of allopurinol treatment was strongest in people who entered the study with the highest serum urate levels, greater than 6.5 mg/dL, an indication that the next step in developing this approach should be targeting it to people with serum urate levels in this range, said Dr. Gaffo, a rheumatologist at the University of Alabama at Birmingham.
“It’s just a matter of finding the right population to see the blood pressure reduction effect,” Dr. Gaffo said in an interview.
He and his associates designed the SURPHER (Serum Urate Reduction to Prevent Hypertension) study to assess the impact of allopurinol treatment in people aged 18-40 years with prehypertension or stage 1 hypertension as defined by U.S. BP standards at the time they launched the study in 2016 (Contemp Clin Trials. 2016 Sep;50:238-44). Enrolled participants had to be nonsmokers; have an estimated glomerular filtration rate of greater than 60 mL/min per 1.73 m2; have a serum urate level of at least 5.0 mg/dL in men and at least 4.0 mg/dL in women; and be without diabetes, antihypertensive medications, prior urate-lowering treatment, or a history of gout. The 99 people who started the study averaged 28 years old, nearly two-thirds were men, 40% were African Americans, and 52% were white. The participants’ average body mass index was nearly 31 kg/m2, and their average BP was 127/81 mm Hg. Average serum urate levels were 6.4 mg/dL in men and 4.9 mg/dL in women. Participants received 300 mg/day allopurinol or placebo, and after 4 weeks crossed to the alternate regimen, with 82 people completing the full protocol. While on allopurinol, serum urate levels fell by an average of 1.3 mg/dL, a statistically significant drop; on placebo, the levels showed no significant change from baseline.
The primary endpoint was the change in BP on allopurinol treatment, which overall showed no statistically significant difference, compared with when participants received placebo. The results also showed no significant impact of allopurinol treatment, compared with placebo, in serum levels of high-sensitivity C-reactive protein, a measure of inflammation. However, for the secondary endpoint of change in endothelial function as measured by a change in flow-mediated dilation (FMD), the results showed a statistically significant effect of allopurinol treatment. While on allopurinol, average FMD increased from 10.3% at baseline to 14.5% on the drug, a 41% relative increase, while on placebo the average FMD rate showed a slight reduction. Allopurinol treatment was safe and well tolerated during the study.
The results also showed that among people with a baseline serum urate level of greater than 6.5 mg/dL (15 of the 82 study completers) systolic BP fell by an average of about 5 mm Hg.
The results suggested that the concept of reducing hyperuricemia in people with early-stage hypertension or prehypertension might be viable for people with higher serum urate levels than most of those enrolled in SURPHER, Dr. Gaffo said. He noted that prior study results in obese adolescents showed that treating hyperuricemia was able to produce a meaningful BP reduction (Hypertension. 2012 Nov;60[5]:1148-56).
SURPHER received no commercial funding. Dr. Gaffo has received research funding from Amgen and AstraZeneca.
MADRID – Using allopurinol to reduce hyperuricemia in young adults with prehypertension or stage 1 hypertension failed to significantly lower blood pressure but succeeded in significantly improving endothelial function as measured by increased flow-mediated arterial dilation in a single-center crossover study with 82 participants.
The finding of improved endothelial function suggests that reducing hyperuricemia may be a new way to manage hypertension or prevent progression to stage 1 hypertension, improve cardiovascular health, and ultimately cut cardiovascular events, Angelo L. Gaffo, MD, said at the European Congress of Rheumatology. The results indicated that the BP-lowering effect of allopurinol treatment was strongest in people who entered the study with the highest serum urate levels, greater than 6.5 mg/dL, an indication that the next step in developing this approach should be targeting it to people with serum urate levels in this range, said Dr. Gaffo, a rheumatologist at the University of Alabama at Birmingham.
“It’s just a matter of finding the right population to see the blood pressure reduction effect,” Dr. Gaffo said in an interview.
He and his associates designed the SURPHER (Serum Urate Reduction to Prevent Hypertension) study to assess the impact of allopurinol treatment in people aged 18-40 years with prehypertension or stage 1 hypertension as defined by U.S. BP standards at the time they launched the study in 2016 (Contemp Clin Trials. 2016 Sep;50:238-44). Enrolled participants had to be nonsmokers; have an estimated glomerular filtration rate of greater than 60 mL/min per 1.73 m2; have a serum urate level of at least 5.0 mg/dL in men and at least 4.0 mg/dL in women; and be without diabetes, antihypertensive medications, prior urate-lowering treatment, or a history of gout. The 99 people who started the study averaged 28 years old, nearly two-thirds were men, 40% were African Americans, and 52% were white. The participants’ average body mass index was nearly 31 kg/m2, and their average BP was 127/81 mm Hg. Average serum urate levels were 6.4 mg/dL in men and 4.9 mg/dL in women. Participants received 300 mg/day allopurinol or placebo, and after 4 weeks crossed to the alternate regimen, with 82 people completing the full protocol. While on allopurinol, serum urate levels fell by an average of 1.3 mg/dL, a statistically significant drop; on placebo, the levels showed no significant change from baseline.
The primary endpoint was the change in BP on allopurinol treatment, which overall showed no statistically significant difference, compared with when participants received placebo. The results also showed no significant impact of allopurinol treatment, compared with placebo, in serum levels of high-sensitivity C-reactive protein, a measure of inflammation. However, for the secondary endpoint of change in endothelial function as measured by a change in flow-mediated dilation (FMD), the results showed a statistically significant effect of allopurinol treatment. While on allopurinol, average FMD increased from 10.3% at baseline to 14.5% on the drug, a 41% relative increase, while on placebo the average FMD rate showed a slight reduction. Allopurinol treatment was safe and well tolerated during the study.
The results also showed that among people with a baseline serum urate level of greater than 6.5 mg/dL (15 of the 82 study completers) systolic BP fell by an average of about 5 mm Hg.
The results suggested that the concept of reducing hyperuricemia in people with early-stage hypertension or prehypertension might be viable for people with higher serum urate levels than most of those enrolled in SURPHER, Dr. Gaffo said. He noted that prior study results in obese adolescents showed that treating hyperuricemia was able to produce a meaningful BP reduction (Hypertension. 2012 Nov;60[5]:1148-56).
SURPHER received no commercial funding. Dr. Gaffo has received research funding from Amgen and AstraZeneca.
MADRID – Using allopurinol to reduce hyperuricemia in young adults with prehypertension or stage 1 hypertension failed to significantly lower blood pressure but succeeded in significantly improving endothelial function as measured by increased flow-mediated arterial dilation in a single-center crossover study with 82 participants.
The finding of improved endothelial function suggests that reducing hyperuricemia may be a new way to manage hypertension or prevent progression to stage 1 hypertension, improve cardiovascular health, and ultimately cut cardiovascular events, Angelo L. Gaffo, MD, said at the European Congress of Rheumatology. The results indicated that the BP-lowering effect of allopurinol treatment was strongest in people who entered the study with the highest serum urate levels, greater than 6.5 mg/dL, an indication that the next step in developing this approach should be targeting it to people with serum urate levels in this range, said Dr. Gaffo, a rheumatologist at the University of Alabama at Birmingham.
“It’s just a matter of finding the right population to see the blood pressure reduction effect,” Dr. Gaffo said in an interview.
He and his associates designed the SURPHER (Serum Urate Reduction to Prevent Hypertension) study to assess the impact of allopurinol treatment in people aged 18-40 years with prehypertension or stage 1 hypertension as defined by U.S. BP standards at the time they launched the study in 2016 (Contemp Clin Trials. 2016 Sep;50:238-44). Enrolled participants had to be nonsmokers; have an estimated glomerular filtration rate of greater than 60 mL/min per 1.73 m2; have a serum urate level of at least 5.0 mg/dL in men and at least 4.0 mg/dL in women; and be without diabetes, antihypertensive medications, prior urate-lowering treatment, or a history of gout. The 99 people who started the study averaged 28 years old, nearly two-thirds were men, 40% were African Americans, and 52% were white. The participants’ average body mass index was nearly 31 kg/m2, and their average BP was 127/81 mm Hg. Average serum urate levels were 6.4 mg/dL in men and 4.9 mg/dL in women. Participants received 300 mg/day allopurinol or placebo, and after 4 weeks crossed to the alternate regimen, with 82 people completing the full protocol. While on allopurinol, serum urate levels fell by an average of 1.3 mg/dL, a statistically significant drop; on placebo, the levels showed no significant change from baseline.
The primary endpoint was the change in BP on allopurinol treatment, which overall showed no statistically significant difference, compared with when participants received placebo. The results also showed no significant impact of allopurinol treatment, compared with placebo, in serum levels of high-sensitivity C-reactive protein, a measure of inflammation. However, for the secondary endpoint of change in endothelial function as measured by a change in flow-mediated dilation (FMD), the results showed a statistically significant effect of allopurinol treatment. While on allopurinol, average FMD increased from 10.3% at baseline to 14.5% on the drug, a 41% relative increase, while on placebo the average FMD rate showed a slight reduction. Allopurinol treatment was safe and well tolerated during the study.
The results also showed that among people with a baseline serum urate level of greater than 6.5 mg/dL (15 of the 82 study completers) systolic BP fell by an average of about 5 mm Hg.
The results suggested that the concept of reducing hyperuricemia in people with early-stage hypertension or prehypertension might be viable for people with higher serum urate levels than most of those enrolled in SURPHER, Dr. Gaffo said. He noted that prior study results in obese adolescents showed that treating hyperuricemia was able to produce a meaningful BP reduction (Hypertension. 2012 Nov;60[5]:1148-56).
SURPHER received no commercial funding. Dr. Gaffo has received research funding from Amgen and AstraZeneca.
REPORTING FROM EULAR 2019 CONGRESS
Tofacitinib shows safety during real-world RA use
MADRID – The Janus kinase inhibitor tofacitinib had a safety profile mostly similar to that of biologic drugs in a review of more than 8,600 U.S. rheumatoid arthritis patients enrolled in a national registry during 2012-2017, the first 5 years when tofacitinib was on the U.S. market.
The “reassuring” safety performance of tofacitinib (Xeljanz) compared with biologic agents used to treat rheumatoid arthritis (RA) in these registry data notably showed a similar rate of venous thromboembolism (VTE) with tofacitinib treatment compared with biologic drugs, Joel M. Kremer, MD, reported at the European Congress of Rheumatology. It is an important finding because of recent concerns raised about VTE incidence among patients taking tofacitinib or another Janus kinase (JAK) inhibitor, he noted. The registry analysis Dr. Kremer presented showed that patients treated with tofacitinib had slightly more than double the rate of herpes zoster, compared with patients on biologic agents, a finding consistent with prior reports that tofacitinib treatment linked with an almost threefold increased rate of herpes zoster when compared with placebo-treated patients in a series of clinical trials (Arthritis Rheumatol. 2014 Oct;66[10]:2675-84). None of the herpes zoster activations identified in the registry patients on tofacitinib were rated as “serious,” noted Dr. Kremer , professor of medicine at Albany (N.Y.) Medical College.
The analysis he presented used data collected in the Corrona Rheumatoid Arthritis registry during November 2012, the month when tofacitinib received U.S. marketing approval, through December 2017. Data came from RA patients in the registry who began treatment during November 2012–June 2017 with either tofacitinib (1,544 patients) or a biologic agent (7,083 patients). The safety assessment focused on four outcomes: the combined rate of major adverse cardiovascular events (including MI, strokes, and fatal events); the incidence of serious infection; the incidence of any herpes zoster regardless of severity; and VTE. These outcomes were numerous enough to allow for propensity-score matching of patients from the tofacitinib and biologic subgroups to adjust for baseline differences between patients in these two categories, but as of the end of 2017, the cumulative number of VTEs was not high enough to allow for propensity-score adjustment, Dr. Kremer said, so instead he reported the unadjusted numbers. Further data collection should allow an adjusted analysis of VTE within another couple of years, he added. The currently available VTE data were “underpowered” for more rigorous statistical analysis, Dr. Kremer said.
After adjustment, the patients treated with tofacitinib had a 42% lower rate of major cardiovascular events, compared with patients who received a biologic drug, but the difference was not statistically significant, and the two subgroups had virtually identical rates of all serious infections. The incidence of herpes zoster was 2.26-fold more frequent among tofacitinib-treated patients than among those on other biologic agents, a statistically significant difference. The unadjusted VTE analysis showed a rate of 0.19/100 patient-years with tofacitinib treatment, and 0.33/100 patient-years with other biological agents, a difference that was not statistically significant, Dr. Kremer reported. Comparison of the rates of pulmonary embolism and deep vein thrombosis were each not statistically different between the two treatment subgroups.
Concern about possibly increased rates of VTE with the use of tofacitinib or other JAK inhibitors arose recently primarily because of two reports. In February 2019, the Food and Drug Administration released a safety announcement that data from an ongoing, postmarketing study of tofacitinib showed an elevated rate of RA patients with pulmonary embolism when they received an off-label, 10-mg twice-daily dosage of the drug, twice the labeled maximum dosage for this population. (The labeling for tofacitinib allows for a maximum dosage of 10 mg twice daily for patients treated for ulcerative colitis.) In addition, a recent report on another JAK inhibitor approved for U.S. marketing for RA treatment, baricitinib (Olumiant), documented a possible excess of VTE events among patients treated with this drug, compared with those who received placebo (Arthritis Rheumatol. 2019 Jan 21. doi: 10.1002/art.40841).
Regarding the now well-described excess of herpes zoster with tofacitinib treatment, Dr. Kremer said that perhaps the best way to address this in a patient who seems to be at risk is to prophylactically vaccinate the patient with the recombinant, adjuvanted zoster vaccine (Shingrix). However, this means withdrawing disease-modifying treatment from the RA patient for 3 weeks at the time of each of two vaccinations, with the possibility of flare induced by the adjuvant, he explained in an interview. The risks and benefits of this approach have not been investigated, he noted, and the Corrona data he studied came almost entirely from the period before Shingrix came onto the U.S. market following its approval in late 2017.
Dr. Kremer has been a consultant to and has received research funding from Pfizer, the company that markets tofacitinib. He has been a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Genentech, and Regeneron/Sanofi, and has received research funding from AbbVie, Eli Lilly, Genentech, and Novartis. One of the coauthors on the report is a Pfizer employee.
SOURCE: Kremer JM et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):82-3; Abstract OP0028. doi: 10.1136/annrheumdis-2019-eular.621.
MADRID – The Janus kinase inhibitor tofacitinib had a safety profile mostly similar to that of biologic drugs in a review of more than 8,600 U.S. rheumatoid arthritis patients enrolled in a national registry during 2012-2017, the first 5 years when tofacitinib was on the U.S. market.
The “reassuring” safety performance of tofacitinib (Xeljanz) compared with biologic agents used to treat rheumatoid arthritis (RA) in these registry data notably showed a similar rate of venous thromboembolism (VTE) with tofacitinib treatment compared with biologic drugs, Joel M. Kremer, MD, reported at the European Congress of Rheumatology. It is an important finding because of recent concerns raised about VTE incidence among patients taking tofacitinib or another Janus kinase (JAK) inhibitor, he noted. The registry analysis Dr. Kremer presented showed that patients treated with tofacitinib had slightly more than double the rate of herpes zoster, compared with patients on biologic agents, a finding consistent with prior reports that tofacitinib treatment linked with an almost threefold increased rate of herpes zoster when compared with placebo-treated patients in a series of clinical trials (Arthritis Rheumatol. 2014 Oct;66[10]:2675-84). None of the herpes zoster activations identified in the registry patients on tofacitinib were rated as “serious,” noted Dr. Kremer , professor of medicine at Albany (N.Y.) Medical College.
The analysis he presented used data collected in the Corrona Rheumatoid Arthritis registry during November 2012, the month when tofacitinib received U.S. marketing approval, through December 2017. Data came from RA patients in the registry who began treatment during November 2012–June 2017 with either tofacitinib (1,544 patients) or a biologic agent (7,083 patients). The safety assessment focused on four outcomes: the combined rate of major adverse cardiovascular events (including MI, strokes, and fatal events); the incidence of serious infection; the incidence of any herpes zoster regardless of severity; and VTE. These outcomes were numerous enough to allow for propensity-score matching of patients from the tofacitinib and biologic subgroups to adjust for baseline differences between patients in these two categories, but as of the end of 2017, the cumulative number of VTEs was not high enough to allow for propensity-score adjustment, Dr. Kremer said, so instead he reported the unadjusted numbers. Further data collection should allow an adjusted analysis of VTE within another couple of years, he added. The currently available VTE data were “underpowered” for more rigorous statistical analysis, Dr. Kremer said.
After adjustment, the patients treated with tofacitinib had a 42% lower rate of major cardiovascular events, compared with patients who received a biologic drug, but the difference was not statistically significant, and the two subgroups had virtually identical rates of all serious infections. The incidence of herpes zoster was 2.26-fold more frequent among tofacitinib-treated patients than among those on other biologic agents, a statistically significant difference. The unadjusted VTE analysis showed a rate of 0.19/100 patient-years with tofacitinib treatment, and 0.33/100 patient-years with other biological agents, a difference that was not statistically significant, Dr. Kremer reported. Comparison of the rates of pulmonary embolism and deep vein thrombosis were each not statistically different between the two treatment subgroups.
Concern about possibly increased rates of VTE with the use of tofacitinib or other JAK inhibitors arose recently primarily because of two reports. In February 2019, the Food and Drug Administration released a safety announcement that data from an ongoing, postmarketing study of tofacitinib showed an elevated rate of RA patients with pulmonary embolism when they received an off-label, 10-mg twice-daily dosage of the drug, twice the labeled maximum dosage for this population. (The labeling for tofacitinib allows for a maximum dosage of 10 mg twice daily for patients treated for ulcerative colitis.) In addition, a recent report on another JAK inhibitor approved for U.S. marketing for RA treatment, baricitinib (Olumiant), documented a possible excess of VTE events among patients treated with this drug, compared with those who received placebo (Arthritis Rheumatol. 2019 Jan 21. doi: 10.1002/art.40841).
Regarding the now well-described excess of herpes zoster with tofacitinib treatment, Dr. Kremer said that perhaps the best way to address this in a patient who seems to be at risk is to prophylactically vaccinate the patient with the recombinant, adjuvanted zoster vaccine (Shingrix). However, this means withdrawing disease-modifying treatment from the RA patient for 3 weeks at the time of each of two vaccinations, with the possibility of flare induced by the adjuvant, he explained in an interview. The risks and benefits of this approach have not been investigated, he noted, and the Corrona data he studied came almost entirely from the period before Shingrix came onto the U.S. market following its approval in late 2017.
Dr. Kremer has been a consultant to and has received research funding from Pfizer, the company that markets tofacitinib. He has been a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Genentech, and Regeneron/Sanofi, and has received research funding from AbbVie, Eli Lilly, Genentech, and Novartis. One of the coauthors on the report is a Pfizer employee.
SOURCE: Kremer JM et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):82-3; Abstract OP0028. doi: 10.1136/annrheumdis-2019-eular.621.
MADRID – The Janus kinase inhibitor tofacitinib had a safety profile mostly similar to that of biologic drugs in a review of more than 8,600 U.S. rheumatoid arthritis patients enrolled in a national registry during 2012-2017, the first 5 years when tofacitinib was on the U.S. market.
The “reassuring” safety performance of tofacitinib (Xeljanz) compared with biologic agents used to treat rheumatoid arthritis (RA) in these registry data notably showed a similar rate of venous thromboembolism (VTE) with tofacitinib treatment compared with biologic drugs, Joel M. Kremer, MD, reported at the European Congress of Rheumatology. It is an important finding because of recent concerns raised about VTE incidence among patients taking tofacitinib or another Janus kinase (JAK) inhibitor, he noted. The registry analysis Dr. Kremer presented showed that patients treated with tofacitinib had slightly more than double the rate of herpes zoster, compared with patients on biologic agents, a finding consistent with prior reports that tofacitinib treatment linked with an almost threefold increased rate of herpes zoster when compared with placebo-treated patients in a series of clinical trials (Arthritis Rheumatol. 2014 Oct;66[10]:2675-84). None of the herpes zoster activations identified in the registry patients on tofacitinib were rated as “serious,” noted Dr. Kremer , professor of medicine at Albany (N.Y.) Medical College.
The analysis he presented used data collected in the Corrona Rheumatoid Arthritis registry during November 2012, the month when tofacitinib received U.S. marketing approval, through December 2017. Data came from RA patients in the registry who began treatment during November 2012–June 2017 with either tofacitinib (1,544 patients) or a biologic agent (7,083 patients). The safety assessment focused on four outcomes: the combined rate of major adverse cardiovascular events (including MI, strokes, and fatal events); the incidence of serious infection; the incidence of any herpes zoster regardless of severity; and VTE. These outcomes were numerous enough to allow for propensity-score matching of patients from the tofacitinib and biologic subgroups to adjust for baseline differences between patients in these two categories, but as of the end of 2017, the cumulative number of VTEs was not high enough to allow for propensity-score adjustment, Dr. Kremer said, so instead he reported the unadjusted numbers. Further data collection should allow an adjusted analysis of VTE within another couple of years, he added. The currently available VTE data were “underpowered” for more rigorous statistical analysis, Dr. Kremer said.
After adjustment, the patients treated with tofacitinib had a 42% lower rate of major cardiovascular events, compared with patients who received a biologic drug, but the difference was not statistically significant, and the two subgroups had virtually identical rates of all serious infections. The incidence of herpes zoster was 2.26-fold more frequent among tofacitinib-treated patients than among those on other biologic agents, a statistically significant difference. The unadjusted VTE analysis showed a rate of 0.19/100 patient-years with tofacitinib treatment, and 0.33/100 patient-years with other biological agents, a difference that was not statistically significant, Dr. Kremer reported. Comparison of the rates of pulmonary embolism and deep vein thrombosis were each not statistically different between the two treatment subgroups.
Concern about possibly increased rates of VTE with the use of tofacitinib or other JAK inhibitors arose recently primarily because of two reports. In February 2019, the Food and Drug Administration released a safety announcement that data from an ongoing, postmarketing study of tofacitinib showed an elevated rate of RA patients with pulmonary embolism when they received an off-label, 10-mg twice-daily dosage of the drug, twice the labeled maximum dosage for this population. (The labeling for tofacitinib allows for a maximum dosage of 10 mg twice daily for patients treated for ulcerative colitis.) In addition, a recent report on another JAK inhibitor approved for U.S. marketing for RA treatment, baricitinib (Olumiant), documented a possible excess of VTE events among patients treated with this drug, compared with those who received placebo (Arthritis Rheumatol. 2019 Jan 21. doi: 10.1002/art.40841).
Regarding the now well-described excess of herpes zoster with tofacitinib treatment, Dr. Kremer said that perhaps the best way to address this in a patient who seems to be at risk is to prophylactically vaccinate the patient with the recombinant, adjuvanted zoster vaccine (Shingrix). However, this means withdrawing disease-modifying treatment from the RA patient for 3 weeks at the time of each of two vaccinations, with the possibility of flare induced by the adjuvant, he explained in an interview. The risks and benefits of this approach have not been investigated, he noted, and the Corrona data he studied came almost entirely from the period before Shingrix came onto the U.S. market following its approval in late 2017.
Dr. Kremer has been a consultant to and has received research funding from Pfizer, the company that markets tofacitinib. He has been a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Genentech, and Regeneron/Sanofi, and has received research funding from AbbVie, Eli Lilly, Genentech, and Novartis. One of the coauthors on the report is a Pfizer employee.
SOURCE: Kremer JM et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):82-3; Abstract OP0028. doi: 10.1136/annrheumdis-2019-eular.621.
REPORTING FROM THE EULAR 2019 CONGRESS
Pivotal trial shows HFrEF benefits from baroreceptor stimulation
SAN FRANCISCO – Baroreflex activation therapy met all four of its primary endpoints in its U.S. pivotal trial of 264 patients with advanced heart failure with reduced ejection fraction who were ineligible for cardiac resynchronization therapy.
The results showed that ongoing baroreflex activation therapy (BAT) via a single, stimulating electrode surgically placed on a patient’s carotid artery led to statistically significant and clinically meaningful improvements in quality of life and functional capacity while also reducing the level of a biomarker of heart failure severity in patients already on guideline-directed medical therapy, Michael R. Zile, MD, said at the annual scientific sessions of the Heart Rhythm Society. He estimated that the device is appropriate for perhaps a third or more of patients with heart failure with reduced ejection fraction (HFrEF), specifically patients with New York Heart Association functional class III disease who are not candidates for treatment with cardiac resynchronization therapy (CRT) and with a blood level of N-terminal pro–brain natriuretic peptide (NT-proBNP) of less than 1,600 pg/mL, a cutoff that excludes patients with very severe class III HFrEF and focuses on those who benefited in the study.
“To our knowledge, this is the first successful pivotal trial of device-based neuromodulation therapy in HFrEF patients,” said Dr. Zile, professor of medicine at the Medical University of South Carolina in Charleston. “We think that BAT fills an unmet need” in a large number of HFrEF patients. He stressed that the placement of the single, 2-mm, unilateral electrode on the baroreceptor-containing carotid sinus is an “extremely safe and simple” surgery. The electrode attaches to a small, subcutaneously placed generator.
Dr. Zile attributed the treatment’s success, in contrast to a prior, failed attempt to treat HFrEF by vagus nerve stimulation (J Am Coll Cardiol. 2016 Jul 12;68[2]:147-56) to BAT’s action via the patient’s brain, which processes the afferent signal it receives from stimulation to in turn inhibit sympathetic activation and upregulate parasympathetic innervation, with both actions benefiting HFrEF patients. “The integrated autonomic balance is the real difference with this device,” he said. Other helpful effects from BAT are reduced heart rate, reduced cardiac remodeling, increased vasodilation, a decrease in elevated blood pressure, increased diuresis, and a drop in renin secretion. The pivotal trial built on findings from a phase 2 study (JACC Heart Fail. 2015 Jun;3[6]:487-96).
The BeAT-HF (Barostim Neo - Baroreflex Activation Therapy for Heart Failure) trial enrolled patients with class III HFrEF with a left ventricular ejection fraction of 35% or less and a 6-minute walk distance of 150-400 m, who were ineligible for CRT, on optimal medical therapy, and who had an elevated NT-proBNP level. After the study randomized 271 patients to either BAT or ongoing medical therapy only (without use of a sham procedure or sham BAT), the results showed a statistically significant benefit for three of the four primary endpoints. Patients treated with BAT for 6 months had statistically significant and clinically meaningful improvements in their quality of life scores as measured on the Minnesota Living With Heart Failure Questionnaire, in their function as measured by the 6-min walk distance, and in the treatment’s safety, based on the combined rate of major adverse neurological and cardiovascular events, which occurred in 6% of patients treated with BAT, which was significantly better than the study’s prespecified performance goal of 15%.
However, for the fourth primary endpoint – reduction in blood levels of NT-proBNP – the BAT-treated patients showed no significant improvement, compared with the controls. The design of BeAT-HF called for consultation with the Food and Drug Administration in such a situation, and further data analysis showed that the problem may have been that some enrolled patients entered with extremely elevated levels of this biomarker. The agency authorized an added protocol that randomized 102 additional patients that matched the initial cohort but had a requirement for an NT-proBNP level of less than 1,600 pg/mL. The 6-month outcomes of these patients were combined with the previously determined outcomes for 162 of the original 271 patients who entered with NT-proBNP levels within the specified limit, producing a total, final study group of 264 patients, of whom 120 received BAT and completed 6-month follow-up, and 125 received medical therapy only and had 6-month follow-up. These patients averaged about 63 years of age, and 20% were women. On average they were on four heart failure medications, and more than three-quarters also had an implanted cardiac device.
The results from an analysis of this cohort showed a statistically significant, 25% relative reduction in blood levels of NT-proBNP in the BAT patients, compared with the controls, and it also confirmed statistically significant and meaningful improvements in quality of life and function on BAT, compared with controls. The 14-point average improvement in the quality of life score in BAT patients, compared with the controls, on the Minnesota Living With Heart Failure Questionnaire was nearly triple the point improvement that’s considered clinically meaningful and hence was “very convincing” about the treatment’s efficacy, noted Dr. Zile, who is also director of cardiology at the VA Medical Center in Charleston. The 25% drop in average NT-proBNP levels “predicts a marked reduction in morbidity and mortality.” He added that researchers have developed a percutaneous, transcatheter method for placing the carotid electrode that will soon undergo clinical testing.
These results “reconfirm the safety of BAT,” but are limited by a relatively short follow-up of 6 months, no data on survival benefit, and by not having echocardiographic data on possible cardiac remodeling, commented Sanjeev Saksena, MD, medical director of the Electrophysiology Research Foundation in Warren, N.J.
BeAT-HF was sponsored by CVRx, the company developing the baroreflex activation device. Dr. Zile has been a consultant to CVRx and to Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, and Novartis. Dr. Saksena had no disclosures.
SOURCE: Zile MR. Heart Rhythm 2019, Abstract, S-LBCT01-04.
The results that Dr. Zile reported are obviously very promising. It was a huge step forward when researchers identified medical treatments that can safely manipulate the autonomic nervous system in patients with heart failure with reduced ejection fraction. Now we are asking what else we can do because we have run into limits on what we can accomplish with drugs alone. The BeAT-HF study is a step in that direction.
Andrew D. Krahn, MD, is professor of medicine and head of cardiology at the University of British Columbia and St. Paul’s Hospital in Vancouver. He has been a consultant to Medtronic and he has received research funding from Boston Scientific and Medtronic. He made these comments as a discussant for BeAT-HF.
The results that Dr. Zile reported are obviously very promising. It was a huge step forward when researchers identified medical treatments that can safely manipulate the autonomic nervous system in patients with heart failure with reduced ejection fraction. Now we are asking what else we can do because we have run into limits on what we can accomplish with drugs alone. The BeAT-HF study is a step in that direction.
Andrew D. Krahn, MD, is professor of medicine and head of cardiology at the University of British Columbia and St. Paul’s Hospital in Vancouver. He has been a consultant to Medtronic and he has received research funding from Boston Scientific and Medtronic. He made these comments as a discussant for BeAT-HF.
The results that Dr. Zile reported are obviously very promising. It was a huge step forward when researchers identified medical treatments that can safely manipulate the autonomic nervous system in patients with heart failure with reduced ejection fraction. Now we are asking what else we can do because we have run into limits on what we can accomplish with drugs alone. The BeAT-HF study is a step in that direction.
Andrew D. Krahn, MD, is professor of medicine and head of cardiology at the University of British Columbia and St. Paul’s Hospital in Vancouver. He has been a consultant to Medtronic and he has received research funding from Boston Scientific and Medtronic. He made these comments as a discussant for BeAT-HF.
SAN FRANCISCO – Baroreflex activation therapy met all four of its primary endpoints in its U.S. pivotal trial of 264 patients with advanced heart failure with reduced ejection fraction who were ineligible for cardiac resynchronization therapy.
The results showed that ongoing baroreflex activation therapy (BAT) via a single, stimulating electrode surgically placed on a patient’s carotid artery led to statistically significant and clinically meaningful improvements in quality of life and functional capacity while also reducing the level of a biomarker of heart failure severity in patients already on guideline-directed medical therapy, Michael R. Zile, MD, said at the annual scientific sessions of the Heart Rhythm Society. He estimated that the device is appropriate for perhaps a third or more of patients with heart failure with reduced ejection fraction (HFrEF), specifically patients with New York Heart Association functional class III disease who are not candidates for treatment with cardiac resynchronization therapy (CRT) and with a blood level of N-terminal pro–brain natriuretic peptide (NT-proBNP) of less than 1,600 pg/mL, a cutoff that excludes patients with very severe class III HFrEF and focuses on those who benefited in the study.
“To our knowledge, this is the first successful pivotal trial of device-based neuromodulation therapy in HFrEF patients,” said Dr. Zile, professor of medicine at the Medical University of South Carolina in Charleston. “We think that BAT fills an unmet need” in a large number of HFrEF patients. He stressed that the placement of the single, 2-mm, unilateral electrode on the baroreceptor-containing carotid sinus is an “extremely safe and simple” surgery. The electrode attaches to a small, subcutaneously placed generator.
Dr. Zile attributed the treatment’s success, in contrast to a prior, failed attempt to treat HFrEF by vagus nerve stimulation (J Am Coll Cardiol. 2016 Jul 12;68[2]:147-56) to BAT’s action via the patient’s brain, which processes the afferent signal it receives from stimulation to in turn inhibit sympathetic activation and upregulate parasympathetic innervation, with both actions benefiting HFrEF patients. “The integrated autonomic balance is the real difference with this device,” he said. Other helpful effects from BAT are reduced heart rate, reduced cardiac remodeling, increased vasodilation, a decrease in elevated blood pressure, increased diuresis, and a drop in renin secretion. The pivotal trial built on findings from a phase 2 study (JACC Heart Fail. 2015 Jun;3[6]:487-96).
The BeAT-HF (Barostim Neo - Baroreflex Activation Therapy for Heart Failure) trial enrolled patients with class III HFrEF with a left ventricular ejection fraction of 35% or less and a 6-minute walk distance of 150-400 m, who were ineligible for CRT, on optimal medical therapy, and who had an elevated NT-proBNP level. After the study randomized 271 patients to either BAT or ongoing medical therapy only (without use of a sham procedure or sham BAT), the results showed a statistically significant benefit for three of the four primary endpoints. Patients treated with BAT for 6 months had statistically significant and clinically meaningful improvements in their quality of life scores as measured on the Minnesota Living With Heart Failure Questionnaire, in their function as measured by the 6-min walk distance, and in the treatment’s safety, based on the combined rate of major adverse neurological and cardiovascular events, which occurred in 6% of patients treated with BAT, which was significantly better than the study’s prespecified performance goal of 15%.
However, for the fourth primary endpoint – reduction in blood levels of NT-proBNP – the BAT-treated patients showed no significant improvement, compared with the controls. The design of BeAT-HF called for consultation with the Food and Drug Administration in such a situation, and further data analysis showed that the problem may have been that some enrolled patients entered with extremely elevated levels of this biomarker. The agency authorized an added protocol that randomized 102 additional patients that matched the initial cohort but had a requirement for an NT-proBNP level of less than 1,600 pg/mL. The 6-month outcomes of these patients were combined with the previously determined outcomes for 162 of the original 271 patients who entered with NT-proBNP levels within the specified limit, producing a total, final study group of 264 patients, of whom 120 received BAT and completed 6-month follow-up, and 125 received medical therapy only and had 6-month follow-up. These patients averaged about 63 years of age, and 20% were women. On average they were on four heart failure medications, and more than three-quarters also had an implanted cardiac device.
The results from an analysis of this cohort showed a statistically significant, 25% relative reduction in blood levels of NT-proBNP in the BAT patients, compared with the controls, and it also confirmed statistically significant and meaningful improvements in quality of life and function on BAT, compared with controls. The 14-point average improvement in the quality of life score in BAT patients, compared with the controls, on the Minnesota Living With Heart Failure Questionnaire was nearly triple the point improvement that’s considered clinically meaningful and hence was “very convincing” about the treatment’s efficacy, noted Dr. Zile, who is also director of cardiology at the VA Medical Center in Charleston. The 25% drop in average NT-proBNP levels “predicts a marked reduction in morbidity and mortality.” He added that researchers have developed a percutaneous, transcatheter method for placing the carotid electrode that will soon undergo clinical testing.
These results “reconfirm the safety of BAT,” but are limited by a relatively short follow-up of 6 months, no data on survival benefit, and by not having echocardiographic data on possible cardiac remodeling, commented Sanjeev Saksena, MD, medical director of the Electrophysiology Research Foundation in Warren, N.J.
BeAT-HF was sponsored by CVRx, the company developing the baroreflex activation device. Dr. Zile has been a consultant to CVRx and to Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, and Novartis. Dr. Saksena had no disclosures.
SOURCE: Zile MR. Heart Rhythm 2019, Abstract, S-LBCT01-04.
SAN FRANCISCO – Baroreflex activation therapy met all four of its primary endpoints in its U.S. pivotal trial of 264 patients with advanced heart failure with reduced ejection fraction who were ineligible for cardiac resynchronization therapy.
The results showed that ongoing baroreflex activation therapy (BAT) via a single, stimulating electrode surgically placed on a patient’s carotid artery led to statistically significant and clinically meaningful improvements in quality of life and functional capacity while also reducing the level of a biomarker of heart failure severity in patients already on guideline-directed medical therapy, Michael R. Zile, MD, said at the annual scientific sessions of the Heart Rhythm Society. He estimated that the device is appropriate for perhaps a third or more of patients with heart failure with reduced ejection fraction (HFrEF), specifically patients with New York Heart Association functional class III disease who are not candidates for treatment with cardiac resynchronization therapy (CRT) and with a blood level of N-terminal pro–brain natriuretic peptide (NT-proBNP) of less than 1,600 pg/mL, a cutoff that excludes patients with very severe class III HFrEF and focuses on those who benefited in the study.
“To our knowledge, this is the first successful pivotal trial of device-based neuromodulation therapy in HFrEF patients,” said Dr. Zile, professor of medicine at the Medical University of South Carolina in Charleston. “We think that BAT fills an unmet need” in a large number of HFrEF patients. He stressed that the placement of the single, 2-mm, unilateral electrode on the baroreceptor-containing carotid sinus is an “extremely safe and simple” surgery. The electrode attaches to a small, subcutaneously placed generator.
Dr. Zile attributed the treatment’s success, in contrast to a prior, failed attempt to treat HFrEF by vagus nerve stimulation (J Am Coll Cardiol. 2016 Jul 12;68[2]:147-56) to BAT’s action via the patient’s brain, which processes the afferent signal it receives from stimulation to in turn inhibit sympathetic activation and upregulate parasympathetic innervation, with both actions benefiting HFrEF patients. “The integrated autonomic balance is the real difference with this device,” he said. Other helpful effects from BAT are reduced heart rate, reduced cardiac remodeling, increased vasodilation, a decrease in elevated blood pressure, increased diuresis, and a drop in renin secretion. The pivotal trial built on findings from a phase 2 study (JACC Heart Fail. 2015 Jun;3[6]:487-96).
The BeAT-HF (Barostim Neo - Baroreflex Activation Therapy for Heart Failure) trial enrolled patients with class III HFrEF with a left ventricular ejection fraction of 35% or less and a 6-minute walk distance of 150-400 m, who were ineligible for CRT, on optimal medical therapy, and who had an elevated NT-proBNP level. After the study randomized 271 patients to either BAT or ongoing medical therapy only (without use of a sham procedure or sham BAT), the results showed a statistically significant benefit for three of the four primary endpoints. Patients treated with BAT for 6 months had statistically significant and clinically meaningful improvements in their quality of life scores as measured on the Minnesota Living With Heart Failure Questionnaire, in their function as measured by the 6-min walk distance, and in the treatment’s safety, based on the combined rate of major adverse neurological and cardiovascular events, which occurred in 6% of patients treated with BAT, which was significantly better than the study’s prespecified performance goal of 15%.
However, for the fourth primary endpoint – reduction in blood levels of NT-proBNP – the BAT-treated patients showed no significant improvement, compared with the controls. The design of BeAT-HF called for consultation with the Food and Drug Administration in such a situation, and further data analysis showed that the problem may have been that some enrolled patients entered with extremely elevated levels of this biomarker. The agency authorized an added protocol that randomized 102 additional patients that matched the initial cohort but had a requirement for an NT-proBNP level of less than 1,600 pg/mL. The 6-month outcomes of these patients were combined with the previously determined outcomes for 162 of the original 271 patients who entered with NT-proBNP levels within the specified limit, producing a total, final study group of 264 patients, of whom 120 received BAT and completed 6-month follow-up, and 125 received medical therapy only and had 6-month follow-up. These patients averaged about 63 years of age, and 20% were women. On average they were on four heart failure medications, and more than three-quarters also had an implanted cardiac device.
The results from an analysis of this cohort showed a statistically significant, 25% relative reduction in blood levels of NT-proBNP in the BAT patients, compared with the controls, and it also confirmed statistically significant and meaningful improvements in quality of life and function on BAT, compared with controls. The 14-point average improvement in the quality of life score in BAT patients, compared with the controls, on the Minnesota Living With Heart Failure Questionnaire was nearly triple the point improvement that’s considered clinically meaningful and hence was “very convincing” about the treatment’s efficacy, noted Dr. Zile, who is also director of cardiology at the VA Medical Center in Charleston. The 25% drop in average NT-proBNP levels “predicts a marked reduction in morbidity and mortality.” He added that researchers have developed a percutaneous, transcatheter method for placing the carotid electrode that will soon undergo clinical testing.
These results “reconfirm the safety of BAT,” but are limited by a relatively short follow-up of 6 months, no data on survival benefit, and by not having echocardiographic data on possible cardiac remodeling, commented Sanjeev Saksena, MD, medical director of the Electrophysiology Research Foundation in Warren, N.J.
BeAT-HF was sponsored by CVRx, the company developing the baroreflex activation device. Dr. Zile has been a consultant to CVRx and to Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, and Novartis. Dr. Saksena had no disclosures.
SOURCE: Zile MR. Heart Rhythm 2019, Abstract, S-LBCT01-04.
REPORTING FROM HEART RHYTHM 2019
Updated systematic review of aspirin primary prevention shows benefits, risks
Using daily aspirin treatment for the primary prevention of cardiovascular events remains an individualized decision that needs to balance a person’s risks for ischemic events and bleeding, according to results from a new systematic review of 15 randomized, aspirin-prevention trials, including results from 3 major trials that researchers reported during 2018.
“The findings suggest that the decision to use aspirin for primary prevention should be tailored to the individual patients based on estimated atherosclerotic cardiovascular disease risk and perceived bleeding risk, as well as patient preferences regarding the types of event prevented versus potential bleeding caused,” Jawahar L. Mehta, MD, and his associates wrote in an article published on June 10 in the Journal of the American College of Cardiology.
The authors also concluded that if a person decides to use aspirin for primary prevention, then a low dose of 100 mg/day or less is recommended.
This new systematic review follows two reviews published earlier in 2019 that reached roughly similar conclusions after analyzing largely the same randomized trial data, including the same three major trials from 2018. One of these prior reviews included data from 13 trials and a total of 164,225 people (JAMA. 2019 Jan 22;321[3]:277-87). The second review had data from 11 trials with 157,248 people (Eur Heart J. 2019 Feb 14;40[7]:607-17). The newly published review used data collected by 15 trials from 165,502 people.
The three 2018 trials that triggered the updated data assessments were the ARRIVE trial, with 12,546 people randomized (Lancet. 2018 Sep 22;392[10152]:1036-46), the ASPREE trial, with 19,114 people randomized (New Engl J Med. 2018 Oct 18;379[16]:1509-18), and the ASCEND trial, with 15,480 people randomized (New Engl J Med. 2018 Oct 18;379[16]:1529-39).
As stated in the new report from Dr. Mehta, a professor of medicine at the University of Arkansas for Medical Sciences in Little Rock, and his associates, the recent trial results from 2018 added new data from more than 45,000 additional subjects, a development that warranted a reappraisal of the evidence for aspirin’s efficacy and safety for primary prevention in contemporary practice.
The major findings from the analysis by Dr. Mehta and his associates were that in adults without a history of cardiovascular disease, daily aspirin use reduced the incidence of MIs, with a number needed to treat (NNT) of 357; reduced ischemic stroke (NNT, 500), reduced transient ischemic attack (NNT, 370), and reduced the overall, combined rate of all major adverse cardiovascular events (NNT, 263). But on the safety side, daily aspirin led to an increased rate of major bleeding episodes, with a number needed to harm (NNH) of 222, increased intracranial bleeds (NNH, 1,000), and an increase in gastrointestinal bleeds (NNH, 385).
The analysis “demonstrates a potential reduction of net benefit with aspirin in the contemporary era,” the authors concluded. They also noted that the benefits from aspirin prevention were, as expected, “more pronounced” among people with a higher estimated risk from atherosclerotic cardiovascular disease.
The systematic review findings came against the backdrop of a recently released primary prevention guideline from the American College of Cardiology and American Heart Association (J Am Coll Card. 2019 Mar. doi: 10.1016/j.jacc.2019.03.010). The guideline said that aspirin prophylaxis for primary prevention “might be considered” for adults aged 40-70 years, but should not be used for people who are older than 70, and also should not be given to people with an increased risk for bleeding. In general, the experts who produced this guideline said that aspirin prophylaxis should be infrequent.
The new analysis also found no reduction in the incidence of cancer or cancer-related death linked with aspirin use for primary prevention. The systematic review published earlier in 2019 in JAMA also found no link between aspirin use and cancer incidence or mortality. The review from the European Heart Journal did not report on the link between aspirin use and cancer incidence or mortality.
Dr. Mehta has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Medimmune, and Pfizer, and has received grant support from AstraZeneca, Bayer, and Boehringer Ingelheim.
On Twitter @mitchelzoler
SOURCE: Abdelaziz HK et al. J Am Coll Cardiol. 2019 Jun 10. doi: 10.1016/j.jacc.2019.03.501.
The three trials published in 2018 that added important new data on primary prevention for cardiovascular disease with aspirin must ideally be interpreted within the context of the totality of evidence on this subject. This was achieved in the analysis reported by Dr. Mehta and his associates, as well as in other more recent publications.
Making a decision about using aspirin for primary prevention in individuals based on trial data is very challenging because it requires weighing a modest potential benefit that people gain from daily aspirin for preventing a first cardiovascular event against the modest risk of an adverse bleeding event. It does not suffice simply to compare the number of cardiovascular and bleeding events, because those two types of events do not have the same immediate or long-term consequences. Each patient must make a personal choice between the risks and benefits.
The greatest potential benefit from aspirin prophylaxis seems to be in people with increased cardiovascular risk but with no increased bleeding risk. In general, this means people aged 50-59 years old, and also possibly those aged 60-69 years old if their estimated 10-year cardiovascular disease risk is more than 10%. It may make more sense to first focus on other risk-reducing steps, such as smoking cessation, blood pressure control, and statin treatment. After that, prophylactic aspirin may be reasonable for people who retain a 10-year cardiovascular disease risk of more than 10% who are also not at increased bleeding risk. That seems to make it prudent to avoid aspirin for primary prevention once people reach the age of 70 years, although people who have been taking aspirin safely for a period of time before reaching 70 might reasonably consider continuing the prophylaxis for a period of time.
This and similar reviews continue to have major limitations. The duration of the trials they reviewed, a mean of 6.4 years, is insufficient to understand the full effect from aspirin prophylaxis. Also, none of the recent reviews used a patient-level meta-analysis, which could better help us understand aspirin’s action in key subgroups, such as women, patients with diabetes, and patients on treatments such as statins that reduce their cardiovascular risk.
Michael Pignone, MD, is professor and chair of medicine at the University of Texas Dell Medical School in Austin. He had no disclosures. He made these comments in an editorial that accompanied the report (J Am Coll Cardiol. 2019 Jun 10. doi: 10.1016/j.jacc.2019.03.502).
The three trials published in 2018 that added important new data on primary prevention for cardiovascular disease with aspirin must ideally be interpreted within the context of the totality of evidence on this subject. This was achieved in the analysis reported by Dr. Mehta and his associates, as well as in other more recent publications.
Making a decision about using aspirin for primary prevention in individuals based on trial data is very challenging because it requires weighing a modest potential benefit that people gain from daily aspirin for preventing a first cardiovascular event against the modest risk of an adverse bleeding event. It does not suffice simply to compare the number of cardiovascular and bleeding events, because those two types of events do not have the same immediate or long-term consequences. Each patient must make a personal choice between the risks and benefits.
The greatest potential benefit from aspirin prophylaxis seems to be in people with increased cardiovascular risk but with no increased bleeding risk. In general, this means people aged 50-59 years old, and also possibly those aged 60-69 years old if their estimated 10-year cardiovascular disease risk is more than 10%. It may make more sense to first focus on other risk-reducing steps, such as smoking cessation, blood pressure control, and statin treatment. After that, prophylactic aspirin may be reasonable for people who retain a 10-year cardiovascular disease risk of more than 10% who are also not at increased bleeding risk. That seems to make it prudent to avoid aspirin for primary prevention once people reach the age of 70 years, although people who have been taking aspirin safely for a period of time before reaching 70 might reasonably consider continuing the prophylaxis for a period of time.
This and similar reviews continue to have major limitations. The duration of the trials they reviewed, a mean of 6.4 years, is insufficient to understand the full effect from aspirin prophylaxis. Also, none of the recent reviews used a patient-level meta-analysis, which could better help us understand aspirin’s action in key subgroups, such as women, patients with diabetes, and patients on treatments such as statins that reduce their cardiovascular risk.
Michael Pignone, MD, is professor and chair of medicine at the University of Texas Dell Medical School in Austin. He had no disclosures. He made these comments in an editorial that accompanied the report (J Am Coll Cardiol. 2019 Jun 10. doi: 10.1016/j.jacc.2019.03.502).
The three trials published in 2018 that added important new data on primary prevention for cardiovascular disease with aspirin must ideally be interpreted within the context of the totality of evidence on this subject. This was achieved in the analysis reported by Dr. Mehta and his associates, as well as in other more recent publications.
Making a decision about using aspirin for primary prevention in individuals based on trial data is very challenging because it requires weighing a modest potential benefit that people gain from daily aspirin for preventing a first cardiovascular event against the modest risk of an adverse bleeding event. It does not suffice simply to compare the number of cardiovascular and bleeding events, because those two types of events do not have the same immediate or long-term consequences. Each patient must make a personal choice between the risks and benefits.
The greatest potential benefit from aspirin prophylaxis seems to be in people with increased cardiovascular risk but with no increased bleeding risk. In general, this means people aged 50-59 years old, and also possibly those aged 60-69 years old if their estimated 10-year cardiovascular disease risk is more than 10%. It may make more sense to first focus on other risk-reducing steps, such as smoking cessation, blood pressure control, and statin treatment. After that, prophylactic aspirin may be reasonable for people who retain a 10-year cardiovascular disease risk of more than 10% who are also not at increased bleeding risk. That seems to make it prudent to avoid aspirin for primary prevention once people reach the age of 70 years, although people who have been taking aspirin safely for a period of time before reaching 70 might reasonably consider continuing the prophylaxis for a period of time.
This and similar reviews continue to have major limitations. The duration of the trials they reviewed, a mean of 6.4 years, is insufficient to understand the full effect from aspirin prophylaxis. Also, none of the recent reviews used a patient-level meta-analysis, which could better help us understand aspirin’s action in key subgroups, such as women, patients with diabetes, and patients on treatments such as statins that reduce their cardiovascular risk.
Michael Pignone, MD, is professor and chair of medicine at the University of Texas Dell Medical School in Austin. He had no disclosures. He made these comments in an editorial that accompanied the report (J Am Coll Cardiol. 2019 Jun 10. doi: 10.1016/j.jacc.2019.03.502).
Using daily aspirin treatment for the primary prevention of cardiovascular events remains an individualized decision that needs to balance a person’s risks for ischemic events and bleeding, according to results from a new systematic review of 15 randomized, aspirin-prevention trials, including results from 3 major trials that researchers reported during 2018.
“The findings suggest that the decision to use aspirin for primary prevention should be tailored to the individual patients based on estimated atherosclerotic cardiovascular disease risk and perceived bleeding risk, as well as patient preferences regarding the types of event prevented versus potential bleeding caused,” Jawahar L. Mehta, MD, and his associates wrote in an article published on June 10 in the Journal of the American College of Cardiology.
The authors also concluded that if a person decides to use aspirin for primary prevention, then a low dose of 100 mg/day or less is recommended.
This new systematic review follows two reviews published earlier in 2019 that reached roughly similar conclusions after analyzing largely the same randomized trial data, including the same three major trials from 2018. One of these prior reviews included data from 13 trials and a total of 164,225 people (JAMA. 2019 Jan 22;321[3]:277-87). The second review had data from 11 trials with 157,248 people (Eur Heart J. 2019 Feb 14;40[7]:607-17). The newly published review used data collected by 15 trials from 165,502 people.
The three 2018 trials that triggered the updated data assessments were the ARRIVE trial, with 12,546 people randomized (Lancet. 2018 Sep 22;392[10152]:1036-46), the ASPREE trial, with 19,114 people randomized (New Engl J Med. 2018 Oct 18;379[16]:1509-18), and the ASCEND trial, with 15,480 people randomized (New Engl J Med. 2018 Oct 18;379[16]:1529-39).
As stated in the new report from Dr. Mehta, a professor of medicine at the University of Arkansas for Medical Sciences in Little Rock, and his associates, the recent trial results from 2018 added new data from more than 45,000 additional subjects, a development that warranted a reappraisal of the evidence for aspirin’s efficacy and safety for primary prevention in contemporary practice.
The major findings from the analysis by Dr. Mehta and his associates were that in adults without a history of cardiovascular disease, daily aspirin use reduced the incidence of MIs, with a number needed to treat (NNT) of 357; reduced ischemic stroke (NNT, 500), reduced transient ischemic attack (NNT, 370), and reduced the overall, combined rate of all major adverse cardiovascular events (NNT, 263). But on the safety side, daily aspirin led to an increased rate of major bleeding episodes, with a number needed to harm (NNH) of 222, increased intracranial bleeds (NNH, 1,000), and an increase in gastrointestinal bleeds (NNH, 385).
The analysis “demonstrates a potential reduction of net benefit with aspirin in the contemporary era,” the authors concluded. They also noted that the benefits from aspirin prevention were, as expected, “more pronounced” among people with a higher estimated risk from atherosclerotic cardiovascular disease.
The systematic review findings came against the backdrop of a recently released primary prevention guideline from the American College of Cardiology and American Heart Association (J Am Coll Card. 2019 Mar. doi: 10.1016/j.jacc.2019.03.010). The guideline said that aspirin prophylaxis for primary prevention “might be considered” for adults aged 40-70 years, but should not be used for people who are older than 70, and also should not be given to people with an increased risk for bleeding. In general, the experts who produced this guideline said that aspirin prophylaxis should be infrequent.
The new analysis also found no reduction in the incidence of cancer or cancer-related death linked with aspirin use for primary prevention. The systematic review published earlier in 2019 in JAMA also found no link between aspirin use and cancer incidence or mortality. The review from the European Heart Journal did not report on the link between aspirin use and cancer incidence or mortality.
Dr. Mehta has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Medimmune, and Pfizer, and has received grant support from AstraZeneca, Bayer, and Boehringer Ingelheim.
On Twitter @mitchelzoler
SOURCE: Abdelaziz HK et al. J Am Coll Cardiol. 2019 Jun 10. doi: 10.1016/j.jacc.2019.03.501.
Using daily aspirin treatment for the primary prevention of cardiovascular events remains an individualized decision that needs to balance a person’s risks for ischemic events and bleeding, according to results from a new systematic review of 15 randomized, aspirin-prevention trials, including results from 3 major trials that researchers reported during 2018.
“The findings suggest that the decision to use aspirin for primary prevention should be tailored to the individual patients based on estimated atherosclerotic cardiovascular disease risk and perceived bleeding risk, as well as patient preferences regarding the types of event prevented versus potential bleeding caused,” Jawahar L. Mehta, MD, and his associates wrote in an article published on June 10 in the Journal of the American College of Cardiology.
The authors also concluded that if a person decides to use aspirin for primary prevention, then a low dose of 100 mg/day or less is recommended.
This new systematic review follows two reviews published earlier in 2019 that reached roughly similar conclusions after analyzing largely the same randomized trial data, including the same three major trials from 2018. One of these prior reviews included data from 13 trials and a total of 164,225 people (JAMA. 2019 Jan 22;321[3]:277-87). The second review had data from 11 trials with 157,248 people (Eur Heart J. 2019 Feb 14;40[7]:607-17). The newly published review used data collected by 15 trials from 165,502 people.
The three 2018 trials that triggered the updated data assessments were the ARRIVE trial, with 12,546 people randomized (Lancet. 2018 Sep 22;392[10152]:1036-46), the ASPREE trial, with 19,114 people randomized (New Engl J Med. 2018 Oct 18;379[16]:1509-18), and the ASCEND trial, with 15,480 people randomized (New Engl J Med. 2018 Oct 18;379[16]:1529-39).
As stated in the new report from Dr. Mehta, a professor of medicine at the University of Arkansas for Medical Sciences in Little Rock, and his associates, the recent trial results from 2018 added new data from more than 45,000 additional subjects, a development that warranted a reappraisal of the evidence for aspirin’s efficacy and safety for primary prevention in contemporary practice.
The major findings from the analysis by Dr. Mehta and his associates were that in adults without a history of cardiovascular disease, daily aspirin use reduced the incidence of MIs, with a number needed to treat (NNT) of 357; reduced ischemic stroke (NNT, 500), reduced transient ischemic attack (NNT, 370), and reduced the overall, combined rate of all major adverse cardiovascular events (NNT, 263). But on the safety side, daily aspirin led to an increased rate of major bleeding episodes, with a number needed to harm (NNH) of 222, increased intracranial bleeds (NNH, 1,000), and an increase in gastrointestinal bleeds (NNH, 385).
The analysis “demonstrates a potential reduction of net benefit with aspirin in the contemporary era,” the authors concluded. They also noted that the benefits from aspirin prevention were, as expected, “more pronounced” among people with a higher estimated risk from atherosclerotic cardiovascular disease.
The systematic review findings came against the backdrop of a recently released primary prevention guideline from the American College of Cardiology and American Heart Association (J Am Coll Card. 2019 Mar. doi: 10.1016/j.jacc.2019.03.010). The guideline said that aspirin prophylaxis for primary prevention “might be considered” for adults aged 40-70 years, but should not be used for people who are older than 70, and also should not be given to people with an increased risk for bleeding. In general, the experts who produced this guideline said that aspirin prophylaxis should be infrequent.
The new analysis also found no reduction in the incidence of cancer or cancer-related death linked with aspirin use for primary prevention. The systematic review published earlier in 2019 in JAMA also found no link between aspirin use and cancer incidence or mortality. The review from the European Heart Journal did not report on the link between aspirin use and cancer incidence or mortality.
Dr. Mehta has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Medimmune, and Pfizer, and has received grant support from AstraZeneca, Bayer, and Boehringer Ingelheim.
On Twitter @mitchelzoler
SOURCE: Abdelaziz HK et al. J Am Coll Cardiol. 2019 Jun 10. doi: 10.1016/j.jacc.2019.03.501.
FROM JACC
Key clinical point: Cumulative trial results continue to show that aspirin primary prevention cuts CVD events while boosting major bleeds.
Major finding: Aspirin prophylaxis cut cardiovascular events with an NNT of 263, but increased major bleeds with an NNH of 222.
Study details: Systematic review of data from 165,502 people enrolled in 15 randomized trials.
Disclosures: Dr. Mehta has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Medimmune, and Pfizer, and has received grant support from AstraZeneca, Bayer, and Boehringer Ingelheim.
Source: Abdelaziz HK et al. J Am Coll Cardiol. 2019 Jun 10. doi: 10.1016/j.jacc.2019.03.501.
DOACs surpass warfarin in low-weight AFib patients
SAN FRANCISCO – The direct-acting anticoagulants, as a class, were more effective and at least as safe as warfarin in low-weight and very-low-weight patients with atrial fibrillation in an adjusted analysis of real-world outcomes data from more than 21,000 Korean patients.
The analysis also showed that the direct-acting oral anticoagulants (DOACs) had the best safety and efficacy on low-weight patients when used at the labeled dosages, with blunted efficacy and safety at dosages that either exceeded or fell short of labeled levels, So-Ryoung Lee, MD, said at the annual scientific sessions of the Heart Rhythm Society.
The overall superiority of DOACs by both efficacy and safety also generally extended to the subgroup of very-low-weight patients, those with weights of less than 50 kg. In this subgroup, which was 28% of the total population studied, the composite adverse event outcome occurred 33% less often among patients treated with a DOAC relative to patients treated with warfarin, a statistically significant difference, said Dr. Lee, a cardiologist at Seoul (South Korea) National University Hospital. Among all patients with weights of 60 kg (132 pounds) or less, the composite outcome occurred 34% less often in the DOAC-treated patients relative to the warfarin-treated patients, also a statistically significant difference.
Dr. Lee and colleagues used a Korean National Health Insurance database that included information on more than 600,000 adults with atrial fibrillation (AFib) as of January 2013. The researchers whittled this down to 21,678 patients who began for the first time treatment with an oral anticoagulant starting during or after January 2014; had no history of a stroke, intracranial hemorrhage, or gastrointestinal bleed; and weighed no more than 60 kg. This cohort included 7,575 (35%) who received warfarin treatment, and 14,103 (65%) who received a DOAC. Within the DOAC-treated group, 42% received rivaroxaban (Xarelto), 26% dabigatran (Pradaxa), 24% apixaban (Eliquis), and 8% edoxaban (Savaysa).
To account for baseline differences in demographics and comorbidities between the patients treated with a DOAC and those who received warfarin, Dr. Lee and her associates did propensity score adjustment, which resulted in similar cohorts of 6,692 patients treated with warfarin and 12,810 patients treated with a DOAC. The average age of these patients was 73 years, a third were men, and the average body mass index was just over 22 kg/m2.
The events that the researchers tallied during follow-up through December 2016 included rates of all-cause death, ischemic stroke, intracranial hemorrhage, hospitalization for GI bleeding, hospitalization for major bleeding, and the composite of these five outcomes.
In the propensity-score adjusted full cohort of all patients who weighed 60 kg or less, the rate of each of these five outcomes, as well as the composite outcome, occurred statistically significantly less often among the DOAC-treated patients than in those on warfarin. The reductions ranged from a 41% lower incidence of ischemic stroke on DOAC treatment compared with warfarin treatment, to an 18% reduced rate of hospitalization for a GI bleed, compared with warfarin-treated patients. In the subgroup of patients who weighed less than 50 kg (110 pounds), the reductions ranged from a 41% cut in ischemic stroke on a DOAC compared with warfarin to a 24% relative reduction in the rate of hospitalization for a major bleed, a difference that just reached statistical significance. The outcome of hospitalization for a GI bleed showed no significant between-group difference among very-low-weight patients, but the rates of intracranial hemorrhage and all-cause death also showed statistically significant lower rates among DOAC-treated patients.
Nearly two-thirds of the patients on a DOAC received the label-appropriate dose of the drug, but 31% received a dosage that was below the labeled level while 4% received a dosage above the labeled level. An analysis that divided the NOAC patients by the appropriateness of their treatment dosages showed that patients on the correct dosages fared best. For example, in the total cohort of patients who weighed 60 kg or less, those on the correct DOAC dosage had a 9.1% rate of the combined endpoint. Patients on a low DOAC dosage did about as well as did the patients on warfarin, with a combined event rate of 11.6% in each of these subgroups. The worst outcomes occurred among the small number of patients on an inappropriately-high DOAC dosage, with a combined event rate of 15.4%. The researchers found a similar pattern among patients who weighed less than 50 kg.
Dr. Lee had no disclosures.
SOURCE: Lee SR et al. HRS 2019, Abstract S-AB30-05.
SAN FRANCISCO – The direct-acting anticoagulants, as a class, were more effective and at least as safe as warfarin in low-weight and very-low-weight patients with atrial fibrillation in an adjusted analysis of real-world outcomes data from more than 21,000 Korean patients.
The analysis also showed that the direct-acting oral anticoagulants (DOACs) had the best safety and efficacy on low-weight patients when used at the labeled dosages, with blunted efficacy and safety at dosages that either exceeded or fell short of labeled levels, So-Ryoung Lee, MD, said at the annual scientific sessions of the Heart Rhythm Society.
The overall superiority of DOACs by both efficacy and safety also generally extended to the subgroup of very-low-weight patients, those with weights of less than 50 kg. In this subgroup, which was 28% of the total population studied, the composite adverse event outcome occurred 33% less often among patients treated with a DOAC relative to patients treated with warfarin, a statistically significant difference, said Dr. Lee, a cardiologist at Seoul (South Korea) National University Hospital. Among all patients with weights of 60 kg (132 pounds) or less, the composite outcome occurred 34% less often in the DOAC-treated patients relative to the warfarin-treated patients, also a statistically significant difference.
Dr. Lee and colleagues used a Korean National Health Insurance database that included information on more than 600,000 adults with atrial fibrillation (AFib) as of January 2013. The researchers whittled this down to 21,678 patients who began for the first time treatment with an oral anticoagulant starting during or after January 2014; had no history of a stroke, intracranial hemorrhage, or gastrointestinal bleed; and weighed no more than 60 kg. This cohort included 7,575 (35%) who received warfarin treatment, and 14,103 (65%) who received a DOAC. Within the DOAC-treated group, 42% received rivaroxaban (Xarelto), 26% dabigatran (Pradaxa), 24% apixaban (Eliquis), and 8% edoxaban (Savaysa).
To account for baseline differences in demographics and comorbidities between the patients treated with a DOAC and those who received warfarin, Dr. Lee and her associates did propensity score adjustment, which resulted in similar cohorts of 6,692 patients treated with warfarin and 12,810 patients treated with a DOAC. The average age of these patients was 73 years, a third were men, and the average body mass index was just over 22 kg/m2.
The events that the researchers tallied during follow-up through December 2016 included rates of all-cause death, ischemic stroke, intracranial hemorrhage, hospitalization for GI bleeding, hospitalization for major bleeding, and the composite of these five outcomes.
In the propensity-score adjusted full cohort of all patients who weighed 60 kg or less, the rate of each of these five outcomes, as well as the composite outcome, occurred statistically significantly less often among the DOAC-treated patients than in those on warfarin. The reductions ranged from a 41% lower incidence of ischemic stroke on DOAC treatment compared with warfarin treatment, to an 18% reduced rate of hospitalization for a GI bleed, compared with warfarin-treated patients. In the subgroup of patients who weighed less than 50 kg (110 pounds), the reductions ranged from a 41% cut in ischemic stroke on a DOAC compared with warfarin to a 24% relative reduction in the rate of hospitalization for a major bleed, a difference that just reached statistical significance. The outcome of hospitalization for a GI bleed showed no significant between-group difference among very-low-weight patients, but the rates of intracranial hemorrhage and all-cause death also showed statistically significant lower rates among DOAC-treated patients.
Nearly two-thirds of the patients on a DOAC received the label-appropriate dose of the drug, but 31% received a dosage that was below the labeled level while 4% received a dosage above the labeled level. An analysis that divided the NOAC patients by the appropriateness of their treatment dosages showed that patients on the correct dosages fared best. For example, in the total cohort of patients who weighed 60 kg or less, those on the correct DOAC dosage had a 9.1% rate of the combined endpoint. Patients on a low DOAC dosage did about as well as did the patients on warfarin, with a combined event rate of 11.6% in each of these subgroups. The worst outcomes occurred among the small number of patients on an inappropriately-high DOAC dosage, with a combined event rate of 15.4%. The researchers found a similar pattern among patients who weighed less than 50 kg.
Dr. Lee had no disclosures.
SOURCE: Lee SR et al. HRS 2019, Abstract S-AB30-05.
SAN FRANCISCO – The direct-acting anticoagulants, as a class, were more effective and at least as safe as warfarin in low-weight and very-low-weight patients with atrial fibrillation in an adjusted analysis of real-world outcomes data from more than 21,000 Korean patients.
The analysis also showed that the direct-acting oral anticoagulants (DOACs) had the best safety and efficacy on low-weight patients when used at the labeled dosages, with blunted efficacy and safety at dosages that either exceeded or fell short of labeled levels, So-Ryoung Lee, MD, said at the annual scientific sessions of the Heart Rhythm Society.
The overall superiority of DOACs by both efficacy and safety also generally extended to the subgroup of very-low-weight patients, those with weights of less than 50 kg. In this subgroup, which was 28% of the total population studied, the composite adverse event outcome occurred 33% less often among patients treated with a DOAC relative to patients treated with warfarin, a statistically significant difference, said Dr. Lee, a cardiologist at Seoul (South Korea) National University Hospital. Among all patients with weights of 60 kg (132 pounds) or less, the composite outcome occurred 34% less often in the DOAC-treated patients relative to the warfarin-treated patients, also a statistically significant difference.
Dr. Lee and colleagues used a Korean National Health Insurance database that included information on more than 600,000 adults with atrial fibrillation (AFib) as of January 2013. The researchers whittled this down to 21,678 patients who began for the first time treatment with an oral anticoagulant starting during or after January 2014; had no history of a stroke, intracranial hemorrhage, or gastrointestinal bleed; and weighed no more than 60 kg. This cohort included 7,575 (35%) who received warfarin treatment, and 14,103 (65%) who received a DOAC. Within the DOAC-treated group, 42% received rivaroxaban (Xarelto), 26% dabigatran (Pradaxa), 24% apixaban (Eliquis), and 8% edoxaban (Savaysa).
To account for baseline differences in demographics and comorbidities between the patients treated with a DOAC and those who received warfarin, Dr. Lee and her associates did propensity score adjustment, which resulted in similar cohorts of 6,692 patients treated with warfarin and 12,810 patients treated with a DOAC. The average age of these patients was 73 years, a third were men, and the average body mass index was just over 22 kg/m2.
The events that the researchers tallied during follow-up through December 2016 included rates of all-cause death, ischemic stroke, intracranial hemorrhage, hospitalization for GI bleeding, hospitalization for major bleeding, and the composite of these five outcomes.
In the propensity-score adjusted full cohort of all patients who weighed 60 kg or less, the rate of each of these five outcomes, as well as the composite outcome, occurred statistically significantly less often among the DOAC-treated patients than in those on warfarin. The reductions ranged from a 41% lower incidence of ischemic stroke on DOAC treatment compared with warfarin treatment, to an 18% reduced rate of hospitalization for a GI bleed, compared with warfarin-treated patients. In the subgroup of patients who weighed less than 50 kg (110 pounds), the reductions ranged from a 41% cut in ischemic stroke on a DOAC compared with warfarin to a 24% relative reduction in the rate of hospitalization for a major bleed, a difference that just reached statistical significance. The outcome of hospitalization for a GI bleed showed no significant between-group difference among very-low-weight patients, but the rates of intracranial hemorrhage and all-cause death also showed statistically significant lower rates among DOAC-treated patients.
Nearly two-thirds of the patients on a DOAC received the label-appropriate dose of the drug, but 31% received a dosage that was below the labeled level while 4% received a dosage above the labeled level. An analysis that divided the NOAC patients by the appropriateness of their treatment dosages showed that patients on the correct dosages fared best. For example, in the total cohort of patients who weighed 60 kg or less, those on the correct DOAC dosage had a 9.1% rate of the combined endpoint. Patients on a low DOAC dosage did about as well as did the patients on warfarin, with a combined event rate of 11.6% in each of these subgroups. The worst outcomes occurred among the small number of patients on an inappropriately-high DOAC dosage, with a combined event rate of 15.4%. The researchers found a similar pattern among patients who weighed less than 50 kg.
Dr. Lee had no disclosures.
SOURCE: Lee SR et al. HRS 2019, Abstract S-AB30-05.
REPORTING FROM HEART RHYTHM 2019