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Has radial access PCI been overhyped?
NEW ORLEANS – , Michel R. Le May, MD, reported at the annual meeting of the American College of Cardiology.
Our findings suggest that adequately trained operators should be able to achieve similar results using either radial or femoral access for primary PCI,” declared Dr. Le May, professor of medicine at the University of Ottawa Heart Institute.
This is a controversial issue. European cardiologists have led a strong push for preferential use of radial access, citing reduced bleeding risk and an associated reduction in 30-day mortality. And this movement has spread to North America. But the evidence doesn’t convincingly support this position, the cardiologist said. He noted that of nine prior RCTs of radial versus the more traditional femoral access for primary PCI in STEMI, seven showed no difference in mortality. Nor did SAFARI-STEMI, which at 2,292 randomized STEMI patients was the second-largest trial to date.
SAFARI-STEMI was conducted at five high-volume Canadian PCI centers. Participating interventional cardiologists averaged 250 PCIs per year and were proficient in both access approaches. The study plan was to enroll 5,000 STEMI patients, but the trial was stopped after results were in for the first 2,292 because outcomes in the two study arms were so similar that the trial’s data safety monitoring board deemed it futile to continue.
The primary outcome was 30-day mortality. The rate was 1.5% in the radial access group and 1.3% in the femoral access group, with no differences among various subgroups.
Nor were there any between-group significant difference in the secondary endpoints of reinfarction (1.8% with radial, 1.6% with femoral), stroke (1.0% versus 0.4%), or the composite of death, reinfarction, or stroke, which occurred in 4.0% of the radial access group and 3.4% of the femoral group. Rates of non-CABG TIMI major or minor bleeding at 30 days were closely similar, as was need for transfusion. Definite or probable stent thrombosis occurred in 1.5% of the radial and 1.1% of the femoral groups.
Time from arrival at the PCI center to first balloon inflation was 47 minutes in the radial access group and significantly shorter at 44 minutes with femoral access, a noteworthy finding in the setting of STEMI, where time is myocardium. Fluoroscopy time was 1.2 minutes shorter in the femoral access group as well.
The reaction
Discussant Jacqueline E. Tamis-Holland, MD, said that, although she recently switched over to a radial access-first approach, her take away from SAFARI-STEMI is “It’s okay to do femoral.
“I think it’s comforting to the femoralists who are struggling to say, ‘I do a good femoral job and I don’t necessarily want to transition my STEMI patients to radial,’ ” said Dr. Tamis-Holland, associate director for the Mount Sinai St. Luke’s cardiac cath labs in New York.
Session cochair Martin B. Leon, MD, embraced the SAFARI-STEMI results with gusto.
“I’ve been tortured over the past 5 years by my junior interventional colleagues saying that, unless you’re doing transradial for STEMIs, that you’re not only out of step with the modern era of PCI, but you’re really moving against the evidence. And this study brings it back to a center position, where if you do a very-high-quality transfemoral approach, it is no different from transradial, not just from the standpoint of mortality but also bleeding complications. So I think we should aspire to be better transfemoral interventionalists, and if we do then there probably isn’t that much of a difference,” said Dr. Leon, professor of medicine at Columbia University in New York.
But discussant Sunil V. Rao, MD, who has championed radial access in the United States, was skeptical. “I think the results you achieved with femoral access in this trial are quite remarkable. We know from the registry data that those results are difficult to achieve in clinical practice.
“I would caution that the trial was stopped early, so I think it’s very challenging to try to apply this so as to influence our practice definitively,” said Dr. Rao of Duke University, Durham, N.C.
He asked Dr. Le May what advice he could give to femoralists in community practice to up their game and achieve results comparable to those in SAFARI-STEMI.
“We have to pay attention to their puncture,” Dr. Le May replied. “We use fluoroscopic guidance, and there are others who use ultrasound. We pay attention to the anticoagulation and antiplatelet therapy we use for these patients. We use GP IIb/IIIa inhibitors less today, and smaller sheaths. More than 90% of patients got ticagrelor before going to the cath lab. We’ve borrowed some of the techniques that the radial access people use.”
At a postpresentation ACC press conference, he indicated that it was difficult to recruit patients for the trial in the current strongly pro–radial access climate.
“I think there are people who think that, seriously, the horse is out of the barn, and it’s game over for the femoral. There is a mindset out there where people think that it’s just wrong to do a femoral approach,” said Dr. Le May. “We had comments that it’s not even ethical to randomize such patients.”
In fact, the issue is “very debatable,” he asserted, noting that radial artery occlusion is emerging as an important complication. And he suspects that cardiologists who strive to do 80%-90% of their percutaneous coronary interventions via the transradial route may become deskilled at using the femoral approach. That becomes a real concern when there is a problem in accessing the radial artery or need arises for a device that requires femoral access.
“I am of the school of thought that, given the results of our trial, we should teach people that you’re not a femoralist or a radialist. You should be an interventionalist that can do either and flip from one side to the other and be comfortable in doing that,” Dr. Le May concluded.
He reported having no conflicts regarding the study, funded by the Canadian Institutes of Health Research.
NEW ORLEANS – , Michel R. Le May, MD, reported at the annual meeting of the American College of Cardiology.
Our findings suggest that adequately trained operators should be able to achieve similar results using either radial or femoral access for primary PCI,” declared Dr. Le May, professor of medicine at the University of Ottawa Heart Institute.
This is a controversial issue. European cardiologists have led a strong push for preferential use of radial access, citing reduced bleeding risk and an associated reduction in 30-day mortality. And this movement has spread to North America. But the evidence doesn’t convincingly support this position, the cardiologist said. He noted that of nine prior RCTs of radial versus the more traditional femoral access for primary PCI in STEMI, seven showed no difference in mortality. Nor did SAFARI-STEMI, which at 2,292 randomized STEMI patients was the second-largest trial to date.
SAFARI-STEMI was conducted at five high-volume Canadian PCI centers. Participating interventional cardiologists averaged 250 PCIs per year and were proficient in both access approaches. The study plan was to enroll 5,000 STEMI patients, but the trial was stopped after results were in for the first 2,292 because outcomes in the two study arms were so similar that the trial’s data safety monitoring board deemed it futile to continue.
The primary outcome was 30-day mortality. The rate was 1.5% in the radial access group and 1.3% in the femoral access group, with no differences among various subgroups.
Nor were there any between-group significant difference in the secondary endpoints of reinfarction (1.8% with radial, 1.6% with femoral), stroke (1.0% versus 0.4%), or the composite of death, reinfarction, or stroke, which occurred in 4.0% of the radial access group and 3.4% of the femoral group. Rates of non-CABG TIMI major or minor bleeding at 30 days were closely similar, as was need for transfusion. Definite or probable stent thrombosis occurred in 1.5% of the radial and 1.1% of the femoral groups.
Time from arrival at the PCI center to first balloon inflation was 47 minutes in the radial access group and significantly shorter at 44 minutes with femoral access, a noteworthy finding in the setting of STEMI, where time is myocardium. Fluoroscopy time was 1.2 minutes shorter in the femoral access group as well.
The reaction
Discussant Jacqueline E. Tamis-Holland, MD, said that, although she recently switched over to a radial access-first approach, her take away from SAFARI-STEMI is “It’s okay to do femoral.
“I think it’s comforting to the femoralists who are struggling to say, ‘I do a good femoral job and I don’t necessarily want to transition my STEMI patients to radial,’ ” said Dr. Tamis-Holland, associate director for the Mount Sinai St. Luke’s cardiac cath labs in New York.
Session cochair Martin B. Leon, MD, embraced the SAFARI-STEMI results with gusto.
“I’ve been tortured over the past 5 years by my junior interventional colleagues saying that, unless you’re doing transradial for STEMIs, that you’re not only out of step with the modern era of PCI, but you’re really moving against the evidence. And this study brings it back to a center position, where if you do a very-high-quality transfemoral approach, it is no different from transradial, not just from the standpoint of mortality but also bleeding complications. So I think we should aspire to be better transfemoral interventionalists, and if we do then there probably isn’t that much of a difference,” said Dr. Leon, professor of medicine at Columbia University in New York.
But discussant Sunil V. Rao, MD, who has championed radial access in the United States, was skeptical. “I think the results you achieved with femoral access in this trial are quite remarkable. We know from the registry data that those results are difficult to achieve in clinical practice.
“I would caution that the trial was stopped early, so I think it’s very challenging to try to apply this so as to influence our practice definitively,” said Dr. Rao of Duke University, Durham, N.C.
He asked Dr. Le May what advice he could give to femoralists in community practice to up their game and achieve results comparable to those in SAFARI-STEMI.
“We have to pay attention to their puncture,” Dr. Le May replied. “We use fluoroscopic guidance, and there are others who use ultrasound. We pay attention to the anticoagulation and antiplatelet therapy we use for these patients. We use GP IIb/IIIa inhibitors less today, and smaller sheaths. More than 90% of patients got ticagrelor before going to the cath lab. We’ve borrowed some of the techniques that the radial access people use.”
At a postpresentation ACC press conference, he indicated that it was difficult to recruit patients for the trial in the current strongly pro–radial access climate.
“I think there are people who think that, seriously, the horse is out of the barn, and it’s game over for the femoral. There is a mindset out there where people think that it’s just wrong to do a femoral approach,” said Dr. Le May. “We had comments that it’s not even ethical to randomize such patients.”
In fact, the issue is “very debatable,” he asserted, noting that radial artery occlusion is emerging as an important complication. And he suspects that cardiologists who strive to do 80%-90% of their percutaneous coronary interventions via the transradial route may become deskilled at using the femoral approach. That becomes a real concern when there is a problem in accessing the radial artery or need arises for a device that requires femoral access.
“I am of the school of thought that, given the results of our trial, we should teach people that you’re not a femoralist or a radialist. You should be an interventionalist that can do either and flip from one side to the other and be comfortable in doing that,” Dr. Le May concluded.
He reported having no conflicts regarding the study, funded by the Canadian Institutes of Health Research.
NEW ORLEANS – , Michel R. Le May, MD, reported at the annual meeting of the American College of Cardiology.
Our findings suggest that adequately trained operators should be able to achieve similar results using either radial or femoral access for primary PCI,” declared Dr. Le May, professor of medicine at the University of Ottawa Heart Institute.
This is a controversial issue. European cardiologists have led a strong push for preferential use of radial access, citing reduced bleeding risk and an associated reduction in 30-day mortality. And this movement has spread to North America. But the evidence doesn’t convincingly support this position, the cardiologist said. He noted that of nine prior RCTs of radial versus the more traditional femoral access for primary PCI in STEMI, seven showed no difference in mortality. Nor did SAFARI-STEMI, which at 2,292 randomized STEMI patients was the second-largest trial to date.
SAFARI-STEMI was conducted at five high-volume Canadian PCI centers. Participating interventional cardiologists averaged 250 PCIs per year and were proficient in both access approaches. The study plan was to enroll 5,000 STEMI patients, but the trial was stopped after results were in for the first 2,292 because outcomes in the two study arms were so similar that the trial’s data safety monitoring board deemed it futile to continue.
The primary outcome was 30-day mortality. The rate was 1.5% in the radial access group and 1.3% in the femoral access group, with no differences among various subgroups.
Nor were there any between-group significant difference in the secondary endpoints of reinfarction (1.8% with radial, 1.6% with femoral), stroke (1.0% versus 0.4%), or the composite of death, reinfarction, or stroke, which occurred in 4.0% of the radial access group and 3.4% of the femoral group. Rates of non-CABG TIMI major or minor bleeding at 30 days were closely similar, as was need for transfusion. Definite or probable stent thrombosis occurred in 1.5% of the radial and 1.1% of the femoral groups.
Time from arrival at the PCI center to first balloon inflation was 47 minutes in the radial access group and significantly shorter at 44 minutes with femoral access, a noteworthy finding in the setting of STEMI, where time is myocardium. Fluoroscopy time was 1.2 minutes shorter in the femoral access group as well.
The reaction
Discussant Jacqueline E. Tamis-Holland, MD, said that, although she recently switched over to a radial access-first approach, her take away from SAFARI-STEMI is “It’s okay to do femoral.
“I think it’s comforting to the femoralists who are struggling to say, ‘I do a good femoral job and I don’t necessarily want to transition my STEMI patients to radial,’ ” said Dr. Tamis-Holland, associate director for the Mount Sinai St. Luke’s cardiac cath labs in New York.
Session cochair Martin B. Leon, MD, embraced the SAFARI-STEMI results with gusto.
“I’ve been tortured over the past 5 years by my junior interventional colleagues saying that, unless you’re doing transradial for STEMIs, that you’re not only out of step with the modern era of PCI, but you’re really moving against the evidence. And this study brings it back to a center position, where if you do a very-high-quality transfemoral approach, it is no different from transradial, not just from the standpoint of mortality but also bleeding complications. So I think we should aspire to be better transfemoral interventionalists, and if we do then there probably isn’t that much of a difference,” said Dr. Leon, professor of medicine at Columbia University in New York.
But discussant Sunil V. Rao, MD, who has championed radial access in the United States, was skeptical. “I think the results you achieved with femoral access in this trial are quite remarkable. We know from the registry data that those results are difficult to achieve in clinical practice.
“I would caution that the trial was stopped early, so I think it’s very challenging to try to apply this so as to influence our practice definitively,” said Dr. Rao of Duke University, Durham, N.C.
He asked Dr. Le May what advice he could give to femoralists in community practice to up their game and achieve results comparable to those in SAFARI-STEMI.
“We have to pay attention to their puncture,” Dr. Le May replied. “We use fluoroscopic guidance, and there are others who use ultrasound. We pay attention to the anticoagulation and antiplatelet therapy we use for these patients. We use GP IIb/IIIa inhibitors less today, and smaller sheaths. More than 90% of patients got ticagrelor before going to the cath lab. We’ve borrowed some of the techniques that the radial access people use.”
At a postpresentation ACC press conference, he indicated that it was difficult to recruit patients for the trial in the current strongly pro–radial access climate.
“I think there are people who think that, seriously, the horse is out of the barn, and it’s game over for the femoral. There is a mindset out there where people think that it’s just wrong to do a femoral approach,” said Dr. Le May. “We had comments that it’s not even ethical to randomize such patients.”
In fact, the issue is “very debatable,” he asserted, noting that radial artery occlusion is emerging as an important complication. And he suspects that cardiologists who strive to do 80%-90% of their percutaneous coronary interventions via the transradial route may become deskilled at using the femoral approach. That becomes a real concern when there is a problem in accessing the radial artery or need arises for a device that requires femoral access.
“I am of the school of thought that, given the results of our trial, we should teach people that you’re not a femoralist or a radialist. You should be an interventionalist that can do either and flip from one side to the other and be comfortable in doing that,” Dr. Le May concluded.
He reported having no conflicts regarding the study, funded by the Canadian Institutes of Health Research.
REPORTING FROM ACC 19
Consider 9-mm surgical margins for MIS
WAIKOLOA, HAWAII – The widely utilized 5-mm surgical margins for excision of melanoma in situ are inadequate in many cases, Christopher B. Zachary, MD, said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
“You probably should be considering more like 9- or 10-mm margins for melanoma in situ,” advised Dr. Zachary, professor and chair of the department of dermatology at the University of California, Irvine.
This has been a controversial matter. The recommendation for the long-standard 5-mm margins for excision of melanoma in situ (MIS) date back to a 1992 consensus opinion. Since then, however, persuasive data have emerged showing that 5-mm margins are often inadequate for clearance, and the latest American Academy of Dermatology guidelines for the management of primary cutaneous melanoma recommend margins of 5-10 mm (J Am Acad Dermatol. 2019 Jan;80[1]:208-50).
Dr. Zachary’s advice to go on the high side of that 5- to 10-mm zone is based in large part on studies led by John A Zitelli, MD, of the University of Pittsburgh. More than 20 years ago, Dr. Zitelli and his coinvestigators published a provocative prospective series of 535 patients whose melanomas – in situ or invasive – were excised via Mohs micrographic surgery with frozen section examination of the margins. A 9-mm margin successfully removed 95% of the melanomas, a 12-mm margin removed 97%, and a 6-mm margin successfully excised only 83% of the lesions (J Am Acad Dermatol. 1997 Sep;37(3 Pt 1):422-9).
In a follow-up study, Dr. Zitelli and his colleagues reported on a prospective series of 1,072 patients with 1,120 MIS, all excised by Mohs micrographic surgery with frozen sections (J Am Acad Dermatol. 2012 Mar;66[3]:438-44). They determined that 86% of the MIS were completely cleared using a 6-mm margin, compared with 98.9% excised with a 9 mm margin, a statistically significant difference (P less than .001).
Support for Dr. Zitelli’s stance that 5-mm margins for MIS are inadequate was provided by dermatologic surgeons at the Mayo Clinic in Scottsdale, Ariz. Of 46 patients who underwent Mohs micrographic surgery with immunostaining for excision of MIS, margins of 6 mm achieved clearance in only half of them. Surgical excision margins of 15 mm were required to successfully clear 96% of the MIS (Dermatol Surg. 2000 Aug;26[8]:771-84).
Quite a few hands shot up when Dr. Zachary asked how many members of his audience utilize 5-mm margins for surgical excision of MIS.
“That had been my practice as well until quite recently,” he said.
Dr. Zachary reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
WAIKOLOA, HAWAII – The widely utilized 5-mm surgical margins for excision of melanoma in situ are inadequate in many cases, Christopher B. Zachary, MD, said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
“You probably should be considering more like 9- or 10-mm margins for melanoma in situ,” advised Dr. Zachary, professor and chair of the department of dermatology at the University of California, Irvine.
This has been a controversial matter. The recommendation for the long-standard 5-mm margins for excision of melanoma in situ (MIS) date back to a 1992 consensus opinion. Since then, however, persuasive data have emerged showing that 5-mm margins are often inadequate for clearance, and the latest American Academy of Dermatology guidelines for the management of primary cutaneous melanoma recommend margins of 5-10 mm (J Am Acad Dermatol. 2019 Jan;80[1]:208-50).
Dr. Zachary’s advice to go on the high side of that 5- to 10-mm zone is based in large part on studies led by John A Zitelli, MD, of the University of Pittsburgh. More than 20 years ago, Dr. Zitelli and his coinvestigators published a provocative prospective series of 535 patients whose melanomas – in situ or invasive – were excised via Mohs micrographic surgery with frozen section examination of the margins. A 9-mm margin successfully removed 95% of the melanomas, a 12-mm margin removed 97%, and a 6-mm margin successfully excised only 83% of the lesions (J Am Acad Dermatol. 1997 Sep;37(3 Pt 1):422-9).
In a follow-up study, Dr. Zitelli and his colleagues reported on a prospective series of 1,072 patients with 1,120 MIS, all excised by Mohs micrographic surgery with frozen sections (J Am Acad Dermatol. 2012 Mar;66[3]:438-44). They determined that 86% of the MIS were completely cleared using a 6-mm margin, compared with 98.9% excised with a 9 mm margin, a statistically significant difference (P less than .001).
Support for Dr. Zitelli’s stance that 5-mm margins for MIS are inadequate was provided by dermatologic surgeons at the Mayo Clinic in Scottsdale, Ariz. Of 46 patients who underwent Mohs micrographic surgery with immunostaining for excision of MIS, margins of 6 mm achieved clearance in only half of them. Surgical excision margins of 15 mm were required to successfully clear 96% of the MIS (Dermatol Surg. 2000 Aug;26[8]:771-84).
Quite a few hands shot up when Dr. Zachary asked how many members of his audience utilize 5-mm margins for surgical excision of MIS.
“That had been my practice as well until quite recently,” he said.
Dr. Zachary reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
WAIKOLOA, HAWAII – The widely utilized 5-mm surgical margins for excision of melanoma in situ are inadequate in many cases, Christopher B. Zachary, MD, said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
“You probably should be considering more like 9- or 10-mm margins for melanoma in situ,” advised Dr. Zachary, professor and chair of the department of dermatology at the University of California, Irvine.
This has been a controversial matter. The recommendation for the long-standard 5-mm margins for excision of melanoma in situ (MIS) date back to a 1992 consensus opinion. Since then, however, persuasive data have emerged showing that 5-mm margins are often inadequate for clearance, and the latest American Academy of Dermatology guidelines for the management of primary cutaneous melanoma recommend margins of 5-10 mm (J Am Acad Dermatol. 2019 Jan;80[1]:208-50).
Dr. Zachary’s advice to go on the high side of that 5- to 10-mm zone is based in large part on studies led by John A Zitelli, MD, of the University of Pittsburgh. More than 20 years ago, Dr. Zitelli and his coinvestigators published a provocative prospective series of 535 patients whose melanomas – in situ or invasive – were excised via Mohs micrographic surgery with frozen section examination of the margins. A 9-mm margin successfully removed 95% of the melanomas, a 12-mm margin removed 97%, and a 6-mm margin successfully excised only 83% of the lesions (J Am Acad Dermatol. 1997 Sep;37(3 Pt 1):422-9).
In a follow-up study, Dr. Zitelli and his colleagues reported on a prospective series of 1,072 patients with 1,120 MIS, all excised by Mohs micrographic surgery with frozen sections (J Am Acad Dermatol. 2012 Mar;66[3]:438-44). They determined that 86% of the MIS were completely cleared using a 6-mm margin, compared with 98.9% excised with a 9 mm margin, a statistically significant difference (P less than .001).
Support for Dr. Zitelli’s stance that 5-mm margins for MIS are inadequate was provided by dermatologic surgeons at the Mayo Clinic in Scottsdale, Ariz. Of 46 patients who underwent Mohs micrographic surgery with immunostaining for excision of MIS, margins of 6 mm achieved clearance in only half of them. Surgical excision margins of 15 mm were required to successfully clear 96% of the MIS (Dermatol Surg. 2000 Aug;26[8]:771-84).
Quite a few hands shot up when Dr. Zachary asked how many members of his audience utilize 5-mm margins for surgical excision of MIS.
“That had been my practice as well until quite recently,” he said.
Dr. Zachary reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM SDEF HAWAII DERMATOLOGY SEMINAR
Ticagrelor reversal agent looks promising
NEW ORLEANS – A novel targeted ticagrelor reversal agent demonstrated rapid and sustained reversal of the potent antiplatelet agent in a phase 1 proof-of-concept study, Deepak L. Bhatt, MD, reported at the annual meeting of the American College of Cardiology.
“Hopefully the FDA will view this as something that really is a breakthrough,” commented Dr. Bhatt, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard University, both in Boston.
Why a breakthrough? Because despite recent major advances in the ability to reverse the action of the direct-acting oral anticoagulants and thereby greatly improve their safety margin, there have been no parallel developments with regard to the potent antiplatelet agents ticagrelor (Brilinta), prasugrel (Effient), and clopidogrel. The effects of these antiplatelet drugs take 3-5 days to dissipate after they’ve been stopped, which is highly problematic when they’ve induced catastrophic bleeding or a patient requires emergent or urgent surgery, the cardiologist explained.
“The ability to reverse tigracelor’s antiplatelet effects rapidly could distinguish it from other antiplatelet agents such as prasugrel or even generic clopidogrel and, for that matter, even aspirin,” Dr. Bhatt said.
The ticagrelor reversal agent, known for now as PB2452, is an intravenously administered recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment. It binds specifically and with high affinity to ticagrelor and its active metabolite. In the phase 1, placebo-controlled, double-blind study conducted in 64 healthy volunteers pretreated with ticagrelor for 48 hours, it reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.
The only adverse events observed in blinded assessment were minor injection site issues.
PB2452 is specific to ticagrelor and will not reverse the activity of other potent antiplatelet agents. Indeed, because of their chemical structure, neither prasugrel nor clopidogrel is reversible, according to Dr. Bhatt.
He said the developmental game plan for the ticagrelor reversal agent is initially to get it approved by the Food and Drug Administration for ticagrelor-related catastrophic bleeding, such as intracranial hemorrhage, since there is a recognized major unmet need in such situations. But as shown in the phase 1 study, BP2452 is potentially titratable by varying the size of the initial bolus dose and the dosing and duration of the subsequent infusion. So after initial approval for catastrophic bleeding, it makes sense to branch out and conduct further studies establishing the reversal agent’s value for prevention of bleeding complications caused by ticagrelor. An example might be a patient on ticagrelor because she recently received a stent in her left main coronary artery who falls and breaks her hip, and her surgeon says she needs surgery right away.
“If someone on ticagrelor came in with an intracranial hemorrhage, you’d want rapid reversal and have it sustained for as many days as the neurologist advises, whereas maybe if someone came in on ticagrelor after placement of a left main stent and you needed to do a lumbar puncture, you’d want to reverse the antiplatelet effect for the LP, and then if things go smoothly you’d want to get the ticagrelor back on board so the stent doesn’t thrombose. But that type of more precise dosing will require further work,” according to the cardiologist.
Discussant Barbara S. Wiggins, PharmD, commented, “We’ve been fortunate to have reversal agents come out for oral anticoagulants, but in terms of antiplatelet activity we’ve not been able to be successful with platelet transfusions. So having a reversal agent added to our armamentarium certainly is something that’s desirable.”
The phase 1 study of PB2452 indicates the monoclonal antibody checks the key boxes one looks for in a reversal agent: quick onset, long duration of effect, lack of a rebound in platelet activity after drug cessation, and potential for tailored titration. Of course, data on efficacy outcomes will also be necessary, noted Dr. Wiggins, a clinical pharmacologist at the Medical University of South Carolina, Charleston.
She added that she was favorably impressed that Dr. Bhatt and his coinvestigators went to the trouble of convincingly demonstrating reversal of ticagrelor’s antiplatelet effects using three different assays: light transmission aggregometry, which is considered the standard, as well as the point-of-care VerifyNow P2Y12 assay and the modified CY-QUANT assay.
The phase 1 study was funded by PhaseBio Pharmaceuticals. Dr. Bhatt reported the company provided a research grant directly to Brigham and Women’s Hospital.
Simultaneous with Dr. Bhatt’s presentation, the study results were published online (N Engl J Med. 2019 Mar 17. doi: 10.1056/NEJMoa1901778).
NEW ORLEANS – A novel targeted ticagrelor reversal agent demonstrated rapid and sustained reversal of the potent antiplatelet agent in a phase 1 proof-of-concept study, Deepak L. Bhatt, MD, reported at the annual meeting of the American College of Cardiology.
“Hopefully the FDA will view this as something that really is a breakthrough,” commented Dr. Bhatt, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard University, both in Boston.
Why a breakthrough? Because despite recent major advances in the ability to reverse the action of the direct-acting oral anticoagulants and thereby greatly improve their safety margin, there have been no parallel developments with regard to the potent antiplatelet agents ticagrelor (Brilinta), prasugrel (Effient), and clopidogrel. The effects of these antiplatelet drugs take 3-5 days to dissipate after they’ve been stopped, which is highly problematic when they’ve induced catastrophic bleeding or a patient requires emergent or urgent surgery, the cardiologist explained.
“The ability to reverse tigracelor’s antiplatelet effects rapidly could distinguish it from other antiplatelet agents such as prasugrel or even generic clopidogrel and, for that matter, even aspirin,” Dr. Bhatt said.
The ticagrelor reversal agent, known for now as PB2452, is an intravenously administered recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment. It binds specifically and with high affinity to ticagrelor and its active metabolite. In the phase 1, placebo-controlled, double-blind study conducted in 64 healthy volunteers pretreated with ticagrelor for 48 hours, it reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.
The only adverse events observed in blinded assessment were minor injection site issues.
PB2452 is specific to ticagrelor and will not reverse the activity of other potent antiplatelet agents. Indeed, because of their chemical structure, neither prasugrel nor clopidogrel is reversible, according to Dr. Bhatt.
He said the developmental game plan for the ticagrelor reversal agent is initially to get it approved by the Food and Drug Administration for ticagrelor-related catastrophic bleeding, such as intracranial hemorrhage, since there is a recognized major unmet need in such situations. But as shown in the phase 1 study, BP2452 is potentially titratable by varying the size of the initial bolus dose and the dosing and duration of the subsequent infusion. So after initial approval for catastrophic bleeding, it makes sense to branch out and conduct further studies establishing the reversal agent’s value for prevention of bleeding complications caused by ticagrelor. An example might be a patient on ticagrelor because she recently received a stent in her left main coronary artery who falls and breaks her hip, and her surgeon says she needs surgery right away.
“If someone on ticagrelor came in with an intracranial hemorrhage, you’d want rapid reversal and have it sustained for as many days as the neurologist advises, whereas maybe if someone came in on ticagrelor after placement of a left main stent and you needed to do a lumbar puncture, you’d want to reverse the antiplatelet effect for the LP, and then if things go smoothly you’d want to get the ticagrelor back on board so the stent doesn’t thrombose. But that type of more precise dosing will require further work,” according to the cardiologist.
Discussant Barbara S. Wiggins, PharmD, commented, “We’ve been fortunate to have reversal agents come out for oral anticoagulants, but in terms of antiplatelet activity we’ve not been able to be successful with platelet transfusions. So having a reversal agent added to our armamentarium certainly is something that’s desirable.”
The phase 1 study of PB2452 indicates the monoclonal antibody checks the key boxes one looks for in a reversal agent: quick onset, long duration of effect, lack of a rebound in platelet activity after drug cessation, and potential for tailored titration. Of course, data on efficacy outcomes will also be necessary, noted Dr. Wiggins, a clinical pharmacologist at the Medical University of South Carolina, Charleston.
She added that she was favorably impressed that Dr. Bhatt and his coinvestigators went to the trouble of convincingly demonstrating reversal of ticagrelor’s antiplatelet effects using three different assays: light transmission aggregometry, which is considered the standard, as well as the point-of-care VerifyNow P2Y12 assay and the modified CY-QUANT assay.
The phase 1 study was funded by PhaseBio Pharmaceuticals. Dr. Bhatt reported the company provided a research grant directly to Brigham and Women’s Hospital.
Simultaneous with Dr. Bhatt’s presentation, the study results were published online (N Engl J Med. 2019 Mar 17. doi: 10.1056/NEJMoa1901778).
NEW ORLEANS – A novel targeted ticagrelor reversal agent demonstrated rapid and sustained reversal of the potent antiplatelet agent in a phase 1 proof-of-concept study, Deepak L. Bhatt, MD, reported at the annual meeting of the American College of Cardiology.
“Hopefully the FDA will view this as something that really is a breakthrough,” commented Dr. Bhatt, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard University, both in Boston.
Why a breakthrough? Because despite recent major advances in the ability to reverse the action of the direct-acting oral anticoagulants and thereby greatly improve their safety margin, there have been no parallel developments with regard to the potent antiplatelet agents ticagrelor (Brilinta), prasugrel (Effient), and clopidogrel. The effects of these antiplatelet drugs take 3-5 days to dissipate after they’ve been stopped, which is highly problematic when they’ve induced catastrophic bleeding or a patient requires emergent or urgent surgery, the cardiologist explained.
“The ability to reverse tigracelor’s antiplatelet effects rapidly could distinguish it from other antiplatelet agents such as prasugrel or even generic clopidogrel and, for that matter, even aspirin,” Dr. Bhatt said.
The ticagrelor reversal agent, known for now as PB2452, is an intravenously administered recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment. It binds specifically and with high affinity to ticagrelor and its active metabolite. In the phase 1, placebo-controlled, double-blind study conducted in 64 healthy volunteers pretreated with ticagrelor for 48 hours, it reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.
The only adverse events observed in blinded assessment were minor injection site issues.
PB2452 is specific to ticagrelor and will not reverse the activity of other potent antiplatelet agents. Indeed, because of their chemical structure, neither prasugrel nor clopidogrel is reversible, according to Dr. Bhatt.
He said the developmental game plan for the ticagrelor reversal agent is initially to get it approved by the Food and Drug Administration for ticagrelor-related catastrophic bleeding, such as intracranial hemorrhage, since there is a recognized major unmet need in such situations. But as shown in the phase 1 study, BP2452 is potentially titratable by varying the size of the initial bolus dose and the dosing and duration of the subsequent infusion. So after initial approval for catastrophic bleeding, it makes sense to branch out and conduct further studies establishing the reversal agent’s value for prevention of bleeding complications caused by ticagrelor. An example might be a patient on ticagrelor because she recently received a stent in her left main coronary artery who falls and breaks her hip, and her surgeon says she needs surgery right away.
“If someone on ticagrelor came in with an intracranial hemorrhage, you’d want rapid reversal and have it sustained for as many days as the neurologist advises, whereas maybe if someone came in on ticagrelor after placement of a left main stent and you needed to do a lumbar puncture, you’d want to reverse the antiplatelet effect for the LP, and then if things go smoothly you’d want to get the ticagrelor back on board so the stent doesn’t thrombose. But that type of more precise dosing will require further work,” according to the cardiologist.
Discussant Barbara S. Wiggins, PharmD, commented, “We’ve been fortunate to have reversal agents come out for oral anticoagulants, but in terms of antiplatelet activity we’ve not been able to be successful with platelet transfusions. So having a reversal agent added to our armamentarium certainly is something that’s desirable.”
The phase 1 study of PB2452 indicates the monoclonal antibody checks the key boxes one looks for in a reversal agent: quick onset, long duration of effect, lack of a rebound in platelet activity after drug cessation, and potential for tailored titration. Of course, data on efficacy outcomes will also be necessary, noted Dr. Wiggins, a clinical pharmacologist at the Medical University of South Carolina, Charleston.
She added that she was favorably impressed that Dr. Bhatt and his coinvestigators went to the trouble of convincingly demonstrating reversal of ticagrelor’s antiplatelet effects using three different assays: light transmission aggregometry, which is considered the standard, as well as the point-of-care VerifyNow P2Y12 assay and the modified CY-QUANT assay.
The phase 1 study was funded by PhaseBio Pharmaceuticals. Dr. Bhatt reported the company provided a research grant directly to Brigham and Women’s Hospital.
Simultaneous with Dr. Bhatt’s presentation, the study results were published online (N Engl J Med. 2019 Mar 17. doi: 10.1056/NEJMoa1901778).
REPORTING FROM ACC 19
Key clinical point: Oral ticagrelor’s antiplatelet effect was reversed within 5 minutes by a novel targeted monoclonal antibody.
Major finding: A novel targeted monoclonal antibody reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.
Study details: This phase 1 study included 64 healthy subjects pretreated with 48 hours of ticagrelor before receiving various doses of the reversal agent or placebo.
Disclosures: The study was funded by PhaseBio Pharmaceuticals, which provided a research grant directly to Brigham and Women’s Hospital.
Use time-appropriate scar improvement sequencing
WAIKOLOA, HAWAII – , according to American Academy of Dermatology President-elect George J. Hruza, MD – and he’s got a raft of them.
“There are going to be situations where your scars aren’t going to be as wonderful as you’d like, or even if they’re pretty good, you might improve them further if you do some modifications,” he observed at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
He became convinced of the importance of having a large toolbox for scar improvement in part as a result of an Australian prospective study of 576 patients surveyed 6-9 months following skin cancer surgery. Far and away the most important factor influencing patients’ overall perception of their experience wasn’t the cost, pain, quality of nursing care, complications, wait time prior to surgery, or gratitude that they’d successfully had a cancer removed. It was their perception of the scar (J Am Acad Dermatol. 2007 Sep;57[3]:445-53).
To be effective, interventions for scar improvement need to be timed in sync with the three phases of cellular activity involved in wound healing. For example, neurotoxin injections are effective during the first few days of the initial acute inflammation period, when cellular migration is active. Silicone and taping are of value when employed long term, starting at about 1 month and continuing for 3-6 months, throughout the neovascularization/granulation phase, then the time of fibroblast proliferation and matrix formation that follows, and even beyond. Pulsed dye and fractionated ablative lasers are best utilized to reshape matrix formation, starting at about 2 weeks. Intervention using dermabrasion or fillers has to wait for the scar to be a bit more mature, at about 2 months; utilized earlier these can cause dehiscence, explained Dr. Hruza of St. Louis University.
He shared what he called his “scar improvement hierarchy,” the sequence of interventions he turns to from the most to least often. But he began with prevention, noting that more than 2 decades ago, he and his coinvestigators demonstrated that running horizontal mattress sutures for primary closures of facial wounds provide better cosmetic results, with a final scar that’s smoother and flatter than the more commonly used simple running sutures (Dermatol Surg. 2005 Oct;31[10]:1313-6).
Scar improvement sequence
Massage. “I recommend this to almost every patient. I have them start at about 6 weeks and do it for several months. It’s really more like kneading dough, not rubbing. You want the skin pressing on the bone underneath,” according to Dr. Hruza. Various investigators have suggested that scar massage works by increasing hydration and capillary proliferation, while promoting desensitization, but the evidence is really anecdotal.
“I think it’s mainly tincture of time. Scars get better on their own,” he observed. Regardless, massage allows patients the satisfaction of actively participating in their own recovery.
Intralesional triamcinolone. Dr. Hruza calls this “our big friend.”
“I find that 90% of the time when you look at a thickened scar and you think, ‘Oh gee, I’m going to have to do some scar revision, the intralesional triamcinolone takes care of the problem,” he said. He usually injects the site at about 6 weeks post surgery using 10 mg/mL. If the response is inadequate he reinjects about a month later using 20 mg/mL. He generally avoids going to 40 mg/mL for facial scars. The goal is to make therapeutic use of the steroid’s major side effect – atrophy – to shrink the thickened scar. But because this can be a tricky business, of late he has turned increasingly to intralesional triamcinolone and 5-fluorouracil (5-FU).
Intralesional triamcinolone plus 5-FU. This combination causes less atrophy, hypopigmentation, and telangiectasias than full-on triamcinolone. He injects 0.9 mL of 5-FU at 50 mg/mL and 0.1 mL of triamcinolone at 40 mg/mL into and under the scar. The 5-FU inhibits fibroblast proliferation. It is rated pregnancy category D, so he avoids using it in women of childbearing age.
Spot dermabrasion. “To me, this is the go-to. After my intralesional steroids, if the scar hasn’t fully smoothed out, then I go to dermabrasion or the spot CO2 laser,” Dr. Hruza said.
“Dermabrasion is an old technology, but it’s actually still very useful,” he continued. “Do it at 6-10 weeks; that’s the sweet spot. Do it sooner and you can get into problems with dehiscence. And if you do it later than 10 weeks the improvement is much less because everything is stabilized and the collagen is set.” He uses a diamond fraise to abrade and sculpt, rather than sandpaper, which doesn’t allow him to go sufficiently deep once bleeding starts and the sandpaper gets wet.
Spot conventional CO2 or Er:YAG laser resurfacing. “I really find in my hands these ablative techniques are much more effective than using a fractionated laser, which only gives you a little bit of improvement,” he said.
Pulsed dye laser. Very effective for red, thickened scars. Dr. Hruza does two to four treatments at 4-week intervals. At wavelengths of 585-595 nm, a pulse of 0.5-1.5 millisecs, and 4-5 Joules/cm2, there is only minimal purpura.
The pulsed dye laser can also be employed preventively starting at the time of suture removal and then again at 4-6 weeks in order to reduce hypertrophy. “It’s something to consider in areas like the chest, upper back, and shoulders, where you’re trying to prevent problems. The only danger is occasionally patients have dehiscence,” according to the dermatologic surgeon.
Fractionated nonablative laser. Four or five treatments are typically required in order to achieve significant resurfacing.
Micropore tape. Dr. Hruza finds this works just as well as topical silicone gel sheets, rolls, and gels, all of which are quite expensive. A roll of micropore tape costs only a few dollars and will last a patient for a couple months. Patients are taught to apply the tape at the time of suture removal in a line parallel to the suture line, replacing the tape when it begins to peel off. As with the vastly more expensive silicone products, the tape needs to be left on 12-24 hours per day for 3-6 months in order to achieve a flat white scar. The benefit is thought to come from relief of mechanical stress coupled with occlusion.
Botulinum toxin A and other neurotoxins. Inject into muscle near the wound edges right after closing the wound, using 1-3 units at 1- to 3-cm intervals in order to prevent scar formation, Dr. Hruza advised. If the wound is on one side of the face, the other side needs to receive injections as well in order to spare the patient from several months of cosmetically undesirable asymmetry. However, Dr. Hruza rarely utilizes neurotoxin injections. “It’s a cost issue. I’m in the Midwest, where a lot of insurers are unwilling to pay for it,” he explained.
Flap defatting. Here the surgeon opens the flap and keeps digging with scalpel and scissors until the scar is slightly depressed, since there is likely to be some recurrence. Then it’s time to resuture the flap.
Technical scar revision procedures. The simplest of these is Z-plasty, which entails making two skin incisions to create a Z-shaped incision, then flipping the two sides to reorient the scar. The Z-plasty has two major uses: correction of a retracted lip or medial canthus webbing. “If you get either of these, Z-plasty is the way to go,” Dr. Hruza said.
Fillers for atrophic scars. “To me, this is the last thing to go to. The reason is that, if a patient has skin cancer surgery, they don’t expect to pay extra to improve that scar. And I can do dermabrasion with no incremental product cost to the practice,” he commented. The technique entails making a subcision to create a pocket for the filler. The products marketed as Restylane Silk, Belotero, and Radiesse all yield good results, he said.
Dr. Hruza reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
WAIKOLOA, HAWAII – , according to American Academy of Dermatology President-elect George J. Hruza, MD – and he’s got a raft of them.
“There are going to be situations where your scars aren’t going to be as wonderful as you’d like, or even if they’re pretty good, you might improve them further if you do some modifications,” he observed at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
He became convinced of the importance of having a large toolbox for scar improvement in part as a result of an Australian prospective study of 576 patients surveyed 6-9 months following skin cancer surgery. Far and away the most important factor influencing patients’ overall perception of their experience wasn’t the cost, pain, quality of nursing care, complications, wait time prior to surgery, or gratitude that they’d successfully had a cancer removed. It was their perception of the scar (J Am Acad Dermatol. 2007 Sep;57[3]:445-53).
To be effective, interventions for scar improvement need to be timed in sync with the three phases of cellular activity involved in wound healing. For example, neurotoxin injections are effective during the first few days of the initial acute inflammation period, when cellular migration is active. Silicone and taping are of value when employed long term, starting at about 1 month and continuing for 3-6 months, throughout the neovascularization/granulation phase, then the time of fibroblast proliferation and matrix formation that follows, and even beyond. Pulsed dye and fractionated ablative lasers are best utilized to reshape matrix formation, starting at about 2 weeks. Intervention using dermabrasion or fillers has to wait for the scar to be a bit more mature, at about 2 months; utilized earlier these can cause dehiscence, explained Dr. Hruza of St. Louis University.
He shared what he called his “scar improvement hierarchy,” the sequence of interventions he turns to from the most to least often. But he began with prevention, noting that more than 2 decades ago, he and his coinvestigators demonstrated that running horizontal mattress sutures for primary closures of facial wounds provide better cosmetic results, with a final scar that’s smoother and flatter than the more commonly used simple running sutures (Dermatol Surg. 2005 Oct;31[10]:1313-6).
Scar improvement sequence
Massage. “I recommend this to almost every patient. I have them start at about 6 weeks and do it for several months. It’s really more like kneading dough, not rubbing. You want the skin pressing on the bone underneath,” according to Dr. Hruza. Various investigators have suggested that scar massage works by increasing hydration and capillary proliferation, while promoting desensitization, but the evidence is really anecdotal.
“I think it’s mainly tincture of time. Scars get better on their own,” he observed. Regardless, massage allows patients the satisfaction of actively participating in their own recovery.
Intralesional triamcinolone. Dr. Hruza calls this “our big friend.”
“I find that 90% of the time when you look at a thickened scar and you think, ‘Oh gee, I’m going to have to do some scar revision, the intralesional triamcinolone takes care of the problem,” he said. He usually injects the site at about 6 weeks post surgery using 10 mg/mL. If the response is inadequate he reinjects about a month later using 20 mg/mL. He generally avoids going to 40 mg/mL for facial scars. The goal is to make therapeutic use of the steroid’s major side effect – atrophy – to shrink the thickened scar. But because this can be a tricky business, of late he has turned increasingly to intralesional triamcinolone and 5-fluorouracil (5-FU).
Intralesional triamcinolone plus 5-FU. This combination causes less atrophy, hypopigmentation, and telangiectasias than full-on triamcinolone. He injects 0.9 mL of 5-FU at 50 mg/mL and 0.1 mL of triamcinolone at 40 mg/mL into and under the scar. The 5-FU inhibits fibroblast proliferation. It is rated pregnancy category D, so he avoids using it in women of childbearing age.
Spot dermabrasion. “To me, this is the go-to. After my intralesional steroids, if the scar hasn’t fully smoothed out, then I go to dermabrasion or the spot CO2 laser,” Dr. Hruza said.
“Dermabrasion is an old technology, but it’s actually still very useful,” he continued. “Do it at 6-10 weeks; that’s the sweet spot. Do it sooner and you can get into problems with dehiscence. And if you do it later than 10 weeks the improvement is much less because everything is stabilized and the collagen is set.” He uses a diamond fraise to abrade and sculpt, rather than sandpaper, which doesn’t allow him to go sufficiently deep once bleeding starts and the sandpaper gets wet.
Spot conventional CO2 or Er:YAG laser resurfacing. “I really find in my hands these ablative techniques are much more effective than using a fractionated laser, which only gives you a little bit of improvement,” he said.
Pulsed dye laser. Very effective for red, thickened scars. Dr. Hruza does two to four treatments at 4-week intervals. At wavelengths of 585-595 nm, a pulse of 0.5-1.5 millisecs, and 4-5 Joules/cm2, there is only minimal purpura.
The pulsed dye laser can also be employed preventively starting at the time of suture removal and then again at 4-6 weeks in order to reduce hypertrophy. “It’s something to consider in areas like the chest, upper back, and shoulders, where you’re trying to prevent problems. The only danger is occasionally patients have dehiscence,” according to the dermatologic surgeon.
Fractionated nonablative laser. Four or five treatments are typically required in order to achieve significant resurfacing.
Micropore tape. Dr. Hruza finds this works just as well as topical silicone gel sheets, rolls, and gels, all of which are quite expensive. A roll of micropore tape costs only a few dollars and will last a patient for a couple months. Patients are taught to apply the tape at the time of suture removal in a line parallel to the suture line, replacing the tape when it begins to peel off. As with the vastly more expensive silicone products, the tape needs to be left on 12-24 hours per day for 3-6 months in order to achieve a flat white scar. The benefit is thought to come from relief of mechanical stress coupled with occlusion.
Botulinum toxin A and other neurotoxins. Inject into muscle near the wound edges right after closing the wound, using 1-3 units at 1- to 3-cm intervals in order to prevent scar formation, Dr. Hruza advised. If the wound is on one side of the face, the other side needs to receive injections as well in order to spare the patient from several months of cosmetically undesirable asymmetry. However, Dr. Hruza rarely utilizes neurotoxin injections. “It’s a cost issue. I’m in the Midwest, where a lot of insurers are unwilling to pay for it,” he explained.
Flap defatting. Here the surgeon opens the flap and keeps digging with scalpel and scissors until the scar is slightly depressed, since there is likely to be some recurrence. Then it’s time to resuture the flap.
Technical scar revision procedures. The simplest of these is Z-plasty, which entails making two skin incisions to create a Z-shaped incision, then flipping the two sides to reorient the scar. The Z-plasty has two major uses: correction of a retracted lip or medial canthus webbing. “If you get either of these, Z-plasty is the way to go,” Dr. Hruza said.
Fillers for atrophic scars. “To me, this is the last thing to go to. The reason is that, if a patient has skin cancer surgery, they don’t expect to pay extra to improve that scar. And I can do dermabrasion with no incremental product cost to the practice,” he commented. The technique entails making a subcision to create a pocket for the filler. The products marketed as Restylane Silk, Belotero, and Radiesse all yield good results, he said.
Dr. Hruza reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
WAIKOLOA, HAWAII – , according to American Academy of Dermatology President-elect George J. Hruza, MD – and he’s got a raft of them.
“There are going to be situations where your scars aren’t going to be as wonderful as you’d like, or even if they’re pretty good, you might improve them further if you do some modifications,” he observed at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
He became convinced of the importance of having a large toolbox for scar improvement in part as a result of an Australian prospective study of 576 patients surveyed 6-9 months following skin cancer surgery. Far and away the most important factor influencing patients’ overall perception of their experience wasn’t the cost, pain, quality of nursing care, complications, wait time prior to surgery, or gratitude that they’d successfully had a cancer removed. It was their perception of the scar (J Am Acad Dermatol. 2007 Sep;57[3]:445-53).
To be effective, interventions for scar improvement need to be timed in sync with the three phases of cellular activity involved in wound healing. For example, neurotoxin injections are effective during the first few days of the initial acute inflammation period, when cellular migration is active. Silicone and taping are of value when employed long term, starting at about 1 month and continuing for 3-6 months, throughout the neovascularization/granulation phase, then the time of fibroblast proliferation and matrix formation that follows, and even beyond. Pulsed dye and fractionated ablative lasers are best utilized to reshape matrix formation, starting at about 2 weeks. Intervention using dermabrasion or fillers has to wait for the scar to be a bit more mature, at about 2 months; utilized earlier these can cause dehiscence, explained Dr. Hruza of St. Louis University.
He shared what he called his “scar improvement hierarchy,” the sequence of interventions he turns to from the most to least often. But he began with prevention, noting that more than 2 decades ago, he and his coinvestigators demonstrated that running horizontal mattress sutures for primary closures of facial wounds provide better cosmetic results, with a final scar that’s smoother and flatter than the more commonly used simple running sutures (Dermatol Surg. 2005 Oct;31[10]:1313-6).
Scar improvement sequence
Massage. “I recommend this to almost every patient. I have them start at about 6 weeks and do it for several months. It’s really more like kneading dough, not rubbing. You want the skin pressing on the bone underneath,” according to Dr. Hruza. Various investigators have suggested that scar massage works by increasing hydration and capillary proliferation, while promoting desensitization, but the evidence is really anecdotal.
“I think it’s mainly tincture of time. Scars get better on their own,” he observed. Regardless, massage allows patients the satisfaction of actively participating in their own recovery.
Intralesional triamcinolone. Dr. Hruza calls this “our big friend.”
“I find that 90% of the time when you look at a thickened scar and you think, ‘Oh gee, I’m going to have to do some scar revision, the intralesional triamcinolone takes care of the problem,” he said. He usually injects the site at about 6 weeks post surgery using 10 mg/mL. If the response is inadequate he reinjects about a month later using 20 mg/mL. He generally avoids going to 40 mg/mL for facial scars. The goal is to make therapeutic use of the steroid’s major side effect – atrophy – to shrink the thickened scar. But because this can be a tricky business, of late he has turned increasingly to intralesional triamcinolone and 5-fluorouracil (5-FU).
Intralesional triamcinolone plus 5-FU. This combination causes less atrophy, hypopigmentation, and telangiectasias than full-on triamcinolone. He injects 0.9 mL of 5-FU at 50 mg/mL and 0.1 mL of triamcinolone at 40 mg/mL into and under the scar. The 5-FU inhibits fibroblast proliferation. It is rated pregnancy category D, so he avoids using it in women of childbearing age.
Spot dermabrasion. “To me, this is the go-to. After my intralesional steroids, if the scar hasn’t fully smoothed out, then I go to dermabrasion or the spot CO2 laser,” Dr. Hruza said.
“Dermabrasion is an old technology, but it’s actually still very useful,” he continued. “Do it at 6-10 weeks; that’s the sweet spot. Do it sooner and you can get into problems with dehiscence. And if you do it later than 10 weeks the improvement is much less because everything is stabilized and the collagen is set.” He uses a diamond fraise to abrade and sculpt, rather than sandpaper, which doesn’t allow him to go sufficiently deep once bleeding starts and the sandpaper gets wet.
Spot conventional CO2 or Er:YAG laser resurfacing. “I really find in my hands these ablative techniques are much more effective than using a fractionated laser, which only gives you a little bit of improvement,” he said.
Pulsed dye laser. Very effective for red, thickened scars. Dr. Hruza does two to four treatments at 4-week intervals. At wavelengths of 585-595 nm, a pulse of 0.5-1.5 millisecs, and 4-5 Joules/cm2, there is only minimal purpura.
The pulsed dye laser can also be employed preventively starting at the time of suture removal and then again at 4-6 weeks in order to reduce hypertrophy. “It’s something to consider in areas like the chest, upper back, and shoulders, where you’re trying to prevent problems. The only danger is occasionally patients have dehiscence,” according to the dermatologic surgeon.
Fractionated nonablative laser. Four or five treatments are typically required in order to achieve significant resurfacing.
Micropore tape. Dr. Hruza finds this works just as well as topical silicone gel sheets, rolls, and gels, all of which are quite expensive. A roll of micropore tape costs only a few dollars and will last a patient for a couple months. Patients are taught to apply the tape at the time of suture removal in a line parallel to the suture line, replacing the tape when it begins to peel off. As with the vastly more expensive silicone products, the tape needs to be left on 12-24 hours per day for 3-6 months in order to achieve a flat white scar. The benefit is thought to come from relief of mechanical stress coupled with occlusion.
Botulinum toxin A and other neurotoxins. Inject into muscle near the wound edges right after closing the wound, using 1-3 units at 1- to 3-cm intervals in order to prevent scar formation, Dr. Hruza advised. If the wound is on one side of the face, the other side needs to receive injections as well in order to spare the patient from several months of cosmetically undesirable asymmetry. However, Dr. Hruza rarely utilizes neurotoxin injections. “It’s a cost issue. I’m in the Midwest, where a lot of insurers are unwilling to pay for it,” he explained.
Flap defatting. Here the surgeon opens the flap and keeps digging with scalpel and scissors until the scar is slightly depressed, since there is likely to be some recurrence. Then it’s time to resuture the flap.
Technical scar revision procedures. The simplest of these is Z-plasty, which entails making two skin incisions to create a Z-shaped incision, then flipping the two sides to reorient the scar. The Z-plasty has two major uses: correction of a retracted lip or medial canthus webbing. “If you get either of these, Z-plasty is the way to go,” Dr. Hruza said.
Fillers for atrophic scars. “To me, this is the last thing to go to. The reason is that, if a patient has skin cancer surgery, they don’t expect to pay extra to improve that scar. And I can do dermabrasion with no incremental product cost to the practice,” he commented. The technique entails making a subcision to create a pocket for the filler. The products marketed as Restylane Silk, Belotero, and Radiesse all yield good results, he said.
Dr. Hruza reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM SDEF HAWAII DERMATOLOGY SEMINAR
Biologics boost work outcomes in axial spondyloarthritis
MAUI, HAWAII – Biologic therapy improves work-related outcomes in patients with axial spondyloarthritis, according to a report from the British Society for Rheumatology Biologics Register.
“This gets to the issue of cost/benefit. But with benefit you have to look at the big picture. These are expensive drugs, but if these expensive drugs have societal benefits by keeping people at work, you have to throw that into the equation when you think about the value proposition of these agents,” Eric M. Ruderman, MD, observed in highlighting the British study at the 2019 Rheumatology Winter Clinical Symposium.
In drawing attention to this and other developments during the past year in the field of axial spondyloarthritis (SpA) outside the realm of pharmacologic randomized trials, he and copanelist Arthur Kavanaugh, MD, highlighted trends in diagnostic imaging for the disorder, where MRI’s stock may be going down while color Doppler ultrasound’s is rising, as well as a novel online tool designed to get individuals with a high probability of SpA into a rheumatologist’s office without years of bouncing around between other types of health care providers.
Biologics boost work performance
The British Society for Rheumatology Biologics Register study included 577 patients at 83 centers in Great Britain who met Assessment of SpondyloArthritis International Society criteria for radiographic or nonradiographic SpA, all of whom were employed and biologic-naive when they enrolled in the registry (Ann Rheum Dis. 2018 Nov;77[11]:1578-84). Upon enrollment, 28% of them were placed on adalimumab (Humira), etanercept (Enbrel), or certolizumab pegol (Cimzia) based upon physician recommendation. Work outcomes at the start and end of the first year in the registry were compared between SpA patients on biologic therapy or not using the validated Work Productivity and Activity Impairment Index, a patient self-report measure.
After propensity score adjustment to account for between-group differences, SpA patients on biologic therapy demonstrated a 9.4% reduction in presenteeism – that is, on-site work underperformance and productivity loss – compared with those not on a biologic. The group on biologics also averaged a 13.9% greater improvement from baseline in overall work impairment than did patients not on a biologic and a 19.2% greater improvement in overall activity impairment, which encompasses leisure activities. This works out to more than half a day of additional full productivity per week 12 months after starting on a biologic.
The investigators decided to confirm their findings by conducting what they believe to be the first-ever meta-analysis to quantify the impact of biologic therapy for SpA on work participation. The meta-analysis included five studies with 1,109 participants. The results: Biologic therapy was associated with significantly greater improvements in presenteeism, overall work impairment, and overall activity impairment, as in the British registry study, but was also no significant impact on work absenteeism, just as was the case in the registry study. The investigators noted that presenteeism is a much bigger problem than absenteeism in patients with SpA. They hypothesized that absenteeism is a relatively late-stage development in work impairment that isn’t reversible by biologic therapy alone.
“This is superimportant data,” commented Dr. Kavanaugh, professor of medicine at the University of California, San Diego.
Pharmacoeconomic analyses typically rely upon quality-of-life metrics and express cost/benefit in terms of QALYs, or quality-adjusted life-years, gained by utilization of a therapy. That’s a measure of particular importance from a payer’s perspective, but QALYs typically don’t incorporate work outcome data and other aspects of the wider societal costs and benefits of a therapy since they aren’t addressed in short-term, randomized, controlled trials.
“Work data are a more realistic way to do this: actual data on people getting back to their jobs,” the rheumatologist said.
Online accrual of likely SpA patients
The average delay between symptom onset and diagnosis of SpA is 7-9 years. Dr. Ruderman was favorably impressed by the Identification of the Optimal Referral Strategy for Early Diagnosis of Axial Spondyloarthritis (OptiRef) study of an outside-the-box online self-referral tool presented at the 2018 annual meeting of the American College of Rheumatology.
The German investigators placed advertisements in subways directing interested riders with back pain to a website where they completed what the rheumatologists called the Berlin referral tool. If they indicated they had experienced chronic back pain for more than 3 months with onset before age 45 and had at least one additional clue of SpA – inflammatory back pain symptoms, a good response to NSAIDs, psoriasis, inflammatory bowel disease, uveitis, a positive family history for SpA, an elevated C-reactive protein, HLA-B27 positivity, or peripheral symptoms suggestive of arthritis and/or enthesitis – they got an appointment with a rheumatologist straightaway.
“How do you get these people with back pain and potentially axial spondyloarthritis to see us? We’ve all seen patients stuck for years with orthopedists and physiatrists and chiropractors, and they finally get to you and you figure out what they have in a couple minutes and start them on effective therapy. This is an online tool that may pick up axial spondyloarthritis patients not identified by primary care,” explained Dr. Ruderman, professor of medicine at Northwestern University in Chicago.
The study included 362 patients evaluated for suspected SpA by participating rheumatologists. Half made it to the rheumatologist by way of physician referral after experiencing back pain for a mean duration of 6.5 years; the other half came via the Berlin referral tool. A total of 39.2% of patients in the physician-referral group and 19.3% in the self-referral group were ultimately diagnosed with SpA.
“It’s not 100%. You’d never expect it to be. But I think all of us would say if you get five people and one of them turns out to have the real deal, it’s worth it to have this kind of method available to get people into your office and away from the four MRIs and the epidural steroid injections and potentially even the surgery before they get to you,” Dr. Ruderman commented.
Dr. Kavanaugh noted with approval that women accounted for 44% of the referrals from physicians and 57% of those who were self-referred.
“This is a way to get female patients, where you don’t suspect axial spondyloarthritis as much – and you don’t find it if you don’t suspect it. Any way to get a real patient into your office to offer them appropriate therapy is great,” he said.
MRI is no gold standard for SpA diagnosis
Dr. Ruderman drew attention to the MASH study, a Danish cross-sectional study of the effectiveness of MRI imaging of the sacroiliac joints in differentiating patients with SpA from other individuals who engage in hard physical work. The study, presented at the 2018 European Congress of Rheumatology, featured blinded reading of the MRIs of 204 participants, all aged 45 years or less. The study population, not all of whom had back pain for at least 2 months, included 41 patients known to have SpA as well as 23 distance runners, 26 room cleaners, 46 women who had given birth within the past year, 25 people with a herniated lumbar disc, and 29 healthy men.
The key finding was that while mean Spondyloarthritis Research Consortium of Canada sacroiliac joint MRI scores for inflammation, fatty deposition, and erosions were higher in the SpA group, many of the same changes were present to a lesser degree in the others.
“The takeaway is this is a clinical diagnosis and you can’t make the diagnosis just based on the imaging, regardless of what the radiologist is reporting. You have to put it in context,” the rheumatologist said.
“This adds to a growing body of evidence that says MRI is not the gold standard for diagnosing axial spondyloarthritis,” Dr. Kavanaugh added. “In other studies, you see those kinds of changes in active military, snowboarders, hockey players. So like with every diagnostic test, we have to wrestle with the fact that the more sensitive it is, the less specific it is, and vice versa.”
What about color Doppler ultrasound?
Argentinian rheumatologists used color Doppler ultrasound to look for sacroiliitis in 198 joints evaluated in 99 consecutive patients with inflammatory back pain and suspected SpA without a definitive diagnosis. All participants also had an MRI scan and clinical evaluation as well. At the joint level, ultrasound had a sensitivity of 60% and specificity of 93% for diagnosis of sacroiliitis. For diagnosis of SpA, the positive predictive value was 79% and the negative predictive value was 59% (J Rheumatol. 2018 Dec 15. doi: 10.3899/jrheum.180550).
“I don’t think this suggests that ultrasound replaces MRI, but MRI is a more expensive test and harder to get, and if you could get some information with an ultrasound done properly in the office it might be an interesting way to identify those patients who truly have axial spondyloarthritis and inflammatory sacroiliitis. That specificity of 93% is pretty good,” Dr. Ruderman noted.
“What about doing this: If it’s positive then you don’t need the MRI and maybe you do an injection at that time, but if it’s negative you do the MRI?” Dr. Kavanaugh asked.
Orrin M. Troum, MD, a pioneer in the use of extremity MRI in the United States for evaluation of patients with inflammatory peripheral arthritis, had reservations.
“Availability and cost are important, but one of the distinctions between MRI and ultrasound is that you can’t see bone marrow edema. I think that’s one of the classic features of MRI that’s important here,” according to Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles.
Dr. Kavanaugh asked Paul Emery, MD, a renowned authority on the use of ultrasound in rheumatology, for his thoughts.
“We don’t use ultrasound for sacroiliitis. It’s too unreliable,” said Dr. Emery, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center. “It’s such a big decision to start a biologic for an ankylosing spondyloarthritis patient that none of our people who use ultrasound rely on it.”
Dr. Ruderman and Dr. Kavanaugh reported receiving research funding from and serving as consultants to numerous pharmaceutical companies.
MAUI, HAWAII – Biologic therapy improves work-related outcomes in patients with axial spondyloarthritis, according to a report from the British Society for Rheumatology Biologics Register.
“This gets to the issue of cost/benefit. But with benefit you have to look at the big picture. These are expensive drugs, but if these expensive drugs have societal benefits by keeping people at work, you have to throw that into the equation when you think about the value proposition of these agents,” Eric M. Ruderman, MD, observed in highlighting the British study at the 2019 Rheumatology Winter Clinical Symposium.
In drawing attention to this and other developments during the past year in the field of axial spondyloarthritis (SpA) outside the realm of pharmacologic randomized trials, he and copanelist Arthur Kavanaugh, MD, highlighted trends in diagnostic imaging for the disorder, where MRI’s stock may be going down while color Doppler ultrasound’s is rising, as well as a novel online tool designed to get individuals with a high probability of SpA into a rheumatologist’s office without years of bouncing around between other types of health care providers.
Biologics boost work performance
The British Society for Rheumatology Biologics Register study included 577 patients at 83 centers in Great Britain who met Assessment of SpondyloArthritis International Society criteria for radiographic or nonradiographic SpA, all of whom were employed and biologic-naive when they enrolled in the registry (Ann Rheum Dis. 2018 Nov;77[11]:1578-84). Upon enrollment, 28% of them were placed on adalimumab (Humira), etanercept (Enbrel), or certolizumab pegol (Cimzia) based upon physician recommendation. Work outcomes at the start and end of the first year in the registry were compared between SpA patients on biologic therapy or not using the validated Work Productivity and Activity Impairment Index, a patient self-report measure.
After propensity score adjustment to account for between-group differences, SpA patients on biologic therapy demonstrated a 9.4% reduction in presenteeism – that is, on-site work underperformance and productivity loss – compared with those not on a biologic. The group on biologics also averaged a 13.9% greater improvement from baseline in overall work impairment than did patients not on a biologic and a 19.2% greater improvement in overall activity impairment, which encompasses leisure activities. This works out to more than half a day of additional full productivity per week 12 months after starting on a biologic.
The investigators decided to confirm their findings by conducting what they believe to be the first-ever meta-analysis to quantify the impact of biologic therapy for SpA on work participation. The meta-analysis included five studies with 1,109 participants. The results: Biologic therapy was associated with significantly greater improvements in presenteeism, overall work impairment, and overall activity impairment, as in the British registry study, but was also no significant impact on work absenteeism, just as was the case in the registry study. The investigators noted that presenteeism is a much bigger problem than absenteeism in patients with SpA. They hypothesized that absenteeism is a relatively late-stage development in work impairment that isn’t reversible by biologic therapy alone.
“This is superimportant data,” commented Dr. Kavanaugh, professor of medicine at the University of California, San Diego.
Pharmacoeconomic analyses typically rely upon quality-of-life metrics and express cost/benefit in terms of QALYs, or quality-adjusted life-years, gained by utilization of a therapy. That’s a measure of particular importance from a payer’s perspective, but QALYs typically don’t incorporate work outcome data and other aspects of the wider societal costs and benefits of a therapy since they aren’t addressed in short-term, randomized, controlled trials.
“Work data are a more realistic way to do this: actual data on people getting back to their jobs,” the rheumatologist said.
Online accrual of likely SpA patients
The average delay between symptom onset and diagnosis of SpA is 7-9 years. Dr. Ruderman was favorably impressed by the Identification of the Optimal Referral Strategy for Early Diagnosis of Axial Spondyloarthritis (OptiRef) study of an outside-the-box online self-referral tool presented at the 2018 annual meeting of the American College of Rheumatology.
The German investigators placed advertisements in subways directing interested riders with back pain to a website where they completed what the rheumatologists called the Berlin referral tool. If they indicated they had experienced chronic back pain for more than 3 months with onset before age 45 and had at least one additional clue of SpA – inflammatory back pain symptoms, a good response to NSAIDs, psoriasis, inflammatory bowel disease, uveitis, a positive family history for SpA, an elevated C-reactive protein, HLA-B27 positivity, or peripheral symptoms suggestive of arthritis and/or enthesitis – they got an appointment with a rheumatologist straightaway.
“How do you get these people with back pain and potentially axial spondyloarthritis to see us? We’ve all seen patients stuck for years with orthopedists and physiatrists and chiropractors, and they finally get to you and you figure out what they have in a couple minutes and start them on effective therapy. This is an online tool that may pick up axial spondyloarthritis patients not identified by primary care,” explained Dr. Ruderman, professor of medicine at Northwestern University in Chicago.
The study included 362 patients evaluated for suspected SpA by participating rheumatologists. Half made it to the rheumatologist by way of physician referral after experiencing back pain for a mean duration of 6.5 years; the other half came via the Berlin referral tool. A total of 39.2% of patients in the physician-referral group and 19.3% in the self-referral group were ultimately diagnosed with SpA.
“It’s not 100%. You’d never expect it to be. But I think all of us would say if you get five people and one of them turns out to have the real deal, it’s worth it to have this kind of method available to get people into your office and away from the four MRIs and the epidural steroid injections and potentially even the surgery before they get to you,” Dr. Ruderman commented.
Dr. Kavanaugh noted with approval that women accounted for 44% of the referrals from physicians and 57% of those who were self-referred.
“This is a way to get female patients, where you don’t suspect axial spondyloarthritis as much – and you don’t find it if you don’t suspect it. Any way to get a real patient into your office to offer them appropriate therapy is great,” he said.
MRI is no gold standard for SpA diagnosis
Dr. Ruderman drew attention to the MASH study, a Danish cross-sectional study of the effectiveness of MRI imaging of the sacroiliac joints in differentiating patients with SpA from other individuals who engage in hard physical work. The study, presented at the 2018 European Congress of Rheumatology, featured blinded reading of the MRIs of 204 participants, all aged 45 years or less. The study population, not all of whom had back pain for at least 2 months, included 41 patients known to have SpA as well as 23 distance runners, 26 room cleaners, 46 women who had given birth within the past year, 25 people with a herniated lumbar disc, and 29 healthy men.
The key finding was that while mean Spondyloarthritis Research Consortium of Canada sacroiliac joint MRI scores for inflammation, fatty deposition, and erosions were higher in the SpA group, many of the same changes were present to a lesser degree in the others.
“The takeaway is this is a clinical diagnosis and you can’t make the diagnosis just based on the imaging, regardless of what the radiologist is reporting. You have to put it in context,” the rheumatologist said.
“This adds to a growing body of evidence that says MRI is not the gold standard for diagnosing axial spondyloarthritis,” Dr. Kavanaugh added. “In other studies, you see those kinds of changes in active military, snowboarders, hockey players. So like with every diagnostic test, we have to wrestle with the fact that the more sensitive it is, the less specific it is, and vice versa.”
What about color Doppler ultrasound?
Argentinian rheumatologists used color Doppler ultrasound to look for sacroiliitis in 198 joints evaluated in 99 consecutive patients with inflammatory back pain and suspected SpA without a definitive diagnosis. All participants also had an MRI scan and clinical evaluation as well. At the joint level, ultrasound had a sensitivity of 60% and specificity of 93% for diagnosis of sacroiliitis. For diagnosis of SpA, the positive predictive value was 79% and the negative predictive value was 59% (J Rheumatol. 2018 Dec 15. doi: 10.3899/jrheum.180550).
“I don’t think this suggests that ultrasound replaces MRI, but MRI is a more expensive test and harder to get, and if you could get some information with an ultrasound done properly in the office it might be an interesting way to identify those patients who truly have axial spondyloarthritis and inflammatory sacroiliitis. That specificity of 93% is pretty good,” Dr. Ruderman noted.
“What about doing this: If it’s positive then you don’t need the MRI and maybe you do an injection at that time, but if it’s negative you do the MRI?” Dr. Kavanaugh asked.
Orrin M. Troum, MD, a pioneer in the use of extremity MRI in the United States for evaluation of patients with inflammatory peripheral arthritis, had reservations.
“Availability and cost are important, but one of the distinctions between MRI and ultrasound is that you can’t see bone marrow edema. I think that’s one of the classic features of MRI that’s important here,” according to Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles.
Dr. Kavanaugh asked Paul Emery, MD, a renowned authority on the use of ultrasound in rheumatology, for his thoughts.
“We don’t use ultrasound for sacroiliitis. It’s too unreliable,” said Dr. Emery, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center. “It’s such a big decision to start a biologic for an ankylosing spondyloarthritis patient that none of our people who use ultrasound rely on it.”
Dr. Ruderman and Dr. Kavanaugh reported receiving research funding from and serving as consultants to numerous pharmaceutical companies.
MAUI, HAWAII – Biologic therapy improves work-related outcomes in patients with axial spondyloarthritis, according to a report from the British Society for Rheumatology Biologics Register.
“This gets to the issue of cost/benefit. But with benefit you have to look at the big picture. These are expensive drugs, but if these expensive drugs have societal benefits by keeping people at work, you have to throw that into the equation when you think about the value proposition of these agents,” Eric M. Ruderman, MD, observed in highlighting the British study at the 2019 Rheumatology Winter Clinical Symposium.
In drawing attention to this and other developments during the past year in the field of axial spondyloarthritis (SpA) outside the realm of pharmacologic randomized trials, he and copanelist Arthur Kavanaugh, MD, highlighted trends in diagnostic imaging for the disorder, where MRI’s stock may be going down while color Doppler ultrasound’s is rising, as well as a novel online tool designed to get individuals with a high probability of SpA into a rheumatologist’s office without years of bouncing around between other types of health care providers.
Biologics boost work performance
The British Society for Rheumatology Biologics Register study included 577 patients at 83 centers in Great Britain who met Assessment of SpondyloArthritis International Society criteria for radiographic or nonradiographic SpA, all of whom were employed and biologic-naive when they enrolled in the registry (Ann Rheum Dis. 2018 Nov;77[11]:1578-84). Upon enrollment, 28% of them were placed on adalimumab (Humira), etanercept (Enbrel), or certolizumab pegol (Cimzia) based upon physician recommendation. Work outcomes at the start and end of the first year in the registry were compared between SpA patients on biologic therapy or not using the validated Work Productivity and Activity Impairment Index, a patient self-report measure.
After propensity score adjustment to account for between-group differences, SpA patients on biologic therapy demonstrated a 9.4% reduction in presenteeism – that is, on-site work underperformance and productivity loss – compared with those not on a biologic. The group on biologics also averaged a 13.9% greater improvement from baseline in overall work impairment than did patients not on a biologic and a 19.2% greater improvement in overall activity impairment, which encompasses leisure activities. This works out to more than half a day of additional full productivity per week 12 months after starting on a biologic.
The investigators decided to confirm their findings by conducting what they believe to be the first-ever meta-analysis to quantify the impact of biologic therapy for SpA on work participation. The meta-analysis included five studies with 1,109 participants. The results: Biologic therapy was associated with significantly greater improvements in presenteeism, overall work impairment, and overall activity impairment, as in the British registry study, but was also no significant impact on work absenteeism, just as was the case in the registry study. The investigators noted that presenteeism is a much bigger problem than absenteeism in patients with SpA. They hypothesized that absenteeism is a relatively late-stage development in work impairment that isn’t reversible by biologic therapy alone.
“This is superimportant data,” commented Dr. Kavanaugh, professor of medicine at the University of California, San Diego.
Pharmacoeconomic analyses typically rely upon quality-of-life metrics and express cost/benefit in terms of QALYs, or quality-adjusted life-years, gained by utilization of a therapy. That’s a measure of particular importance from a payer’s perspective, but QALYs typically don’t incorporate work outcome data and other aspects of the wider societal costs and benefits of a therapy since they aren’t addressed in short-term, randomized, controlled trials.
“Work data are a more realistic way to do this: actual data on people getting back to their jobs,” the rheumatologist said.
Online accrual of likely SpA patients
The average delay between symptom onset and diagnosis of SpA is 7-9 years. Dr. Ruderman was favorably impressed by the Identification of the Optimal Referral Strategy for Early Diagnosis of Axial Spondyloarthritis (OptiRef) study of an outside-the-box online self-referral tool presented at the 2018 annual meeting of the American College of Rheumatology.
The German investigators placed advertisements in subways directing interested riders with back pain to a website where they completed what the rheumatologists called the Berlin referral tool. If they indicated they had experienced chronic back pain for more than 3 months with onset before age 45 and had at least one additional clue of SpA – inflammatory back pain symptoms, a good response to NSAIDs, psoriasis, inflammatory bowel disease, uveitis, a positive family history for SpA, an elevated C-reactive protein, HLA-B27 positivity, or peripheral symptoms suggestive of arthritis and/or enthesitis – they got an appointment with a rheumatologist straightaway.
“How do you get these people with back pain and potentially axial spondyloarthritis to see us? We’ve all seen patients stuck for years with orthopedists and physiatrists and chiropractors, and they finally get to you and you figure out what they have in a couple minutes and start them on effective therapy. This is an online tool that may pick up axial spondyloarthritis patients not identified by primary care,” explained Dr. Ruderman, professor of medicine at Northwestern University in Chicago.
The study included 362 patients evaluated for suspected SpA by participating rheumatologists. Half made it to the rheumatologist by way of physician referral after experiencing back pain for a mean duration of 6.5 years; the other half came via the Berlin referral tool. A total of 39.2% of patients in the physician-referral group and 19.3% in the self-referral group were ultimately diagnosed with SpA.
“It’s not 100%. You’d never expect it to be. But I think all of us would say if you get five people and one of them turns out to have the real deal, it’s worth it to have this kind of method available to get people into your office and away from the four MRIs and the epidural steroid injections and potentially even the surgery before they get to you,” Dr. Ruderman commented.
Dr. Kavanaugh noted with approval that women accounted for 44% of the referrals from physicians and 57% of those who were self-referred.
“This is a way to get female patients, where you don’t suspect axial spondyloarthritis as much – and you don’t find it if you don’t suspect it. Any way to get a real patient into your office to offer them appropriate therapy is great,” he said.
MRI is no gold standard for SpA diagnosis
Dr. Ruderman drew attention to the MASH study, a Danish cross-sectional study of the effectiveness of MRI imaging of the sacroiliac joints in differentiating patients with SpA from other individuals who engage in hard physical work. The study, presented at the 2018 European Congress of Rheumatology, featured blinded reading of the MRIs of 204 participants, all aged 45 years or less. The study population, not all of whom had back pain for at least 2 months, included 41 patients known to have SpA as well as 23 distance runners, 26 room cleaners, 46 women who had given birth within the past year, 25 people with a herniated lumbar disc, and 29 healthy men.
The key finding was that while mean Spondyloarthritis Research Consortium of Canada sacroiliac joint MRI scores for inflammation, fatty deposition, and erosions were higher in the SpA group, many of the same changes were present to a lesser degree in the others.
“The takeaway is this is a clinical diagnosis and you can’t make the diagnosis just based on the imaging, regardless of what the radiologist is reporting. You have to put it in context,” the rheumatologist said.
“This adds to a growing body of evidence that says MRI is not the gold standard for diagnosing axial spondyloarthritis,” Dr. Kavanaugh added. “In other studies, you see those kinds of changes in active military, snowboarders, hockey players. So like with every diagnostic test, we have to wrestle with the fact that the more sensitive it is, the less specific it is, and vice versa.”
What about color Doppler ultrasound?
Argentinian rheumatologists used color Doppler ultrasound to look for sacroiliitis in 198 joints evaluated in 99 consecutive patients with inflammatory back pain and suspected SpA without a definitive diagnosis. All participants also had an MRI scan and clinical evaluation as well. At the joint level, ultrasound had a sensitivity of 60% and specificity of 93% for diagnosis of sacroiliitis. For diagnosis of SpA, the positive predictive value was 79% and the negative predictive value was 59% (J Rheumatol. 2018 Dec 15. doi: 10.3899/jrheum.180550).
“I don’t think this suggests that ultrasound replaces MRI, but MRI is a more expensive test and harder to get, and if you could get some information with an ultrasound done properly in the office it might be an interesting way to identify those patients who truly have axial spondyloarthritis and inflammatory sacroiliitis. That specificity of 93% is pretty good,” Dr. Ruderman noted.
“What about doing this: If it’s positive then you don’t need the MRI and maybe you do an injection at that time, but if it’s negative you do the MRI?” Dr. Kavanaugh asked.
Orrin M. Troum, MD, a pioneer in the use of extremity MRI in the United States for evaluation of patients with inflammatory peripheral arthritis, had reservations.
“Availability and cost are important, but one of the distinctions between MRI and ultrasound is that you can’t see bone marrow edema. I think that’s one of the classic features of MRI that’s important here,” according to Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles.
Dr. Kavanaugh asked Paul Emery, MD, a renowned authority on the use of ultrasound in rheumatology, for his thoughts.
“We don’t use ultrasound for sacroiliitis. It’s too unreliable,” said Dr. Emery, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center. “It’s such a big decision to start a biologic for an ankylosing spondyloarthritis patient that none of our people who use ultrasound rely on it.”
Dr. Ruderman and Dr. Kavanaugh reported receiving research funding from and serving as consultants to numerous pharmaceutical companies.
REPORTING FROM RWCS 2019
Low-flow, low-gradient aortic stenosis with preserved LVEF: a special situation
SNOWMASS, COLO. – A patient who presents with symptomatic low-flow, low-gradient severe aortic stenosis, hypertension, and preserved left ventricular ejection fraction (LVEF) is often referred straightaway for consideration of aortic valve replacement. Not so fast – these patients actually constitute a special case for whom two essential questions must be answered before proceeding to that stage, Rick A. Nishimura, MD, said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
The first question is, What happens to the patient’s symptoms upon control of the hypertension?
“Almost all of these patients with low-flow severe aortic stenosis with preserved ejection fraction are going to be hypertensive. Treat the hypertension first. If they become asymptomatic, you don’t need to intervene. The aortic stenosis wasn’t causing their symptoms. You can afford to continue to watch them,” according to Dr. Nishimura, professor of cardiovascular diseases and hypertension at the Mayo Clinic in Rochester, Minn.
An aortic valve area of less than 1.0 cm2 is a prerequisite for surgical or transcatheter aortic valve replacement. So the second key question is this, Does the patient have truly severe aortic stenosis (AS), or is it instead a case of pseudo-AS in which the small aortic valve area noted on echocardiography is caused by low flow secondary to a small left ventricle with a low stroke volume?
“If you increase the flow and remeasure the aortic valve area, you’ll find that a lot of these patients don’t have a really small aortic valve area of less than 1.0 cm2. You might find the aortic valve area pops up to 1.4-1.6 cm2,” he explained.
These patients with symptomatic low-flow, low-gradient severe AS with preserved LVEF are quite common.
“I don’t know why, but we’re seeing more and more of these patients. I think 10 years ago we just kind of ignored them. We thought we’d made a mistake in our calculations. But in fact if you’re very meticulous about your calculations, 30%-40% of your aortic stenosis patients fit into this category,” the cardiologist said.
Moreover, if these patients undergo aortic valve replacement when their symptoms stemmed from poorly controlled hypertension and/or pseudo-AS, they are not going to benefit from this major intervention, he added.
This issue was addressed, albeit briefly and obliquely, in the American Heart Association/ACC guidelines for management of patients with valvular heart disease, for which Dr. Nishimura served as first author and cochair of the writing committee (Circulation. 2014 Jun 10;129[23]:e521-643) as well as for the 2017 focused update of the guidelines.
The guidelines give a IIa recommendation to aortic valve replacement as “reasonable” in “symptomatic patients with low-flow/low-gradient severe AS (stage D3) with an LVEF 50% or greater, a calcified aortic valve with significantly reduced leaflet motion, and a valve area 1.0 cm2 or less only if clinical, hemodynamic, and anatomic data support valve obstruction as the most likely cause of symptoms and data recorded when the patient is normotensive.”
Dr. Nishimura chose the 50th annual meeting of the storied ACC Snowmass conference to elaborate upon that brief guidance. He explained that these patients with low-flow, low-gradient symptomatic “severe” AS with preserved LVEF and hypertension have two resistors in a series.
“You have a resistor at the aortic valve area but probably a greater resistor in the systemic circulation. They have high resistance at the arterial level and diastolic dysfunction due to ventricular-vascular coupling,” the cardiologist continued.
Checking for pseudo-AS in these patients is a matter of boosting their low transvalvular flow. This can be accomplished by increasing their cardiac output via monitored exercise or by pharmacologic afterload reduction.
“We’re exercising these patients in the cath lab, but you could also do it in the echocardiographic laboratory. With exercise, if cardiac output increases and the aortic valve area increases without significant change in the aortic valve mean gradient, the patient probably doesn’t have truly severe AS,” according to Dr. Nishimura.
One reason referral centers are seeing a lot more of these patients during the last decade is an influential study by Canadian investigators entitled “Paradoxical low-flow, low-gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival.” Those investigators warned “this condition may often be misdiagnosed, which leads to a neglect and/or underestimation of symptoms and an inappropriate delay of aortic valve replacement surgery” (Circulation. 2007 Jun 5;115(22):2856-64).
This report led to a great deal of interest in performing aortic valve replacement in such patients during a period when transcatheter replacement was really taking off.
When an audience member asked how commonly such patients have undergone inappropriate aortic valve replacement, Michael J. Mack, MD, took the question.
“I don’t think it’s a huge number,” said Dr. Mack, medical director of cardiovascular surgery at the Baylor Health Care System in Plano, Tex. “This is the patient group we wring our hands about most. We know they don’t do as well with aortic valve replacement as patients with high-gradient AS with a low or normal ejection fraction. We’re loathe to treat them. I think most centers are.”
SNOWMASS, COLO. – A patient who presents with symptomatic low-flow, low-gradient severe aortic stenosis, hypertension, and preserved left ventricular ejection fraction (LVEF) is often referred straightaway for consideration of aortic valve replacement. Not so fast – these patients actually constitute a special case for whom two essential questions must be answered before proceeding to that stage, Rick A. Nishimura, MD, said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
The first question is, What happens to the patient’s symptoms upon control of the hypertension?
“Almost all of these patients with low-flow severe aortic stenosis with preserved ejection fraction are going to be hypertensive. Treat the hypertension first. If they become asymptomatic, you don’t need to intervene. The aortic stenosis wasn’t causing their symptoms. You can afford to continue to watch them,” according to Dr. Nishimura, professor of cardiovascular diseases and hypertension at the Mayo Clinic in Rochester, Minn.
An aortic valve area of less than 1.0 cm2 is a prerequisite for surgical or transcatheter aortic valve replacement. So the second key question is this, Does the patient have truly severe aortic stenosis (AS), or is it instead a case of pseudo-AS in which the small aortic valve area noted on echocardiography is caused by low flow secondary to a small left ventricle with a low stroke volume?
“If you increase the flow and remeasure the aortic valve area, you’ll find that a lot of these patients don’t have a really small aortic valve area of less than 1.0 cm2. You might find the aortic valve area pops up to 1.4-1.6 cm2,” he explained.
These patients with symptomatic low-flow, low-gradient severe AS with preserved LVEF are quite common.
“I don’t know why, but we’re seeing more and more of these patients. I think 10 years ago we just kind of ignored them. We thought we’d made a mistake in our calculations. But in fact if you’re very meticulous about your calculations, 30%-40% of your aortic stenosis patients fit into this category,” the cardiologist said.
Moreover, if these patients undergo aortic valve replacement when their symptoms stemmed from poorly controlled hypertension and/or pseudo-AS, they are not going to benefit from this major intervention, he added.
This issue was addressed, albeit briefly and obliquely, in the American Heart Association/ACC guidelines for management of patients with valvular heart disease, for which Dr. Nishimura served as first author and cochair of the writing committee (Circulation. 2014 Jun 10;129[23]:e521-643) as well as for the 2017 focused update of the guidelines.
The guidelines give a IIa recommendation to aortic valve replacement as “reasonable” in “symptomatic patients with low-flow/low-gradient severe AS (stage D3) with an LVEF 50% or greater, a calcified aortic valve with significantly reduced leaflet motion, and a valve area 1.0 cm2 or less only if clinical, hemodynamic, and anatomic data support valve obstruction as the most likely cause of symptoms and data recorded when the patient is normotensive.”
Dr. Nishimura chose the 50th annual meeting of the storied ACC Snowmass conference to elaborate upon that brief guidance. He explained that these patients with low-flow, low-gradient symptomatic “severe” AS with preserved LVEF and hypertension have two resistors in a series.
“You have a resistor at the aortic valve area but probably a greater resistor in the systemic circulation. They have high resistance at the arterial level and diastolic dysfunction due to ventricular-vascular coupling,” the cardiologist continued.
Checking for pseudo-AS in these patients is a matter of boosting their low transvalvular flow. This can be accomplished by increasing their cardiac output via monitored exercise or by pharmacologic afterload reduction.
“We’re exercising these patients in the cath lab, but you could also do it in the echocardiographic laboratory. With exercise, if cardiac output increases and the aortic valve area increases without significant change in the aortic valve mean gradient, the patient probably doesn’t have truly severe AS,” according to Dr. Nishimura.
One reason referral centers are seeing a lot more of these patients during the last decade is an influential study by Canadian investigators entitled “Paradoxical low-flow, low-gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival.” Those investigators warned “this condition may often be misdiagnosed, which leads to a neglect and/or underestimation of symptoms and an inappropriate delay of aortic valve replacement surgery” (Circulation. 2007 Jun 5;115(22):2856-64).
This report led to a great deal of interest in performing aortic valve replacement in such patients during a period when transcatheter replacement was really taking off.
When an audience member asked how commonly such patients have undergone inappropriate aortic valve replacement, Michael J. Mack, MD, took the question.
“I don’t think it’s a huge number,” said Dr. Mack, medical director of cardiovascular surgery at the Baylor Health Care System in Plano, Tex. “This is the patient group we wring our hands about most. We know they don’t do as well with aortic valve replacement as patients with high-gradient AS with a low or normal ejection fraction. We’re loathe to treat them. I think most centers are.”
SNOWMASS, COLO. – A patient who presents with symptomatic low-flow, low-gradient severe aortic stenosis, hypertension, and preserved left ventricular ejection fraction (LVEF) is often referred straightaway for consideration of aortic valve replacement. Not so fast – these patients actually constitute a special case for whom two essential questions must be answered before proceeding to that stage, Rick A. Nishimura, MD, said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
The first question is, What happens to the patient’s symptoms upon control of the hypertension?
“Almost all of these patients with low-flow severe aortic stenosis with preserved ejection fraction are going to be hypertensive. Treat the hypertension first. If they become asymptomatic, you don’t need to intervene. The aortic stenosis wasn’t causing their symptoms. You can afford to continue to watch them,” according to Dr. Nishimura, professor of cardiovascular diseases and hypertension at the Mayo Clinic in Rochester, Minn.
An aortic valve area of less than 1.0 cm2 is a prerequisite for surgical or transcatheter aortic valve replacement. So the second key question is this, Does the patient have truly severe aortic stenosis (AS), or is it instead a case of pseudo-AS in which the small aortic valve area noted on echocardiography is caused by low flow secondary to a small left ventricle with a low stroke volume?
“If you increase the flow and remeasure the aortic valve area, you’ll find that a lot of these patients don’t have a really small aortic valve area of less than 1.0 cm2. You might find the aortic valve area pops up to 1.4-1.6 cm2,” he explained.
These patients with symptomatic low-flow, low-gradient severe AS with preserved LVEF are quite common.
“I don’t know why, but we’re seeing more and more of these patients. I think 10 years ago we just kind of ignored them. We thought we’d made a mistake in our calculations. But in fact if you’re very meticulous about your calculations, 30%-40% of your aortic stenosis patients fit into this category,” the cardiologist said.
Moreover, if these patients undergo aortic valve replacement when their symptoms stemmed from poorly controlled hypertension and/or pseudo-AS, they are not going to benefit from this major intervention, he added.
This issue was addressed, albeit briefly and obliquely, in the American Heart Association/ACC guidelines for management of patients with valvular heart disease, for which Dr. Nishimura served as first author and cochair of the writing committee (Circulation. 2014 Jun 10;129[23]:e521-643) as well as for the 2017 focused update of the guidelines.
The guidelines give a IIa recommendation to aortic valve replacement as “reasonable” in “symptomatic patients with low-flow/low-gradient severe AS (stage D3) with an LVEF 50% or greater, a calcified aortic valve with significantly reduced leaflet motion, and a valve area 1.0 cm2 or less only if clinical, hemodynamic, and anatomic data support valve obstruction as the most likely cause of symptoms and data recorded when the patient is normotensive.”
Dr. Nishimura chose the 50th annual meeting of the storied ACC Snowmass conference to elaborate upon that brief guidance. He explained that these patients with low-flow, low-gradient symptomatic “severe” AS with preserved LVEF and hypertension have two resistors in a series.
“You have a resistor at the aortic valve area but probably a greater resistor in the systemic circulation. They have high resistance at the arterial level and diastolic dysfunction due to ventricular-vascular coupling,” the cardiologist continued.
Checking for pseudo-AS in these patients is a matter of boosting their low transvalvular flow. This can be accomplished by increasing their cardiac output via monitored exercise or by pharmacologic afterload reduction.
“We’re exercising these patients in the cath lab, but you could also do it in the echocardiographic laboratory. With exercise, if cardiac output increases and the aortic valve area increases without significant change in the aortic valve mean gradient, the patient probably doesn’t have truly severe AS,” according to Dr. Nishimura.
One reason referral centers are seeing a lot more of these patients during the last decade is an influential study by Canadian investigators entitled “Paradoxical low-flow, low-gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival.” Those investigators warned “this condition may often be misdiagnosed, which leads to a neglect and/or underestimation of symptoms and an inappropriate delay of aortic valve replacement surgery” (Circulation. 2007 Jun 5;115(22):2856-64).
This report led to a great deal of interest in performing aortic valve replacement in such patients during a period when transcatheter replacement was really taking off.
When an audience member asked how commonly such patients have undergone inappropriate aortic valve replacement, Michael J. Mack, MD, took the question.
“I don’t think it’s a huge number,” said Dr. Mack, medical director of cardiovascular surgery at the Baylor Health Care System in Plano, Tex. “This is the patient group we wring our hands about most. We know they don’t do as well with aortic valve replacement as patients with high-gradient AS with a low or normal ejection fraction. We’re loathe to treat them. I think most centers are.”
REPORTING FROM ACC SNOWMASS 2019
Abstinence by moderate drinkers improves their AFib
NEW ORLEANS – Abstinence from alcohol on the part of moderate drinkers with atrial fibrillation resulted in clinically meaningful improvement in their arrhythmia in the randomized controlled Alcohol-AF trial, Aleksandr Voskoboinik, MBBS, reported at the annual meeting of the American College of Cardiology.
The benefits of abstinence included significant reductions in the AFib recurrence rate, total AFib burden, and symptom severity. And the payoff extended beyond the arrhythmia: The abstinent group also averaged a 12–mm Hg drop in systolic blood pressure and dropped 3 kg of body weight over the course of the 6-month trial, added Dr. Voskoboinik, a cardiologist at the Baker Heart & Diabetes Institute at the University of Melbourne.
“We would conclude that significant reduction in alcohol intake should be considered as part of the lifestyle intervention in moderate drinkers with AFib,” he said.
Some physicians already advise alcohol abstinence for moderate drinkers with AFib, but until now such recommendations were not evidence based. Instead, the guidance was based on extrapolation from the well-established harmful effects of heavy drinking and binge drinking on AFib as well as epidemiologic studies.
“We wanted to provide some evidence base for physicians to say, ‘If I have motivated patients, here’s what’s potentially achievable,’” he explained.
The key word here is “motivated.” Conducting the Alcohol-AF trial made clear that many moderate drinkers with AFib enjoy their beverages more than they hate having their arrhythmia. Indeed, out of 697 moderate-drinking patients with paroxysmal or persistent AFib who were deemed good candidates and were approached about study participation, more than 500 were excluded because they were flat out unwilling to consider abstinence. After Dr. Voskoboinik and his coinvestigators shortened the planned trial duration from 12 months to 6 because so many recruits were unwilling to abstain for a full year, 140 of the initial 697 patients were randomized to abstinence or continuation of their usual consumption. Thirty percent of them had previously undergone AFib ablation.
The Alcohol-AF study was a multicenter, prospective, open-label study conducted at six Australian hospitals. All subjects underwent comprehensive rhythm monitoring via an implantable loop recorder or an existing pacemaker. Twice daily they triggered the AliveCor mobile phone app together with Holter monitoring. Patients assigned to abstinence were counseled to abstain completely, got written and verbal advice to help with compliance, and had contact with the investigators on a monthly basis. They also underwent urine testing to monitor compliance. All study participants kept a weekly alcohol intake diary, reviewed monthly by investigators.
Participants averaged 17 standard drinks per week at enrollment. Two-thirds were primarily wine drinkers. At the 6-month mark, patients in the abstinence arm averaged two drinks per week, for an 88% reduction from baseline, and 43 of the 70, or 61%, had remained completely abstinent. The control arm averaged a 20% reduction in weekly consumption.
One of the two co-primary endpoints was recurrent AFib episodes lasting for at least 30 seconds. The rate was 53% in the abstinence group and 73% in controls. The time to first recurrence averaged 118 days in the abstinence group, compared to 86 days in controls, for a 37% prolongation through abstinence.
The other primary endpoint was total AFib burden. During the 6-month study, the abstinence group spent a mean of 5.6% of their time in AFib, compared to 8.2% in controls. The median times were 0.5% and 1.2%.
In a multivariate analysis, neither AFib type, duration, history of AFib ablation, age, nor gender predicted AFib recurrence. In fact, the only significant predictor was alcohol abstinence, which conferred a 48% reduction in risk.
Symptom severity, a secondary endpoint, showed an impressive between-group difference at follow-up. Ten percent of patients in the abstinence group had moderate or severe symptoms at follow-up as assessed via the European Heart Rhythm Association score of atrial fibrillation, compared to 32% of controls, for an absolute 22% difference. And 90% of the abstinence group had no or mild symptoms, as did 68% of controls. Nine percent of the abstinence group had an AFib-related hospitalization, as did 20% of controls.
Cardiac MRI, performed in all subjects, showed that the abstinence group experienced a significant reduction in left atrial area, from 29.5 cm2 at baseline to 27.1 cm2 at follow-up. They also experienced significant improvement in left atrial mechanical function, with their left atrial emptying fraction climbing from 42% to 50%.
The 3-kg weight loss from a baseline of 90 kg in the abstinent group represented a 0.7 kg/m2 reduction in body mass index.
In terms of the likely mechanism of benefit of alcohol abstinence in moderate drinkers, Dr. Voskoboinik noted that he and his colleagues recently demonstrated that regular moderate alcohol consumption, but not mild intake, is associated with potentially explanatory atrial electrical and structural changes, including conduction slowing, lower global bipolar atrial voltage, and an increase in complex atrial potentials (Heart Rhythm. 2019 Feb;16[2]:251-9).
Alcohol has been shown to be linked with AFib through multiple mechanisms. Alcohol has adverse effects on the atrial substrate, including promotion of left atrial remodeling, dilation, and fibrosis via oxidative stress, and alcohol has a contributory role in hypertension and obstructive sleep apnea. Alcohol can act as an acute trigger of AFib through binge drinking – the holiday heart syndrome – which causes autonomic changes, electrolyte abnormalities, and electrophysiologic effects, he continued.
Epidemiologic evidence in support of the notion that moderate drinking increases the risk of AFib includes a Swedish meta-analysis of seven prospective studies comprising 12,554 patients with AFib. The researchers concluded that the relative risk of AFib rose by about 8% with each drink per day, compared with the risk of a reference group composed of current drinkers at a rate of less than one drink per week (J Am Coll Cardiol. 2014 Jul 22;64[3]:281-9).
Although discussants were wowed by the 61% complete abstinence rate in the trial, Dr. Voskoboinik cautioned that the study participants were a highly motivated subset of the universe of moderate drinkers with AFib. And even so, “It was an incredibly challenging study to run,” he said.
“I think lifestyle change is a challenge, and with alcohol particularly so, because alcohol is so ubiquitous in our society. I think the important key message for us as physicians is to take an alcohol history and have a discussion with the patient. And we now have some data to show them. But at the end of the day, it’s up to the patient in conjunction with the physician,” he observed.
Discussant Annabelle S. Volgman, MD, noted that 85% of study participants were men, and because of important differences in AFib between men and women, she doesn’t consider the findings applicable to women.
“You need to redo the study in women,” advised Dr. Volgman, professor of medicine at Rush University, Chicago, and director of the Rush Heart Center for Women.
She suggested that an interventional trial such as this one is a great opportunity to utilize wearable device technology, such as the Apple Watch, which can detect irregular pulse rhythms as demonstrated in the Apple Heart Study. This technology is especially popular with younger individuals.
“A lot of young men and women drink a lot of alcohol,” Dr. Volgman noted.
“That’s a great idea. It gets around a problem with AliveCor, which can miss episodes while you’re sleeping,” Dr. Voskoboinik replied.
He reported having no financial conflicts regarding the investigator-initiated and -funded Alcohol-AF trial.
SOURCE: Voskoboinik A. ACC 19, Session 413-08.
NEW ORLEANS – Abstinence from alcohol on the part of moderate drinkers with atrial fibrillation resulted in clinically meaningful improvement in their arrhythmia in the randomized controlled Alcohol-AF trial, Aleksandr Voskoboinik, MBBS, reported at the annual meeting of the American College of Cardiology.
The benefits of abstinence included significant reductions in the AFib recurrence rate, total AFib burden, and symptom severity. And the payoff extended beyond the arrhythmia: The abstinent group also averaged a 12–mm Hg drop in systolic blood pressure and dropped 3 kg of body weight over the course of the 6-month trial, added Dr. Voskoboinik, a cardiologist at the Baker Heart & Diabetes Institute at the University of Melbourne.
“We would conclude that significant reduction in alcohol intake should be considered as part of the lifestyle intervention in moderate drinkers with AFib,” he said.
Some physicians already advise alcohol abstinence for moderate drinkers with AFib, but until now such recommendations were not evidence based. Instead, the guidance was based on extrapolation from the well-established harmful effects of heavy drinking and binge drinking on AFib as well as epidemiologic studies.
“We wanted to provide some evidence base for physicians to say, ‘If I have motivated patients, here’s what’s potentially achievable,’” he explained.
The key word here is “motivated.” Conducting the Alcohol-AF trial made clear that many moderate drinkers with AFib enjoy their beverages more than they hate having their arrhythmia. Indeed, out of 697 moderate-drinking patients with paroxysmal or persistent AFib who were deemed good candidates and were approached about study participation, more than 500 were excluded because they were flat out unwilling to consider abstinence. After Dr. Voskoboinik and his coinvestigators shortened the planned trial duration from 12 months to 6 because so many recruits were unwilling to abstain for a full year, 140 of the initial 697 patients were randomized to abstinence or continuation of their usual consumption. Thirty percent of them had previously undergone AFib ablation.
The Alcohol-AF study was a multicenter, prospective, open-label study conducted at six Australian hospitals. All subjects underwent comprehensive rhythm monitoring via an implantable loop recorder or an existing pacemaker. Twice daily they triggered the AliveCor mobile phone app together with Holter monitoring. Patients assigned to abstinence were counseled to abstain completely, got written and verbal advice to help with compliance, and had contact with the investigators on a monthly basis. They also underwent urine testing to monitor compliance. All study participants kept a weekly alcohol intake diary, reviewed monthly by investigators.
Participants averaged 17 standard drinks per week at enrollment. Two-thirds were primarily wine drinkers. At the 6-month mark, patients in the abstinence arm averaged two drinks per week, for an 88% reduction from baseline, and 43 of the 70, or 61%, had remained completely abstinent. The control arm averaged a 20% reduction in weekly consumption.
One of the two co-primary endpoints was recurrent AFib episodes lasting for at least 30 seconds. The rate was 53% in the abstinence group and 73% in controls. The time to first recurrence averaged 118 days in the abstinence group, compared to 86 days in controls, for a 37% prolongation through abstinence.
The other primary endpoint was total AFib burden. During the 6-month study, the abstinence group spent a mean of 5.6% of their time in AFib, compared to 8.2% in controls. The median times were 0.5% and 1.2%.
In a multivariate analysis, neither AFib type, duration, history of AFib ablation, age, nor gender predicted AFib recurrence. In fact, the only significant predictor was alcohol abstinence, which conferred a 48% reduction in risk.
Symptom severity, a secondary endpoint, showed an impressive between-group difference at follow-up. Ten percent of patients in the abstinence group had moderate or severe symptoms at follow-up as assessed via the European Heart Rhythm Association score of atrial fibrillation, compared to 32% of controls, for an absolute 22% difference. And 90% of the abstinence group had no or mild symptoms, as did 68% of controls. Nine percent of the abstinence group had an AFib-related hospitalization, as did 20% of controls.
Cardiac MRI, performed in all subjects, showed that the abstinence group experienced a significant reduction in left atrial area, from 29.5 cm2 at baseline to 27.1 cm2 at follow-up. They also experienced significant improvement in left atrial mechanical function, with their left atrial emptying fraction climbing from 42% to 50%.
The 3-kg weight loss from a baseline of 90 kg in the abstinent group represented a 0.7 kg/m2 reduction in body mass index.
In terms of the likely mechanism of benefit of alcohol abstinence in moderate drinkers, Dr. Voskoboinik noted that he and his colleagues recently demonstrated that regular moderate alcohol consumption, but not mild intake, is associated with potentially explanatory atrial electrical and structural changes, including conduction slowing, lower global bipolar atrial voltage, and an increase in complex atrial potentials (Heart Rhythm. 2019 Feb;16[2]:251-9).
Alcohol has been shown to be linked with AFib through multiple mechanisms. Alcohol has adverse effects on the atrial substrate, including promotion of left atrial remodeling, dilation, and fibrosis via oxidative stress, and alcohol has a contributory role in hypertension and obstructive sleep apnea. Alcohol can act as an acute trigger of AFib through binge drinking – the holiday heart syndrome – which causes autonomic changes, electrolyte abnormalities, and electrophysiologic effects, he continued.
Epidemiologic evidence in support of the notion that moderate drinking increases the risk of AFib includes a Swedish meta-analysis of seven prospective studies comprising 12,554 patients with AFib. The researchers concluded that the relative risk of AFib rose by about 8% with each drink per day, compared with the risk of a reference group composed of current drinkers at a rate of less than one drink per week (J Am Coll Cardiol. 2014 Jul 22;64[3]:281-9).
Although discussants were wowed by the 61% complete abstinence rate in the trial, Dr. Voskoboinik cautioned that the study participants were a highly motivated subset of the universe of moderate drinkers with AFib. And even so, “It was an incredibly challenging study to run,” he said.
“I think lifestyle change is a challenge, and with alcohol particularly so, because alcohol is so ubiquitous in our society. I think the important key message for us as physicians is to take an alcohol history and have a discussion with the patient. And we now have some data to show them. But at the end of the day, it’s up to the patient in conjunction with the physician,” he observed.
Discussant Annabelle S. Volgman, MD, noted that 85% of study participants were men, and because of important differences in AFib between men and women, she doesn’t consider the findings applicable to women.
“You need to redo the study in women,” advised Dr. Volgman, professor of medicine at Rush University, Chicago, and director of the Rush Heart Center for Women.
She suggested that an interventional trial such as this one is a great opportunity to utilize wearable device technology, such as the Apple Watch, which can detect irregular pulse rhythms as demonstrated in the Apple Heart Study. This technology is especially popular with younger individuals.
“A lot of young men and women drink a lot of alcohol,” Dr. Volgman noted.
“That’s a great idea. It gets around a problem with AliveCor, which can miss episodes while you’re sleeping,” Dr. Voskoboinik replied.
He reported having no financial conflicts regarding the investigator-initiated and -funded Alcohol-AF trial.
SOURCE: Voskoboinik A. ACC 19, Session 413-08.
NEW ORLEANS – Abstinence from alcohol on the part of moderate drinkers with atrial fibrillation resulted in clinically meaningful improvement in their arrhythmia in the randomized controlled Alcohol-AF trial, Aleksandr Voskoboinik, MBBS, reported at the annual meeting of the American College of Cardiology.
The benefits of abstinence included significant reductions in the AFib recurrence rate, total AFib burden, and symptom severity. And the payoff extended beyond the arrhythmia: The abstinent group also averaged a 12–mm Hg drop in systolic blood pressure and dropped 3 kg of body weight over the course of the 6-month trial, added Dr. Voskoboinik, a cardiologist at the Baker Heart & Diabetes Institute at the University of Melbourne.
“We would conclude that significant reduction in alcohol intake should be considered as part of the lifestyle intervention in moderate drinkers with AFib,” he said.
Some physicians already advise alcohol abstinence for moderate drinkers with AFib, but until now such recommendations were not evidence based. Instead, the guidance was based on extrapolation from the well-established harmful effects of heavy drinking and binge drinking on AFib as well as epidemiologic studies.
“We wanted to provide some evidence base for physicians to say, ‘If I have motivated patients, here’s what’s potentially achievable,’” he explained.
The key word here is “motivated.” Conducting the Alcohol-AF trial made clear that many moderate drinkers with AFib enjoy their beverages more than they hate having their arrhythmia. Indeed, out of 697 moderate-drinking patients with paroxysmal or persistent AFib who were deemed good candidates and were approached about study participation, more than 500 were excluded because they were flat out unwilling to consider abstinence. After Dr. Voskoboinik and his coinvestigators shortened the planned trial duration from 12 months to 6 because so many recruits were unwilling to abstain for a full year, 140 of the initial 697 patients were randomized to abstinence or continuation of their usual consumption. Thirty percent of them had previously undergone AFib ablation.
The Alcohol-AF study was a multicenter, prospective, open-label study conducted at six Australian hospitals. All subjects underwent comprehensive rhythm monitoring via an implantable loop recorder or an existing pacemaker. Twice daily they triggered the AliveCor mobile phone app together with Holter monitoring. Patients assigned to abstinence were counseled to abstain completely, got written and verbal advice to help with compliance, and had contact with the investigators on a monthly basis. They also underwent urine testing to monitor compliance. All study participants kept a weekly alcohol intake diary, reviewed monthly by investigators.
Participants averaged 17 standard drinks per week at enrollment. Two-thirds were primarily wine drinkers. At the 6-month mark, patients in the abstinence arm averaged two drinks per week, for an 88% reduction from baseline, and 43 of the 70, or 61%, had remained completely abstinent. The control arm averaged a 20% reduction in weekly consumption.
One of the two co-primary endpoints was recurrent AFib episodes lasting for at least 30 seconds. The rate was 53% in the abstinence group and 73% in controls. The time to first recurrence averaged 118 days in the abstinence group, compared to 86 days in controls, for a 37% prolongation through abstinence.
The other primary endpoint was total AFib burden. During the 6-month study, the abstinence group spent a mean of 5.6% of their time in AFib, compared to 8.2% in controls. The median times were 0.5% and 1.2%.
In a multivariate analysis, neither AFib type, duration, history of AFib ablation, age, nor gender predicted AFib recurrence. In fact, the only significant predictor was alcohol abstinence, which conferred a 48% reduction in risk.
Symptom severity, a secondary endpoint, showed an impressive between-group difference at follow-up. Ten percent of patients in the abstinence group had moderate or severe symptoms at follow-up as assessed via the European Heart Rhythm Association score of atrial fibrillation, compared to 32% of controls, for an absolute 22% difference. And 90% of the abstinence group had no or mild symptoms, as did 68% of controls. Nine percent of the abstinence group had an AFib-related hospitalization, as did 20% of controls.
Cardiac MRI, performed in all subjects, showed that the abstinence group experienced a significant reduction in left atrial area, from 29.5 cm2 at baseline to 27.1 cm2 at follow-up. They also experienced significant improvement in left atrial mechanical function, with their left atrial emptying fraction climbing from 42% to 50%.
The 3-kg weight loss from a baseline of 90 kg in the abstinent group represented a 0.7 kg/m2 reduction in body mass index.
In terms of the likely mechanism of benefit of alcohol abstinence in moderate drinkers, Dr. Voskoboinik noted that he and his colleagues recently demonstrated that regular moderate alcohol consumption, but not mild intake, is associated with potentially explanatory atrial electrical and structural changes, including conduction slowing, lower global bipolar atrial voltage, and an increase in complex atrial potentials (Heart Rhythm. 2019 Feb;16[2]:251-9).
Alcohol has been shown to be linked with AFib through multiple mechanisms. Alcohol has adverse effects on the atrial substrate, including promotion of left atrial remodeling, dilation, and fibrosis via oxidative stress, and alcohol has a contributory role in hypertension and obstructive sleep apnea. Alcohol can act as an acute trigger of AFib through binge drinking – the holiday heart syndrome – which causes autonomic changes, electrolyte abnormalities, and electrophysiologic effects, he continued.
Epidemiologic evidence in support of the notion that moderate drinking increases the risk of AFib includes a Swedish meta-analysis of seven prospective studies comprising 12,554 patients with AFib. The researchers concluded that the relative risk of AFib rose by about 8% with each drink per day, compared with the risk of a reference group composed of current drinkers at a rate of less than one drink per week (J Am Coll Cardiol. 2014 Jul 22;64[3]:281-9).
Although discussants were wowed by the 61% complete abstinence rate in the trial, Dr. Voskoboinik cautioned that the study participants were a highly motivated subset of the universe of moderate drinkers with AFib. And even so, “It was an incredibly challenging study to run,” he said.
“I think lifestyle change is a challenge, and with alcohol particularly so, because alcohol is so ubiquitous in our society. I think the important key message for us as physicians is to take an alcohol history and have a discussion with the patient. And we now have some data to show them. But at the end of the day, it’s up to the patient in conjunction with the physician,” he observed.
Discussant Annabelle S. Volgman, MD, noted that 85% of study participants were men, and because of important differences in AFib between men and women, she doesn’t consider the findings applicable to women.
“You need to redo the study in women,” advised Dr. Volgman, professor of medicine at Rush University, Chicago, and director of the Rush Heart Center for Women.
She suggested that an interventional trial such as this one is a great opportunity to utilize wearable device technology, such as the Apple Watch, which can detect irregular pulse rhythms as demonstrated in the Apple Heart Study. This technology is especially popular with younger individuals.
“A lot of young men and women drink a lot of alcohol,” Dr. Volgman noted.
“That’s a great idea. It gets around a problem with AliveCor, which can miss episodes while you’re sleeping,” Dr. Voskoboinik replied.
He reported having no financial conflicts regarding the investigator-initiated and -funded Alcohol-AF trial.
SOURCE: Voskoboinik A. ACC 19, Session 413-08.
REPORTING FROM ACC 19
Industry-funded rheumatology RCTs are higher quality
MAUI, HAWAII – Industry-funded randomized, controlled clinical trials published in the three top-rated rheumatology journals during the past 20 years are of significantly higher overall quality than the nonindustry-funded ones, Michael Putman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
Dr. Putman, a second-year rheumatology fellow at Northwestern University, Chicago, analyzed all randomized, controlled trials (RCTs) of pharmacotherapy featuring a comparator – either placebo or an active agent – published in 1998, 2008, and 2018 in Annals of the Rheumatic Diseases, Rheumatology, and Arthritis & Rheumatology.
His main takeaway: “Rheumatologic interventions seem to work pretty well. The mean absolute risk reduction in the trials is 17.5%, so the average number of patients who need to be treated with a rheumatologic intervention is about five. This is why it’s such a great specialty to be a part of: A lot of our patients get better.”
He created an RCT quality rating scale that captured the strength of study design, methodology, and findings based upon whether a randomized trial used a double-blind design; identified a prespecified primary outcome; and featured patient-reported outcomes, power calculations, sensitivity analysis, adjustment for multiple hypotheses, and intention-to-treat analysis. He then applied the rating scale to the 85 published RCTs in the three study years.
Of note, 84% of the trials published in 2018 were industry funded, up from 74% in 2008 and 1998.
“Industry funds the vast majority of studies. Industry studies are significantly more likely to be appropriately double blinded, report patient-reported outcome measures, use intention to treat, and they have a higher overall quality,” according to Dr. Putman.
Indeed, the industry-funded studies averaged a 66% score on his quality grading scale, compared with 45% for nonindustry-funded studies.
Utilization of most of the quality metrics remained stable over time. The exceptions: Incorporation of intent-to-treat analysis increased from 58% in 1998 to 87% in 2018, and sensitivity analysis was employed in just 5% of the trials published in 1998, compared with 37% in 2008 and 26% in 2018.
The most important change over the past 2 decades, in his view, has been the shrinking proportion of RCTs featuring an active-drug, head-to-head comparator arm. In 1998, 42% of studies featured that design; for example, comparing methotrexate to sulfasalazine. By 2018, that figure had dropped to just 13%.
“Most of our trials today compare an active compound, such an interleukin-17 inhibitor, to a placebo. I think that’s a big change in how we do things,” Dr. Putman observed. “With 84% of our studies being funded by industry, the incentives in medicine right now don’t support active comparator research. It’s harder to show a difference between two things that work than it is to show a difference between something and nothing.”
However, he’d welcome a revival of head-to-head active comparator trials.
“I’d really love to have that happen,” he said. “We have basic questions we haven’t answered yet about a lot of our basic drugs: Like in myositis, should you start with Imuran [azathioprine], CellCept [mycophenolate mofetil], or methotrexate?”
Another striking change over time has been the dwindling proportion of published trials with a statistically significant finding for the primary outcome: 79% in 1998, 46% in 2008, and 36% last year. Dr. Putman suspects the explanation lies in the steady improvement in the effectiveness of standard background therapy for many conditions, which makes it tougher to show a striking difference between the add-on study drug and add-on placebo.
“We’re a victim of our own success,” he commented.
In any event, many key secondary outcomes in the RCTs were positive, even when the primary endpoint wasn’t, according to Dr. Putman, and there was a notable dearth of completely negative clinical RCTs published in the three top journals.
“The more cynical interpretation is there’s an incredible amount of publication bias, where we’re only publishing studies that show an effect and the journals or investigators are censoring the ones that don’t. The more charitable explanation, which is probably also true, is that by the time you get to putting on an RCT you kind of think, ‘This thing works.’ You’re not testing random stuff, so your pretest probability of a drug being effective when it enters into an RCT is probably shifted toward effectiveness,” Dr. Putman speculated.
He reported having no financial conflicts regarding his study.
MAUI, HAWAII – Industry-funded randomized, controlled clinical trials published in the three top-rated rheumatology journals during the past 20 years are of significantly higher overall quality than the nonindustry-funded ones, Michael Putman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
Dr. Putman, a second-year rheumatology fellow at Northwestern University, Chicago, analyzed all randomized, controlled trials (RCTs) of pharmacotherapy featuring a comparator – either placebo or an active agent – published in 1998, 2008, and 2018 in Annals of the Rheumatic Diseases, Rheumatology, and Arthritis & Rheumatology.
His main takeaway: “Rheumatologic interventions seem to work pretty well. The mean absolute risk reduction in the trials is 17.5%, so the average number of patients who need to be treated with a rheumatologic intervention is about five. This is why it’s such a great specialty to be a part of: A lot of our patients get better.”
He created an RCT quality rating scale that captured the strength of study design, methodology, and findings based upon whether a randomized trial used a double-blind design; identified a prespecified primary outcome; and featured patient-reported outcomes, power calculations, sensitivity analysis, adjustment for multiple hypotheses, and intention-to-treat analysis. He then applied the rating scale to the 85 published RCTs in the three study years.
Of note, 84% of the trials published in 2018 were industry funded, up from 74% in 2008 and 1998.
“Industry funds the vast majority of studies. Industry studies are significantly more likely to be appropriately double blinded, report patient-reported outcome measures, use intention to treat, and they have a higher overall quality,” according to Dr. Putman.
Indeed, the industry-funded studies averaged a 66% score on his quality grading scale, compared with 45% for nonindustry-funded studies.
Utilization of most of the quality metrics remained stable over time. The exceptions: Incorporation of intent-to-treat analysis increased from 58% in 1998 to 87% in 2018, and sensitivity analysis was employed in just 5% of the trials published in 1998, compared with 37% in 2008 and 26% in 2018.
The most important change over the past 2 decades, in his view, has been the shrinking proportion of RCTs featuring an active-drug, head-to-head comparator arm. In 1998, 42% of studies featured that design; for example, comparing methotrexate to sulfasalazine. By 2018, that figure had dropped to just 13%.
“Most of our trials today compare an active compound, such an interleukin-17 inhibitor, to a placebo. I think that’s a big change in how we do things,” Dr. Putman observed. “With 84% of our studies being funded by industry, the incentives in medicine right now don’t support active comparator research. It’s harder to show a difference between two things that work than it is to show a difference between something and nothing.”
However, he’d welcome a revival of head-to-head active comparator trials.
“I’d really love to have that happen,” he said. “We have basic questions we haven’t answered yet about a lot of our basic drugs: Like in myositis, should you start with Imuran [azathioprine], CellCept [mycophenolate mofetil], or methotrexate?”
Another striking change over time has been the dwindling proportion of published trials with a statistically significant finding for the primary outcome: 79% in 1998, 46% in 2008, and 36% last year. Dr. Putman suspects the explanation lies in the steady improvement in the effectiveness of standard background therapy for many conditions, which makes it tougher to show a striking difference between the add-on study drug and add-on placebo.
“We’re a victim of our own success,” he commented.
In any event, many key secondary outcomes in the RCTs were positive, even when the primary endpoint wasn’t, according to Dr. Putman, and there was a notable dearth of completely negative clinical RCTs published in the three top journals.
“The more cynical interpretation is there’s an incredible amount of publication bias, where we’re only publishing studies that show an effect and the journals or investigators are censoring the ones that don’t. The more charitable explanation, which is probably also true, is that by the time you get to putting on an RCT you kind of think, ‘This thing works.’ You’re not testing random stuff, so your pretest probability of a drug being effective when it enters into an RCT is probably shifted toward effectiveness,” Dr. Putman speculated.
He reported having no financial conflicts regarding his study.
MAUI, HAWAII – Industry-funded randomized, controlled clinical trials published in the three top-rated rheumatology journals during the past 20 years are of significantly higher overall quality than the nonindustry-funded ones, Michael Putman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
Dr. Putman, a second-year rheumatology fellow at Northwestern University, Chicago, analyzed all randomized, controlled trials (RCTs) of pharmacotherapy featuring a comparator – either placebo or an active agent – published in 1998, 2008, and 2018 in Annals of the Rheumatic Diseases, Rheumatology, and Arthritis & Rheumatology.
His main takeaway: “Rheumatologic interventions seem to work pretty well. The mean absolute risk reduction in the trials is 17.5%, so the average number of patients who need to be treated with a rheumatologic intervention is about five. This is why it’s such a great specialty to be a part of: A lot of our patients get better.”
He created an RCT quality rating scale that captured the strength of study design, methodology, and findings based upon whether a randomized trial used a double-blind design; identified a prespecified primary outcome; and featured patient-reported outcomes, power calculations, sensitivity analysis, adjustment for multiple hypotheses, and intention-to-treat analysis. He then applied the rating scale to the 85 published RCTs in the three study years.
Of note, 84% of the trials published in 2018 were industry funded, up from 74% in 2008 and 1998.
“Industry funds the vast majority of studies. Industry studies are significantly more likely to be appropriately double blinded, report patient-reported outcome measures, use intention to treat, and they have a higher overall quality,” according to Dr. Putman.
Indeed, the industry-funded studies averaged a 66% score on his quality grading scale, compared with 45% for nonindustry-funded studies.
Utilization of most of the quality metrics remained stable over time. The exceptions: Incorporation of intent-to-treat analysis increased from 58% in 1998 to 87% in 2018, and sensitivity analysis was employed in just 5% of the trials published in 1998, compared with 37% in 2008 and 26% in 2018.
The most important change over the past 2 decades, in his view, has been the shrinking proportion of RCTs featuring an active-drug, head-to-head comparator arm. In 1998, 42% of studies featured that design; for example, comparing methotrexate to sulfasalazine. By 2018, that figure had dropped to just 13%.
“Most of our trials today compare an active compound, such an interleukin-17 inhibitor, to a placebo. I think that’s a big change in how we do things,” Dr. Putman observed. “With 84% of our studies being funded by industry, the incentives in medicine right now don’t support active comparator research. It’s harder to show a difference between two things that work than it is to show a difference between something and nothing.”
However, he’d welcome a revival of head-to-head active comparator trials.
“I’d really love to have that happen,” he said. “We have basic questions we haven’t answered yet about a lot of our basic drugs: Like in myositis, should you start with Imuran [azathioprine], CellCept [mycophenolate mofetil], or methotrexate?”
Another striking change over time has been the dwindling proportion of published trials with a statistically significant finding for the primary outcome: 79% in 1998, 46% in 2008, and 36% last year. Dr. Putman suspects the explanation lies in the steady improvement in the effectiveness of standard background therapy for many conditions, which makes it tougher to show a striking difference between the add-on study drug and add-on placebo.
“We’re a victim of our own success,” he commented.
In any event, many key secondary outcomes in the RCTs were positive, even when the primary endpoint wasn’t, according to Dr. Putman, and there was a notable dearth of completely negative clinical RCTs published in the three top journals.
“The more cynical interpretation is there’s an incredible amount of publication bias, where we’re only publishing studies that show an effect and the journals or investigators are censoring the ones that don’t. The more charitable explanation, which is probably also true, is that by the time you get to putting on an RCT you kind of think, ‘This thing works.’ You’re not testing random stuff, so your pretest probability of a drug being effective when it enters into an RCT is probably shifted toward effectiveness,” Dr. Putman speculated.
He reported having no financial conflicts regarding his study.
REPORTING FROM RWCS 2019
Concomitant methotrexate boosts pegloticase efficacy in gout patients
MAUI, HAWAII – , Orrin M. Troum, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
He cited what he considers to be a practice-changing, prospective, observational, proof-of-concept study presented by John Botson, MD, at the 2018 annual meeting of the American College of Rheumatology.
Dr. Botson, a rheumatologist at Orthopedic Physicians Alaska, in Anchorage, reported on nine patients with refractory tophaceous gout placed on an 8-mg infusion of pegloticase every 2 weeks as third-line therapy. But 1 month beforehand he put them on oral methotrexate at 15 mg once weekly along with folic acid at 1 mg/day in an effort to prevent the development of treatment-limiting anti-pegloticase antibodies. It’s the same strategy rheumatologists often use when patients with rheumatoid arthritis on a tumor necrosis factor inhibitor begin to develop anti-drug antibodies.
At the time of the ACR meeting, all nine patients had received at least nine infusions, and six had received at least 12 infusions over the course of 6 months. The response rate was 100%, defined as more than 80% of serum uric acid levels being below 6.0 mg/dL. All patients stayed on methotrexate with no dose adjustment. And there were no infusion reactions. In contrast, the response rate in the randomized trials of pegloticase was only 42%, and 26% of pegloticase recipients experienced infusion reactions within 6 months.
“Although this is not [Food and Drug Administration] approved, it makes a lot of sense. From my standpoint, this is something that I’m doing now for my patients starting on pegloticase if there’s no contraindication to using methotrexate,” said Dr. Troum, a rheumatologist at the University of Southern California in Los Angeles.
“I’ve been doing this, too. This really did change my practice,” added his fellow panelist Alvin F. Wells, MD, PhD, director of the Rheumatology and Immunotherapy Center in Franklin, Wisc.
When they asked for a show of hands, only a handful of audience members indicated they are now using methotrexate in conjunction with pegloticase in their tophaceous gout patients.
Dr. Wells said his sole reservation about the practice involves using methotrexate in patients with an elevated creatinine level. What about using azathioprine or corticosteroids instead? he asked.
Dr. Troum replied that he monitors those patients carefully but sticks with the methotrexate because it’s only for a few months, which is the time frame in which patients are especially vulnerable to experiencing loss of response to pegloticase due to development of anti-drug antibodies.
Dr. Botson, who was in the Maui audience, rose to give a study update. With additional follow-up, he said, there has still been no signal of loss of response to pegloticase coadministered with methotrexate.
“A lot of us are starting to feel like immunosuppression, whether it’s with methotrexate or something else, is standard of care now,” according to the rheumatologist.
As to prescribing methotrexate in gout patients with renal insufficiency, he continued, he and his colleagues have given the matter quite a bit of thought.
“You’re talking about using methotrexate for 6 months in most of these cases. A lot of the patients who have really bad tophaceous gout already have renal insufficiency, and in the short term we haven’t really seen any problems with that. We work closely with a nephrologist on those cases. And a lot of nephrologists swear – although I don’t think the data are there – that they actually improve their renal function when we start to treat their tophaceous gout,” Dr. Botson said.
Dr. Troum and Dr. Wells reported serving as consultants to and on speakers bureaus for numerous pharmaceutical companies.
MAUI, HAWAII – , Orrin M. Troum, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
He cited what he considers to be a practice-changing, prospective, observational, proof-of-concept study presented by John Botson, MD, at the 2018 annual meeting of the American College of Rheumatology.
Dr. Botson, a rheumatologist at Orthopedic Physicians Alaska, in Anchorage, reported on nine patients with refractory tophaceous gout placed on an 8-mg infusion of pegloticase every 2 weeks as third-line therapy. But 1 month beforehand he put them on oral methotrexate at 15 mg once weekly along with folic acid at 1 mg/day in an effort to prevent the development of treatment-limiting anti-pegloticase antibodies. It’s the same strategy rheumatologists often use when patients with rheumatoid arthritis on a tumor necrosis factor inhibitor begin to develop anti-drug antibodies.
At the time of the ACR meeting, all nine patients had received at least nine infusions, and six had received at least 12 infusions over the course of 6 months. The response rate was 100%, defined as more than 80% of serum uric acid levels being below 6.0 mg/dL. All patients stayed on methotrexate with no dose adjustment. And there were no infusion reactions. In contrast, the response rate in the randomized trials of pegloticase was only 42%, and 26% of pegloticase recipients experienced infusion reactions within 6 months.
“Although this is not [Food and Drug Administration] approved, it makes a lot of sense. From my standpoint, this is something that I’m doing now for my patients starting on pegloticase if there’s no contraindication to using methotrexate,” said Dr. Troum, a rheumatologist at the University of Southern California in Los Angeles.
“I’ve been doing this, too. This really did change my practice,” added his fellow panelist Alvin F. Wells, MD, PhD, director of the Rheumatology and Immunotherapy Center in Franklin, Wisc.
When they asked for a show of hands, only a handful of audience members indicated they are now using methotrexate in conjunction with pegloticase in their tophaceous gout patients.
Dr. Wells said his sole reservation about the practice involves using methotrexate in patients with an elevated creatinine level. What about using azathioprine or corticosteroids instead? he asked.
Dr. Troum replied that he monitors those patients carefully but sticks with the methotrexate because it’s only for a few months, which is the time frame in which patients are especially vulnerable to experiencing loss of response to pegloticase due to development of anti-drug antibodies.
Dr. Botson, who was in the Maui audience, rose to give a study update. With additional follow-up, he said, there has still been no signal of loss of response to pegloticase coadministered with methotrexate.
“A lot of us are starting to feel like immunosuppression, whether it’s with methotrexate or something else, is standard of care now,” according to the rheumatologist.
As to prescribing methotrexate in gout patients with renal insufficiency, he continued, he and his colleagues have given the matter quite a bit of thought.
“You’re talking about using methotrexate for 6 months in most of these cases. A lot of the patients who have really bad tophaceous gout already have renal insufficiency, and in the short term we haven’t really seen any problems with that. We work closely with a nephrologist on those cases. And a lot of nephrologists swear – although I don’t think the data are there – that they actually improve their renal function when we start to treat their tophaceous gout,” Dr. Botson said.
Dr. Troum and Dr. Wells reported serving as consultants to and on speakers bureaus for numerous pharmaceutical companies.
MAUI, HAWAII – , Orrin M. Troum, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
He cited what he considers to be a practice-changing, prospective, observational, proof-of-concept study presented by John Botson, MD, at the 2018 annual meeting of the American College of Rheumatology.
Dr. Botson, a rheumatologist at Orthopedic Physicians Alaska, in Anchorage, reported on nine patients with refractory tophaceous gout placed on an 8-mg infusion of pegloticase every 2 weeks as third-line therapy. But 1 month beforehand he put them on oral methotrexate at 15 mg once weekly along with folic acid at 1 mg/day in an effort to prevent the development of treatment-limiting anti-pegloticase antibodies. It’s the same strategy rheumatologists often use when patients with rheumatoid arthritis on a tumor necrosis factor inhibitor begin to develop anti-drug antibodies.
At the time of the ACR meeting, all nine patients had received at least nine infusions, and six had received at least 12 infusions over the course of 6 months. The response rate was 100%, defined as more than 80% of serum uric acid levels being below 6.0 mg/dL. All patients stayed on methotrexate with no dose adjustment. And there were no infusion reactions. In contrast, the response rate in the randomized trials of pegloticase was only 42%, and 26% of pegloticase recipients experienced infusion reactions within 6 months.
“Although this is not [Food and Drug Administration] approved, it makes a lot of sense. From my standpoint, this is something that I’m doing now for my patients starting on pegloticase if there’s no contraindication to using methotrexate,” said Dr. Troum, a rheumatologist at the University of Southern California in Los Angeles.
“I’ve been doing this, too. This really did change my practice,” added his fellow panelist Alvin F. Wells, MD, PhD, director of the Rheumatology and Immunotherapy Center in Franklin, Wisc.
When they asked for a show of hands, only a handful of audience members indicated they are now using methotrexate in conjunction with pegloticase in their tophaceous gout patients.
Dr. Wells said his sole reservation about the practice involves using methotrexate in patients with an elevated creatinine level. What about using azathioprine or corticosteroids instead? he asked.
Dr. Troum replied that he monitors those patients carefully but sticks with the methotrexate because it’s only for a few months, which is the time frame in which patients are especially vulnerable to experiencing loss of response to pegloticase due to development of anti-drug antibodies.
Dr. Botson, who was in the Maui audience, rose to give a study update. With additional follow-up, he said, there has still been no signal of loss of response to pegloticase coadministered with methotrexate.
“A lot of us are starting to feel like immunosuppression, whether it’s with methotrexate or something else, is standard of care now,” according to the rheumatologist.
As to prescribing methotrexate in gout patients with renal insufficiency, he continued, he and his colleagues have given the matter quite a bit of thought.
“You’re talking about using methotrexate for 6 months in most of these cases. A lot of the patients who have really bad tophaceous gout already have renal insufficiency, and in the short term we haven’t really seen any problems with that. We work closely with a nephrologist on those cases. And a lot of nephrologists swear – although I don’t think the data are there – that they actually improve their renal function when we start to treat their tophaceous gout,” Dr. Botson said.
Dr. Troum and Dr. Wells reported serving as consultants to and on speakers bureaus for numerous pharmaceutical companies.
REPORTING FROM RWCS 2019
TAVR tops surgery in low-risk patients
NEW ORLEANS – Patients with severely symptomatic aortic stenosis at low surgical risk had significantly better key outcomes with transcatheter aortic valve replacement than with surgical valve replacement through 1 year of follow-up in the landmark PARTNER 3 and Evolut Low Risk randomized trials presented at the annual meeting of the American College of Cardiology.
As the two study presenters stepped down from the stage after sharing their results, the packed audience in the meeting’s main arena rose to shower them with a prolonged standing ovation.
“This is a historic moment, and all of us here should recognize it as such,” thundered discussant Eugene Braunwald, MD, professor of medicine at Harvard Medical School, Boston. “We’re going to remember it. We’re going to tell our grandchildren and great grandchildren that we were there at the time these incredible advances in the care of patients with aortic stenosis were presented.”
This was in fact the day that transcatheter aortic valve replacement (TAVR), a relatively young, rapidly evolving nonsurgical technique, finally overtook surgical aortic valve replacement (SAVR), a mature operation first successfully performed back in 1962. Previous large, randomized trials had established that TAVR was superior to SAVR in extreme-risk patients and noninferior to surgery in high- and intermediate-risk patients, yet with the advantage of much quicker recovery. The only remaining question was how TAVR would stack up in low-risk patients, who comprise 80% of those who currently undergo SAVR for aortic stenosis.
“Two separate groups using two separate valves have come to very similar conclusions. This doesn’t double the acceptability, it quadruples it,” Dr. Braunwald said.
PARTNER 3
Martin B. Leon, MD, presented the findings of the PARTNER 3 (Placement of Aortic Transcatheter Valves) trial, in which 1,000 low-risk patients at 71 centers were randomized to TAVR with transfemoral placement of the balloon-expandable Edwards Lifesciences Sapien 3 bioprosthetic valve or to SAVR. The mean age of the patients was 73 years, with a mean Society of Thoracic Surgeons risk score of 1.9%. Operators had to have more than 1 year of experience using the Sapien 3 valve in order to participate in the trial.
At 1 year post procedure, the rate of the primary composite endpoint comprising death, stroke, or cardiovascular rehospitalization was 8.5% in the TAVR group and 15.1% with SAVR, for a highly significant 46% relative risk reduction. All three components of the primary endpoint occurred significantly less often in the TAVR group. And the rate of the key endpoint of death or disabling stroke was 1.0% with TAVR, compared with 2.9% with SAVR, reported Dr. Leon, coprincipal investigator in PARTNER 3 and professor of medicine at Columbia University, New York.
TAVR also outperformed SAVR on all six prespecified major secondary endpoints. These included new-onset atrial fibrillation within 30 days, at 5.0% with TAVR and 39.5% with SAVR; length of index hospitalization at 3 versus 7 days; all stroke at 30 days at 0.6% versus 2.4%; and death or a significant deterioration in quality of life at 30 days as measured by the Kansas City Cardiomyopathy Questionnaire at 3.9% versus 30.6%. There was significantly less life-threatening or major bleeding within 30 days in the TAVR group, by a margin of 3.6% versus 24.5%, and similarly low rates of new pacemaker implantation at 6.5% versus 4.0%. There was, however, a higher 30-day incidence of new left bundle branch block with TAVR, by a margin of 22% versus 8%, which may eventually translate into need for a pacemaker.
“Based upon these findings, TAVR, through 1 year, should be considered the preferred therapy in low-surgical-risk aortic stenosis patients. The PARTNER randomized trials over the past 12 years clearly indicate that the relative value of TAVR, compared with surgery, is independent of surgical risk profiles,” Dr. Leon declared.
Evolut Low Risk
Michael J. Reardon, MD, coprincipal investigator for the Evolut Low Risk study and professor of cardiovascular surgery at Houston Methodist Hospital, reported on 1,468 patients randomized to TAVR with a Medtronic self-expanding, supra-annular bioprosthetic valve or to SAVR. Of them, 22% of patients got the most recent version of the valve, known as the Evolut PRO, 74% got the Evolut R, and the remainder received the first-generation CoreValve.
The primary endpoint – death or disabling stroke – was slightly different from that in PARTNER 3. At 1 year, the rate was 2.9% in the TAVR arm and 4.6% with SAVR, a statistically significant difference, while at 2 years the rate was 5.3% with TAVR and 6.7% with SAVR, a difference that was not significant. Impressively, the rate of the composite of death, disabling stroke, or heart failure hospitalizations through 1 year was 5.6% with TAVR versus 10.2% with SAVR.
“We’ve shown that, with TAVR, you’re more likely to be alive, without a stroke, and outside the hospital. This is exactly what my patients tell me they want when we sit down for shared decision-making and talk about their expectations,” Dr. Reardon said.
Noting the striking similarity of across-the-board outcomes in the two trials, Dr. Reardon concluded, “I think what we’re seeing here is a class effect of TAVR, and we have to recognize it as such.”
Dr. Leon agreed, with a caveat. “I think the class effect for these two versions of TAVR systems is very real. I wouldn’t presume to think that every TAVR device will perform the same way, so I think we need a lot more data on the newer devices that are being introduced.”
The reaction
During the question-and-answer session, the two investigators were asked about stroke rates, which were significantly lower in the TAVR patients even though in the early randomized trials in high-risk patients the stroke rates were twice as high with TAVR than SAVR. The explanation probably lies in a mix of device refinements over time, better techniques, standardized procedures, and careful patient selection, they said.
“If you look at stroke in the TAVR arm in both these trials, we’re almost approaching the background stroke rate in a group of 74-year-olds sitting around in a room,” Dr. Reardon observed.
Both trials will continue to assess participants both clinically and by echocardiography through 10 years, in part to assess TAVR valve durability, but also to evaluate the durability of surgical valves, which isn’t nearly as well established as most people think, according to the investigators.
“There is a myth of surgical bioprosthetic valve immortality. It’s based upon relatively few numbers of patients, largely sponsor-based studies, with numbers at risk at 15-20 years that are extremely low,” Dr. Leon asserted. “The majority of surgical valves being used today and touted as being durable are backed by only 2-4 years of data.”
In contrast, he added, “We have 5-year TAVR data which is absolutely definitive of no early structural valve deterioration.”
Discussant Mayra E. Guerrero, MD, of the Mayo Clinic in Rochester, Minn., expressed concern that “this paradigm shift to ‘TAVR for all’ ” could break the bank for many institutions because the cost of TAVR valves is far greater than for SAVR valves. But she was heartened by the fresh PARTNER 3 and Evolut Low Risk data showing TAVR patients had fewer ICU days, shorter hospital stays, fewer strokes, more frequent discharge home, and a lower rehospitalization rate.
Dr. Reardon was reassuring on this score.
“I am 100% convinced that when we do the financials for these two trials, TAVR is going to be a cost saver and a huge winner,” the surgeon said.
He reported serving as a consultant to Medtronic and receiving research grants from Medtronic and Boston Scientific. Dr. Leon reported receiving research grants from Edwards Lifesciences and St. Jude Medical and acting as a consultant to several medical device companies.
The two trials have been published online by the New England Journal of Medicine.
SOURCES: Leon MB et al. N Engl J Med. 2019 Mar 16. doi: 10.1056/NEJMoa1814052; Reardon MJ et al. N Engl J Med. 2019 Mar 16. doi: 10.1056/NEJMoa1816885.
NEW ORLEANS – Patients with severely symptomatic aortic stenosis at low surgical risk had significantly better key outcomes with transcatheter aortic valve replacement than with surgical valve replacement through 1 year of follow-up in the landmark PARTNER 3 and Evolut Low Risk randomized trials presented at the annual meeting of the American College of Cardiology.
As the two study presenters stepped down from the stage after sharing their results, the packed audience in the meeting’s main arena rose to shower them with a prolonged standing ovation.
“This is a historic moment, and all of us here should recognize it as such,” thundered discussant Eugene Braunwald, MD, professor of medicine at Harvard Medical School, Boston. “We’re going to remember it. We’re going to tell our grandchildren and great grandchildren that we were there at the time these incredible advances in the care of patients with aortic stenosis were presented.”
This was in fact the day that transcatheter aortic valve replacement (TAVR), a relatively young, rapidly evolving nonsurgical technique, finally overtook surgical aortic valve replacement (SAVR), a mature operation first successfully performed back in 1962. Previous large, randomized trials had established that TAVR was superior to SAVR in extreme-risk patients and noninferior to surgery in high- and intermediate-risk patients, yet with the advantage of much quicker recovery. The only remaining question was how TAVR would stack up in low-risk patients, who comprise 80% of those who currently undergo SAVR for aortic stenosis.
“Two separate groups using two separate valves have come to very similar conclusions. This doesn’t double the acceptability, it quadruples it,” Dr. Braunwald said.
PARTNER 3
Martin B. Leon, MD, presented the findings of the PARTNER 3 (Placement of Aortic Transcatheter Valves) trial, in which 1,000 low-risk patients at 71 centers were randomized to TAVR with transfemoral placement of the balloon-expandable Edwards Lifesciences Sapien 3 bioprosthetic valve or to SAVR. The mean age of the patients was 73 years, with a mean Society of Thoracic Surgeons risk score of 1.9%. Operators had to have more than 1 year of experience using the Sapien 3 valve in order to participate in the trial.
At 1 year post procedure, the rate of the primary composite endpoint comprising death, stroke, or cardiovascular rehospitalization was 8.5% in the TAVR group and 15.1% with SAVR, for a highly significant 46% relative risk reduction. All three components of the primary endpoint occurred significantly less often in the TAVR group. And the rate of the key endpoint of death or disabling stroke was 1.0% with TAVR, compared with 2.9% with SAVR, reported Dr. Leon, coprincipal investigator in PARTNER 3 and professor of medicine at Columbia University, New York.
TAVR also outperformed SAVR on all six prespecified major secondary endpoints. These included new-onset atrial fibrillation within 30 days, at 5.0% with TAVR and 39.5% with SAVR; length of index hospitalization at 3 versus 7 days; all stroke at 30 days at 0.6% versus 2.4%; and death or a significant deterioration in quality of life at 30 days as measured by the Kansas City Cardiomyopathy Questionnaire at 3.9% versus 30.6%. There was significantly less life-threatening or major bleeding within 30 days in the TAVR group, by a margin of 3.6% versus 24.5%, and similarly low rates of new pacemaker implantation at 6.5% versus 4.0%. There was, however, a higher 30-day incidence of new left bundle branch block with TAVR, by a margin of 22% versus 8%, which may eventually translate into need for a pacemaker.
“Based upon these findings, TAVR, through 1 year, should be considered the preferred therapy in low-surgical-risk aortic stenosis patients. The PARTNER randomized trials over the past 12 years clearly indicate that the relative value of TAVR, compared with surgery, is independent of surgical risk profiles,” Dr. Leon declared.
Evolut Low Risk
Michael J. Reardon, MD, coprincipal investigator for the Evolut Low Risk study and professor of cardiovascular surgery at Houston Methodist Hospital, reported on 1,468 patients randomized to TAVR with a Medtronic self-expanding, supra-annular bioprosthetic valve or to SAVR. Of them, 22% of patients got the most recent version of the valve, known as the Evolut PRO, 74% got the Evolut R, and the remainder received the first-generation CoreValve.
The primary endpoint – death or disabling stroke – was slightly different from that in PARTNER 3. At 1 year, the rate was 2.9% in the TAVR arm and 4.6% with SAVR, a statistically significant difference, while at 2 years the rate was 5.3% with TAVR and 6.7% with SAVR, a difference that was not significant. Impressively, the rate of the composite of death, disabling stroke, or heart failure hospitalizations through 1 year was 5.6% with TAVR versus 10.2% with SAVR.
“We’ve shown that, with TAVR, you’re more likely to be alive, without a stroke, and outside the hospital. This is exactly what my patients tell me they want when we sit down for shared decision-making and talk about their expectations,” Dr. Reardon said.
Noting the striking similarity of across-the-board outcomes in the two trials, Dr. Reardon concluded, “I think what we’re seeing here is a class effect of TAVR, and we have to recognize it as such.”
Dr. Leon agreed, with a caveat. “I think the class effect for these two versions of TAVR systems is very real. I wouldn’t presume to think that every TAVR device will perform the same way, so I think we need a lot more data on the newer devices that are being introduced.”
The reaction
During the question-and-answer session, the two investigators were asked about stroke rates, which were significantly lower in the TAVR patients even though in the early randomized trials in high-risk patients the stroke rates were twice as high with TAVR than SAVR. The explanation probably lies in a mix of device refinements over time, better techniques, standardized procedures, and careful patient selection, they said.
“If you look at stroke in the TAVR arm in both these trials, we’re almost approaching the background stroke rate in a group of 74-year-olds sitting around in a room,” Dr. Reardon observed.
Both trials will continue to assess participants both clinically and by echocardiography through 10 years, in part to assess TAVR valve durability, but also to evaluate the durability of surgical valves, which isn’t nearly as well established as most people think, according to the investigators.
“There is a myth of surgical bioprosthetic valve immortality. It’s based upon relatively few numbers of patients, largely sponsor-based studies, with numbers at risk at 15-20 years that are extremely low,” Dr. Leon asserted. “The majority of surgical valves being used today and touted as being durable are backed by only 2-4 years of data.”
In contrast, he added, “We have 5-year TAVR data which is absolutely definitive of no early structural valve deterioration.”
Discussant Mayra E. Guerrero, MD, of the Mayo Clinic in Rochester, Minn., expressed concern that “this paradigm shift to ‘TAVR for all’ ” could break the bank for many institutions because the cost of TAVR valves is far greater than for SAVR valves. But she was heartened by the fresh PARTNER 3 and Evolut Low Risk data showing TAVR patients had fewer ICU days, shorter hospital stays, fewer strokes, more frequent discharge home, and a lower rehospitalization rate.
Dr. Reardon was reassuring on this score.
“I am 100% convinced that when we do the financials for these two trials, TAVR is going to be a cost saver and a huge winner,” the surgeon said.
He reported serving as a consultant to Medtronic and receiving research grants from Medtronic and Boston Scientific. Dr. Leon reported receiving research grants from Edwards Lifesciences and St. Jude Medical and acting as a consultant to several medical device companies.
The two trials have been published online by the New England Journal of Medicine.
SOURCES: Leon MB et al. N Engl J Med. 2019 Mar 16. doi: 10.1056/NEJMoa1814052; Reardon MJ et al. N Engl J Med. 2019 Mar 16. doi: 10.1056/NEJMoa1816885.
NEW ORLEANS – Patients with severely symptomatic aortic stenosis at low surgical risk had significantly better key outcomes with transcatheter aortic valve replacement than with surgical valve replacement through 1 year of follow-up in the landmark PARTNER 3 and Evolut Low Risk randomized trials presented at the annual meeting of the American College of Cardiology.
As the two study presenters stepped down from the stage after sharing their results, the packed audience in the meeting’s main arena rose to shower them with a prolonged standing ovation.
“This is a historic moment, and all of us here should recognize it as such,” thundered discussant Eugene Braunwald, MD, professor of medicine at Harvard Medical School, Boston. “We’re going to remember it. We’re going to tell our grandchildren and great grandchildren that we were there at the time these incredible advances in the care of patients with aortic stenosis were presented.”
This was in fact the day that transcatheter aortic valve replacement (TAVR), a relatively young, rapidly evolving nonsurgical technique, finally overtook surgical aortic valve replacement (SAVR), a mature operation first successfully performed back in 1962. Previous large, randomized trials had established that TAVR was superior to SAVR in extreme-risk patients and noninferior to surgery in high- and intermediate-risk patients, yet with the advantage of much quicker recovery. The only remaining question was how TAVR would stack up in low-risk patients, who comprise 80% of those who currently undergo SAVR for aortic stenosis.
“Two separate groups using two separate valves have come to very similar conclusions. This doesn’t double the acceptability, it quadruples it,” Dr. Braunwald said.
PARTNER 3
Martin B. Leon, MD, presented the findings of the PARTNER 3 (Placement of Aortic Transcatheter Valves) trial, in which 1,000 low-risk patients at 71 centers were randomized to TAVR with transfemoral placement of the balloon-expandable Edwards Lifesciences Sapien 3 bioprosthetic valve or to SAVR. The mean age of the patients was 73 years, with a mean Society of Thoracic Surgeons risk score of 1.9%. Operators had to have more than 1 year of experience using the Sapien 3 valve in order to participate in the trial.
At 1 year post procedure, the rate of the primary composite endpoint comprising death, stroke, or cardiovascular rehospitalization was 8.5% in the TAVR group and 15.1% with SAVR, for a highly significant 46% relative risk reduction. All three components of the primary endpoint occurred significantly less often in the TAVR group. And the rate of the key endpoint of death or disabling stroke was 1.0% with TAVR, compared with 2.9% with SAVR, reported Dr. Leon, coprincipal investigator in PARTNER 3 and professor of medicine at Columbia University, New York.
TAVR also outperformed SAVR on all six prespecified major secondary endpoints. These included new-onset atrial fibrillation within 30 days, at 5.0% with TAVR and 39.5% with SAVR; length of index hospitalization at 3 versus 7 days; all stroke at 30 days at 0.6% versus 2.4%; and death or a significant deterioration in quality of life at 30 days as measured by the Kansas City Cardiomyopathy Questionnaire at 3.9% versus 30.6%. There was significantly less life-threatening or major bleeding within 30 days in the TAVR group, by a margin of 3.6% versus 24.5%, and similarly low rates of new pacemaker implantation at 6.5% versus 4.0%. There was, however, a higher 30-day incidence of new left bundle branch block with TAVR, by a margin of 22% versus 8%, which may eventually translate into need for a pacemaker.
“Based upon these findings, TAVR, through 1 year, should be considered the preferred therapy in low-surgical-risk aortic stenosis patients. The PARTNER randomized trials over the past 12 years clearly indicate that the relative value of TAVR, compared with surgery, is independent of surgical risk profiles,” Dr. Leon declared.
Evolut Low Risk
Michael J. Reardon, MD, coprincipal investigator for the Evolut Low Risk study and professor of cardiovascular surgery at Houston Methodist Hospital, reported on 1,468 patients randomized to TAVR with a Medtronic self-expanding, supra-annular bioprosthetic valve or to SAVR. Of them, 22% of patients got the most recent version of the valve, known as the Evolut PRO, 74% got the Evolut R, and the remainder received the first-generation CoreValve.
The primary endpoint – death or disabling stroke – was slightly different from that in PARTNER 3. At 1 year, the rate was 2.9% in the TAVR arm and 4.6% with SAVR, a statistically significant difference, while at 2 years the rate was 5.3% with TAVR and 6.7% with SAVR, a difference that was not significant. Impressively, the rate of the composite of death, disabling stroke, or heart failure hospitalizations through 1 year was 5.6% with TAVR versus 10.2% with SAVR.
“We’ve shown that, with TAVR, you’re more likely to be alive, without a stroke, and outside the hospital. This is exactly what my patients tell me they want when we sit down for shared decision-making and talk about their expectations,” Dr. Reardon said.
Noting the striking similarity of across-the-board outcomes in the two trials, Dr. Reardon concluded, “I think what we’re seeing here is a class effect of TAVR, and we have to recognize it as such.”
Dr. Leon agreed, with a caveat. “I think the class effect for these two versions of TAVR systems is very real. I wouldn’t presume to think that every TAVR device will perform the same way, so I think we need a lot more data on the newer devices that are being introduced.”
The reaction
During the question-and-answer session, the two investigators were asked about stroke rates, which were significantly lower in the TAVR patients even though in the early randomized trials in high-risk patients the stroke rates were twice as high with TAVR than SAVR. The explanation probably lies in a mix of device refinements over time, better techniques, standardized procedures, and careful patient selection, they said.
“If you look at stroke in the TAVR arm in both these trials, we’re almost approaching the background stroke rate in a group of 74-year-olds sitting around in a room,” Dr. Reardon observed.
Both trials will continue to assess participants both clinically and by echocardiography through 10 years, in part to assess TAVR valve durability, but also to evaluate the durability of surgical valves, which isn’t nearly as well established as most people think, according to the investigators.
“There is a myth of surgical bioprosthetic valve immortality. It’s based upon relatively few numbers of patients, largely sponsor-based studies, with numbers at risk at 15-20 years that are extremely low,” Dr. Leon asserted. “The majority of surgical valves being used today and touted as being durable are backed by only 2-4 years of data.”
In contrast, he added, “We have 5-year TAVR data which is absolutely definitive of no early structural valve deterioration.”
Discussant Mayra E. Guerrero, MD, of the Mayo Clinic in Rochester, Minn., expressed concern that “this paradigm shift to ‘TAVR for all’ ” could break the bank for many institutions because the cost of TAVR valves is far greater than for SAVR valves. But she was heartened by the fresh PARTNER 3 and Evolut Low Risk data showing TAVR patients had fewer ICU days, shorter hospital stays, fewer strokes, more frequent discharge home, and a lower rehospitalization rate.
Dr. Reardon was reassuring on this score.
“I am 100% convinced that when we do the financials for these two trials, TAVR is going to be a cost saver and a huge winner,” the surgeon said.
He reported serving as a consultant to Medtronic and receiving research grants from Medtronic and Boston Scientific. Dr. Leon reported receiving research grants from Edwards Lifesciences and St. Jude Medical and acting as a consultant to several medical device companies.
The two trials have been published online by the New England Journal of Medicine.
SOURCES: Leon MB et al. N Engl J Med. 2019 Mar 16. doi: 10.1056/NEJMoa1814052; Reardon MJ et al. N Engl J Med. 2019 Mar 16. doi: 10.1056/NEJMoa1816885.
REPORTING FROM ACC 19