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Opioid crisis brings bonanza for headache research
SAN FRANCISCO – Congressional funding of the National Institutes of Health’s HEAL Initiative represents an unprecedented golden opportunity for research funding on headache and other pain conditions, according to Michael L. Oshinsky, PhD, a neurobiologist who serves as program director for pain and migraine at the National Institute of Neurological Disorders and Stroke (NINDS).
“This is a once-in-a-lifetime opportunity for physician researchers and basic science researchers to identify projects and request funding from NIH. This is an amount of money that doesn’t come along very often. It’s really a once in a lifetime situation, and I implore you to take advantage of this tremendous opportunity,” he urged attendees at the annual meeting of the American Headache Society.
Congress gave the NIH $500 million for the HEAL (Helping to End Addiction Long-term) Initiative to be spent over the course of fiscal years 2018 and 2019. The money is to be split equally on the initiative’s two components: opioid use disorder and pain management.
“We’re going to spend $250 million on pain, be sure of it,” Dr. Oshinsky promised.
Pain management issues cut across all 27 NIH institutes and centers. However, the biggest chunk of the money goes to NINDS, which leads the NIH Pain Consortium, charged with enhancing pain research and promoting collaboration across NIH.
Within NINDS, funding for migraine research has been formally designated as an HPP, or high program priority, according to Dr. Oshinsky.
“Headache research gets funded. It really does. I want to dispel the myth that there isn’t an interest in headache research or migraine research at NIH. Currently, at NINDS, we have more than 60 funded projects that specifically address scientific questions about migraine and headache. That’s more than any other government in the world,” he said.
And it’s not all basic science research related to headache that NINDS is interested in fostering, either. The institute is eager to fund large clinical trials, pediatric headache research, studies of device therapies, and a wealth of other projects.
Among the HEAL initiatives that have already been approved is a project aimed at identifying and validating new pain targets. Another is focused upon finding risk factors with clinically meaningful predictive value for transition from acute to chronic pain, be they biomarkers, imaging findings, or genetic characteristics. Yet another program is an NIH-industry collaboration that aims to identify new treatments for pain that are nonaddictive, nonrewarding, nonsedating, and safe across age groups; candidate biologics, small molecules, devices, and natural products will be screened in vitro and in animal models, with the successful ones moving on to clinical trials.
Funding opportunity announcements are imminent for creation of a planned NIH clinical trials network for pain research, which will conduct phase 2 trials in specialized pain centers. The focus will be on well-characterized pain conditions with high unmet medical need, including headache as well as orofacial, pelvic, gastrointestinal, and cancer pain.
Dr. Oshinsky encouraged academicians to have their fellows apply for the NIH early career development awards known as K awards.
“They are much easier to get than R01 awards and they provide a tremendous opportunity for jump-starting the career of new scientists in the headache field. Have them reach out to me. I can help them through the process, help them develop their project, and get them funded with a K award. And the transition from a K award to an R01 is a much smoother transition,” he said.
Research funding proposals should use the NINDS Common Data Elements for headache, recently updated by more than 40 experts in headache medicine and research.
Dr. Oshinsky said most of the new pain management programs will be funded in fiscal year 2019. These novel programs have to be approved by oversight committees, and that takes time. The reason that the bulk of HEAL Initiative funding in fiscal year 2018 is going for opioid use disorder is that much of that money is being spent on expansion of existing programs, which can quickly be ramped up without the same degree of oversight required for new programs.
SAN FRANCISCO – Congressional funding of the National Institutes of Health’s HEAL Initiative represents an unprecedented golden opportunity for research funding on headache and other pain conditions, according to Michael L. Oshinsky, PhD, a neurobiologist who serves as program director for pain and migraine at the National Institute of Neurological Disorders and Stroke (NINDS).
“This is a once-in-a-lifetime opportunity for physician researchers and basic science researchers to identify projects and request funding from NIH. This is an amount of money that doesn’t come along very often. It’s really a once in a lifetime situation, and I implore you to take advantage of this tremendous opportunity,” he urged attendees at the annual meeting of the American Headache Society.
Congress gave the NIH $500 million for the HEAL (Helping to End Addiction Long-term) Initiative to be spent over the course of fiscal years 2018 and 2019. The money is to be split equally on the initiative’s two components: opioid use disorder and pain management.
“We’re going to spend $250 million on pain, be sure of it,” Dr. Oshinsky promised.
Pain management issues cut across all 27 NIH institutes and centers. However, the biggest chunk of the money goes to NINDS, which leads the NIH Pain Consortium, charged with enhancing pain research and promoting collaboration across NIH.
Within NINDS, funding for migraine research has been formally designated as an HPP, or high program priority, according to Dr. Oshinsky.
“Headache research gets funded. It really does. I want to dispel the myth that there isn’t an interest in headache research or migraine research at NIH. Currently, at NINDS, we have more than 60 funded projects that specifically address scientific questions about migraine and headache. That’s more than any other government in the world,” he said.
And it’s not all basic science research related to headache that NINDS is interested in fostering, either. The institute is eager to fund large clinical trials, pediatric headache research, studies of device therapies, and a wealth of other projects.
Among the HEAL initiatives that have already been approved is a project aimed at identifying and validating new pain targets. Another is focused upon finding risk factors with clinically meaningful predictive value for transition from acute to chronic pain, be they biomarkers, imaging findings, or genetic characteristics. Yet another program is an NIH-industry collaboration that aims to identify new treatments for pain that are nonaddictive, nonrewarding, nonsedating, and safe across age groups; candidate biologics, small molecules, devices, and natural products will be screened in vitro and in animal models, with the successful ones moving on to clinical trials.
Funding opportunity announcements are imminent for creation of a planned NIH clinical trials network for pain research, which will conduct phase 2 trials in specialized pain centers. The focus will be on well-characterized pain conditions with high unmet medical need, including headache as well as orofacial, pelvic, gastrointestinal, and cancer pain.
Dr. Oshinsky encouraged academicians to have their fellows apply for the NIH early career development awards known as K awards.
“They are much easier to get than R01 awards and they provide a tremendous opportunity for jump-starting the career of new scientists in the headache field. Have them reach out to me. I can help them through the process, help them develop their project, and get them funded with a K award. And the transition from a K award to an R01 is a much smoother transition,” he said.
Research funding proposals should use the NINDS Common Data Elements for headache, recently updated by more than 40 experts in headache medicine and research.
Dr. Oshinsky said most of the new pain management programs will be funded in fiscal year 2019. These novel programs have to be approved by oversight committees, and that takes time. The reason that the bulk of HEAL Initiative funding in fiscal year 2018 is going for opioid use disorder is that much of that money is being spent on expansion of existing programs, which can quickly be ramped up without the same degree of oversight required for new programs.
SAN FRANCISCO – Congressional funding of the National Institutes of Health’s HEAL Initiative represents an unprecedented golden opportunity for research funding on headache and other pain conditions, according to Michael L. Oshinsky, PhD, a neurobiologist who serves as program director for pain and migraine at the National Institute of Neurological Disorders and Stroke (NINDS).
“This is a once-in-a-lifetime opportunity for physician researchers and basic science researchers to identify projects and request funding from NIH. This is an amount of money that doesn’t come along very often. It’s really a once in a lifetime situation, and I implore you to take advantage of this tremendous opportunity,” he urged attendees at the annual meeting of the American Headache Society.
Congress gave the NIH $500 million for the HEAL (Helping to End Addiction Long-term) Initiative to be spent over the course of fiscal years 2018 and 2019. The money is to be split equally on the initiative’s two components: opioid use disorder and pain management.
“We’re going to spend $250 million on pain, be sure of it,” Dr. Oshinsky promised.
Pain management issues cut across all 27 NIH institutes and centers. However, the biggest chunk of the money goes to NINDS, which leads the NIH Pain Consortium, charged with enhancing pain research and promoting collaboration across NIH.
Within NINDS, funding for migraine research has been formally designated as an HPP, or high program priority, according to Dr. Oshinsky.
“Headache research gets funded. It really does. I want to dispel the myth that there isn’t an interest in headache research or migraine research at NIH. Currently, at NINDS, we have more than 60 funded projects that specifically address scientific questions about migraine and headache. That’s more than any other government in the world,” he said.
And it’s not all basic science research related to headache that NINDS is interested in fostering, either. The institute is eager to fund large clinical trials, pediatric headache research, studies of device therapies, and a wealth of other projects.
Among the HEAL initiatives that have already been approved is a project aimed at identifying and validating new pain targets. Another is focused upon finding risk factors with clinically meaningful predictive value for transition from acute to chronic pain, be they biomarkers, imaging findings, or genetic characteristics. Yet another program is an NIH-industry collaboration that aims to identify new treatments for pain that are nonaddictive, nonrewarding, nonsedating, and safe across age groups; candidate biologics, small molecules, devices, and natural products will be screened in vitro and in animal models, with the successful ones moving on to clinical trials.
Funding opportunity announcements are imminent for creation of a planned NIH clinical trials network for pain research, which will conduct phase 2 trials in specialized pain centers. The focus will be on well-characterized pain conditions with high unmet medical need, including headache as well as orofacial, pelvic, gastrointestinal, and cancer pain.
Dr. Oshinsky encouraged academicians to have their fellows apply for the NIH early career development awards known as K awards.
“They are much easier to get than R01 awards and they provide a tremendous opportunity for jump-starting the career of new scientists in the headache field. Have them reach out to me. I can help them through the process, help them develop their project, and get them funded with a K award. And the transition from a K award to an R01 is a much smoother transition,” he said.
Research funding proposals should use the NINDS Common Data Elements for headache, recently updated by more than 40 experts in headache medicine and research.
Dr. Oshinsky said most of the new pain management programs will be funded in fiscal year 2019. These novel programs have to be approved by oversight committees, and that takes time. The reason that the bulk of HEAL Initiative funding in fiscal year 2018 is going for opioid use disorder is that much of that money is being spent on expansion of existing programs, which can quickly be ramped up without the same degree of oversight required for new programs.
REPORTING FROM THE AHS ANNUAL MEETING
Internist comanagement of orthopedic inpatients boosts outcomes
NEW ORLEANS – Comanagement of orthopedic inpatients by an internist or hospitalist can improve outcomes in myriad ways, Mary Anderson Wallace, MD, said at the annual meeting of the American College of Physicians.
She focused on patients undergoing total hip or knee arthroplasty (THA/TKA). In 2014, there were 400,000 of them under Medicare alone, accounting for $7 billion in hospitalization costs and nearly as much again in the cost of related postdischarge care.
So, changes in management that improve key outcomes in this population by even a small increment reap huge benefits when spread across this enormous patient population, noted Dr. Wallace, an internist and hospitalist at the University of Colorado, Denver.
Among the examples she highlighted where comanagement can have a favorable impact were optimization of perioperative pain management pathways; how to handle the use of disease-modifying antirheumatic drugs (DMARDs) in patients undergoing THA/TKA; the latest thinking on the appropriateness of low-dose aspirin for deep vein thrombosis (DVT) prophylaxis; a simple way to predict postop delirium in older individuals without known dementia; how to decide which postoperative fevers warrant a costly infectious disease workup; and the optimal wait time from arrival at the hospital with a fractured hip and THA.
These are all issues where a well-informed internist/hospitalist can be of enormous assistance to a busy orthopedic surgeon in providing high-value care, she explained.
Optimizing perioperative pain management pathways
As of 2015, orthopedists ranked as the third highest prescribers of opioids. Impressively, a retrospective cohort study of 641,941 opioid-naive, privately insured patients undergoing 1 of 11 types of surgery demonstrated that TKA was associated with a 5.1-fold increased risk for subsequent chronic opioid use in the first year after surgery, compared with 18 million opioid-naive nonsurgical controls. Indeed, TKA was the highest-risk of the 11 surgical procedures examined (JAMA Intern Med. 2016 Sep 1;176[9]:1286-93).
Another study that points to a need to develop best practices for opioid prescribing in orthopedic surgery – and other types of surgery as well – was a systematic review of six studies of patients who received prescription opioid analgesics in conjunction with seven types of surgery.
Opioid oversupply was identified as a clear problem: 67%-92% of patients in the six studies reported unused opioids. Up to 71% of opioid tablets went unused, mainly because patients felt they’d achieved adequate pain control and didn’t need them. Rates of safe disposal of unused opioids were in the single digits, suggesting that overprescribing provides a large potential reservoir of opioids that can be diverted to nonmedical use (JAMA Surg. 2017 Nov 1;152[11]:1066-71).
Moreover, a recent retrospective study of more than 1 million opioid-naive patients undergoing surgery showed that 56% of them received postoperative opioids. And each additional week of use was associated with a 44% increase in the relative risk of the composite endpoint of opioid dependence, abuse, or overdose. Duration of opioid use was a stronger predictor of this adverse outcome than was dosage (BMJ. 2018 Jan 17;360:j5790).
Other studies have shown that multimodal analgesia is utilized in only 25%-50% of surgical patients, even though it is considered the standard of care. Only 20% of patients undergoing THA/TKA receive peripheral nerve and neuraxial blocks. So, there is an opportunity for optimization of perioperative pain management pathways in orthopedic surgery patients, including avoidance of unnecessary p.r.n. prescribing, to favorably impact the national opioid epidemic, Dr. Wallace observed.
A surprise benefit of multimodal pain management that includes acetaminophen and a nonsteroidal anti-inflammatory agent is that it markedly reduces the incidence of postoperative fevers after total joint arthroplasty, compared with opioid-based pain management.
That was demonstrated in a retrospective study of 2,417 THA/TKAs in which multimodal pain management was used, and 1,484 procedures that relied on opioid-based pain relief. All of the operations were performed by the same three orthopedic surgeons. Only 5% of patients in the multimodal pain management group developed a fever greater than 38.5 degrees Celsius during the first 5 postoperative days, compared with 25% of those in the opioid-based analgesia group.
Moreover, an infectious disease workup was ordered in 2% of the multimodal analgesia group, versus 10% in the opioid-based pain management cohort, with no difference in the positive workup rates between the two groups (Clin Orthop Relat Res. 2014 May;472[5]:1489-95).
“It’s interesting that multimodal pain management has the side effect of putting you in a better position to practice high-value care, with less fever and fewer infectious disease workups,” Dr. Wallace said.
Perioperative management of DMARDs
Recent joint guidelines from the American College of Rheumatology and American Association of Hip and Knee Surgeons specifically address this issue in patients undergoing elective joint replacement (Arthritis Rheumatol. 2017 Aug;69[8]:1538-51).
“The quality of evidence isn’t high, but at least it’s a starting point,” Dr. Wallace said.
Patients with rheumatoid arthritis, systemic lupus erythematosus, spondyloarthropathies, and other rheumatic diseases who are on methotrexate or other nonbiologic DMARDs should be maintained on their current dose, according to the guidelines.
In contrast, all biologic agents should be withheld prior to surgery, which should be scheduled to coincide with the end of the dosing cycle for that specific biologic. The biologic agent should be resumed only once adequate wound healing has occurred, typically about 14 days post-THA/TKA.
Patients on daily glucocorticoids should continue on their current dose; supraphysiologic stress dosing is to be avoided.
Low-dose aspirin for VTE prophylaxis
“It seems like nothing has been such an enduring controversy in the comanagement literature as the question of whether aspirin is an effective prophylactic agent for prevention of DVT post THA/TKA,” according to Dr. Wallace.
She noted that in the space of just 4 years between the eighth and ninth editions of the American College of Chest Physician guidelines, that organization underwent a 180-degree reversal on the issue – whipsawing from a grade 1A recommendation against aspirin in 2008 to a 1B recommendation for it in 2012.
The literature is increasingly supportive of the use of aspirin for venous thromboembolism (VTE) prophylaxis in low-risk THA/TKA patients. Separate guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and the Surgical Care Improvement Project, as well as the chest physicians, support the practice.
The hitch is that there is as yet no single validated risk-stratification protocol. AAOS recommends 325 mg of aspirin twice daily for 6 weeks. But a prospective crossover study of more than 4,600 total joint arthroplasty patients conducted by investigators at Thomas Jefferson University in Philadelphia showed that 81 mg BID for 4 weeks was just as effective as was 325 mg b.i.d., albeit with an incidence of GI bleeding that to their surprise wasn’t significantly lower (J Bone Joint Surg Am. 2017 Jan 18;99[2]:91-8).
Dr. Wallace anticipates definitive answers on VTE prophylaxis to come from the ongoing Patient-Centered Outcomes Research Institute-supported PEPPER (Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement) trial. In that study, roughly 25,000 patients undergoing THA/TKA are being randomized to prophylactic aspirin at 81 mg b.i.d., warfarin at an International Normalized Ratio of 2.0, or rivaroxaban (Xarelto). Endpoints include mortality, VTE, and bleeding. Results are expected in 2021.
Preoperative prediction of postop delirium
Unrecognized preoperative cognitive impairment in older patients without dementia who are undergoing THA/TKA is a common and powerful risk factor for postop delirium and other complications, as demonstrated recently by investigators at Harvard University and affiliated hospitals.
They had 211 patients aged 65 or older, none with known dementia, take the Mini-Cog screening test prior to their surgery. Fully 24% had probable cognitive impairment as reflected in a score of 2 or less out of a possible 5 points on this simple test, which consists of a three-word recall and clock drawing.
“I was very surprised at this high rate. These are patients who are at risk for delirium in the hospital when you’re taking care of them,” Dr. Wallace observed.
In the Harvard study, the incidence of postop delirium was 21% in patients with a Mini-Cog score of 2 or less, compared with 7% who scored 3-5, for an odds ratio of 4.5 in an age-adjusted multivariate analysis. Moreover, 67% of the low scorers were discharged somewhere other than home, in contrast to 34% of patients with a preop Mini-Cog score of 3-5, for an adjusted 3.9-fold increased risk. The group with a Mini-Cog score of 2 or less also had a significantly longer hospital length of stay (Anesthesiology. 2017 Nov;127[5]:765-74).
Perioperative gabapentin is often added to the medication regimen of older surgical patients to reduce postop delirium. The latest evidence indicates that doesn’t work, as demonstrated in a recent 697-patient randomized trial. The incidence of delirium during the first 3 days post surgery as measured by the Confusion Assessment Method was 22.4% in patients randomized to 900 mg of gabapentin per day, and 20.8% with placebo. Nearly 200 participants had THA or TKA, and in that subgroup, there was an even stronger – albeit still not statistically significant – trend for a higher delirium rate with gabapentin than with placebo (Anesthesiology. 2017 Oct.127[4]:633-44).
“Think twice about adding gabapentin to the pain regimen for THA/TKA/spine patients for the purpose of preventing postop delirium,” she advised.
When is postop fever a concern?
Up to half of patients develop fever early after THA/TKA. In most cases, this is a self-limited ancillary effect of cytokine release, with the temperature peaking on postop day 1-2.
Three strong predictors of a positive infectious disease workup are fever after postop day 3, with an associated 23.3-fold increased risk; multiple days of fever, with an odds ratio of 8.6; and a maximum temperature greater than 39.0 degrees Celsius, with a 2.4-fold increased risk. In this 7-year-old study, the cost of infectious disease workup per change in patient management was a hefty $8,209 (J Arthroplasty. 2010 Sep;25[6 Suppl]:43-8).
A retrospective study of nearly 125,000 THA/TKA patients in the American College of Surgeons National Surgical Quality Improvement Program database has important implications for clinical surveillance for postop adverse events. Stroke occurred early, on median postop day 1. The median time of acute MI and pulmonary embolism was postop day 3, and pneumonia day 4.
The key take-home message was that the median time to DVT was postop day 6, by which point most patients had been discharged. Thus, 60% of postoperative DVTs occurred after discharge. And the time to diagnosis of DVT differed markedly by surgical procedure: The median day of diagnosis was day 5 in TKA patients, compared with day 13 for THA patients. Sixty-eight percent of urinary tract infections occurred post discharge. Sepsis occurred on median day 10 post surgery, surgical site infections on day 17 (Clin Orthop Relat Res. 2017 Dec;475[12]:2952-9).
In light of ever-shortening hospital lengths of stay, Dr. Wallace noted, the findings underscore the importance of comprehensive predischarge patient counseling.
Optimal time window for hip fracture surgery
AAOS guidelines recommend that hip fracture surgery should take place within 48 hours, assuming medical comorbidities are stabilized, because complication rates go up with longer wait times.
But that is controversial. A University of Toronto retrospective cohort study of 42,430 adults with hip fracture treated at 72 Canadian hospitals during 2009-2014 found that the inflection point was 24 hours. Among 13,731 patients whose elapsed time from hospital arrival to surgery was 24 hours or less, 30-day mortality was 5.8%, significantly less than the 6.5% rate in an equal number of propensity score–matched patients with a longer wait time.
The 90- and 365-day mortality rates in the patients who received surgery within 24 hours were 10.7% and 19.3%, both significantly lower than the 12.0% and 21.6% figures in patients with longer wait times.
For the 30-day composite outcome of death, myocardial infarction, pulmonary embolism, DVT, or pneumonia, the rates were 10.1% and 12.2% – again, statistically significant and clinically meaningful. The 90- and 365-day composite outcomes followed suit (JAMA. 2017 Nov 28;318[20]:1994-2003).
But the Canadian study won’t be the final word. The ongoing international multicenter HIP ATTACK (Hip Fracture Accelerated Surgical Treatment and Care Track) trial is comparing outcomes in 3,000 patients randomized to hip fracture surgery within 6 hours versus 24 hours. Endpoints include mortality, myocardial infarction, pulmonary embolism, pneumonia, stroke, sepsis, and life-threatening and major bleeding.
Dr. Wallace reported having no financial conflicts regarding her presentation.
NEW ORLEANS – Comanagement of orthopedic inpatients by an internist or hospitalist can improve outcomes in myriad ways, Mary Anderson Wallace, MD, said at the annual meeting of the American College of Physicians.
She focused on patients undergoing total hip or knee arthroplasty (THA/TKA). In 2014, there were 400,000 of them under Medicare alone, accounting for $7 billion in hospitalization costs and nearly as much again in the cost of related postdischarge care.
So, changes in management that improve key outcomes in this population by even a small increment reap huge benefits when spread across this enormous patient population, noted Dr. Wallace, an internist and hospitalist at the University of Colorado, Denver.
Among the examples she highlighted where comanagement can have a favorable impact were optimization of perioperative pain management pathways; how to handle the use of disease-modifying antirheumatic drugs (DMARDs) in patients undergoing THA/TKA; the latest thinking on the appropriateness of low-dose aspirin for deep vein thrombosis (DVT) prophylaxis; a simple way to predict postop delirium in older individuals without known dementia; how to decide which postoperative fevers warrant a costly infectious disease workup; and the optimal wait time from arrival at the hospital with a fractured hip and THA.
These are all issues where a well-informed internist/hospitalist can be of enormous assistance to a busy orthopedic surgeon in providing high-value care, she explained.
Optimizing perioperative pain management pathways
As of 2015, orthopedists ranked as the third highest prescribers of opioids. Impressively, a retrospective cohort study of 641,941 opioid-naive, privately insured patients undergoing 1 of 11 types of surgery demonstrated that TKA was associated with a 5.1-fold increased risk for subsequent chronic opioid use in the first year after surgery, compared with 18 million opioid-naive nonsurgical controls. Indeed, TKA was the highest-risk of the 11 surgical procedures examined (JAMA Intern Med. 2016 Sep 1;176[9]:1286-93).
Another study that points to a need to develop best practices for opioid prescribing in orthopedic surgery – and other types of surgery as well – was a systematic review of six studies of patients who received prescription opioid analgesics in conjunction with seven types of surgery.
Opioid oversupply was identified as a clear problem: 67%-92% of patients in the six studies reported unused opioids. Up to 71% of opioid tablets went unused, mainly because patients felt they’d achieved adequate pain control and didn’t need them. Rates of safe disposal of unused opioids were in the single digits, suggesting that overprescribing provides a large potential reservoir of opioids that can be diverted to nonmedical use (JAMA Surg. 2017 Nov 1;152[11]:1066-71).
Moreover, a recent retrospective study of more than 1 million opioid-naive patients undergoing surgery showed that 56% of them received postoperative opioids. And each additional week of use was associated with a 44% increase in the relative risk of the composite endpoint of opioid dependence, abuse, or overdose. Duration of opioid use was a stronger predictor of this adverse outcome than was dosage (BMJ. 2018 Jan 17;360:j5790).
Other studies have shown that multimodal analgesia is utilized in only 25%-50% of surgical patients, even though it is considered the standard of care. Only 20% of patients undergoing THA/TKA receive peripheral nerve and neuraxial blocks. So, there is an opportunity for optimization of perioperative pain management pathways in orthopedic surgery patients, including avoidance of unnecessary p.r.n. prescribing, to favorably impact the national opioid epidemic, Dr. Wallace observed.
A surprise benefit of multimodal pain management that includes acetaminophen and a nonsteroidal anti-inflammatory agent is that it markedly reduces the incidence of postoperative fevers after total joint arthroplasty, compared with opioid-based pain management.
That was demonstrated in a retrospective study of 2,417 THA/TKAs in which multimodal pain management was used, and 1,484 procedures that relied on opioid-based pain relief. All of the operations were performed by the same three orthopedic surgeons. Only 5% of patients in the multimodal pain management group developed a fever greater than 38.5 degrees Celsius during the first 5 postoperative days, compared with 25% of those in the opioid-based analgesia group.
Moreover, an infectious disease workup was ordered in 2% of the multimodal analgesia group, versus 10% in the opioid-based pain management cohort, with no difference in the positive workup rates between the two groups (Clin Orthop Relat Res. 2014 May;472[5]:1489-95).
“It’s interesting that multimodal pain management has the side effect of putting you in a better position to practice high-value care, with less fever and fewer infectious disease workups,” Dr. Wallace said.
Perioperative management of DMARDs
Recent joint guidelines from the American College of Rheumatology and American Association of Hip and Knee Surgeons specifically address this issue in patients undergoing elective joint replacement (Arthritis Rheumatol. 2017 Aug;69[8]:1538-51).
“The quality of evidence isn’t high, but at least it’s a starting point,” Dr. Wallace said.
Patients with rheumatoid arthritis, systemic lupus erythematosus, spondyloarthropathies, and other rheumatic diseases who are on methotrexate or other nonbiologic DMARDs should be maintained on their current dose, according to the guidelines.
In contrast, all biologic agents should be withheld prior to surgery, which should be scheduled to coincide with the end of the dosing cycle for that specific biologic. The biologic agent should be resumed only once adequate wound healing has occurred, typically about 14 days post-THA/TKA.
Patients on daily glucocorticoids should continue on their current dose; supraphysiologic stress dosing is to be avoided.
Low-dose aspirin for VTE prophylaxis
“It seems like nothing has been such an enduring controversy in the comanagement literature as the question of whether aspirin is an effective prophylactic agent for prevention of DVT post THA/TKA,” according to Dr. Wallace.
She noted that in the space of just 4 years between the eighth and ninth editions of the American College of Chest Physician guidelines, that organization underwent a 180-degree reversal on the issue – whipsawing from a grade 1A recommendation against aspirin in 2008 to a 1B recommendation for it in 2012.
The literature is increasingly supportive of the use of aspirin for venous thromboembolism (VTE) prophylaxis in low-risk THA/TKA patients. Separate guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and the Surgical Care Improvement Project, as well as the chest physicians, support the practice.
The hitch is that there is as yet no single validated risk-stratification protocol. AAOS recommends 325 mg of aspirin twice daily for 6 weeks. But a prospective crossover study of more than 4,600 total joint arthroplasty patients conducted by investigators at Thomas Jefferson University in Philadelphia showed that 81 mg BID for 4 weeks was just as effective as was 325 mg b.i.d., albeit with an incidence of GI bleeding that to their surprise wasn’t significantly lower (J Bone Joint Surg Am. 2017 Jan 18;99[2]:91-8).
Dr. Wallace anticipates definitive answers on VTE prophylaxis to come from the ongoing Patient-Centered Outcomes Research Institute-supported PEPPER (Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement) trial. In that study, roughly 25,000 patients undergoing THA/TKA are being randomized to prophylactic aspirin at 81 mg b.i.d., warfarin at an International Normalized Ratio of 2.0, or rivaroxaban (Xarelto). Endpoints include mortality, VTE, and bleeding. Results are expected in 2021.
Preoperative prediction of postop delirium
Unrecognized preoperative cognitive impairment in older patients without dementia who are undergoing THA/TKA is a common and powerful risk factor for postop delirium and other complications, as demonstrated recently by investigators at Harvard University and affiliated hospitals.
They had 211 patients aged 65 or older, none with known dementia, take the Mini-Cog screening test prior to their surgery. Fully 24% had probable cognitive impairment as reflected in a score of 2 or less out of a possible 5 points on this simple test, which consists of a three-word recall and clock drawing.
“I was very surprised at this high rate. These are patients who are at risk for delirium in the hospital when you’re taking care of them,” Dr. Wallace observed.
In the Harvard study, the incidence of postop delirium was 21% in patients with a Mini-Cog score of 2 or less, compared with 7% who scored 3-5, for an odds ratio of 4.5 in an age-adjusted multivariate analysis. Moreover, 67% of the low scorers were discharged somewhere other than home, in contrast to 34% of patients with a preop Mini-Cog score of 3-5, for an adjusted 3.9-fold increased risk. The group with a Mini-Cog score of 2 or less also had a significantly longer hospital length of stay (Anesthesiology. 2017 Nov;127[5]:765-74).
Perioperative gabapentin is often added to the medication regimen of older surgical patients to reduce postop delirium. The latest evidence indicates that doesn’t work, as demonstrated in a recent 697-patient randomized trial. The incidence of delirium during the first 3 days post surgery as measured by the Confusion Assessment Method was 22.4% in patients randomized to 900 mg of gabapentin per day, and 20.8% with placebo. Nearly 200 participants had THA or TKA, and in that subgroup, there was an even stronger – albeit still not statistically significant – trend for a higher delirium rate with gabapentin than with placebo (Anesthesiology. 2017 Oct.127[4]:633-44).
“Think twice about adding gabapentin to the pain regimen for THA/TKA/spine patients for the purpose of preventing postop delirium,” she advised.
When is postop fever a concern?
Up to half of patients develop fever early after THA/TKA. In most cases, this is a self-limited ancillary effect of cytokine release, with the temperature peaking on postop day 1-2.
Three strong predictors of a positive infectious disease workup are fever after postop day 3, with an associated 23.3-fold increased risk; multiple days of fever, with an odds ratio of 8.6; and a maximum temperature greater than 39.0 degrees Celsius, with a 2.4-fold increased risk. In this 7-year-old study, the cost of infectious disease workup per change in patient management was a hefty $8,209 (J Arthroplasty. 2010 Sep;25[6 Suppl]:43-8).
A retrospective study of nearly 125,000 THA/TKA patients in the American College of Surgeons National Surgical Quality Improvement Program database has important implications for clinical surveillance for postop adverse events. Stroke occurred early, on median postop day 1. The median time of acute MI and pulmonary embolism was postop day 3, and pneumonia day 4.
The key take-home message was that the median time to DVT was postop day 6, by which point most patients had been discharged. Thus, 60% of postoperative DVTs occurred after discharge. And the time to diagnosis of DVT differed markedly by surgical procedure: The median day of diagnosis was day 5 in TKA patients, compared with day 13 for THA patients. Sixty-eight percent of urinary tract infections occurred post discharge. Sepsis occurred on median day 10 post surgery, surgical site infections on day 17 (Clin Orthop Relat Res. 2017 Dec;475[12]:2952-9).
In light of ever-shortening hospital lengths of stay, Dr. Wallace noted, the findings underscore the importance of comprehensive predischarge patient counseling.
Optimal time window for hip fracture surgery
AAOS guidelines recommend that hip fracture surgery should take place within 48 hours, assuming medical comorbidities are stabilized, because complication rates go up with longer wait times.
But that is controversial. A University of Toronto retrospective cohort study of 42,430 adults with hip fracture treated at 72 Canadian hospitals during 2009-2014 found that the inflection point was 24 hours. Among 13,731 patients whose elapsed time from hospital arrival to surgery was 24 hours or less, 30-day mortality was 5.8%, significantly less than the 6.5% rate in an equal number of propensity score–matched patients with a longer wait time.
The 90- and 365-day mortality rates in the patients who received surgery within 24 hours were 10.7% and 19.3%, both significantly lower than the 12.0% and 21.6% figures in patients with longer wait times.
For the 30-day composite outcome of death, myocardial infarction, pulmonary embolism, DVT, or pneumonia, the rates were 10.1% and 12.2% – again, statistically significant and clinically meaningful. The 90- and 365-day composite outcomes followed suit (JAMA. 2017 Nov 28;318[20]:1994-2003).
But the Canadian study won’t be the final word. The ongoing international multicenter HIP ATTACK (Hip Fracture Accelerated Surgical Treatment and Care Track) trial is comparing outcomes in 3,000 patients randomized to hip fracture surgery within 6 hours versus 24 hours. Endpoints include mortality, myocardial infarction, pulmonary embolism, pneumonia, stroke, sepsis, and life-threatening and major bleeding.
Dr. Wallace reported having no financial conflicts regarding her presentation.
NEW ORLEANS – Comanagement of orthopedic inpatients by an internist or hospitalist can improve outcomes in myriad ways, Mary Anderson Wallace, MD, said at the annual meeting of the American College of Physicians.
She focused on patients undergoing total hip or knee arthroplasty (THA/TKA). In 2014, there were 400,000 of them under Medicare alone, accounting for $7 billion in hospitalization costs and nearly as much again in the cost of related postdischarge care.
So, changes in management that improve key outcomes in this population by even a small increment reap huge benefits when spread across this enormous patient population, noted Dr. Wallace, an internist and hospitalist at the University of Colorado, Denver.
Among the examples she highlighted where comanagement can have a favorable impact were optimization of perioperative pain management pathways; how to handle the use of disease-modifying antirheumatic drugs (DMARDs) in patients undergoing THA/TKA; the latest thinking on the appropriateness of low-dose aspirin for deep vein thrombosis (DVT) prophylaxis; a simple way to predict postop delirium in older individuals without known dementia; how to decide which postoperative fevers warrant a costly infectious disease workup; and the optimal wait time from arrival at the hospital with a fractured hip and THA.
These are all issues where a well-informed internist/hospitalist can be of enormous assistance to a busy orthopedic surgeon in providing high-value care, she explained.
Optimizing perioperative pain management pathways
As of 2015, orthopedists ranked as the third highest prescribers of opioids. Impressively, a retrospective cohort study of 641,941 opioid-naive, privately insured patients undergoing 1 of 11 types of surgery demonstrated that TKA was associated with a 5.1-fold increased risk for subsequent chronic opioid use in the first year after surgery, compared with 18 million opioid-naive nonsurgical controls. Indeed, TKA was the highest-risk of the 11 surgical procedures examined (JAMA Intern Med. 2016 Sep 1;176[9]:1286-93).
Another study that points to a need to develop best practices for opioid prescribing in orthopedic surgery – and other types of surgery as well – was a systematic review of six studies of patients who received prescription opioid analgesics in conjunction with seven types of surgery.
Opioid oversupply was identified as a clear problem: 67%-92% of patients in the six studies reported unused opioids. Up to 71% of opioid tablets went unused, mainly because patients felt they’d achieved adequate pain control and didn’t need them. Rates of safe disposal of unused opioids were in the single digits, suggesting that overprescribing provides a large potential reservoir of opioids that can be diverted to nonmedical use (JAMA Surg. 2017 Nov 1;152[11]:1066-71).
Moreover, a recent retrospective study of more than 1 million opioid-naive patients undergoing surgery showed that 56% of them received postoperative opioids. And each additional week of use was associated with a 44% increase in the relative risk of the composite endpoint of opioid dependence, abuse, or overdose. Duration of opioid use was a stronger predictor of this adverse outcome than was dosage (BMJ. 2018 Jan 17;360:j5790).
Other studies have shown that multimodal analgesia is utilized in only 25%-50% of surgical patients, even though it is considered the standard of care. Only 20% of patients undergoing THA/TKA receive peripheral nerve and neuraxial blocks. So, there is an opportunity for optimization of perioperative pain management pathways in orthopedic surgery patients, including avoidance of unnecessary p.r.n. prescribing, to favorably impact the national opioid epidemic, Dr. Wallace observed.
A surprise benefit of multimodal pain management that includes acetaminophen and a nonsteroidal anti-inflammatory agent is that it markedly reduces the incidence of postoperative fevers after total joint arthroplasty, compared with opioid-based pain management.
That was demonstrated in a retrospective study of 2,417 THA/TKAs in which multimodal pain management was used, and 1,484 procedures that relied on opioid-based pain relief. All of the operations were performed by the same three orthopedic surgeons. Only 5% of patients in the multimodal pain management group developed a fever greater than 38.5 degrees Celsius during the first 5 postoperative days, compared with 25% of those in the opioid-based analgesia group.
Moreover, an infectious disease workup was ordered in 2% of the multimodal analgesia group, versus 10% in the opioid-based pain management cohort, with no difference in the positive workup rates between the two groups (Clin Orthop Relat Res. 2014 May;472[5]:1489-95).
“It’s interesting that multimodal pain management has the side effect of putting you in a better position to practice high-value care, with less fever and fewer infectious disease workups,” Dr. Wallace said.
Perioperative management of DMARDs
Recent joint guidelines from the American College of Rheumatology and American Association of Hip and Knee Surgeons specifically address this issue in patients undergoing elective joint replacement (Arthritis Rheumatol. 2017 Aug;69[8]:1538-51).
“The quality of evidence isn’t high, but at least it’s a starting point,” Dr. Wallace said.
Patients with rheumatoid arthritis, systemic lupus erythematosus, spondyloarthropathies, and other rheumatic diseases who are on methotrexate or other nonbiologic DMARDs should be maintained on their current dose, according to the guidelines.
In contrast, all biologic agents should be withheld prior to surgery, which should be scheduled to coincide with the end of the dosing cycle for that specific biologic. The biologic agent should be resumed only once adequate wound healing has occurred, typically about 14 days post-THA/TKA.
Patients on daily glucocorticoids should continue on their current dose; supraphysiologic stress dosing is to be avoided.
Low-dose aspirin for VTE prophylaxis
“It seems like nothing has been such an enduring controversy in the comanagement literature as the question of whether aspirin is an effective prophylactic agent for prevention of DVT post THA/TKA,” according to Dr. Wallace.
She noted that in the space of just 4 years between the eighth and ninth editions of the American College of Chest Physician guidelines, that organization underwent a 180-degree reversal on the issue – whipsawing from a grade 1A recommendation against aspirin in 2008 to a 1B recommendation for it in 2012.
The literature is increasingly supportive of the use of aspirin for venous thromboembolism (VTE) prophylaxis in low-risk THA/TKA patients. Separate guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and the Surgical Care Improvement Project, as well as the chest physicians, support the practice.
The hitch is that there is as yet no single validated risk-stratification protocol. AAOS recommends 325 mg of aspirin twice daily for 6 weeks. But a prospective crossover study of more than 4,600 total joint arthroplasty patients conducted by investigators at Thomas Jefferson University in Philadelphia showed that 81 mg BID for 4 weeks was just as effective as was 325 mg b.i.d., albeit with an incidence of GI bleeding that to their surprise wasn’t significantly lower (J Bone Joint Surg Am. 2017 Jan 18;99[2]:91-8).
Dr. Wallace anticipates definitive answers on VTE prophylaxis to come from the ongoing Patient-Centered Outcomes Research Institute-supported PEPPER (Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement) trial. In that study, roughly 25,000 patients undergoing THA/TKA are being randomized to prophylactic aspirin at 81 mg b.i.d., warfarin at an International Normalized Ratio of 2.0, or rivaroxaban (Xarelto). Endpoints include mortality, VTE, and bleeding. Results are expected in 2021.
Preoperative prediction of postop delirium
Unrecognized preoperative cognitive impairment in older patients without dementia who are undergoing THA/TKA is a common and powerful risk factor for postop delirium and other complications, as demonstrated recently by investigators at Harvard University and affiliated hospitals.
They had 211 patients aged 65 or older, none with known dementia, take the Mini-Cog screening test prior to their surgery. Fully 24% had probable cognitive impairment as reflected in a score of 2 or less out of a possible 5 points on this simple test, which consists of a three-word recall and clock drawing.
“I was very surprised at this high rate. These are patients who are at risk for delirium in the hospital when you’re taking care of them,” Dr. Wallace observed.
In the Harvard study, the incidence of postop delirium was 21% in patients with a Mini-Cog score of 2 or less, compared with 7% who scored 3-5, for an odds ratio of 4.5 in an age-adjusted multivariate analysis. Moreover, 67% of the low scorers were discharged somewhere other than home, in contrast to 34% of patients with a preop Mini-Cog score of 3-5, for an adjusted 3.9-fold increased risk. The group with a Mini-Cog score of 2 or less also had a significantly longer hospital length of stay (Anesthesiology. 2017 Nov;127[5]:765-74).
Perioperative gabapentin is often added to the medication regimen of older surgical patients to reduce postop delirium. The latest evidence indicates that doesn’t work, as demonstrated in a recent 697-patient randomized trial. The incidence of delirium during the first 3 days post surgery as measured by the Confusion Assessment Method was 22.4% in patients randomized to 900 mg of gabapentin per day, and 20.8% with placebo. Nearly 200 participants had THA or TKA, and in that subgroup, there was an even stronger – albeit still not statistically significant – trend for a higher delirium rate with gabapentin than with placebo (Anesthesiology. 2017 Oct.127[4]:633-44).
“Think twice about adding gabapentin to the pain regimen for THA/TKA/spine patients for the purpose of preventing postop delirium,” she advised.
When is postop fever a concern?
Up to half of patients develop fever early after THA/TKA. In most cases, this is a self-limited ancillary effect of cytokine release, with the temperature peaking on postop day 1-2.
Three strong predictors of a positive infectious disease workup are fever after postop day 3, with an associated 23.3-fold increased risk; multiple days of fever, with an odds ratio of 8.6; and a maximum temperature greater than 39.0 degrees Celsius, with a 2.4-fold increased risk. In this 7-year-old study, the cost of infectious disease workup per change in patient management was a hefty $8,209 (J Arthroplasty. 2010 Sep;25[6 Suppl]:43-8).
A retrospective study of nearly 125,000 THA/TKA patients in the American College of Surgeons National Surgical Quality Improvement Program database has important implications for clinical surveillance for postop adverse events. Stroke occurred early, on median postop day 1. The median time of acute MI and pulmonary embolism was postop day 3, and pneumonia day 4.
The key take-home message was that the median time to DVT was postop day 6, by which point most patients had been discharged. Thus, 60% of postoperative DVTs occurred after discharge. And the time to diagnosis of DVT differed markedly by surgical procedure: The median day of diagnosis was day 5 in TKA patients, compared with day 13 for THA patients. Sixty-eight percent of urinary tract infections occurred post discharge. Sepsis occurred on median day 10 post surgery, surgical site infections on day 17 (Clin Orthop Relat Res. 2017 Dec;475[12]:2952-9).
In light of ever-shortening hospital lengths of stay, Dr. Wallace noted, the findings underscore the importance of comprehensive predischarge patient counseling.
Optimal time window for hip fracture surgery
AAOS guidelines recommend that hip fracture surgery should take place within 48 hours, assuming medical comorbidities are stabilized, because complication rates go up with longer wait times.
But that is controversial. A University of Toronto retrospective cohort study of 42,430 adults with hip fracture treated at 72 Canadian hospitals during 2009-2014 found that the inflection point was 24 hours. Among 13,731 patients whose elapsed time from hospital arrival to surgery was 24 hours or less, 30-day mortality was 5.8%, significantly less than the 6.5% rate in an equal number of propensity score–matched patients with a longer wait time.
The 90- and 365-day mortality rates in the patients who received surgery within 24 hours were 10.7% and 19.3%, both significantly lower than the 12.0% and 21.6% figures in patients with longer wait times.
For the 30-day composite outcome of death, myocardial infarction, pulmonary embolism, DVT, or pneumonia, the rates were 10.1% and 12.2% – again, statistically significant and clinically meaningful. The 90- and 365-day composite outcomes followed suit (JAMA. 2017 Nov 28;318[20]:1994-2003).
But the Canadian study won’t be the final word. The ongoing international multicenter HIP ATTACK (Hip Fracture Accelerated Surgical Treatment and Care Track) trial is comparing outcomes in 3,000 patients randomized to hip fracture surgery within 6 hours versus 24 hours. Endpoints include mortality, myocardial infarction, pulmonary embolism, pneumonia, stroke, sepsis, and life-threatening and major bleeding.
Dr. Wallace reported having no financial conflicts regarding her presentation.
REPORTING FROM ACP INTERNAL MEDICINE
Culotte stenting impresses in CELTIC Bifurcation Study
PARIS – Technical success rates were high and major adverse events impressively low with a two-stent culotte strategy using contemporary drug-eluting stents for coronary bifurcation lesions in the randomized CELTIC Bifurcation Study.
“We initiated this study because of a conviction that the story isn’t finished with bifurcation stenting. We’re very much under the impression that the accepted wisdom of a conservative approach is, we think, not correct, and the issue needs to be kept open,” said Dr. Foley, an interventional cardiologist at Beaumont Hospital in Dublin.
The widely accepted provisional single-stent strategy is based on early-days randomized trial evidence using first-generation drug-eluting stents and older techniques that are no longer relevant in contemporary practice. Moreover, this conservative single-stent approach doesn’t address the important issue of ischemia arising from large side branches, he asserted.
“I’ve always been fond of culotte stenting myself because I think it’s a very elegant, simple, repeatable strategy, and with modern stents it becomes easier for modest-volume operators to carry it out well. We’ve kept on trying to convert new colleagues and older colleagues who are set in their ways,” Dr. Foley said.
The CELTIC Bifurcation Study was an investigator-initiated trial in which 177 patients at nine centers in Ireland and the United Kingdom were randomized to culotte stenting using either two-connector, third-generation Synergy everolimus-eluting stents or the three-connector, second-generation Xience everolimus-eluting stents. All participants had Medina 1,1,1 coronary bifurcation lesions, which were left anterior descending/diagonal lesions in more than 80% of cases. A radial approach was used in more than 95% of the procedures. The indication for percutaneous coronary intervention was stable angina in more than 60% of cases. The rate of technical procedural success with final kissing balloon inflation exceeded 96%. The primary outcome – a MACCE (major adverse cardiovascular and cerebrovascular events) composite of death, MI, cerebrovascular accident, and target vessel revascularization over the course of 9 months – occurred in 5.9% of patients: 8.6% of the Synergy group and 3.7% with Xience stents, a nonsignificant difference. This MACCE rate was considerably lower than the 10% figure that the investigators had expected on the basis of published studies of PCI in these complex bifurcation lesions.
“The results were better than expected,” the cardiologist said. “We don’t get excited that easily, to be honest, but nonetheless we’re a little bit excited that the overall MACCE rate in this complex lesion presentation was 5.9%.”
Discussant Volker Schächinger, MD, director of cardiology at Fulda (Germany) Hospital, observed: “It’s always good to reassess what are believed to be answered questions when there are new devices available.” But why not compare culotte stenting to the provisional single-stent strategy? he asked.
“We think provisional versus culotte stenting has been thrashed to death already. And you’d need a bigger trial than we had funding for,” Dr. Foley replied.
“Many of us use the DK [double kissing] crush technique,” another panelist said. “It’s very popular. But if you look at bench testing, perhaps culotte is a better approach by many parameters. So I think it was important for you to highlight the value of culotte and how it can be done properly.”
Discussant James Nolan, MD, a cardiologist at the University Hospital of North Staffordshire (England), said, “The most critical thing with these bifurcation procedures is the operators and how they do it. So you have to do the culotte to the standard done in this trial. If you do a sloppy culotte, it’s not going to be great. It’s probably more important to deliver an excellently performed procedure, whatever it is. You’ll get a better result if you’re good at what you’re doing rather than selecting one procedure or another.”
Dr. Foley agreed, adding: “In some of the DK crush versus culotte randomized trials, I’m not convinced that culotte was done the way I would suggest it should be done.”
Operators in the CELTIC Bifurcation Study were asked to follow a standardized culotte procedure: predilate both limbs of the bifurcation, keep both wires in place, deploy the first stent in the side branch unless the main branch was awkwardly angulated, then cross by going from distally into the optimized first stent, and placing the second stent proximal to the first stent so that the two stents overlap in the proximal main vessel.
“We call that ‘nailing it down,’ ” he explained.
The procedure is completed by sequential high-pressure kissing balloon dilatation of both branches, with intravascular ultrasound or optical coherence tomography recommended but not required.
Simultaneously with this presentation, the study results were published online (EuroIntervention 2018 Jun 8;14[3]:e318-24).
The CELTIC Bifurcation Study was funded by an unrestricted grant from Boston Scientific. Dr. Foley reported having no financial conflicts of interest regarding the study.
PARIS – Technical success rates were high and major adverse events impressively low with a two-stent culotte strategy using contemporary drug-eluting stents for coronary bifurcation lesions in the randomized CELTIC Bifurcation Study.
“We initiated this study because of a conviction that the story isn’t finished with bifurcation stenting. We’re very much under the impression that the accepted wisdom of a conservative approach is, we think, not correct, and the issue needs to be kept open,” said Dr. Foley, an interventional cardiologist at Beaumont Hospital in Dublin.
The widely accepted provisional single-stent strategy is based on early-days randomized trial evidence using first-generation drug-eluting stents and older techniques that are no longer relevant in contemporary practice. Moreover, this conservative single-stent approach doesn’t address the important issue of ischemia arising from large side branches, he asserted.
“I’ve always been fond of culotte stenting myself because I think it’s a very elegant, simple, repeatable strategy, and with modern stents it becomes easier for modest-volume operators to carry it out well. We’ve kept on trying to convert new colleagues and older colleagues who are set in their ways,” Dr. Foley said.
The CELTIC Bifurcation Study was an investigator-initiated trial in which 177 patients at nine centers in Ireland and the United Kingdom were randomized to culotte stenting using either two-connector, third-generation Synergy everolimus-eluting stents or the three-connector, second-generation Xience everolimus-eluting stents. All participants had Medina 1,1,1 coronary bifurcation lesions, which were left anterior descending/diagonal lesions in more than 80% of cases. A radial approach was used in more than 95% of the procedures. The indication for percutaneous coronary intervention was stable angina in more than 60% of cases. The rate of technical procedural success with final kissing balloon inflation exceeded 96%. The primary outcome – a MACCE (major adverse cardiovascular and cerebrovascular events) composite of death, MI, cerebrovascular accident, and target vessel revascularization over the course of 9 months – occurred in 5.9% of patients: 8.6% of the Synergy group and 3.7% with Xience stents, a nonsignificant difference. This MACCE rate was considerably lower than the 10% figure that the investigators had expected on the basis of published studies of PCI in these complex bifurcation lesions.
“The results were better than expected,” the cardiologist said. “We don’t get excited that easily, to be honest, but nonetheless we’re a little bit excited that the overall MACCE rate in this complex lesion presentation was 5.9%.”
Discussant Volker Schächinger, MD, director of cardiology at Fulda (Germany) Hospital, observed: “It’s always good to reassess what are believed to be answered questions when there are new devices available.” But why not compare culotte stenting to the provisional single-stent strategy? he asked.
“We think provisional versus culotte stenting has been thrashed to death already. And you’d need a bigger trial than we had funding for,” Dr. Foley replied.
“Many of us use the DK [double kissing] crush technique,” another panelist said. “It’s very popular. But if you look at bench testing, perhaps culotte is a better approach by many parameters. So I think it was important for you to highlight the value of culotte and how it can be done properly.”
Discussant James Nolan, MD, a cardiologist at the University Hospital of North Staffordshire (England), said, “The most critical thing with these bifurcation procedures is the operators and how they do it. So you have to do the culotte to the standard done in this trial. If you do a sloppy culotte, it’s not going to be great. It’s probably more important to deliver an excellently performed procedure, whatever it is. You’ll get a better result if you’re good at what you’re doing rather than selecting one procedure or another.”
Dr. Foley agreed, adding: “In some of the DK crush versus culotte randomized trials, I’m not convinced that culotte was done the way I would suggest it should be done.”
Operators in the CELTIC Bifurcation Study were asked to follow a standardized culotte procedure: predilate both limbs of the bifurcation, keep both wires in place, deploy the first stent in the side branch unless the main branch was awkwardly angulated, then cross by going from distally into the optimized first stent, and placing the second stent proximal to the first stent so that the two stents overlap in the proximal main vessel.
“We call that ‘nailing it down,’ ” he explained.
The procedure is completed by sequential high-pressure kissing balloon dilatation of both branches, with intravascular ultrasound or optical coherence tomography recommended but not required.
Simultaneously with this presentation, the study results were published online (EuroIntervention 2018 Jun 8;14[3]:e318-24).
The CELTIC Bifurcation Study was funded by an unrestricted grant from Boston Scientific. Dr. Foley reported having no financial conflicts of interest regarding the study.
PARIS – Technical success rates were high and major adverse events impressively low with a two-stent culotte strategy using contemporary drug-eluting stents for coronary bifurcation lesions in the randomized CELTIC Bifurcation Study.
“We initiated this study because of a conviction that the story isn’t finished with bifurcation stenting. We’re very much under the impression that the accepted wisdom of a conservative approach is, we think, not correct, and the issue needs to be kept open,” said Dr. Foley, an interventional cardiologist at Beaumont Hospital in Dublin.
The widely accepted provisional single-stent strategy is based on early-days randomized trial evidence using first-generation drug-eluting stents and older techniques that are no longer relevant in contemporary practice. Moreover, this conservative single-stent approach doesn’t address the important issue of ischemia arising from large side branches, he asserted.
“I’ve always been fond of culotte stenting myself because I think it’s a very elegant, simple, repeatable strategy, and with modern stents it becomes easier for modest-volume operators to carry it out well. We’ve kept on trying to convert new colleagues and older colleagues who are set in their ways,” Dr. Foley said.
The CELTIC Bifurcation Study was an investigator-initiated trial in which 177 patients at nine centers in Ireland and the United Kingdom were randomized to culotte stenting using either two-connector, third-generation Synergy everolimus-eluting stents or the three-connector, second-generation Xience everolimus-eluting stents. All participants had Medina 1,1,1 coronary bifurcation lesions, which were left anterior descending/diagonal lesions in more than 80% of cases. A radial approach was used in more than 95% of the procedures. The indication for percutaneous coronary intervention was stable angina in more than 60% of cases. The rate of technical procedural success with final kissing balloon inflation exceeded 96%. The primary outcome – a MACCE (major adverse cardiovascular and cerebrovascular events) composite of death, MI, cerebrovascular accident, and target vessel revascularization over the course of 9 months – occurred in 5.9% of patients: 8.6% of the Synergy group and 3.7% with Xience stents, a nonsignificant difference. This MACCE rate was considerably lower than the 10% figure that the investigators had expected on the basis of published studies of PCI in these complex bifurcation lesions.
“The results were better than expected,” the cardiologist said. “We don’t get excited that easily, to be honest, but nonetheless we’re a little bit excited that the overall MACCE rate in this complex lesion presentation was 5.9%.”
Discussant Volker Schächinger, MD, director of cardiology at Fulda (Germany) Hospital, observed: “It’s always good to reassess what are believed to be answered questions when there are new devices available.” But why not compare culotte stenting to the provisional single-stent strategy? he asked.
“We think provisional versus culotte stenting has been thrashed to death already. And you’d need a bigger trial than we had funding for,” Dr. Foley replied.
“Many of us use the DK [double kissing] crush technique,” another panelist said. “It’s very popular. But if you look at bench testing, perhaps culotte is a better approach by many parameters. So I think it was important for you to highlight the value of culotte and how it can be done properly.”
Discussant James Nolan, MD, a cardiologist at the University Hospital of North Staffordshire (England), said, “The most critical thing with these bifurcation procedures is the operators and how they do it. So you have to do the culotte to the standard done in this trial. If you do a sloppy culotte, it’s not going to be great. It’s probably more important to deliver an excellently performed procedure, whatever it is. You’ll get a better result if you’re good at what you’re doing rather than selecting one procedure or another.”
Dr. Foley agreed, adding: “In some of the DK crush versus culotte randomized trials, I’m not convinced that culotte was done the way I would suggest it should be done.”
Operators in the CELTIC Bifurcation Study were asked to follow a standardized culotte procedure: predilate both limbs of the bifurcation, keep both wires in place, deploy the first stent in the side branch unless the main branch was awkwardly angulated, then cross by going from distally into the optimized first stent, and placing the second stent proximal to the first stent so that the two stents overlap in the proximal main vessel.
“We call that ‘nailing it down,’ ” he explained.
The procedure is completed by sequential high-pressure kissing balloon dilatation of both branches, with intravascular ultrasound or optical coherence tomography recommended but not required.
Simultaneously with this presentation, the study results were published online (EuroIntervention 2018 Jun 8;14[3]:e318-24).
The CELTIC Bifurcation Study was funded by an unrestricted grant from Boston Scientific. Dr. Foley reported having no financial conflicts of interest regarding the study.
REPORTING FROM EUROPCR 2018
Key clinical point: .
Major finding: The 9-month MACCE rate following culotte stenting for bifurcation lesions was 5.9%, with no significant difference between patients randomized to the Xience or Synergy stents.
Study details: This multicenter randomized trial comprised 177 patients with coronary bifurcation lesions who underwent culotte stenting with either Xience or Synergy everolimus-eluting stents.
Disclosures: The presenter reported having no financial conflicts regarding the study, funded by an unrestricted grant from Boston Scientific.
Bivalent HPV vaccine brings no significant increase in 38 potential adverse outcomes
MALMO, SWEDEN – in a nationwide, retrospective cohort study.
“Anxiety and fear regarding adverse events are still very much alive and are associated with lack of acceptance of HPV vaccination,” Jozica Skufca, DVM, MIPH, observed while presenting the study findings at the annual meeting of the European Society for Paediatric Infectious Diseases.
“These results contribute valid evidence to combat public skepticism, anxiety, fears of adverse events, and possible opposition to HPV vaccination and consequently can contribute to increase HPV vaccination coverage in Finland as well as elsewhere,” added Dr. Skufca, who conducted this research while at the Finnish National Institute for Health and Welfare but is now an epidemiologist at P95, a privately held epidemiology and pharmacovigilance consulting firm in Heverlee, Belgium.
Finland introduced the bivalent HPV vaccine known as Cervarix, which is directed against HPV types 16 and 18, into the nation’s vaccination program in November 2013. The target population were girls aged 11-13 years, with catch-up vaccination at ages 14-15 years until 2015.
Dr. Skufca utilized Finland’s comprehensive system of national health care registries to conduct a study of all 240,605 Finnish girls aged 11-15 years who were eligible for the bivalent HPV vaccine from November 2013 to December 2016. Only 56% of the target population, or 134,615 girls, were actually vaccinated. All were subsequently followed for more than a year.
The investigators compared vaccinated and unvaccinated groups in terms of the subsequent rates of 38 selected outcomes of national and international interest. These included celiac disease, chronic fatigue syndrome, type 1 diabetes, Guillain-Barré syndrome, postural orthostatic tachycardia syndrome, ulcerative colitis, venous thromboembolism, psoriasis, vitiligo, scleroderma, autism, poyarteritis nodosa, asthma, Raynaud’s disease, systemic lupus erythematosus, Bell’s palsy, polycystic ovaries, juvenile arthritis, Hashimoto’s disease, and many others.
HPV vaccination rates varied considerably between hospital districts, so the results were adjusted for that potential confounder. Risks also were adjusted for the number of hospital visits 1-2 years prior to vaccination, because healthier girls – those with fewer hospital visits – turned out to be more likely to get vaccinated.
The study’s main result was that HPV vaccination wasn’t associated with a significantly higher risk of any of the 38 adverse outcomes. To the contrary, vaccination was associated with significantly reduced risk of several of them: The risk of chronic fatigue syndrome was reduced by 25%, epilepsy and recurrent seizures were reduced by 28%, the risk of Henoch-Schönlein purpura was an adjusted 52% lower in children vaccinated against HPV, and the risk of malaise and fatigue was reduced by 24%.
Dr. Skufca drew particular attention to the 400% increased risk of Guillain-Barré syndrome in vaccinated children. While this may look impressive, it wasn’t a statistically significant difference. Guillain-Barré was a rare event, with only six cases occurring during 186,934 person-years of follow-up of vaccinated individuals and a single case in unvaccinated girls. Two cases occurred within 180 days after vaccination, for an adjusted 200% increase in risk, which was nonsignificant.
Another two cases occurred more than 365 days postvaccination, for a whopping 3100% increased risk, compared with unvaccinated children; however, this too was a nonstatistically significant finding, with extraordinarily broad confidence intervals of 1.59-652.4. And there is no plausible mechanism to account for a true association between HPV vaccination and a complication, such as this, occurring more than 1 year later. It appeared to be a matter of chance, she added.
However, session cochair Ron Dagan, MD, commented that vaccine skeptics won’t find the Guillain-Barré findings reassuring.
“With HPV vaccination, there are a lot of issues related to mass perception. You say it’s not statistically significant, but some people will say, ‘Forget about the statistics – look at the confidence intervals, the risk could be more than 600 times increased.’ How do you answer this? It’s not easy, especially when we’re talking about a vaccine which has a strong adjuvant,” said Dr. Dagan, director of the pediatric infectious disease unit at Soroka University Medical Center and professor of pediatrics and infectious diseases at the Ben-Gurion University of the Negev, both in Beer-Sheva, Israel.
“I completely agree, how to communicate results to the public is one of the most challenging things. They don’t understand about statistics,” Dr. Skufca replied.
The ball is now in the court of the Finnish health ministry, she added. These study results are brand new. Ministry officials are now going over the details and developing a strategy to communicate the results to the media, the public, and affected families.
The study was funded by the Finnish National Institute for Health and Welfare. Dr. Skufca reported receiving research grants from GlaxoSmithKline and Pfizer.
MALMO, SWEDEN – in a nationwide, retrospective cohort study.
“Anxiety and fear regarding adverse events are still very much alive and are associated with lack of acceptance of HPV vaccination,” Jozica Skufca, DVM, MIPH, observed while presenting the study findings at the annual meeting of the European Society for Paediatric Infectious Diseases.
“These results contribute valid evidence to combat public skepticism, anxiety, fears of adverse events, and possible opposition to HPV vaccination and consequently can contribute to increase HPV vaccination coverage in Finland as well as elsewhere,” added Dr. Skufca, who conducted this research while at the Finnish National Institute for Health and Welfare but is now an epidemiologist at P95, a privately held epidemiology and pharmacovigilance consulting firm in Heverlee, Belgium.
Finland introduced the bivalent HPV vaccine known as Cervarix, which is directed against HPV types 16 and 18, into the nation’s vaccination program in November 2013. The target population were girls aged 11-13 years, with catch-up vaccination at ages 14-15 years until 2015.
Dr. Skufca utilized Finland’s comprehensive system of national health care registries to conduct a study of all 240,605 Finnish girls aged 11-15 years who were eligible for the bivalent HPV vaccine from November 2013 to December 2016. Only 56% of the target population, or 134,615 girls, were actually vaccinated. All were subsequently followed for more than a year.
The investigators compared vaccinated and unvaccinated groups in terms of the subsequent rates of 38 selected outcomes of national and international interest. These included celiac disease, chronic fatigue syndrome, type 1 diabetes, Guillain-Barré syndrome, postural orthostatic tachycardia syndrome, ulcerative colitis, venous thromboembolism, psoriasis, vitiligo, scleroderma, autism, poyarteritis nodosa, asthma, Raynaud’s disease, systemic lupus erythematosus, Bell’s palsy, polycystic ovaries, juvenile arthritis, Hashimoto’s disease, and many others.
HPV vaccination rates varied considerably between hospital districts, so the results were adjusted for that potential confounder. Risks also were adjusted for the number of hospital visits 1-2 years prior to vaccination, because healthier girls – those with fewer hospital visits – turned out to be more likely to get vaccinated.
The study’s main result was that HPV vaccination wasn’t associated with a significantly higher risk of any of the 38 adverse outcomes. To the contrary, vaccination was associated with significantly reduced risk of several of them: The risk of chronic fatigue syndrome was reduced by 25%, epilepsy and recurrent seizures were reduced by 28%, the risk of Henoch-Schönlein purpura was an adjusted 52% lower in children vaccinated against HPV, and the risk of malaise and fatigue was reduced by 24%.
Dr. Skufca drew particular attention to the 400% increased risk of Guillain-Barré syndrome in vaccinated children. While this may look impressive, it wasn’t a statistically significant difference. Guillain-Barré was a rare event, with only six cases occurring during 186,934 person-years of follow-up of vaccinated individuals and a single case in unvaccinated girls. Two cases occurred within 180 days after vaccination, for an adjusted 200% increase in risk, which was nonsignificant.
Another two cases occurred more than 365 days postvaccination, for a whopping 3100% increased risk, compared with unvaccinated children; however, this too was a nonstatistically significant finding, with extraordinarily broad confidence intervals of 1.59-652.4. And there is no plausible mechanism to account for a true association between HPV vaccination and a complication, such as this, occurring more than 1 year later. It appeared to be a matter of chance, she added.
However, session cochair Ron Dagan, MD, commented that vaccine skeptics won’t find the Guillain-Barré findings reassuring.
“With HPV vaccination, there are a lot of issues related to mass perception. You say it’s not statistically significant, but some people will say, ‘Forget about the statistics – look at the confidence intervals, the risk could be more than 600 times increased.’ How do you answer this? It’s not easy, especially when we’re talking about a vaccine which has a strong adjuvant,” said Dr. Dagan, director of the pediatric infectious disease unit at Soroka University Medical Center and professor of pediatrics and infectious diseases at the Ben-Gurion University of the Negev, both in Beer-Sheva, Israel.
“I completely agree, how to communicate results to the public is one of the most challenging things. They don’t understand about statistics,” Dr. Skufca replied.
The ball is now in the court of the Finnish health ministry, she added. These study results are brand new. Ministry officials are now going over the details and developing a strategy to communicate the results to the media, the public, and affected families.
The study was funded by the Finnish National Institute for Health and Welfare. Dr. Skufca reported receiving research grants from GlaxoSmithKline and Pfizer.
MALMO, SWEDEN – in a nationwide, retrospective cohort study.
“Anxiety and fear regarding adverse events are still very much alive and are associated with lack of acceptance of HPV vaccination,” Jozica Skufca, DVM, MIPH, observed while presenting the study findings at the annual meeting of the European Society for Paediatric Infectious Diseases.
“These results contribute valid evidence to combat public skepticism, anxiety, fears of adverse events, and possible opposition to HPV vaccination and consequently can contribute to increase HPV vaccination coverage in Finland as well as elsewhere,” added Dr. Skufca, who conducted this research while at the Finnish National Institute for Health and Welfare but is now an epidemiologist at P95, a privately held epidemiology and pharmacovigilance consulting firm in Heverlee, Belgium.
Finland introduced the bivalent HPV vaccine known as Cervarix, which is directed against HPV types 16 and 18, into the nation’s vaccination program in November 2013. The target population were girls aged 11-13 years, with catch-up vaccination at ages 14-15 years until 2015.
Dr. Skufca utilized Finland’s comprehensive system of national health care registries to conduct a study of all 240,605 Finnish girls aged 11-15 years who were eligible for the bivalent HPV vaccine from November 2013 to December 2016. Only 56% of the target population, or 134,615 girls, were actually vaccinated. All were subsequently followed for more than a year.
The investigators compared vaccinated and unvaccinated groups in terms of the subsequent rates of 38 selected outcomes of national and international interest. These included celiac disease, chronic fatigue syndrome, type 1 diabetes, Guillain-Barré syndrome, postural orthostatic tachycardia syndrome, ulcerative colitis, venous thromboembolism, psoriasis, vitiligo, scleroderma, autism, poyarteritis nodosa, asthma, Raynaud’s disease, systemic lupus erythematosus, Bell’s palsy, polycystic ovaries, juvenile arthritis, Hashimoto’s disease, and many others.
HPV vaccination rates varied considerably between hospital districts, so the results were adjusted for that potential confounder. Risks also were adjusted for the number of hospital visits 1-2 years prior to vaccination, because healthier girls – those with fewer hospital visits – turned out to be more likely to get vaccinated.
The study’s main result was that HPV vaccination wasn’t associated with a significantly higher risk of any of the 38 adverse outcomes. To the contrary, vaccination was associated with significantly reduced risk of several of them: The risk of chronic fatigue syndrome was reduced by 25%, epilepsy and recurrent seizures were reduced by 28%, the risk of Henoch-Schönlein purpura was an adjusted 52% lower in children vaccinated against HPV, and the risk of malaise and fatigue was reduced by 24%.
Dr. Skufca drew particular attention to the 400% increased risk of Guillain-Barré syndrome in vaccinated children. While this may look impressive, it wasn’t a statistically significant difference. Guillain-Barré was a rare event, with only six cases occurring during 186,934 person-years of follow-up of vaccinated individuals and a single case in unvaccinated girls. Two cases occurred within 180 days after vaccination, for an adjusted 200% increase in risk, which was nonsignificant.
Another two cases occurred more than 365 days postvaccination, for a whopping 3100% increased risk, compared with unvaccinated children; however, this too was a nonstatistically significant finding, with extraordinarily broad confidence intervals of 1.59-652.4. And there is no plausible mechanism to account for a true association between HPV vaccination and a complication, such as this, occurring more than 1 year later. It appeared to be a matter of chance, she added.
However, session cochair Ron Dagan, MD, commented that vaccine skeptics won’t find the Guillain-Barré findings reassuring.
“With HPV vaccination, there are a lot of issues related to mass perception. You say it’s not statistically significant, but some people will say, ‘Forget about the statistics – look at the confidence intervals, the risk could be more than 600 times increased.’ How do you answer this? It’s not easy, especially when we’re talking about a vaccine which has a strong adjuvant,” said Dr. Dagan, director of the pediatric infectious disease unit at Soroka University Medical Center and professor of pediatrics and infectious diseases at the Ben-Gurion University of the Negev, both in Beer-Sheva, Israel.
“I completely agree, how to communicate results to the public is one of the most challenging things. They don’t understand about statistics,” Dr. Skufca replied.
The ball is now in the court of the Finnish health ministry, she added. These study results are brand new. Ministry officials are now going over the details and developing a strategy to communicate the results to the media, the public, and affected families.
The study was funded by the Finnish National Institute for Health and Welfare. Dr. Skufca reported receiving research grants from GlaxoSmithKline and Pfizer.
REPORTING FROM ESPID 2018
Key clinical point: Human papillomavirus vaccination poses no significant increased risk of numerous potential adverse outcomes.
Major finding: There was no significantly increased risk of any of 38 potential adverse outcomes in girls aged 11-15 years following administration of a bivalent HPV vaccine.
Study details: This was a retrospective cohort study including more than 240,000 Finnish girls eligible for HPV vaccination following its introduction into the national immunization program.
Disclosures: The study was sponsored by the Finnish National Institute for Health and Welfare. The presenter reported receiving research grants from GlaxoSmithKline and Pfizer.
How to identify DVT faster in pediatric osteomyelitis
MALMO, SWEDEN – Early identification of deep vein thrombosis in children with acute hematogenous osteomyelitis is critical given the need to plan anticoagulation management around the high likelihood that such patients will undergo multiple surgeries, Lawson A.B. Copley, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
He and his coinvestigators have identified a handful of risk factors helpful in expediting recognition of deep vein thrombosis (DVT) in children with suspected invasive infection of the musculoskeletal system.
“To improve the rate and timing of identification of DVT, we recommend performing early screening ultrasound on all children with these risk factors who are suspected of having acute hematogenous osteomyelitis,” declared Dr. Copley, professor of orthopaedic surgery and pediatrics at the University of Texas, Dallas.
Delayed diagnosis of DVT in the setting of acute hematogenous osteomyelitis (AHO) is common. Indeed, in a review of the experience at Children’s Medical Center Dallas during 2012-2014, the average time delay from ICU admission in patients suspected of having AHO to identification of DVT by ultrasound was 6.3 days.
“We’ve changed some things on the basis of that study in order to accelerate that timeline,” he explained.
Their major change was to identify actionable risk factors for DVT. This was accomplished by conducting a retrospective study of the EHR of nearly 902,000 Texas children during 2008-2016.
The study demonstrated that children with AHO complicated by DVT are, from the get-go, very different from AHO patients without DVT. They have higher illness severity of illness, are more likely to be admitted to the ICU, are prone to methicillin-resistant Staphylococcus aureus infection with prolonged bacteremia, and are much more likely to undergo multiple surgeries. Moreover, children with AHO and DVT differed substantially from other children with DVT: The dual diagnosis children lacked comorbid conditions, were prone to septic pulmonary emboli, didn’t develop postthrombotic syndrome marked by chronic venous stasis and ulcerations, and had invariably negative coagulopathy workups.
“There is no need, we feel, to perform a hypercoagulopathy workup in children with AHO complicated by DVT,” Dr. Copley said.
Drilling deeper into the data, he and his coinvestigators identified 224 new cases of DVT in the study population, for a prevalence of 2.5 per 10,000 children, along with 466 children with AHO. A total of 6% of children with AHO had DVT, and 12.1% of all children with DVT had AHO. The researchers then compared the demographics, laboratory parameters, and treatment in three cohorts: the 196 children with DVT without AHO, 28 with both AHO and DVT, and 438 with AHO without DVT.
Through this analysis, they came up with a list of risk factors warranting early screening ultrasound in children suspected of having AHO:
- An initial C-reactive protein level above 8 mg/dL, which was present in all 28 dual diagnosis children.
- ICU admission, which occurred in 19 of 28 (68%) children.
- A severity of illness score of at least 7 on a 10-point scale during the first several days in the hospital, present in 27 of the 28 children. The severity of illness scale was developed and validated by Dr. Copley and coworkers (J Pediatr Orthop. 2016 Oct 12. doi: 10.1097/BPO.0000000000000879).
- Bacteremia in the initial blood culture, present in 23 of 28 patients (82%).
- Just under 90% of the children with AHO and DVT had methicillin-resistant S. aureus, compared with 20% of those with AHO without DVT.
- Septic pulmonary emboli visualized on chest x-ray, a complication that occurred in 64% of the dual diagnosis group versus just 1% of patients with DVT without AHO.
- A band percentage of white blood cells greater than 1.5%, present in 86% of children with AHO and DVT.
More than 90% of children with AHO and DVT underwent surgery, with a mean of 2.7 surgeries per child, in contrast to the group with AHO without DVT, 55% of whom had surgery, with a mean of 0.7 surgeries per child.
Of note, there was no significant difference in the occurrence of pulmonary embolism between children with DVT without AHO versus those with DVT and AHO, with a rate of about 10% in both groups.
Dr. Copley reported having no relevant financial conflicts.
MALMO, SWEDEN – Early identification of deep vein thrombosis in children with acute hematogenous osteomyelitis is critical given the need to plan anticoagulation management around the high likelihood that such patients will undergo multiple surgeries, Lawson A.B. Copley, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
He and his coinvestigators have identified a handful of risk factors helpful in expediting recognition of deep vein thrombosis (DVT) in children with suspected invasive infection of the musculoskeletal system.
“To improve the rate and timing of identification of DVT, we recommend performing early screening ultrasound on all children with these risk factors who are suspected of having acute hematogenous osteomyelitis,” declared Dr. Copley, professor of orthopaedic surgery and pediatrics at the University of Texas, Dallas.
Delayed diagnosis of DVT in the setting of acute hematogenous osteomyelitis (AHO) is common. Indeed, in a review of the experience at Children’s Medical Center Dallas during 2012-2014, the average time delay from ICU admission in patients suspected of having AHO to identification of DVT by ultrasound was 6.3 days.
“We’ve changed some things on the basis of that study in order to accelerate that timeline,” he explained.
Their major change was to identify actionable risk factors for DVT. This was accomplished by conducting a retrospective study of the EHR of nearly 902,000 Texas children during 2008-2016.
The study demonstrated that children with AHO complicated by DVT are, from the get-go, very different from AHO patients without DVT. They have higher illness severity of illness, are more likely to be admitted to the ICU, are prone to methicillin-resistant Staphylococcus aureus infection with prolonged bacteremia, and are much more likely to undergo multiple surgeries. Moreover, children with AHO and DVT differed substantially from other children with DVT: The dual diagnosis children lacked comorbid conditions, were prone to septic pulmonary emboli, didn’t develop postthrombotic syndrome marked by chronic venous stasis and ulcerations, and had invariably negative coagulopathy workups.
“There is no need, we feel, to perform a hypercoagulopathy workup in children with AHO complicated by DVT,” Dr. Copley said.
Drilling deeper into the data, he and his coinvestigators identified 224 new cases of DVT in the study population, for a prevalence of 2.5 per 10,000 children, along with 466 children with AHO. A total of 6% of children with AHO had DVT, and 12.1% of all children with DVT had AHO. The researchers then compared the demographics, laboratory parameters, and treatment in three cohorts: the 196 children with DVT without AHO, 28 with both AHO and DVT, and 438 with AHO without DVT.
Through this analysis, they came up with a list of risk factors warranting early screening ultrasound in children suspected of having AHO:
- An initial C-reactive protein level above 8 mg/dL, which was present in all 28 dual diagnosis children.
- ICU admission, which occurred in 19 of 28 (68%) children.
- A severity of illness score of at least 7 on a 10-point scale during the first several days in the hospital, present in 27 of the 28 children. The severity of illness scale was developed and validated by Dr. Copley and coworkers (J Pediatr Orthop. 2016 Oct 12. doi: 10.1097/BPO.0000000000000879).
- Bacteremia in the initial blood culture, present in 23 of 28 patients (82%).
- Just under 90% of the children with AHO and DVT had methicillin-resistant S. aureus, compared with 20% of those with AHO without DVT.
- Septic pulmonary emboli visualized on chest x-ray, a complication that occurred in 64% of the dual diagnosis group versus just 1% of patients with DVT without AHO.
- A band percentage of white blood cells greater than 1.5%, present in 86% of children with AHO and DVT.
More than 90% of children with AHO and DVT underwent surgery, with a mean of 2.7 surgeries per child, in contrast to the group with AHO without DVT, 55% of whom had surgery, with a mean of 0.7 surgeries per child.
Of note, there was no significant difference in the occurrence of pulmonary embolism between children with DVT without AHO versus those with DVT and AHO, with a rate of about 10% in both groups.
Dr. Copley reported having no relevant financial conflicts.
MALMO, SWEDEN – Early identification of deep vein thrombosis in children with acute hematogenous osteomyelitis is critical given the need to plan anticoagulation management around the high likelihood that such patients will undergo multiple surgeries, Lawson A.B. Copley, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
He and his coinvestigators have identified a handful of risk factors helpful in expediting recognition of deep vein thrombosis (DVT) in children with suspected invasive infection of the musculoskeletal system.
“To improve the rate and timing of identification of DVT, we recommend performing early screening ultrasound on all children with these risk factors who are suspected of having acute hematogenous osteomyelitis,” declared Dr. Copley, professor of orthopaedic surgery and pediatrics at the University of Texas, Dallas.
Delayed diagnosis of DVT in the setting of acute hematogenous osteomyelitis (AHO) is common. Indeed, in a review of the experience at Children’s Medical Center Dallas during 2012-2014, the average time delay from ICU admission in patients suspected of having AHO to identification of DVT by ultrasound was 6.3 days.
“We’ve changed some things on the basis of that study in order to accelerate that timeline,” he explained.
Their major change was to identify actionable risk factors for DVT. This was accomplished by conducting a retrospective study of the EHR of nearly 902,000 Texas children during 2008-2016.
The study demonstrated that children with AHO complicated by DVT are, from the get-go, very different from AHO patients without DVT. They have higher illness severity of illness, are more likely to be admitted to the ICU, are prone to methicillin-resistant Staphylococcus aureus infection with prolonged bacteremia, and are much more likely to undergo multiple surgeries. Moreover, children with AHO and DVT differed substantially from other children with DVT: The dual diagnosis children lacked comorbid conditions, were prone to septic pulmonary emboli, didn’t develop postthrombotic syndrome marked by chronic venous stasis and ulcerations, and had invariably negative coagulopathy workups.
“There is no need, we feel, to perform a hypercoagulopathy workup in children with AHO complicated by DVT,” Dr. Copley said.
Drilling deeper into the data, he and his coinvestigators identified 224 new cases of DVT in the study population, for a prevalence of 2.5 per 10,000 children, along with 466 children with AHO. A total of 6% of children with AHO had DVT, and 12.1% of all children with DVT had AHO. The researchers then compared the demographics, laboratory parameters, and treatment in three cohorts: the 196 children with DVT without AHO, 28 with both AHO and DVT, and 438 with AHO without DVT.
Through this analysis, they came up with a list of risk factors warranting early screening ultrasound in children suspected of having AHO:
- An initial C-reactive protein level above 8 mg/dL, which was present in all 28 dual diagnosis children.
- ICU admission, which occurred in 19 of 28 (68%) children.
- A severity of illness score of at least 7 on a 10-point scale during the first several days in the hospital, present in 27 of the 28 children. The severity of illness scale was developed and validated by Dr. Copley and coworkers (J Pediatr Orthop. 2016 Oct 12. doi: 10.1097/BPO.0000000000000879).
- Bacteremia in the initial blood culture, present in 23 of 28 patients (82%).
- Just under 90% of the children with AHO and DVT had methicillin-resistant S. aureus, compared with 20% of those with AHO without DVT.
- Septic pulmonary emboli visualized on chest x-ray, a complication that occurred in 64% of the dual diagnosis group versus just 1% of patients with DVT without AHO.
- A band percentage of white blood cells greater than 1.5%, present in 86% of children with AHO and DVT.
More than 90% of children with AHO and DVT underwent surgery, with a mean of 2.7 surgeries per child, in contrast to the group with AHO without DVT, 55% of whom had surgery, with a mean of 0.7 surgeries per child.
Of note, there was no significant difference in the occurrence of pulmonary embolism between children with DVT without AHO versus those with DVT and AHO, with a rate of about 10% in both groups.
Dr. Copley reported having no relevant financial conflicts.
REPORTING FROM ESPID 2018
Key clinical point: Osteomyelitis patients with deep vein thrombosis are much sicker than those without DVT.
Major finding:
Study details: This was a retrospective study of the medical records of more than 900,000 Texas children.
Disclosures: Dr. Copley reported having no relevant financial conflicts.
Migraine treatment insights offered for noninvasive vagus nerve stimulation
SAN FRANCISCO – Now that noninvasive vagus nerve stimulation using a small handheld device has earned clearance from the Food and Drug Administration for acute treatment of migraine attacks, investigators are pouring over data from the major clinical trials to gain post hoc insight into how to optimize use of the gammaCore device in routine clinical practice.
The answer is to use it early in the course of an attack and use it often, Eric Liebler said at the annual meeting of the American Headache Society.
“Our motto here in the U.S. is to get the device and use it as many times as you want during the month. There are no pharmacologic side effects, no drug-drug interactions, and no risk of overusing it that we are aware of at this point. So if you give it to a patient who’s able to say, ‘Wait a second – I don’t feel good, I have premonitory symptoms,’ if they use it, then they’re likely to feel better, with a clinically relevant reduction of at least 1 point when treating a migraine while it’s mild,” according to Mr. Liebler, senior vice president for neurology at electroCore, of Basking Ridge, N.J., which markets the noninvasive vagus nerve stimulation (nVNS) gammaCore device.
The device received FDA clearance for acute treatment of migraine in January 2018 following regulatory approval in the spring of 2017 for treatment of episodic cluster headache.
Mr. Liebler presented key highlights of the recently published pivotal PRESTO trial (Prospective Study of nVNS for the Acute Treatment of Migraine), a randomized, double-blind, multicenter, sham-controlled study of 243 adults under age 50 years who experienced 3-8 migraine attacks per month (Neurology. 2018 Jun 15. doi: 10.1212/WNL.0000000000005857).
“This study provides Class I evidence that, for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free post stimulation,” Mr. Liebler declared.
During the 4-week, double-blind treatment period, 48% of the active nVNS group met the International Headache Society definition of pain relief, which meant at least a 1-point reduction in migraine severity on a 0-3 point pain scale at 120 minutes in at least 50% of treated migraine episodes without using rescue medications. This was a significantly better result than the 32% rate seen in patients in the control group who were given a sham device that emitted a perceptible but ineffective signal.
Similar results were documented during the subsequent 4-week, open-label treatment period, during which the control group was switched over to a functioning gammaCore.
“You can tell your patients they have a reliable chance of having a response more often than not,” according to Mr. Liebler.
What else can physicians tell their migraine patients to expect regarding efficacy? The pain-free responder rate at 120 minutes in PRESTO and other studies is similar to rates reported in meta-analyses of oral triptan therapy but without any drug side effects or limitations on frequency of use. Furthermore, the need for rescue medication at any time during a migraine attack was significantly lower with nVNS than it was with sham treatment, by a margin of 48%-63%.
“If they use this device, they’re often able to save that triptan for when they wake up in the morning and they’re already at a 3 in migraine severity,” he observed.
Also, nVNS is fast-acting: At 30 minutes from onset of pain in the first treated attack, 27% of the nVNS group had experienced pain relief, compared with 19% of controls.
The tolerability profile of the device therapy was outstanding, with no treatment discontinuations in the active treatment arm and only occasional reports of mild transient application site discomfort.
Asked about insurance coverage, Mr. Liebler said broad coverage is coming, but it’s not here yet.
“Insurers don’t really want to pay for anything, and devices confuse them even more than drugs. But we’re getting there because of the quality of the evidence. They were really having a good time telling us we didn’t have any published papers, and now that we’ve given them a class I study published in Neurology, they’ve said they had to review it. CVS will cover it starting Jan. 1,” he continued.
Planning is underway for additional clinical trials of the gammaCore for prevention of episodic migraine, acute treatment of attacks in adolescents, and for use in pregnancy.
Using the nVNS device
This nVNS device produces a proprietary, low-voltage electrical signal with a 24-volt peak voltage and a 60-mA peak output current. In the PRESTO study, patients were instructed to self-administer bilateral 120-second stimulations to the right and left sides of their necks within 20 minutes of pain onset. If the pain hadn’t improved within 15 minutes, they were to repeat the stimulations.
In a post hoc analysis of the PREVA (Prevention and Acute treatment of chronic cluster headache) study (Cephalalgia. 2016;36[6]:534-46), investigators determined that the mean reduction in the number of cluster headache attacks was significantly greater in patients who used the device to treat at least 77% of their attacks. That had a bigger preventive effect than did the number of stimulations a patient applied per day.
The PRESTO and PREVA trials were sponsored by electroCore, where Mr. Liebler is employed.
SAN FRANCISCO – Now that noninvasive vagus nerve stimulation using a small handheld device has earned clearance from the Food and Drug Administration for acute treatment of migraine attacks, investigators are pouring over data from the major clinical trials to gain post hoc insight into how to optimize use of the gammaCore device in routine clinical practice.
The answer is to use it early in the course of an attack and use it often, Eric Liebler said at the annual meeting of the American Headache Society.
“Our motto here in the U.S. is to get the device and use it as many times as you want during the month. There are no pharmacologic side effects, no drug-drug interactions, and no risk of overusing it that we are aware of at this point. So if you give it to a patient who’s able to say, ‘Wait a second – I don’t feel good, I have premonitory symptoms,’ if they use it, then they’re likely to feel better, with a clinically relevant reduction of at least 1 point when treating a migraine while it’s mild,” according to Mr. Liebler, senior vice president for neurology at electroCore, of Basking Ridge, N.J., which markets the noninvasive vagus nerve stimulation (nVNS) gammaCore device.
The device received FDA clearance for acute treatment of migraine in January 2018 following regulatory approval in the spring of 2017 for treatment of episodic cluster headache.
Mr. Liebler presented key highlights of the recently published pivotal PRESTO trial (Prospective Study of nVNS for the Acute Treatment of Migraine), a randomized, double-blind, multicenter, sham-controlled study of 243 adults under age 50 years who experienced 3-8 migraine attacks per month (Neurology. 2018 Jun 15. doi: 10.1212/WNL.0000000000005857).
“This study provides Class I evidence that, for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free post stimulation,” Mr. Liebler declared.
During the 4-week, double-blind treatment period, 48% of the active nVNS group met the International Headache Society definition of pain relief, which meant at least a 1-point reduction in migraine severity on a 0-3 point pain scale at 120 minutes in at least 50% of treated migraine episodes without using rescue medications. This was a significantly better result than the 32% rate seen in patients in the control group who were given a sham device that emitted a perceptible but ineffective signal.
Similar results were documented during the subsequent 4-week, open-label treatment period, during which the control group was switched over to a functioning gammaCore.
“You can tell your patients they have a reliable chance of having a response more often than not,” according to Mr. Liebler.
What else can physicians tell their migraine patients to expect regarding efficacy? The pain-free responder rate at 120 minutes in PRESTO and other studies is similar to rates reported in meta-analyses of oral triptan therapy but without any drug side effects or limitations on frequency of use. Furthermore, the need for rescue medication at any time during a migraine attack was significantly lower with nVNS than it was with sham treatment, by a margin of 48%-63%.
“If they use this device, they’re often able to save that triptan for when they wake up in the morning and they’re already at a 3 in migraine severity,” he observed.
Also, nVNS is fast-acting: At 30 minutes from onset of pain in the first treated attack, 27% of the nVNS group had experienced pain relief, compared with 19% of controls.
The tolerability profile of the device therapy was outstanding, with no treatment discontinuations in the active treatment arm and only occasional reports of mild transient application site discomfort.
Asked about insurance coverage, Mr. Liebler said broad coverage is coming, but it’s not here yet.
“Insurers don’t really want to pay for anything, and devices confuse them even more than drugs. But we’re getting there because of the quality of the evidence. They were really having a good time telling us we didn’t have any published papers, and now that we’ve given them a class I study published in Neurology, they’ve said they had to review it. CVS will cover it starting Jan. 1,” he continued.
Planning is underway for additional clinical trials of the gammaCore for prevention of episodic migraine, acute treatment of attacks in adolescents, and for use in pregnancy.
Using the nVNS device
This nVNS device produces a proprietary, low-voltage electrical signal with a 24-volt peak voltage and a 60-mA peak output current. In the PRESTO study, patients were instructed to self-administer bilateral 120-second stimulations to the right and left sides of their necks within 20 minutes of pain onset. If the pain hadn’t improved within 15 minutes, they were to repeat the stimulations.
In a post hoc analysis of the PREVA (Prevention and Acute treatment of chronic cluster headache) study (Cephalalgia. 2016;36[6]:534-46), investigators determined that the mean reduction in the number of cluster headache attacks was significantly greater in patients who used the device to treat at least 77% of their attacks. That had a bigger preventive effect than did the number of stimulations a patient applied per day.
The PRESTO and PREVA trials were sponsored by electroCore, where Mr. Liebler is employed.
SAN FRANCISCO – Now that noninvasive vagus nerve stimulation using a small handheld device has earned clearance from the Food and Drug Administration for acute treatment of migraine attacks, investigators are pouring over data from the major clinical trials to gain post hoc insight into how to optimize use of the gammaCore device in routine clinical practice.
The answer is to use it early in the course of an attack and use it often, Eric Liebler said at the annual meeting of the American Headache Society.
“Our motto here in the U.S. is to get the device and use it as many times as you want during the month. There are no pharmacologic side effects, no drug-drug interactions, and no risk of overusing it that we are aware of at this point. So if you give it to a patient who’s able to say, ‘Wait a second – I don’t feel good, I have premonitory symptoms,’ if they use it, then they’re likely to feel better, with a clinically relevant reduction of at least 1 point when treating a migraine while it’s mild,” according to Mr. Liebler, senior vice president for neurology at electroCore, of Basking Ridge, N.J., which markets the noninvasive vagus nerve stimulation (nVNS) gammaCore device.
The device received FDA clearance for acute treatment of migraine in January 2018 following regulatory approval in the spring of 2017 for treatment of episodic cluster headache.
Mr. Liebler presented key highlights of the recently published pivotal PRESTO trial (Prospective Study of nVNS for the Acute Treatment of Migraine), a randomized, double-blind, multicenter, sham-controlled study of 243 adults under age 50 years who experienced 3-8 migraine attacks per month (Neurology. 2018 Jun 15. doi: 10.1212/WNL.0000000000005857).
“This study provides Class I evidence that, for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free post stimulation,” Mr. Liebler declared.
During the 4-week, double-blind treatment period, 48% of the active nVNS group met the International Headache Society definition of pain relief, which meant at least a 1-point reduction in migraine severity on a 0-3 point pain scale at 120 minutes in at least 50% of treated migraine episodes without using rescue medications. This was a significantly better result than the 32% rate seen in patients in the control group who were given a sham device that emitted a perceptible but ineffective signal.
Similar results were documented during the subsequent 4-week, open-label treatment period, during which the control group was switched over to a functioning gammaCore.
“You can tell your patients they have a reliable chance of having a response more often than not,” according to Mr. Liebler.
What else can physicians tell their migraine patients to expect regarding efficacy? The pain-free responder rate at 120 minutes in PRESTO and other studies is similar to rates reported in meta-analyses of oral triptan therapy but without any drug side effects or limitations on frequency of use. Furthermore, the need for rescue medication at any time during a migraine attack was significantly lower with nVNS than it was with sham treatment, by a margin of 48%-63%.
“If they use this device, they’re often able to save that triptan for when they wake up in the morning and they’re already at a 3 in migraine severity,” he observed.
Also, nVNS is fast-acting: At 30 minutes from onset of pain in the first treated attack, 27% of the nVNS group had experienced pain relief, compared with 19% of controls.
The tolerability profile of the device therapy was outstanding, with no treatment discontinuations in the active treatment arm and only occasional reports of mild transient application site discomfort.
Asked about insurance coverage, Mr. Liebler said broad coverage is coming, but it’s not here yet.
“Insurers don’t really want to pay for anything, and devices confuse them even more than drugs. But we’re getting there because of the quality of the evidence. They were really having a good time telling us we didn’t have any published papers, and now that we’ve given them a class I study published in Neurology, they’ve said they had to review it. CVS will cover it starting Jan. 1,” he continued.
Planning is underway for additional clinical trials of the gammaCore for prevention of episodic migraine, acute treatment of attacks in adolescents, and for use in pregnancy.
Using the nVNS device
This nVNS device produces a proprietary, low-voltage electrical signal with a 24-volt peak voltage and a 60-mA peak output current. In the PRESTO study, patients were instructed to self-administer bilateral 120-second stimulations to the right and left sides of their necks within 20 minutes of pain onset. If the pain hadn’t improved within 15 minutes, they were to repeat the stimulations.
In a post hoc analysis of the PREVA (Prevention and Acute treatment of chronic cluster headache) study (Cephalalgia. 2016;36[6]:534-46), investigators determined that the mean reduction in the number of cluster headache attacks was significantly greater in patients who used the device to treat at least 77% of their attacks. That had a bigger preventive effect than did the number of stimulations a patient applied per day.
The PRESTO and PREVA trials were sponsored by electroCore, where Mr. Liebler is employed.
EXPERT ANALYSIS FROM THE AHS ANNUAL MEETING
Immunogenicity of two-dose Gardasil 9 persists at 36 months
MALMO, SWEDEN – Robust human papillomavirus antibody responses persist through 36 months in boys and girls who received two doses of the 9-valent HPV vaccine known as Gardasil 9 at age 9-14 years, according to an open-label randomized immunogenicity study conducted in 15 countries.
This is reassuring news supportive of regulatory decisions made in 2016/2017 to license the more convenient two-dose schedule in the United States, European Union, Canada, and other countries, Rosybel Drury, PhD, observed in reporting the results at the annual meeting of the European Society for Paediatric Infectious Diseases.
Moreover, HPV type-specific antibody levels at 36 months post vaccination in boys and girls who received two doses were similar to or greater than in the 36-month follow-up of adolescent and young adult females who received three doses at ages 16-26 years.
“This result supports the bridging of efficacy findings in young women receiving three doses to girls and boys receiving two doses,” according to Dr. Drury, a vaccine scientist at Merck Sharp & Dohme in Lyon, France.
She presented an update of a five-cohort study including roughly 1,500 recipients of either two doses of the 9-valent HPV vaccine given 6 or 12 months apart or three doses administered at 0, 2, and 6 months. Four cohorts were composed of 9- to 14-year-olds. The fifth consisted of adolescent girls and young women who got three doses of Gardasil 9 over the course of 6 months at ages 16-26 years. The previous report from this major study provided only short-term data based upon measurements of immunogenicity obtained 1 month after the last dose of vaccine (JAMA. 2016 Dec. 13;316(22):2411-21).
Anti-HPV geometric mean titers were highest 1 month after completing a two- or three-dose series, dropped off sharply during the next 6-12 months, then declined more slowly through 36 months.
While the demonstration of persistent immunogenicity over 3 years of follow-up was reassuring overall, there was a potential hitch: Significantly lower antibody levels for some HPV types were observed in girls who received two doses of the vaccine than in those who got three. Specifically, levels of anti-HPV antibodies to HPV types 18, 31, 45, and 52 were significantly lower in the girls who got two doses of the 9-valent HPV vaccine than in those who got three doses at the same age. Antibody levels directed against HPV types 6, 11, 16, 33, and 58 were similar in the two patient populations.
“The clinical significance of this finding remains unknown,” Dr. Drury said.
Challenged as to why the study didn’t include a single-dose vaccine arm, which would be the preferred preventive strategy in low-income countries where the burden of anogenital cancers and warts due to HPV is greatest, she replied that while there is great interest in this approach, and some modeling studies suggest it would be beneficial, the study she presented was designed to evaluate immunogenicity over time, not clinical efficacy, which needs to be assessed before single-dose public health programs are implemented.
The study was funded by Merck and presented by a company employee.
MALMO, SWEDEN – Robust human papillomavirus antibody responses persist through 36 months in boys and girls who received two doses of the 9-valent HPV vaccine known as Gardasil 9 at age 9-14 years, according to an open-label randomized immunogenicity study conducted in 15 countries.
This is reassuring news supportive of regulatory decisions made in 2016/2017 to license the more convenient two-dose schedule in the United States, European Union, Canada, and other countries, Rosybel Drury, PhD, observed in reporting the results at the annual meeting of the European Society for Paediatric Infectious Diseases.
Moreover, HPV type-specific antibody levels at 36 months post vaccination in boys and girls who received two doses were similar to or greater than in the 36-month follow-up of adolescent and young adult females who received three doses at ages 16-26 years.
“This result supports the bridging of efficacy findings in young women receiving three doses to girls and boys receiving two doses,” according to Dr. Drury, a vaccine scientist at Merck Sharp & Dohme in Lyon, France.
She presented an update of a five-cohort study including roughly 1,500 recipients of either two doses of the 9-valent HPV vaccine given 6 or 12 months apart or three doses administered at 0, 2, and 6 months. Four cohorts were composed of 9- to 14-year-olds. The fifth consisted of adolescent girls and young women who got three doses of Gardasil 9 over the course of 6 months at ages 16-26 years. The previous report from this major study provided only short-term data based upon measurements of immunogenicity obtained 1 month after the last dose of vaccine (JAMA. 2016 Dec. 13;316(22):2411-21).
Anti-HPV geometric mean titers were highest 1 month after completing a two- or three-dose series, dropped off sharply during the next 6-12 months, then declined more slowly through 36 months.
While the demonstration of persistent immunogenicity over 3 years of follow-up was reassuring overall, there was a potential hitch: Significantly lower antibody levels for some HPV types were observed in girls who received two doses of the vaccine than in those who got three. Specifically, levels of anti-HPV antibodies to HPV types 18, 31, 45, and 52 were significantly lower in the girls who got two doses of the 9-valent HPV vaccine than in those who got three doses at the same age. Antibody levels directed against HPV types 6, 11, 16, 33, and 58 were similar in the two patient populations.
“The clinical significance of this finding remains unknown,” Dr. Drury said.
Challenged as to why the study didn’t include a single-dose vaccine arm, which would be the preferred preventive strategy in low-income countries where the burden of anogenital cancers and warts due to HPV is greatest, she replied that while there is great interest in this approach, and some modeling studies suggest it would be beneficial, the study she presented was designed to evaluate immunogenicity over time, not clinical efficacy, which needs to be assessed before single-dose public health programs are implemented.
The study was funded by Merck and presented by a company employee.
MALMO, SWEDEN – Robust human papillomavirus antibody responses persist through 36 months in boys and girls who received two doses of the 9-valent HPV vaccine known as Gardasil 9 at age 9-14 years, according to an open-label randomized immunogenicity study conducted in 15 countries.
This is reassuring news supportive of regulatory decisions made in 2016/2017 to license the more convenient two-dose schedule in the United States, European Union, Canada, and other countries, Rosybel Drury, PhD, observed in reporting the results at the annual meeting of the European Society for Paediatric Infectious Diseases.
Moreover, HPV type-specific antibody levels at 36 months post vaccination in boys and girls who received two doses were similar to or greater than in the 36-month follow-up of adolescent and young adult females who received three doses at ages 16-26 years.
“This result supports the bridging of efficacy findings in young women receiving three doses to girls and boys receiving two doses,” according to Dr. Drury, a vaccine scientist at Merck Sharp & Dohme in Lyon, France.
She presented an update of a five-cohort study including roughly 1,500 recipients of either two doses of the 9-valent HPV vaccine given 6 or 12 months apart or three doses administered at 0, 2, and 6 months. Four cohorts were composed of 9- to 14-year-olds. The fifth consisted of adolescent girls and young women who got three doses of Gardasil 9 over the course of 6 months at ages 16-26 years. The previous report from this major study provided only short-term data based upon measurements of immunogenicity obtained 1 month after the last dose of vaccine (JAMA. 2016 Dec. 13;316(22):2411-21).
Anti-HPV geometric mean titers were highest 1 month after completing a two- or three-dose series, dropped off sharply during the next 6-12 months, then declined more slowly through 36 months.
While the demonstration of persistent immunogenicity over 3 years of follow-up was reassuring overall, there was a potential hitch: Significantly lower antibody levels for some HPV types were observed in girls who received two doses of the vaccine than in those who got three. Specifically, levels of anti-HPV antibodies to HPV types 18, 31, 45, and 52 were significantly lower in the girls who got two doses of the 9-valent HPV vaccine than in those who got three doses at the same age. Antibody levels directed against HPV types 6, 11, 16, 33, and 58 were similar in the two patient populations.
“The clinical significance of this finding remains unknown,” Dr. Drury said.
Challenged as to why the study didn’t include a single-dose vaccine arm, which would be the preferred preventive strategy in low-income countries where the burden of anogenital cancers and warts due to HPV is greatest, she replied that while there is great interest in this approach, and some modeling studies suggest it would be beneficial, the study she presented was designed to evaluate immunogenicity over time, not clinical efficacy, which needs to be assessed before single-dose public health programs are implemented.
The study was funded by Merck and presented by a company employee.
REPORTING FROM ESPID 2018
Key clinical point:
Major finding: HPV type-specific antibody responses to two doses given at age 9-14 years were as good as or better than in 16- to 26-year-olds who got three doses.
Study details: This prospective open-label immunogenicity study included roughly 1,500 subjects in 15 countries who received either two or three doses of the 9-valent HPV vaccine.
Disclosures: The study was funded by Merck and presented by a company employee.
Device impresses for chronic cluster headache attacks
SAN FRANCISCO – Sphenopalatine ganglion stimulation using an implanted miniature neuromodulation device shows the potential to be a breakthrough nonpharmacologic therapy for acute episodes of chronic cluster headache based upon the results of the sham-controlled Pathway CH-2 study.
Self-administered sphenopalatine ganglion (SPG) stimulation using a wireless hand-held controller not only resulted in a 2.6-fold greater likelihood of providing pain relief within 15 minutes without resort to acute medications, compared with sham stimulation, but the device therapy also led to a significant reduction in cluster headache frequency over time, presumably through its neuromodulatory effects, David W. Dodick, MD, said in presenting the study results at the annual meeting of the American Headache Society.
An additional benefit of SPG stimulation was less need for triptans, with their many side effects. Patients in the active treatment arm of the 28-week sham-controlled portion of the multicenter prospective study used triptans for abortive therapy an average of 3.7 times less per week during the final 4 weeks of that period than they did during the 4-week baseline period, compared with a 1.2-dose per week reduction in the control group, noted Dr. Dodick, principal investigator for the Pathway CH-2 study and professor of neurology at the Mayo Clinic in Scottsdale, Ariz.
Cluster headache pain has been described as one of the most severe forms of pain known to humans. It is extremely disabling. Treatment options leave much to be desired, as detailed in a patient survey presented elsewhere during the meeting.
The 93 participants in the Pathway CH-2 study had a mean 8-year history of chronic cluster headaches. During the 4-week baseline assessment period, they averaged roughly 11 cluster attacks per week. All patients underwent surgical insertion of the miniature ATI Neurostimulator through a small incision in the upper gum. The device was placed deep in the face adjacent to the SPG nerve bundle. Patients were taught to activate the neurostimulator by placing a hand-held controller on the side of the face near the implanted device when a cluster headache attack struck. Participants were randomized to active treatment or sham stimulation, which delivered a mild electric current to the side of the face.
The primary efficacy endpoint was pain relief within 15 minutes of starting SPG stimulation without resort to abortive medications. Sixty-three percent of the SPG neurostimulation group and 29% of sham-treated controls achieved that goal for at least 50% of their headache attacks. Forty-six percent of SPG stimulators were able to attain pain relief within 15 minutes for 75% or more of their attacks. Fifty-seven percent of the active treatment group maintained pain relief at 60 minutes, compared with just 5% of controls.
“We’re used to thinking in terms of responder rates. Roughly half of patients using SPG stimulation had at least a 75% reduction in weekly cluster attacks, 46% of them had at least a 75% reduction in the severity of attacks, and 71% were super-responders, so to speak, with at least a 75% reduction in either attack frequency or severity,” according to Dr. Dodick.
The mean reduction in cluster attack frequency from baseline through 28 weeks was 6.8 fewer attacks per week in the active treatment group, significantly better than the mean 2.6-attack reduction in controls. At 1 year post implantation, the SPG stimulation group averaged 9.4 fewer cluster attacks per week than at baseline.
The ATI SPG Microstimulator System was well tolerated overall. Common treatment-related adverse events limited to the first 30 days after device implantation included numbness, swelling, pain, bruising, and paresthesia secondary to the surgical procedure. Given the discomfort inherent to gum surgery, “I was actually surprised there weren’t more adverse events,” Dr. Dodick said.
Four serious adverse events related to the device or its implantation occurred among the 93 participants: a venous injury, an infection, aspiration during intubation, and an instance of nausea and vomiting. All resolved without sequelae.
The ATI SPG Microstimulator System is investigational in the United States. The system is approved by European authorities for acute treatment of cluster headaches and refractory disabling migraine.
Patients speak out about shortcomings of cluster headache treatment
Elsewhere at the meeting, Emmanuelle Schindler, MD, PhD, a neurologist at Yale University in New Haven, Conn., reported on 493 participants in the Clusterbusters Medication Use Survey. The results provided a sobering picture of the shortcomings of current cluster headache treatments from the patient perspective.
Two-thirds of subjects had episodic cluster headache, while the remainder had the chronic form. Roughly 11% of subjects reported limiting adverse events caused by their abortive and/or preventive medications. A similar percentage reported resistance to all approved preventive drugs. Inconsistency of medication efficacy was a common theme. The survey respondents want novel treatments that are safe and effective. And they expressed a wish that more primary care physicians were well informed about cluster headaches; many of the individuals with cluster headache reported difficulty in reaching a knowledgeable headache specialist.
The Pathway CH-2 study was funded by Autonomic Technologies Inc. Dr. Dodick serves as a consultant to that company and numerous others. Dr. Schindler’s survey was funded by Clusterbusters, a nonprofit research organization.
SOURCE: Dodick DW, AHS 2018, Abstract PS112LB.
SAN FRANCISCO – Sphenopalatine ganglion stimulation using an implanted miniature neuromodulation device shows the potential to be a breakthrough nonpharmacologic therapy for acute episodes of chronic cluster headache based upon the results of the sham-controlled Pathway CH-2 study.
Self-administered sphenopalatine ganglion (SPG) stimulation using a wireless hand-held controller not only resulted in a 2.6-fold greater likelihood of providing pain relief within 15 minutes without resort to acute medications, compared with sham stimulation, but the device therapy also led to a significant reduction in cluster headache frequency over time, presumably through its neuromodulatory effects, David W. Dodick, MD, said in presenting the study results at the annual meeting of the American Headache Society.
An additional benefit of SPG stimulation was less need for triptans, with their many side effects. Patients in the active treatment arm of the 28-week sham-controlled portion of the multicenter prospective study used triptans for abortive therapy an average of 3.7 times less per week during the final 4 weeks of that period than they did during the 4-week baseline period, compared with a 1.2-dose per week reduction in the control group, noted Dr. Dodick, principal investigator for the Pathway CH-2 study and professor of neurology at the Mayo Clinic in Scottsdale, Ariz.
Cluster headache pain has been described as one of the most severe forms of pain known to humans. It is extremely disabling. Treatment options leave much to be desired, as detailed in a patient survey presented elsewhere during the meeting.
The 93 participants in the Pathway CH-2 study had a mean 8-year history of chronic cluster headaches. During the 4-week baseline assessment period, they averaged roughly 11 cluster attacks per week. All patients underwent surgical insertion of the miniature ATI Neurostimulator through a small incision in the upper gum. The device was placed deep in the face adjacent to the SPG nerve bundle. Patients were taught to activate the neurostimulator by placing a hand-held controller on the side of the face near the implanted device when a cluster headache attack struck. Participants were randomized to active treatment or sham stimulation, which delivered a mild electric current to the side of the face.
The primary efficacy endpoint was pain relief within 15 minutes of starting SPG stimulation without resort to abortive medications. Sixty-three percent of the SPG neurostimulation group and 29% of sham-treated controls achieved that goal for at least 50% of their headache attacks. Forty-six percent of SPG stimulators were able to attain pain relief within 15 minutes for 75% or more of their attacks. Fifty-seven percent of the active treatment group maintained pain relief at 60 minutes, compared with just 5% of controls.
“We’re used to thinking in terms of responder rates. Roughly half of patients using SPG stimulation had at least a 75% reduction in weekly cluster attacks, 46% of them had at least a 75% reduction in the severity of attacks, and 71% were super-responders, so to speak, with at least a 75% reduction in either attack frequency or severity,” according to Dr. Dodick.
The mean reduction in cluster attack frequency from baseline through 28 weeks was 6.8 fewer attacks per week in the active treatment group, significantly better than the mean 2.6-attack reduction in controls. At 1 year post implantation, the SPG stimulation group averaged 9.4 fewer cluster attacks per week than at baseline.
The ATI SPG Microstimulator System was well tolerated overall. Common treatment-related adverse events limited to the first 30 days after device implantation included numbness, swelling, pain, bruising, and paresthesia secondary to the surgical procedure. Given the discomfort inherent to gum surgery, “I was actually surprised there weren’t more adverse events,” Dr. Dodick said.
Four serious adverse events related to the device or its implantation occurred among the 93 participants: a venous injury, an infection, aspiration during intubation, and an instance of nausea and vomiting. All resolved without sequelae.
The ATI SPG Microstimulator System is investigational in the United States. The system is approved by European authorities for acute treatment of cluster headaches and refractory disabling migraine.
Patients speak out about shortcomings of cluster headache treatment
Elsewhere at the meeting, Emmanuelle Schindler, MD, PhD, a neurologist at Yale University in New Haven, Conn., reported on 493 participants in the Clusterbusters Medication Use Survey. The results provided a sobering picture of the shortcomings of current cluster headache treatments from the patient perspective.
Two-thirds of subjects had episodic cluster headache, while the remainder had the chronic form. Roughly 11% of subjects reported limiting adverse events caused by their abortive and/or preventive medications. A similar percentage reported resistance to all approved preventive drugs. Inconsistency of medication efficacy was a common theme. The survey respondents want novel treatments that are safe and effective. And they expressed a wish that more primary care physicians were well informed about cluster headaches; many of the individuals with cluster headache reported difficulty in reaching a knowledgeable headache specialist.
The Pathway CH-2 study was funded by Autonomic Technologies Inc. Dr. Dodick serves as a consultant to that company and numerous others. Dr. Schindler’s survey was funded by Clusterbusters, a nonprofit research organization.
SOURCE: Dodick DW, AHS 2018, Abstract PS112LB.
SAN FRANCISCO – Sphenopalatine ganglion stimulation using an implanted miniature neuromodulation device shows the potential to be a breakthrough nonpharmacologic therapy for acute episodes of chronic cluster headache based upon the results of the sham-controlled Pathway CH-2 study.
Self-administered sphenopalatine ganglion (SPG) stimulation using a wireless hand-held controller not only resulted in a 2.6-fold greater likelihood of providing pain relief within 15 minutes without resort to acute medications, compared with sham stimulation, but the device therapy also led to a significant reduction in cluster headache frequency over time, presumably through its neuromodulatory effects, David W. Dodick, MD, said in presenting the study results at the annual meeting of the American Headache Society.
An additional benefit of SPG stimulation was less need for triptans, with their many side effects. Patients in the active treatment arm of the 28-week sham-controlled portion of the multicenter prospective study used triptans for abortive therapy an average of 3.7 times less per week during the final 4 weeks of that period than they did during the 4-week baseline period, compared with a 1.2-dose per week reduction in the control group, noted Dr. Dodick, principal investigator for the Pathway CH-2 study and professor of neurology at the Mayo Clinic in Scottsdale, Ariz.
Cluster headache pain has been described as one of the most severe forms of pain known to humans. It is extremely disabling. Treatment options leave much to be desired, as detailed in a patient survey presented elsewhere during the meeting.
The 93 participants in the Pathway CH-2 study had a mean 8-year history of chronic cluster headaches. During the 4-week baseline assessment period, they averaged roughly 11 cluster attacks per week. All patients underwent surgical insertion of the miniature ATI Neurostimulator through a small incision in the upper gum. The device was placed deep in the face adjacent to the SPG nerve bundle. Patients were taught to activate the neurostimulator by placing a hand-held controller on the side of the face near the implanted device when a cluster headache attack struck. Participants were randomized to active treatment or sham stimulation, which delivered a mild electric current to the side of the face.
The primary efficacy endpoint was pain relief within 15 minutes of starting SPG stimulation without resort to abortive medications. Sixty-three percent of the SPG neurostimulation group and 29% of sham-treated controls achieved that goal for at least 50% of their headache attacks. Forty-six percent of SPG stimulators were able to attain pain relief within 15 minutes for 75% or more of their attacks. Fifty-seven percent of the active treatment group maintained pain relief at 60 minutes, compared with just 5% of controls.
“We’re used to thinking in terms of responder rates. Roughly half of patients using SPG stimulation had at least a 75% reduction in weekly cluster attacks, 46% of them had at least a 75% reduction in the severity of attacks, and 71% were super-responders, so to speak, with at least a 75% reduction in either attack frequency or severity,” according to Dr. Dodick.
The mean reduction in cluster attack frequency from baseline through 28 weeks was 6.8 fewer attacks per week in the active treatment group, significantly better than the mean 2.6-attack reduction in controls. At 1 year post implantation, the SPG stimulation group averaged 9.4 fewer cluster attacks per week than at baseline.
The ATI SPG Microstimulator System was well tolerated overall. Common treatment-related adverse events limited to the first 30 days after device implantation included numbness, swelling, pain, bruising, and paresthesia secondary to the surgical procedure. Given the discomfort inherent to gum surgery, “I was actually surprised there weren’t more adverse events,” Dr. Dodick said.
Four serious adverse events related to the device or its implantation occurred among the 93 participants: a venous injury, an infection, aspiration during intubation, and an instance of nausea and vomiting. All resolved without sequelae.
The ATI SPG Microstimulator System is investigational in the United States. The system is approved by European authorities for acute treatment of cluster headaches and refractory disabling migraine.
Patients speak out about shortcomings of cluster headache treatment
Elsewhere at the meeting, Emmanuelle Schindler, MD, PhD, a neurologist at Yale University in New Haven, Conn., reported on 493 participants in the Clusterbusters Medication Use Survey. The results provided a sobering picture of the shortcomings of current cluster headache treatments from the patient perspective.
Two-thirds of subjects had episodic cluster headache, while the remainder had the chronic form. Roughly 11% of subjects reported limiting adverse events caused by their abortive and/or preventive medications. A similar percentage reported resistance to all approved preventive drugs. Inconsistency of medication efficacy was a common theme. The survey respondents want novel treatments that are safe and effective. And they expressed a wish that more primary care physicians were well informed about cluster headaches; many of the individuals with cluster headache reported difficulty in reaching a knowledgeable headache specialist.
The Pathway CH-2 study was funded by Autonomic Technologies Inc. Dr. Dodick serves as a consultant to that company and numerous others. Dr. Schindler’s survey was funded by Clusterbusters, a nonprofit research organization.
SOURCE: Dodick DW, AHS 2018, Abstract PS112LB.
REPORTING FROM THE AHS ANNUAL MEETING
Key clinical point: Sphenopalatine ganglion stimulation aborts chronic cluster headache attacks and reduces their frequency.
Major finding: Seventy-one percent of patients with longstanding chronic cluster headaches achieved at least a 75% reduction in either attack frequency or severity by using a sphenopalatine ganglion stimulation device.
Study details: This was a prospective multicenter study in which 93 chronic cluster headache patients were randomized to sphenopalatine ganglion stimulation or sham stimulation.
Disclosures: The presenter serves as a consultant to Autonomic Technologies Inc., which funded the study, and numerous other companies.
Source: Dodick DW. AHS 2018 Abstract PS112LB.
Firehawk: A new ‘workhorse’ DES
PARIS – The Xience everolimus-eluting coronary stent is widely considered the current standard treatment, implanted by interventional cardiologists far more often than any other drug-eluting stent (DES). But judging from the results of the TARGET All Comers trial, some serious competition may be headed Xience’s way in the form of the new Firehawk rapamycin-eluting, thin-strut stent featuring a biodegradable polymer drug delivery system.
What’s more, the Firehawk offers a theoretical advantage in that the rapamycin is delivered via a polymer that’s fully absorbed by 9 months, leaving behind a bare metal stent made of cobalt chromium. This structure is believed to be less proinflammatory, atherogenic, and thrombogenic over the long haul, compared with a permanent durable polymer, such as that employed in the Xience stent. This should translate into less late restenosis and in-stent thrombosis.
Also, the Firehawk features thin, 86-mcm struts and the rapamycin, also known as sirolimus, is contained in abluminal grooves directed specifically to the vessel wall. As a result, this DES exposes patients to only one-third as much active drug as other DESs. Ninety percent of the rapamycin is released within 90 days after implantation, according to Dr. Baumbach, director of interventional research at Barts Heart Centre in London and president of the European Association of Percutaneous Cardiovascular Interventions.
The TARGET All Comers trial is a prospective, open-label, noninferiority trial comparing the safety and efficacy of the Firehawk with those of Xience stents in 1,656 DES-eligible patients with symptomatic coronary artery disease randomized at 21 centers.
The primary endpoint was the 12-month composite of target lesion failure, comprising rates of cardiac death, target vessel MI, or ischemia-driven target lesion revascularization. In an intention-to-treat analysis, the rate was 6.1% in the Firehawk patients and 5.9% in the Xience recipients. Results for each of the three components of the composite endpoint were similar in the two groups as well.
A secondary endpoint was in-stent late loss as measured by quantitative coronary angiography at 13 months in a 137-patient subgroup. The rate was 0.17 mm in the Firehawk recipients and similar at 0.11 mm in those receiving the Xience stent, again, which provided solid evidence of noninferiority.
The rate of definite stent thrombosis at 1 year was 1.2% in both study arms.
Discussant Giulio Guagliumi, MD, an interventional cardiologist at Pope Giovanni XXIII Hospital in Bergamo, Italy, pronounced the results “quite reassuring.” But where, he asked, is the evidence of late benefit for the completely biodegradable polymer utilized in the Firehawk?
“We would expect to see such an effect later on, after the stent in question becomes a simple bare metal stent as opposed to a stent with a durable polymer. But we don’t have the ultimate answer yet. In this trial we will have an extended follow-up out to 5 years to see whether there is any translation of these differences into clinical benefit,” Dr. Baumbach replied.
Discussion panelist Julinda Mehilli, MD, inquired how this new stent, which has been approved for the European market, will fit into everyday clinical practice.
“We have many biodegradable polymer DES already. We have the Ultimaster, we have Synergy – and now, the Firehawk. What kind of special features does it have? Is it for use in routine practice or in special populations?” asked Dr. Mehilli, director of interventional cardiology at the German Heart Center at the University of Munich.
“That’s of course the question: What’s the unique point of this stent? I think that the unique point is that there is really no unique point. This is a classic workhorse stent. This is a stent with good radial force and all the other features for everyday use,” according to Dr. Baumbach.
Indeed, he and his Barts colleagues did more than 100 cases in TARGET All Comers and found one of the Firehawk’s strengths was its versatility. It performed well in challenging cases, including left main interventions, as well as in more straightforward cases in this all comers trial.
The Firehawk was developed by MicroPort in China, where its safety and efficacy was established in clinical trials totaling more than 1,000 patients. It then moved to Europe, where it has earned regulatory approval. A pivotal U.S. trial is being planned with the Food and Drug Administration, which has indicated that the European TARGET All Comers data can be incorporated in the study.
Dr. Baumbach reported receiving research grants from Abbott and consultation fees from Keystone Heart, MicroPort, Sinomed, and Stentys.
PARIS – The Xience everolimus-eluting coronary stent is widely considered the current standard treatment, implanted by interventional cardiologists far more often than any other drug-eluting stent (DES). But judging from the results of the TARGET All Comers trial, some serious competition may be headed Xience’s way in the form of the new Firehawk rapamycin-eluting, thin-strut stent featuring a biodegradable polymer drug delivery system.
What’s more, the Firehawk offers a theoretical advantage in that the rapamycin is delivered via a polymer that’s fully absorbed by 9 months, leaving behind a bare metal stent made of cobalt chromium. This structure is believed to be less proinflammatory, atherogenic, and thrombogenic over the long haul, compared with a permanent durable polymer, such as that employed in the Xience stent. This should translate into less late restenosis and in-stent thrombosis.
Also, the Firehawk features thin, 86-mcm struts and the rapamycin, also known as sirolimus, is contained in abluminal grooves directed specifically to the vessel wall. As a result, this DES exposes patients to only one-third as much active drug as other DESs. Ninety percent of the rapamycin is released within 90 days after implantation, according to Dr. Baumbach, director of interventional research at Barts Heart Centre in London and president of the European Association of Percutaneous Cardiovascular Interventions.
The TARGET All Comers trial is a prospective, open-label, noninferiority trial comparing the safety and efficacy of the Firehawk with those of Xience stents in 1,656 DES-eligible patients with symptomatic coronary artery disease randomized at 21 centers.
The primary endpoint was the 12-month composite of target lesion failure, comprising rates of cardiac death, target vessel MI, or ischemia-driven target lesion revascularization. In an intention-to-treat analysis, the rate was 6.1% in the Firehawk patients and 5.9% in the Xience recipients. Results for each of the three components of the composite endpoint were similar in the two groups as well.
A secondary endpoint was in-stent late loss as measured by quantitative coronary angiography at 13 months in a 137-patient subgroup. The rate was 0.17 mm in the Firehawk recipients and similar at 0.11 mm in those receiving the Xience stent, again, which provided solid evidence of noninferiority.
The rate of definite stent thrombosis at 1 year was 1.2% in both study arms.
Discussant Giulio Guagliumi, MD, an interventional cardiologist at Pope Giovanni XXIII Hospital in Bergamo, Italy, pronounced the results “quite reassuring.” But where, he asked, is the evidence of late benefit for the completely biodegradable polymer utilized in the Firehawk?
“We would expect to see such an effect later on, after the stent in question becomes a simple bare metal stent as opposed to a stent with a durable polymer. But we don’t have the ultimate answer yet. In this trial we will have an extended follow-up out to 5 years to see whether there is any translation of these differences into clinical benefit,” Dr. Baumbach replied.
Discussion panelist Julinda Mehilli, MD, inquired how this new stent, which has been approved for the European market, will fit into everyday clinical practice.
“We have many biodegradable polymer DES already. We have the Ultimaster, we have Synergy – and now, the Firehawk. What kind of special features does it have? Is it for use in routine practice or in special populations?” asked Dr. Mehilli, director of interventional cardiology at the German Heart Center at the University of Munich.
“That’s of course the question: What’s the unique point of this stent? I think that the unique point is that there is really no unique point. This is a classic workhorse stent. This is a stent with good radial force and all the other features for everyday use,” according to Dr. Baumbach.
Indeed, he and his Barts colleagues did more than 100 cases in TARGET All Comers and found one of the Firehawk’s strengths was its versatility. It performed well in challenging cases, including left main interventions, as well as in more straightforward cases in this all comers trial.
The Firehawk was developed by MicroPort in China, where its safety and efficacy was established in clinical trials totaling more than 1,000 patients. It then moved to Europe, where it has earned regulatory approval. A pivotal U.S. trial is being planned with the Food and Drug Administration, which has indicated that the European TARGET All Comers data can be incorporated in the study.
Dr. Baumbach reported receiving research grants from Abbott and consultation fees from Keystone Heart, MicroPort, Sinomed, and Stentys.
PARIS – The Xience everolimus-eluting coronary stent is widely considered the current standard treatment, implanted by interventional cardiologists far more often than any other drug-eluting stent (DES). But judging from the results of the TARGET All Comers trial, some serious competition may be headed Xience’s way in the form of the new Firehawk rapamycin-eluting, thin-strut stent featuring a biodegradable polymer drug delivery system.
What’s more, the Firehawk offers a theoretical advantage in that the rapamycin is delivered via a polymer that’s fully absorbed by 9 months, leaving behind a bare metal stent made of cobalt chromium. This structure is believed to be less proinflammatory, atherogenic, and thrombogenic over the long haul, compared with a permanent durable polymer, such as that employed in the Xience stent. This should translate into less late restenosis and in-stent thrombosis.
Also, the Firehawk features thin, 86-mcm struts and the rapamycin, also known as sirolimus, is contained in abluminal grooves directed specifically to the vessel wall. As a result, this DES exposes patients to only one-third as much active drug as other DESs. Ninety percent of the rapamycin is released within 90 days after implantation, according to Dr. Baumbach, director of interventional research at Barts Heart Centre in London and president of the European Association of Percutaneous Cardiovascular Interventions.
The TARGET All Comers trial is a prospective, open-label, noninferiority trial comparing the safety and efficacy of the Firehawk with those of Xience stents in 1,656 DES-eligible patients with symptomatic coronary artery disease randomized at 21 centers.
The primary endpoint was the 12-month composite of target lesion failure, comprising rates of cardiac death, target vessel MI, or ischemia-driven target lesion revascularization. In an intention-to-treat analysis, the rate was 6.1% in the Firehawk patients and 5.9% in the Xience recipients. Results for each of the three components of the composite endpoint were similar in the two groups as well.
A secondary endpoint was in-stent late loss as measured by quantitative coronary angiography at 13 months in a 137-patient subgroup. The rate was 0.17 mm in the Firehawk recipients and similar at 0.11 mm in those receiving the Xience stent, again, which provided solid evidence of noninferiority.
The rate of definite stent thrombosis at 1 year was 1.2% in both study arms.
Discussant Giulio Guagliumi, MD, an interventional cardiologist at Pope Giovanni XXIII Hospital in Bergamo, Italy, pronounced the results “quite reassuring.” But where, he asked, is the evidence of late benefit for the completely biodegradable polymer utilized in the Firehawk?
“We would expect to see such an effect later on, after the stent in question becomes a simple bare metal stent as opposed to a stent with a durable polymer. But we don’t have the ultimate answer yet. In this trial we will have an extended follow-up out to 5 years to see whether there is any translation of these differences into clinical benefit,” Dr. Baumbach replied.
Discussion panelist Julinda Mehilli, MD, inquired how this new stent, which has been approved for the European market, will fit into everyday clinical practice.
“We have many biodegradable polymer DES already. We have the Ultimaster, we have Synergy – and now, the Firehawk. What kind of special features does it have? Is it for use in routine practice or in special populations?” asked Dr. Mehilli, director of interventional cardiology at the German Heart Center at the University of Munich.
“That’s of course the question: What’s the unique point of this stent? I think that the unique point is that there is really no unique point. This is a classic workhorse stent. This is a stent with good radial force and all the other features for everyday use,” according to Dr. Baumbach.
Indeed, he and his Barts colleagues did more than 100 cases in TARGET All Comers and found one of the Firehawk’s strengths was its versatility. It performed well in challenging cases, including left main interventions, as well as in more straightforward cases in this all comers trial.
The Firehawk was developed by MicroPort in China, where its safety and efficacy was established in clinical trials totaling more than 1,000 patients. It then moved to Europe, where it has earned regulatory approval. A pivotal U.S. trial is being planned with the Food and Drug Administration, which has indicated that the European TARGET All Comers data can be incorporated in the study.
Dr. Baumbach reported receiving research grants from Abbott and consultation fees from Keystone Heart, MicroPort, Sinomed, and Stentys.
REPORTING FROM EUROPCR 2018
Key clinical point: The Firehawk has established itself as a versatile workhorse coronary stent.
Major finding:
Study details: This open-label international study randomized 1,656 patients with symptomatic CAD to one of two drug-eluting stents.
Disclosures: The TARGET All Comers trial was sponsored by MicroPort. The presenter reported serving as a consultant to MicroPort and other companies.
OnabotulinumtoxinA crushes topiramate in chronic migraine PRO benefits
SAN FRANCISCO – The odds of at least a 50% reduction in headache days per month in chronic migraine patients 32 weeks after randomization to onabotulinumtoxinA for prophylaxis were 394% greater than with topiramate in the multicenter, open-label FORWARD trial, Andrew M. Blumenfeld, MD, reported at the annual meeting of the American Headache Society.
“Impressively, onabotulinumtoxinA showed a more favorable effect on depressive symptoms,” he added. “The overall results suggest that the beneficial effects of onabotulinumtoxinA on a range of PROs may lead to improved adherence.”
The FORWARD trial was a multicenter, open-label, prospective, 36-week study which randomized 282 adult chronic migraine patients to fixed-dose onabotulinumtoxinA at the approved dose of 155 U every 12 weeks or to topiramate (Topamax) titrated over the course of 12 weeks to the approved dose of 50-100 mg/day. However, after 12 weeks on topiramate, patients could elect to discontinue the drug and switch to onabotulinumtoxinA.
This was a trial designed to evaluate effectiveness, which Dr. Blumenfeld defined as the combination of efficacy plus treatment adherence. And treatment adherence with topiramate was poor: 63% of patients discontinued that medication, mainly because of adverse events or lack of efficacy, compared with just 7.9% of the onabotulinumtoxinA group.
The primary endpoint was the proportion of patients who achieved at least a 50% reduction in headache days per month beginning at week 32, compared with their rate during 4 weeks at baseline. Of 142 patients randomized to topiramate, 25 completed 36 weeks of therapy, and 17 of those 25 (68%) achieved at least a 50% reduction in headache days per month. That’s one way to look at it. The other is to examine effectiveness: 17 of 142 topiramate-treated patients (12%) met the primary endpoint. In contrast, 99 of 140 patients assigned to onabotulinumtoxinA completed treatment, and 56 of those 99 (57%) met the primary endpoint. Thus, the neurotoxin therapy had a 40% effectiveness rate. The odds of being at least a 50% responder were 394% greater in the onabotulinumtoxinA group, according to Dr. Blumenfeld.
Secondary endpoints consisted of four PROs: the Headache Impact Test of migraine-related disability (HIT-6), the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP), the Patient Health Questionnaire–9 (PHQ-9), and a cutting edge, not yet fully validated instrument known as the Functional Impact of Migraine Questionnaire, or FIMQ.
The onabotulinumtoxinA group fared significantly better than the topiramate group on all four PROs. But Dr. Blumenfeld singled out the PHQ-9 results as of particular clinical importance. A score of 5 or more is considered evidence of at least mild depression; on average, both groups were depressed at baseline, with a mean score of 6.5 in the onabotulinumtoxinA group and 7.6 in the topiramate group. At week 12, the scores were 5.2 and 6.7, respectively. At week 24, 4.5 versus 7.2. At week 36, the average PHQ-9 score in the onabotulinumtoxinA group was 4.4 – meaning no depression – compared with 7.1 in the topiramate group.
A reduction in HIT-6 scores of more than 2.5 points is considered to represent clinically significant improvement in migraine-related disability. At week 6, the HIT-6 score had fallen by an average of 4.0 points from baseline in the onabotulinumtoxinA group, compared with –2.2 points with topiramate. At week 18, the margin of improvement was –5.1 versus –1.6 points, while at week 36 the average improvement was –5.6 points in the onabotulinumtoxinA group, compared with –1.4 points in the topiramate arm in a last-observation-carried-forward analysis.
Mean baseline scores on the WPAI-SHP were 4.8 in the onabotulinumtoxinA group and 5.1 in those on topiramate. At week 12, the scores had improved to 3.3 and 4.4, respectively, and at week 36, to 3.5 and 4.4, respectively, a significant and clinically meaningful difference.
Mean baseline scores on the FIMQ were 59.8 and 53.9 in the onabotulinumtoxinA and topiramate groups. By week 30, the scores were 37.1 and 47.5, respectively.
The main reasons half of the topiramate patients discontinued were the adverse events classically associated with the drug: paresthesia, cognitive impairment, nausea, and fatigue. None of these were reported by more than 0.5% of onabotulinumtoxinA recipients.
This is not the first study to show superior outcomes with neurotoxin therapy for the prevention of chronic migraine.
“There is a disconnect between the published data and what happens in the community,” Dr. Blumenfeld observed. “In clinical practice, topiramate is listed as first-line therapy for chronic migraine, while onabotulinumtoxinA is third or fourth line.”
Insurers normally balk at covering neurotoxin therapy because it is relatively expensive. But in an era when PROs have taken on new weight with regulatory agencies and payers, the ground may be soon be shifting.
One audience member noted that in the relatively small subgroup of patients who could tolerate topiramate sufficiently to stay on the drug, the outcomes were quite good. Dr. Blumenfeld concurred.
“It’s something that we all see in clinical practice: Those patients who can stay on topiramate, who can tolerate it, do very well. So for the 17 of 25 who stayed on it and had a 50% reduction in headache days, that 68% is a good number, and I think it matches our clinical experience,” he said. “But the key message of this study – and I think this is a different way of looking at the way we assess medications – is to look at efficacy, but also at tolerability and long-term adherence. And the problem with topiramate-treated patients, particularly in chronic migraine, is they have a difficult time staying on the medication long enough to see that good effect.”
The FORWARD trial was sponsored by Allergan. Dr. Blumenfeld serves as a consultant to that company and a half-dozen others.
SOURCE: Blumenfeld AM et al. Headache. 2018 Jun;58(52):75. Abstract IOR06.
SAN FRANCISCO – The odds of at least a 50% reduction in headache days per month in chronic migraine patients 32 weeks after randomization to onabotulinumtoxinA for prophylaxis were 394% greater than with topiramate in the multicenter, open-label FORWARD trial, Andrew M. Blumenfeld, MD, reported at the annual meeting of the American Headache Society.
“Impressively, onabotulinumtoxinA showed a more favorable effect on depressive symptoms,” he added. “The overall results suggest that the beneficial effects of onabotulinumtoxinA on a range of PROs may lead to improved adherence.”
The FORWARD trial was a multicenter, open-label, prospective, 36-week study which randomized 282 adult chronic migraine patients to fixed-dose onabotulinumtoxinA at the approved dose of 155 U every 12 weeks or to topiramate (Topamax) titrated over the course of 12 weeks to the approved dose of 50-100 mg/day. However, after 12 weeks on topiramate, patients could elect to discontinue the drug and switch to onabotulinumtoxinA.
This was a trial designed to evaluate effectiveness, which Dr. Blumenfeld defined as the combination of efficacy plus treatment adherence. And treatment adherence with topiramate was poor: 63% of patients discontinued that medication, mainly because of adverse events or lack of efficacy, compared with just 7.9% of the onabotulinumtoxinA group.
The primary endpoint was the proportion of patients who achieved at least a 50% reduction in headache days per month beginning at week 32, compared with their rate during 4 weeks at baseline. Of 142 patients randomized to topiramate, 25 completed 36 weeks of therapy, and 17 of those 25 (68%) achieved at least a 50% reduction in headache days per month. That’s one way to look at it. The other is to examine effectiveness: 17 of 142 topiramate-treated patients (12%) met the primary endpoint. In contrast, 99 of 140 patients assigned to onabotulinumtoxinA completed treatment, and 56 of those 99 (57%) met the primary endpoint. Thus, the neurotoxin therapy had a 40% effectiveness rate. The odds of being at least a 50% responder were 394% greater in the onabotulinumtoxinA group, according to Dr. Blumenfeld.
Secondary endpoints consisted of four PROs: the Headache Impact Test of migraine-related disability (HIT-6), the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP), the Patient Health Questionnaire–9 (PHQ-9), and a cutting edge, not yet fully validated instrument known as the Functional Impact of Migraine Questionnaire, or FIMQ.
The onabotulinumtoxinA group fared significantly better than the topiramate group on all four PROs. But Dr. Blumenfeld singled out the PHQ-9 results as of particular clinical importance. A score of 5 or more is considered evidence of at least mild depression; on average, both groups were depressed at baseline, with a mean score of 6.5 in the onabotulinumtoxinA group and 7.6 in the topiramate group. At week 12, the scores were 5.2 and 6.7, respectively. At week 24, 4.5 versus 7.2. At week 36, the average PHQ-9 score in the onabotulinumtoxinA group was 4.4 – meaning no depression – compared with 7.1 in the topiramate group.
A reduction in HIT-6 scores of more than 2.5 points is considered to represent clinically significant improvement in migraine-related disability. At week 6, the HIT-6 score had fallen by an average of 4.0 points from baseline in the onabotulinumtoxinA group, compared with –2.2 points with topiramate. At week 18, the margin of improvement was –5.1 versus –1.6 points, while at week 36 the average improvement was –5.6 points in the onabotulinumtoxinA group, compared with –1.4 points in the topiramate arm in a last-observation-carried-forward analysis.
Mean baseline scores on the WPAI-SHP were 4.8 in the onabotulinumtoxinA group and 5.1 in those on topiramate. At week 12, the scores had improved to 3.3 and 4.4, respectively, and at week 36, to 3.5 and 4.4, respectively, a significant and clinically meaningful difference.
Mean baseline scores on the FIMQ were 59.8 and 53.9 in the onabotulinumtoxinA and topiramate groups. By week 30, the scores were 37.1 and 47.5, respectively.
The main reasons half of the topiramate patients discontinued were the adverse events classically associated with the drug: paresthesia, cognitive impairment, nausea, and fatigue. None of these were reported by more than 0.5% of onabotulinumtoxinA recipients.
This is not the first study to show superior outcomes with neurotoxin therapy for the prevention of chronic migraine.
“There is a disconnect between the published data and what happens in the community,” Dr. Blumenfeld observed. “In clinical practice, topiramate is listed as first-line therapy for chronic migraine, while onabotulinumtoxinA is third or fourth line.”
Insurers normally balk at covering neurotoxin therapy because it is relatively expensive. But in an era when PROs have taken on new weight with regulatory agencies and payers, the ground may be soon be shifting.
One audience member noted that in the relatively small subgroup of patients who could tolerate topiramate sufficiently to stay on the drug, the outcomes were quite good. Dr. Blumenfeld concurred.
“It’s something that we all see in clinical practice: Those patients who can stay on topiramate, who can tolerate it, do very well. So for the 17 of 25 who stayed on it and had a 50% reduction in headache days, that 68% is a good number, and I think it matches our clinical experience,” he said. “But the key message of this study – and I think this is a different way of looking at the way we assess medications – is to look at efficacy, but also at tolerability and long-term adherence. And the problem with topiramate-treated patients, particularly in chronic migraine, is they have a difficult time staying on the medication long enough to see that good effect.”
The FORWARD trial was sponsored by Allergan. Dr. Blumenfeld serves as a consultant to that company and a half-dozen others.
SOURCE: Blumenfeld AM et al. Headache. 2018 Jun;58(52):75. Abstract IOR06.
SAN FRANCISCO – The odds of at least a 50% reduction in headache days per month in chronic migraine patients 32 weeks after randomization to onabotulinumtoxinA for prophylaxis were 394% greater than with topiramate in the multicenter, open-label FORWARD trial, Andrew M. Blumenfeld, MD, reported at the annual meeting of the American Headache Society.
“Impressively, onabotulinumtoxinA showed a more favorable effect on depressive symptoms,” he added. “The overall results suggest that the beneficial effects of onabotulinumtoxinA on a range of PROs may lead to improved adherence.”
The FORWARD trial was a multicenter, open-label, prospective, 36-week study which randomized 282 adult chronic migraine patients to fixed-dose onabotulinumtoxinA at the approved dose of 155 U every 12 weeks or to topiramate (Topamax) titrated over the course of 12 weeks to the approved dose of 50-100 mg/day. However, after 12 weeks on topiramate, patients could elect to discontinue the drug and switch to onabotulinumtoxinA.
This was a trial designed to evaluate effectiveness, which Dr. Blumenfeld defined as the combination of efficacy plus treatment adherence. And treatment adherence with topiramate was poor: 63% of patients discontinued that medication, mainly because of adverse events or lack of efficacy, compared with just 7.9% of the onabotulinumtoxinA group.
The primary endpoint was the proportion of patients who achieved at least a 50% reduction in headache days per month beginning at week 32, compared with their rate during 4 weeks at baseline. Of 142 patients randomized to topiramate, 25 completed 36 weeks of therapy, and 17 of those 25 (68%) achieved at least a 50% reduction in headache days per month. That’s one way to look at it. The other is to examine effectiveness: 17 of 142 topiramate-treated patients (12%) met the primary endpoint. In contrast, 99 of 140 patients assigned to onabotulinumtoxinA completed treatment, and 56 of those 99 (57%) met the primary endpoint. Thus, the neurotoxin therapy had a 40% effectiveness rate. The odds of being at least a 50% responder were 394% greater in the onabotulinumtoxinA group, according to Dr. Blumenfeld.
Secondary endpoints consisted of four PROs: the Headache Impact Test of migraine-related disability (HIT-6), the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP), the Patient Health Questionnaire–9 (PHQ-9), and a cutting edge, not yet fully validated instrument known as the Functional Impact of Migraine Questionnaire, or FIMQ.
The onabotulinumtoxinA group fared significantly better than the topiramate group on all four PROs. But Dr. Blumenfeld singled out the PHQ-9 results as of particular clinical importance. A score of 5 or more is considered evidence of at least mild depression; on average, both groups were depressed at baseline, with a mean score of 6.5 in the onabotulinumtoxinA group and 7.6 in the topiramate group. At week 12, the scores were 5.2 and 6.7, respectively. At week 24, 4.5 versus 7.2. At week 36, the average PHQ-9 score in the onabotulinumtoxinA group was 4.4 – meaning no depression – compared with 7.1 in the topiramate group.
A reduction in HIT-6 scores of more than 2.5 points is considered to represent clinically significant improvement in migraine-related disability. At week 6, the HIT-6 score had fallen by an average of 4.0 points from baseline in the onabotulinumtoxinA group, compared with –2.2 points with topiramate. At week 18, the margin of improvement was –5.1 versus –1.6 points, while at week 36 the average improvement was –5.6 points in the onabotulinumtoxinA group, compared with –1.4 points in the topiramate arm in a last-observation-carried-forward analysis.
Mean baseline scores on the WPAI-SHP were 4.8 in the onabotulinumtoxinA group and 5.1 in those on topiramate. At week 12, the scores had improved to 3.3 and 4.4, respectively, and at week 36, to 3.5 and 4.4, respectively, a significant and clinically meaningful difference.
Mean baseline scores on the FIMQ were 59.8 and 53.9 in the onabotulinumtoxinA and topiramate groups. By week 30, the scores were 37.1 and 47.5, respectively.
The main reasons half of the topiramate patients discontinued were the adverse events classically associated with the drug: paresthesia, cognitive impairment, nausea, and fatigue. None of these were reported by more than 0.5% of onabotulinumtoxinA recipients.
This is not the first study to show superior outcomes with neurotoxin therapy for the prevention of chronic migraine.
“There is a disconnect between the published data and what happens in the community,” Dr. Blumenfeld observed. “In clinical practice, topiramate is listed as first-line therapy for chronic migraine, while onabotulinumtoxinA is third or fourth line.”
Insurers normally balk at covering neurotoxin therapy because it is relatively expensive. But in an era when PROs have taken on new weight with regulatory agencies and payers, the ground may be soon be shifting.
One audience member noted that in the relatively small subgroup of patients who could tolerate topiramate sufficiently to stay on the drug, the outcomes were quite good. Dr. Blumenfeld concurred.
“It’s something that we all see in clinical practice: Those patients who can stay on topiramate, who can tolerate it, do very well. So for the 17 of 25 who stayed on it and had a 50% reduction in headache days, that 68% is a good number, and I think it matches our clinical experience,” he said. “But the key message of this study – and I think this is a different way of looking at the way we assess medications – is to look at efficacy, but also at tolerability and long-term adherence. And the problem with topiramate-treated patients, particularly in chronic migraine, is they have a difficult time staying on the medication long enough to see that good effect.”
The FORWARD trial was sponsored by Allergan. Dr. Blumenfeld serves as a consultant to that company and a half-dozen others.
SOURCE: Blumenfeld AM et al. Headache. 2018 Jun;58(52):75. Abstract IOR06.
REPORTING FROM THE AHS ANNUAL MEETING
Key clinical point:
Major finding: The likelihood of at least a 50% reduction in headache days per month in chronic migraine patients during weeks 29-32 versus baseline was nearly 400% greater in those randomized to onabotulinumtoxinA than to topiramate.
Study details: The FORWARD trial was a randomized, multicenter, open-label, 36-week study in 282 chronic migraine patients.
Disclosures: FORWARD was sponsored by Allergan. The presenter serves as a consultant to that company and a half-dozen others.
Source: Blumenfeld AM et al. Headache. 2018 Jun;58(52):75. Abstract IOR06.