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Cost-effective wound healing described with fetal bovine collagen matrix
CHICAGO – A novel, commercially available fetal bovine collagen matrix provides “an ideal wound healing environment” for outpatient treatment of partial and full thickness wounds, ulcers, burns, and surgical wounds, Katarina R. Kesty, MD, declared at the annual meeting of the American College of Mohs Surgery.
“. We applied this product to 46 patients over 10 months and have observed favorable healing times and good cosmesis,” said Dr. Kesty, a dermatology resident at Wake Forest University, Winston-Salem, N.C.
She shared the clinical experience she and her colleagues have accrued with this product, which is called PriMatrix and is manufactured by Integra LifeSciences. She also explained how to successfully code and bill for its use.
“In-office application of this product is cost-effective when compared to similar products applied in the operating room by plastic surgeons and other specialists,” Dr. Kesty noted.
How cost-effective? She provided one example of a patient with a 12.6-cm2 defect on the scalp repaired with fetal bovine collagen matrix. Upon application of the appropriate billing codes, this repair was reimbursed by Medicare to the tune of $1,208. In contrast, another patient at Wake Forest had a 16.6-cm2 Mohs defect on the scalp repaired in the operating room by an oculoplastic surgeon who used split thickness skin grafts. For this procedure, Medicare was billed $30,805.11, and the medical center received $9,241.53 in reimbursement.
“An office repair using this fetal bovine collagen matrix is much more cost-effective,” she observed. “It also saves the patient from the risks of general anesthesia or conscious sedation.”
PriMatrix is a porous acellular collagen matrix derived from fetal bovine dermis. It contains type I and type III collagen, with the latter being particularly effective at attracting growth factors, blood, and angiogenic cytokines in support of dermal regeneration and revascularization. The product is available in solid sheets, mesh, and fenestrated forms in a variety of sizes. It needs to be rehydrated for 1 minute in room temperature saline. It can then be cut to the size of the wound and secured to the wound bed, periosteum, fascia, or cartilage with sutures or staples. The site is then covered with a thick layer of petrolatum and a tie-over bolster.
Dr. Kesty and her dermatology colleagues have applied the matrix to surgical defects ranging in size from 0.2 cm2 to 70 cm2, with an average area of 19 cm2. They have utilized the mesh format most often in order to allow drainage. They found the average healing time when the matrix was applied to exposed bone, periosteum, or perichondrium was 13.8 weeks, compared with 10.8 weeks for subcutaneous wounds.
With the use of the fetal bovine collagen matrix, wounds less than 10 cm2 in size healed in an average of 9.3 weeks, those from 10 cm2 to 25 cm2 in size healed in an average of 10.4 weeks, and wounds larger than 25 cm2 healed in an average of 15.7 weeks.
Coding and reimbursement
PriMatrix has been available for outpatient office use and reimbursement by Medicare since January 2017. Successful reimbursement requires completion of a preauthorization form, which is typically approved on the same day by Medicare and other payers. The proper CPT codes are 1527x, signifying a skin substitute graft less than 100 cm2 in size; Q4110 times the number of 1-cm2 units of PriMatrix utilized; and, when appropriate, ICD10 code Z85.828, for personal history of nonmelanoma skin cancer.
Dr. Kesty reported no financial conflicts of interest.
CHICAGO – A novel, commercially available fetal bovine collagen matrix provides “an ideal wound healing environment” for outpatient treatment of partial and full thickness wounds, ulcers, burns, and surgical wounds, Katarina R. Kesty, MD, declared at the annual meeting of the American College of Mohs Surgery.
“. We applied this product to 46 patients over 10 months and have observed favorable healing times and good cosmesis,” said Dr. Kesty, a dermatology resident at Wake Forest University, Winston-Salem, N.C.
She shared the clinical experience she and her colleagues have accrued with this product, which is called PriMatrix and is manufactured by Integra LifeSciences. She also explained how to successfully code and bill for its use.
“In-office application of this product is cost-effective when compared to similar products applied in the operating room by plastic surgeons and other specialists,” Dr. Kesty noted.
How cost-effective? She provided one example of a patient with a 12.6-cm2 defect on the scalp repaired with fetal bovine collagen matrix. Upon application of the appropriate billing codes, this repair was reimbursed by Medicare to the tune of $1,208. In contrast, another patient at Wake Forest had a 16.6-cm2 Mohs defect on the scalp repaired in the operating room by an oculoplastic surgeon who used split thickness skin grafts. For this procedure, Medicare was billed $30,805.11, and the medical center received $9,241.53 in reimbursement.
“An office repair using this fetal bovine collagen matrix is much more cost-effective,” she observed. “It also saves the patient from the risks of general anesthesia or conscious sedation.”
PriMatrix is a porous acellular collagen matrix derived from fetal bovine dermis. It contains type I and type III collagen, with the latter being particularly effective at attracting growth factors, blood, and angiogenic cytokines in support of dermal regeneration and revascularization. The product is available in solid sheets, mesh, and fenestrated forms in a variety of sizes. It needs to be rehydrated for 1 minute in room temperature saline. It can then be cut to the size of the wound and secured to the wound bed, periosteum, fascia, or cartilage with sutures or staples. The site is then covered with a thick layer of petrolatum and a tie-over bolster.
Dr. Kesty and her dermatology colleagues have applied the matrix to surgical defects ranging in size from 0.2 cm2 to 70 cm2, with an average area of 19 cm2. They have utilized the mesh format most often in order to allow drainage. They found the average healing time when the matrix was applied to exposed bone, periosteum, or perichondrium was 13.8 weeks, compared with 10.8 weeks for subcutaneous wounds.
With the use of the fetal bovine collagen matrix, wounds less than 10 cm2 in size healed in an average of 9.3 weeks, those from 10 cm2 to 25 cm2 in size healed in an average of 10.4 weeks, and wounds larger than 25 cm2 healed in an average of 15.7 weeks.
Coding and reimbursement
PriMatrix has been available for outpatient office use and reimbursement by Medicare since January 2017. Successful reimbursement requires completion of a preauthorization form, which is typically approved on the same day by Medicare and other payers. The proper CPT codes are 1527x, signifying a skin substitute graft less than 100 cm2 in size; Q4110 times the number of 1-cm2 units of PriMatrix utilized; and, when appropriate, ICD10 code Z85.828, for personal history of nonmelanoma skin cancer.
Dr. Kesty reported no financial conflicts of interest.
CHICAGO – A novel, commercially available fetal bovine collagen matrix provides “an ideal wound healing environment” for outpatient treatment of partial and full thickness wounds, ulcers, burns, and surgical wounds, Katarina R. Kesty, MD, declared at the annual meeting of the American College of Mohs Surgery.
“. We applied this product to 46 patients over 10 months and have observed favorable healing times and good cosmesis,” said Dr. Kesty, a dermatology resident at Wake Forest University, Winston-Salem, N.C.
She shared the clinical experience she and her colleagues have accrued with this product, which is called PriMatrix and is manufactured by Integra LifeSciences. She also explained how to successfully code and bill for its use.
“In-office application of this product is cost-effective when compared to similar products applied in the operating room by plastic surgeons and other specialists,” Dr. Kesty noted.
How cost-effective? She provided one example of a patient with a 12.6-cm2 defect on the scalp repaired with fetal bovine collagen matrix. Upon application of the appropriate billing codes, this repair was reimbursed by Medicare to the tune of $1,208. In contrast, another patient at Wake Forest had a 16.6-cm2 Mohs defect on the scalp repaired in the operating room by an oculoplastic surgeon who used split thickness skin grafts. For this procedure, Medicare was billed $30,805.11, and the medical center received $9,241.53 in reimbursement.
“An office repair using this fetal bovine collagen matrix is much more cost-effective,” she observed. “It also saves the patient from the risks of general anesthesia or conscious sedation.”
PriMatrix is a porous acellular collagen matrix derived from fetal bovine dermis. It contains type I and type III collagen, with the latter being particularly effective at attracting growth factors, blood, and angiogenic cytokines in support of dermal regeneration and revascularization. The product is available in solid sheets, mesh, and fenestrated forms in a variety of sizes. It needs to be rehydrated for 1 minute in room temperature saline. It can then be cut to the size of the wound and secured to the wound bed, periosteum, fascia, or cartilage with sutures or staples. The site is then covered with a thick layer of petrolatum and a tie-over bolster.
Dr. Kesty and her dermatology colleagues have applied the matrix to surgical defects ranging in size from 0.2 cm2 to 70 cm2, with an average area of 19 cm2. They have utilized the mesh format most often in order to allow drainage. They found the average healing time when the matrix was applied to exposed bone, periosteum, or perichondrium was 13.8 weeks, compared with 10.8 weeks for subcutaneous wounds.
With the use of the fetal bovine collagen matrix, wounds less than 10 cm2 in size healed in an average of 9.3 weeks, those from 10 cm2 to 25 cm2 in size healed in an average of 10.4 weeks, and wounds larger than 25 cm2 healed in an average of 15.7 weeks.
Coding and reimbursement
PriMatrix has been available for outpatient office use and reimbursement by Medicare since January 2017. Successful reimbursement requires completion of a preauthorization form, which is typically approved on the same day by Medicare and other payers. The proper CPT codes are 1527x, signifying a skin substitute graft less than 100 cm2 in size; Q4110 times the number of 1-cm2 units of PriMatrix utilized; and, when appropriate, ICD10 code Z85.828, for personal history of nonmelanoma skin cancer.
Dr. Kesty reported no financial conflicts of interest.
EXPERT ANALYSIS FROM THE ACMS ANNUAL MEETING
DTPa-HBV-IPV/Hib in infancy maintains lasting immune memory against HBV in teens
MALMO, SWEDEN – Four doses of hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenza type b vaccine given in infancy provides reassuringly long-lasting immune memory against hepatitis B among 14- to 15-year-olds, Tino F. Schwarz, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
He presented the fourth and final study in a series evaluating the antibody persistence and immune memory against hepatitis B (HBV) in recipients of the complete four-dose series of hexavalent DTPa-HBV-IPV/Hib vaccine in infancy. Because exposure to HBV can increase during adolescence, it was essential to determine whether antibody persistence is maintained, explained Dr. Schwarz of Juliusspital Hospital in Wurzburg, Germany.
“As expected, we saw a decrease in anti-HBs [hepatitis B surface antigen] antibody levels over the years, with persistent seroprotection in 85% of children at age 4-5 years, 72% at 7-8 years, 61% at 12-13 years, and now 54% of adolescents at 14-15 years. But we could demonstrate a very strong anamnestic response in the trial. This is good information. It clearly shows that, in patients who are exposed to hepatitis B, we can certainly guarantee that they are protected. It’s a good result for public health. The vaccine is a very robust vaccine which induces a very strong response over the years. It can be boosted, but from an immunologic point of view it is not required,” he said.
The multicenter study included 268 adolescents aged 14-15 years who had received the four-dose hexavalent vaccine series in infancy. Their antibody persistence against anti-HBs was measured, then measured once again 1 month after receiving a challenge dose of monovalent HBV vaccine.
Prechallenge, 105 of the teens were seronegative, 144 were seroprotected as defined by an anti-HBs concentration of at least 10 mIU/mL, and 19 had low seropositivity marked by an antibody level of 6 to less than 10 mIU/mL. Yet 1 month after the booster, which was intended to mimic the impact of real-world exposure to HBV, 83% of the initially seronegative subjects had an anti-HBs concentration of 10 mIU/mL or more, and 67% of them had a level of at least 100 mIU/mL.
“We saw a clear fantastic anamnestic response,” Dr. Schwarz declared.
Overall, 93% of study participants seroconverted, and 87% of them had anti-HBs titers of 100 mIU/mL, “which is the level we’d like to achieve in vaccinees,” he observed.
The booster monovalent HBV vaccine was well tolerated, with one-third of subjects complaining of mild local injection site pain and 30% noting fatigue. But in response to a question posed by session chair Ronald de Groot, MD, emeritus professor of pediatrics at Radboud University in Nijmegen, the Netherlands, Dr. Schwarz said these study results indicate there’s no need for routine boosting in healthy adolescents such as those in the trial. Immunocompromised individuals might be a different story, but they weren’t investigated.
But what about in physicians and surgeons, where protection against HBV infection is essential? Dr. de Groot asked.
“In Germany, we require a titer of 100 mIU/mL or more in medical staff, but we’re quite alone in Europe. Other countries do not require booster vaccination for medical staff. The data we’ve shown here is quite reassuring: If you get exposed, you in effect get a booster. It’s complicated to test surgeons in their offices; better to just rely on the anamnestic response that we’ve demonstrated,” Dr. Schwarz replied.
He reported serving as a consultant to GlaxoSmithKline, which funded the study, as well as to Pfizer and Sanofi Pasteur.
MALMO, SWEDEN – Four doses of hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenza type b vaccine given in infancy provides reassuringly long-lasting immune memory against hepatitis B among 14- to 15-year-olds, Tino F. Schwarz, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
He presented the fourth and final study in a series evaluating the antibody persistence and immune memory against hepatitis B (HBV) in recipients of the complete four-dose series of hexavalent DTPa-HBV-IPV/Hib vaccine in infancy. Because exposure to HBV can increase during adolescence, it was essential to determine whether antibody persistence is maintained, explained Dr. Schwarz of Juliusspital Hospital in Wurzburg, Germany.
“As expected, we saw a decrease in anti-HBs [hepatitis B surface antigen] antibody levels over the years, with persistent seroprotection in 85% of children at age 4-5 years, 72% at 7-8 years, 61% at 12-13 years, and now 54% of adolescents at 14-15 years. But we could demonstrate a very strong anamnestic response in the trial. This is good information. It clearly shows that, in patients who are exposed to hepatitis B, we can certainly guarantee that they are protected. It’s a good result for public health. The vaccine is a very robust vaccine which induces a very strong response over the years. It can be boosted, but from an immunologic point of view it is not required,” he said.
The multicenter study included 268 adolescents aged 14-15 years who had received the four-dose hexavalent vaccine series in infancy. Their antibody persistence against anti-HBs was measured, then measured once again 1 month after receiving a challenge dose of monovalent HBV vaccine.
Prechallenge, 105 of the teens were seronegative, 144 were seroprotected as defined by an anti-HBs concentration of at least 10 mIU/mL, and 19 had low seropositivity marked by an antibody level of 6 to less than 10 mIU/mL. Yet 1 month after the booster, which was intended to mimic the impact of real-world exposure to HBV, 83% of the initially seronegative subjects had an anti-HBs concentration of 10 mIU/mL or more, and 67% of them had a level of at least 100 mIU/mL.
“We saw a clear fantastic anamnestic response,” Dr. Schwarz declared.
Overall, 93% of study participants seroconverted, and 87% of them had anti-HBs titers of 100 mIU/mL, “which is the level we’d like to achieve in vaccinees,” he observed.
The booster monovalent HBV vaccine was well tolerated, with one-third of subjects complaining of mild local injection site pain and 30% noting fatigue. But in response to a question posed by session chair Ronald de Groot, MD, emeritus professor of pediatrics at Radboud University in Nijmegen, the Netherlands, Dr. Schwarz said these study results indicate there’s no need for routine boosting in healthy adolescents such as those in the trial. Immunocompromised individuals might be a different story, but they weren’t investigated.
But what about in physicians and surgeons, where protection against HBV infection is essential? Dr. de Groot asked.
“In Germany, we require a titer of 100 mIU/mL or more in medical staff, but we’re quite alone in Europe. Other countries do not require booster vaccination for medical staff. The data we’ve shown here is quite reassuring: If you get exposed, you in effect get a booster. It’s complicated to test surgeons in their offices; better to just rely on the anamnestic response that we’ve demonstrated,” Dr. Schwarz replied.
He reported serving as a consultant to GlaxoSmithKline, which funded the study, as well as to Pfizer and Sanofi Pasteur.
MALMO, SWEDEN – Four doses of hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenza type b vaccine given in infancy provides reassuringly long-lasting immune memory against hepatitis B among 14- to 15-year-olds, Tino F. Schwarz, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
He presented the fourth and final study in a series evaluating the antibody persistence and immune memory against hepatitis B (HBV) in recipients of the complete four-dose series of hexavalent DTPa-HBV-IPV/Hib vaccine in infancy. Because exposure to HBV can increase during adolescence, it was essential to determine whether antibody persistence is maintained, explained Dr. Schwarz of Juliusspital Hospital in Wurzburg, Germany.
“As expected, we saw a decrease in anti-HBs [hepatitis B surface antigen] antibody levels over the years, with persistent seroprotection in 85% of children at age 4-5 years, 72% at 7-8 years, 61% at 12-13 years, and now 54% of adolescents at 14-15 years. But we could demonstrate a very strong anamnestic response in the trial. This is good information. It clearly shows that, in patients who are exposed to hepatitis B, we can certainly guarantee that they are protected. It’s a good result for public health. The vaccine is a very robust vaccine which induces a very strong response over the years. It can be boosted, but from an immunologic point of view it is not required,” he said.
The multicenter study included 268 adolescents aged 14-15 years who had received the four-dose hexavalent vaccine series in infancy. Their antibody persistence against anti-HBs was measured, then measured once again 1 month after receiving a challenge dose of monovalent HBV vaccine.
Prechallenge, 105 of the teens were seronegative, 144 were seroprotected as defined by an anti-HBs concentration of at least 10 mIU/mL, and 19 had low seropositivity marked by an antibody level of 6 to less than 10 mIU/mL. Yet 1 month after the booster, which was intended to mimic the impact of real-world exposure to HBV, 83% of the initially seronegative subjects had an anti-HBs concentration of 10 mIU/mL or more, and 67% of them had a level of at least 100 mIU/mL.
“We saw a clear fantastic anamnestic response,” Dr. Schwarz declared.
Overall, 93% of study participants seroconverted, and 87% of them had anti-HBs titers of 100 mIU/mL, “which is the level we’d like to achieve in vaccinees,” he observed.
The booster monovalent HBV vaccine was well tolerated, with one-third of subjects complaining of mild local injection site pain and 30% noting fatigue. But in response to a question posed by session chair Ronald de Groot, MD, emeritus professor of pediatrics at Radboud University in Nijmegen, the Netherlands, Dr. Schwarz said these study results indicate there’s no need for routine boosting in healthy adolescents such as those in the trial. Immunocompromised individuals might be a different story, but they weren’t investigated.
But what about in physicians and surgeons, where protection against HBV infection is essential? Dr. de Groot asked.
“In Germany, we require a titer of 100 mIU/mL or more in medical staff, but we’re quite alone in Europe. Other countries do not require booster vaccination for medical staff. The data we’ve shown here is quite reassuring: If you get exposed, you in effect get a booster. It’s complicated to test surgeons in their offices; better to just rely on the anamnestic response that we’ve demonstrated,” Dr. Schwarz replied.
He reported serving as a consultant to GlaxoSmithKline, which funded the study, as well as to Pfizer and Sanofi Pasteur.
REPORTING FROM ESPID 2018
Key clinical point:
Major finding: Ninety-three percent of recipients of four doses of hexavalent DTPa-HBV-IPV/Hib vaccine in infancy were seroprotected against HBV at age 14-15 years.
Study details: This was a prospective study of antibody persistence and immune memory in 268 teens aged 14-15 before and 1 month after receiving a booster challenge HBV monovalent vaccine.
Disclosures: The presenter reported serving as a consultant to GlaxoSmithKline, which funded the study, as well as to Pfizer and Sanofi Pasteur.
Synergy DES shines in acute MI
PARIS – The Synergy bioabsorbable polymer everolimus-eluting stent performed equally well for treatment of acute MI, compared with other newer-generation drug-eluting stents, through 2 years of follow-up in a massive observational study of all patients undergoing percutaneous coronary intervention in Sweden during a recent multiyear period.
This report from the prospective Swedish Coronary Angiography and Angioplasty Registry (SCAAR) was undertaken because, even though the Synergy stent has demonstrated outstanding clinical results in randomized trials and observational studies, the stent’s performance specifically in the setting of acute MI had not previously been investigated, Sergio Buccheri, MD, noted at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.
SCAAR, which documents every PCI performed in Sweden, provided the capability to fill that important knowledge gap in an unselected real-world population of acute MI patients. Dr. Buccheri, of Uppsala (Sweden) University, reported on 36,292 consecutive patients who underwent PCI with a newer-generation drug-eluting stent (DES) in Sweden from March 2013 to September 2016. Forty percent of them had ST-elevation MI. The Synergy stent was used in 4,889 patients. Among the most commonly used newer DES in the other 31,000-plus patients were the Xience Xpedition, the Resolute Integrity and Resolute Onyx, the Orsiro, BioMatrix, and Promus Element Plus and Promus Premier.
The coprimary endpoints in this analysis were the rates of definite stent thrombosis and clinically relevant restenosis at 2 years of follow-up. Stent thrombosis occurred in 0.69% of the Synergy patients and 0.81% of those who received other newer-generation DES, a nonsignificant difference. Similarly, no significant difference was found in the rate of clinically relevant restenosis: 1.48% and 1.25%, respectively.
“,” Dr. Buccheri noted. “These findings may be useful to support a more informed and evidence-based stent selection process in daily clinical practice.”
The key secondary outcomes were all-cause mortality and recurrent MI. Again, there were no significant between-group differences. The cumulative all-cause mortality at 2 years was 10.1% in the Synergy group and 9.1% in the others. Recurrent MI occurred in 6.49% of the Synergy group and 6.32% with other DES.
Patients who received the Synergy stent were on average older, had a higher burden of cardiovascular risk factors, and presented more often with left main, triple-vessel disease or vein graft lesions. For that reason, Dr. Buccheri and his coinvestigators developed a propensity score using an array of covariates to adjust for these differences. Plugging those scores into multivariate Cox regression models, there remained no significant differences between the two groups in the adjusted risk of any of the endpoints.
Operators were advised to use dual antiplatelet therapy for 12 months in all patients. However, SCAAR does not include data on adherence to DAPT, which is a study limitation, Dr. Buccheri noted.
The Synergy stent is made up of a thin strut chromium-platinum platform with a bioabsorbable polymer that releases everolimus. The polymer is completely reabsorbed within 4 months, leaving behind a bare metal stent. In animal models, this has been associated with lower levels of inflammation, compared with permanent polymer DES. And inflammation is thought to be one of the main mechanisms underlying stent failure in the late and very late phases after PCI.
The discussion panel was clearly impressed with – and envious of – the sheer size of the SCAAR study population. As one panelist noted, real-life data of this magnitude can really only be obtained in Sweden. Another panelist confessed: “We’re shy of presenting our own studies when we see these numbers.”
Simultaneously with Dr. Buccheri’s presentation, the SCAAR report was published online (EuroIntervention. 2018 May 24. pii: EIJ-D-18-00392. doi: 10.4244/EIJ-D-18-00392).
SCAAR is funded solely by the Swedish government. This study was supported by a grant from Boston Scientific. Dr. Buccheri reported having no financial conflicts of interest.
PARIS – The Synergy bioabsorbable polymer everolimus-eluting stent performed equally well for treatment of acute MI, compared with other newer-generation drug-eluting stents, through 2 years of follow-up in a massive observational study of all patients undergoing percutaneous coronary intervention in Sweden during a recent multiyear period.
This report from the prospective Swedish Coronary Angiography and Angioplasty Registry (SCAAR) was undertaken because, even though the Synergy stent has demonstrated outstanding clinical results in randomized trials and observational studies, the stent’s performance specifically in the setting of acute MI had not previously been investigated, Sergio Buccheri, MD, noted at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.
SCAAR, which documents every PCI performed in Sweden, provided the capability to fill that important knowledge gap in an unselected real-world population of acute MI patients. Dr. Buccheri, of Uppsala (Sweden) University, reported on 36,292 consecutive patients who underwent PCI with a newer-generation drug-eluting stent (DES) in Sweden from March 2013 to September 2016. Forty percent of them had ST-elevation MI. The Synergy stent was used in 4,889 patients. Among the most commonly used newer DES in the other 31,000-plus patients were the Xience Xpedition, the Resolute Integrity and Resolute Onyx, the Orsiro, BioMatrix, and Promus Element Plus and Promus Premier.
The coprimary endpoints in this analysis were the rates of definite stent thrombosis and clinically relevant restenosis at 2 years of follow-up. Stent thrombosis occurred in 0.69% of the Synergy patients and 0.81% of those who received other newer-generation DES, a nonsignificant difference. Similarly, no significant difference was found in the rate of clinically relevant restenosis: 1.48% and 1.25%, respectively.
“,” Dr. Buccheri noted. “These findings may be useful to support a more informed and evidence-based stent selection process in daily clinical practice.”
The key secondary outcomes were all-cause mortality and recurrent MI. Again, there were no significant between-group differences. The cumulative all-cause mortality at 2 years was 10.1% in the Synergy group and 9.1% in the others. Recurrent MI occurred in 6.49% of the Synergy group and 6.32% with other DES.
Patients who received the Synergy stent were on average older, had a higher burden of cardiovascular risk factors, and presented more often with left main, triple-vessel disease or vein graft lesions. For that reason, Dr. Buccheri and his coinvestigators developed a propensity score using an array of covariates to adjust for these differences. Plugging those scores into multivariate Cox regression models, there remained no significant differences between the two groups in the adjusted risk of any of the endpoints.
Operators were advised to use dual antiplatelet therapy for 12 months in all patients. However, SCAAR does not include data on adherence to DAPT, which is a study limitation, Dr. Buccheri noted.
The Synergy stent is made up of a thin strut chromium-platinum platform with a bioabsorbable polymer that releases everolimus. The polymer is completely reabsorbed within 4 months, leaving behind a bare metal stent. In animal models, this has been associated with lower levels of inflammation, compared with permanent polymer DES. And inflammation is thought to be one of the main mechanisms underlying stent failure in the late and very late phases after PCI.
The discussion panel was clearly impressed with – and envious of – the sheer size of the SCAAR study population. As one panelist noted, real-life data of this magnitude can really only be obtained in Sweden. Another panelist confessed: “We’re shy of presenting our own studies when we see these numbers.”
Simultaneously with Dr. Buccheri’s presentation, the SCAAR report was published online (EuroIntervention. 2018 May 24. pii: EIJ-D-18-00392. doi: 10.4244/EIJ-D-18-00392).
SCAAR is funded solely by the Swedish government. This study was supported by a grant from Boston Scientific. Dr. Buccheri reported having no financial conflicts of interest.
PARIS – The Synergy bioabsorbable polymer everolimus-eluting stent performed equally well for treatment of acute MI, compared with other newer-generation drug-eluting stents, through 2 years of follow-up in a massive observational study of all patients undergoing percutaneous coronary intervention in Sweden during a recent multiyear period.
This report from the prospective Swedish Coronary Angiography and Angioplasty Registry (SCAAR) was undertaken because, even though the Synergy stent has demonstrated outstanding clinical results in randomized trials and observational studies, the stent’s performance specifically in the setting of acute MI had not previously been investigated, Sergio Buccheri, MD, noted at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.
SCAAR, which documents every PCI performed in Sweden, provided the capability to fill that important knowledge gap in an unselected real-world population of acute MI patients. Dr. Buccheri, of Uppsala (Sweden) University, reported on 36,292 consecutive patients who underwent PCI with a newer-generation drug-eluting stent (DES) in Sweden from March 2013 to September 2016. Forty percent of them had ST-elevation MI. The Synergy stent was used in 4,889 patients. Among the most commonly used newer DES in the other 31,000-plus patients were the Xience Xpedition, the Resolute Integrity and Resolute Onyx, the Orsiro, BioMatrix, and Promus Element Plus and Promus Premier.
The coprimary endpoints in this analysis were the rates of definite stent thrombosis and clinically relevant restenosis at 2 years of follow-up. Stent thrombosis occurred in 0.69% of the Synergy patients and 0.81% of those who received other newer-generation DES, a nonsignificant difference. Similarly, no significant difference was found in the rate of clinically relevant restenosis: 1.48% and 1.25%, respectively.
“,” Dr. Buccheri noted. “These findings may be useful to support a more informed and evidence-based stent selection process in daily clinical practice.”
The key secondary outcomes were all-cause mortality and recurrent MI. Again, there were no significant between-group differences. The cumulative all-cause mortality at 2 years was 10.1% in the Synergy group and 9.1% in the others. Recurrent MI occurred in 6.49% of the Synergy group and 6.32% with other DES.
Patients who received the Synergy stent were on average older, had a higher burden of cardiovascular risk factors, and presented more often with left main, triple-vessel disease or vein graft lesions. For that reason, Dr. Buccheri and his coinvestigators developed a propensity score using an array of covariates to adjust for these differences. Plugging those scores into multivariate Cox regression models, there remained no significant differences between the two groups in the adjusted risk of any of the endpoints.
Operators were advised to use dual antiplatelet therapy for 12 months in all patients. However, SCAAR does not include data on adherence to DAPT, which is a study limitation, Dr. Buccheri noted.
The Synergy stent is made up of a thin strut chromium-platinum platform with a bioabsorbable polymer that releases everolimus. The polymer is completely reabsorbed within 4 months, leaving behind a bare metal stent. In animal models, this has been associated with lower levels of inflammation, compared with permanent polymer DES. And inflammation is thought to be one of the main mechanisms underlying stent failure in the late and very late phases after PCI.
The discussion panel was clearly impressed with – and envious of – the sheer size of the SCAAR study population. As one panelist noted, real-life data of this magnitude can really only be obtained in Sweden. Another panelist confessed: “We’re shy of presenting our own studies when we see these numbers.”
Simultaneously with Dr. Buccheri’s presentation, the SCAAR report was published online (EuroIntervention. 2018 May 24. pii: EIJ-D-18-00392. doi: 10.4244/EIJ-D-18-00392).
SCAAR is funded solely by the Swedish government. This study was supported by a grant from Boston Scientific. Dr. Buccheri reported having no financial conflicts of interest.
REPORTING FROM EUROPCR 2018
Key clinical point: Two years post PCI for acute MI, stent thrombosis and restenosis rates in Synergy stent recipients were as low as with other newer-generation drug eluting stents.
Major finding: The 2-year rate of definite stent thrombosis was 0.69% in the Synergy stent group and 0.81% in recipients of other contemporary drug-eluting stents.
Study details: This was an observational study of 36,292 consecutive Swedish patients with acute MI who received the Synergy stent or other newer-generation drug-eluting stents.
Disclosures: The study was funded by a grant from Boston Scientific. The presenter reported having no financial conflicts of interest.
Positive pivotal trials for new headache drugs abound
SAN FRANCISCO – After a lengthy drought in the development of major new headache medications, it was finally raining successful phase 3 clinical trials for novel drugs at the annual meeting of the American Headache Society.
From the podium, as a prelude to presenting one of many positive trials, Richard B. Lipton, MD, was moved to paraphrase Charles Dickens: “ ‘It was the best of times’ ... and these are truly the best of times,” the neurologist observed.
“This morning we’ve heard about seven new molecular entities that are effective in the acute and/or preventive treatment of migraine, a couple of novel ways of delivering older drugs, and some interesting comparative effectiveness research. I have this compulsion to say over and over again – because I also work in Alzheimer’s disease – it just isn’t like this in other fields. This is truly a remarkable time in our field,” observed Dr. Lipton, professor and vice chair of the department of neurology at Albert Einstein College of Medicine in New York.
In addition to new studies of erenumab-aooe, which has been approved as Aimovig, the first-in-class calcitonin gene-related peptide (CGRP) inhibitor for the preventive treatment of migraine, the headache meeting also featured new positive phase 3 results for three other anti-CGRP monoclonal antibodies – galcanezumab, fremanezumab, and eptinezumab – as migraine-preventive therapy, with galcanezumab also demonstrating efficacy in episodic cluster headache; the oral small-molecule CGRP antagonists rimegepant and ubrogepant for acute treatment of migraine attacks; and the selective serotonin 5-HT 1F agonist lasmiditan, also for acute treatment of migraine.
Although the mechanisms of action and therapeutic purposes of the novel agents differ, they share in common what appears to be far better safety and tolerability than the current market leaders, topiramate (Topamax) for migraine prevention and the triptans for acute treatment.
Here are study highlights for the three potential new treatments for acute migraine attacks:
Rimegepant
Dr. Lipton presented the results of two virtually identical phase-3, double-blind, randomized trials in which a total of 2,162 patients with episodic migraine self-administered a 75-mg oral tablet of rimegepant or placebo to treat a single migraine attack when their headache pain reached moderate or severe intensity. The clinical trials, which lacked the customary snazzy acronyms, were simply called Study 301 and Study 302.
The two co-primary endpoints now required by the Food and Drug Administration for candidate agents for acute treatment of migraine attacks are freedom from pain and absence of the most bothersome symptom, both as assessed 2 hours post dose. The oral CGRP receptor antagonist met both endpoints, as well as key secondary endpoints.
In Study 302, for example, the pain-free rate 2 hours post dose was 19.6% in the rimegepant group, significantly higher than the 12% rate in placebo-treated controls. The rate of freedom from the most bothersome symptom, which was photophobia in the majority of patients, was 37.6% in the rimegepant group and 25.2% with placebo.
Dr. Lipton characterized the benefits seen with a single dose of rimegepant as “broad and clinically important.”
“The majority of patients achieved pain relief, durability of benefit at 24 and 48 hours, lower use of rescue medications, and a greater proportion of patients achieved normal function,” the neurologist reported.
The safety and tolerability profiles of rimegepant mirrored those of placebo, he added.
Ubrogepant
Dr. Lipton also presented the results of ACHIEVE II, a multicenter, double-blind, phase 3, placebo-controlled study of the oral CGRP receptor antagonist ubrogepant at 25 or 50 mg versus placebo in 1,355 patients with episodic migraine. Like rimegepant, it met both FDA-required primary endpoints. The pain freedom rate 2 hours post dose was 20.7% with ubrogepant at 25 mg, 21.8% with 50 mg, and 14.3% with placebo. The most bothersome symptom was gone at 2 hours in 34.1% of patients who received the CGRP receptor antagonist at 25 mg, 38.9% of those who got the 50-mg dose, and 27.4% of controls.
David W. Dodick, MD, explained the rationale for CGRP inhibition: CGRP and its receptors are highly expressed in pain-sensitive trigeminal sensory neurons, which innervate the dura and meningeal blood vessels. During the headache phase of migraine, the peptide is released in excess, making CGRP a key player in the pathophysiology of migraine.
Dr. Dodick presented an update focused on secondary endpoints in the phase 3, double-blind ACHIEVE I trial, whose positive co-primary outcomes have previously been reported. The analysis included 1,327 episodic migraine patients who were randomized to ubrogepant at 50 or 100 mg or placebo. Among the notable secondary outcomes was the clinically important rate of pain relief at 2 hours: 61% in both ubrogepant groups, significantly better than the 49% rate with placebo. Also, in terms of pain freedom, the 2-hour rate underestimated the true efficacy patients would experience in clinical practice: the maximum pain freedom rate occurred at 3 hours and was sustained to 8 hours post dose.
At the time study participants took their pill, only 30% indicated they were capable of functioning normally. Two hours later, this was still the case in 29.8% of placebo-treated controls, as compared with 40.6% on ubrogepant at 50 mg and 42.9% who took 100 mg of the drug. The proportion of patients who said they were satisfied or extremely satisfied with their treatment at the 2-hour mark was 24.1% in the placebo arm and 36.3% and 35.8% in the lower- and higher-dose ubrogepant arms, reported Dr. Dodick, professor of neurology at the Mayo Clinic in Scottsdale, Ariz.
Lasmiditan
Sheena K. Aurora, MD, presented the results of SAMURAI and SPARTAN, two randomized, double-blind, phase 3 clinical trials comparing lasmiditan versus placebo for the treatment of acute migraine in a collective 3,701 patients with longstanding episodic migraine, one-third of whom had a history of aura.
Lasmiditan is a novel oral serotonin receptor agonist that penetrates the CNS and selectively targets the 5-HT 1F receptor. The drug doesn’t cause the vasoconstrictive effects that make triptans, which target 5-HT 1B/1D receptors, contraindicated in patients with cardiovascular disease.
Indeed, SPARTAN included patients with known cardiovascular disease. SAMURAI did not; however, migraine is now recognized as an independent cardiovascular risk factor, and 80% of SAMURAI participants had one additional standard cardiovascular risk factor, such as diabetes, smoking, or hypertension.
SAMURAI randomized patients to lasmiditan at 100 or 200 mg or placebo to be taken within 4 hours of migraine onset, when the pain was of at least moderate severity. SPARTAN randomized patients to lasmiditan at 50, 100, or 200 mg or placebo.
A dose-response effect was noted. At 2 hours post dose of lasmiditan at 200 mg, 32.2% of patients in SAMURAI and 38.8% in SPARTAN were pain-free, compared with 15.3% and 21.3% on placebo, respectively. At the top dose of lasmiditan, 40.7% of patients in SAMURAI were free of their most bothersome baseline symptom, as were 48.7% in SPARTAN, with placebo response rates of 29.5% and 33.5%, respectively, for this endpoint. A significant separation from placebo was noted in 1 hour for the pain freedom endpoint, and in about 30 minutes for freedom from the most bothersome symptom, reported Dr. Aurora of Eli Lilly, which sponsored the trials.
Lasmiditan at 50 and 100 mg also significantly outperformed placebo for the co-primary endpoints.
As in the phase 3 trials of the two investigational oral CGRP antagonists, a secondary endpoint in SPARTAN and SAMURAI was pain relief at 2 hours, a lower bar than pain freedom. The rates in the lasmiditan 200 mg arms were 60%-65%, compared with about 40% with placebo.
Treatment-emergent adverse event rates were 11%-15% with placebo and in the 40% range for lasmiditan. Because the drug penetrates the CNS, centrally acting side effects were an issue. Dizziness was the most common, followed by paresthesia, somnolence, then fatigue. The dizziness was dose dependent: In SPARTAN, the complaint was noted in 2.5% of placebo-treated controls, 25.4% of patients on 50 mg of lasmiditan, 36.1% with 100 mg, and 39% at 200 mg.
Chest tightness, a common side effect with triptans, did not occur.
A large multicenter, open-label safety assessment study, called GLADIATOR, is ongoing.
Triptans, what have you done for me lately?
A recurring theme at the headache meeting was the vast unmet need for better treatments for acute migraine attacks.
“You all know very well that triptans have been the most widely prescribed acute treatments for migraine in North America now for decades, but there are people with unmet treatment needs,” Dr. Lipton said. “Depending on how you define it, perhaps 34% of patients do not respond, 30%-40% have attack recurrence, and 3.5 million people have absolute or relative contraindications to triptans among the 40 million people who have migraine in the United States.”
This was underscored by an analysis presented by Aftab Alam, MD, from the MAST (Migraine in America Symptoms and Treatment) study, a nationally representative cohort of 15,133 American adults with migraine and a mean monthly headache frequency of 3.3 days per month. Even though triptans are considered the gold standard acute migraine therapy, only 37% of participants in the detailed 30- to 40-minute survey had ever used a triptan, and just 15.9% of the overall study population were current users. Current triptan users averaged 7.3 headache days per month. A total of 85% of current users took oral formulations, 17% used nasal spray, and 8% utilized injectable triptans.
Among ever-users of triptans, 56.7% had discontinued them. The No.1 reason cited was lack of efficacy, named by 38% of those who stopped oral agents, 40% with the nasal spray, and 26% who discontinued injectables.
The second most common reason for triptan discontinuation was side effects, the most common of which was dizziness, followed by nausea and fatigue. Lack of insurance coverage was cited by only 6% of patients as a reason they discontinued triptans.
These MAST results suggest “there is a lot of unmet need in this area,” commented Dr. Alam, director of clinical development and medical affairs at Dr. Reddy’s Laboratories, Princeton, N.J. The MAST study was funded by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories.
Dr. Lipton reported serving as a consultant to more than a dozen pharmaceutical and medical device companies and holding stock options for Biohaven Pharmaceuticals, which is developing rimegepant.
Dr. Dodick reported serving as a consultant to Allergan, which sponsored the ubrogepant studies, as well as numerous other companies.
SOURCES: AHS Annual Meeting Abstracts. Alam A et al. Headache. 2018;58(Suppl 2):68. Abstract OR11; Wietecha L et al. Headache. 2018;58(Suppl 2):73. Abstract IOR02; Dodick D et al. AHS 2018 Abstract IOR01LB; Lipton R et al. AHS 2018 Abstract IOR02LB.
SAN FRANCISCO – After a lengthy drought in the development of major new headache medications, it was finally raining successful phase 3 clinical trials for novel drugs at the annual meeting of the American Headache Society.
From the podium, as a prelude to presenting one of many positive trials, Richard B. Lipton, MD, was moved to paraphrase Charles Dickens: “ ‘It was the best of times’ ... and these are truly the best of times,” the neurologist observed.
“This morning we’ve heard about seven new molecular entities that are effective in the acute and/or preventive treatment of migraine, a couple of novel ways of delivering older drugs, and some interesting comparative effectiveness research. I have this compulsion to say over and over again – because I also work in Alzheimer’s disease – it just isn’t like this in other fields. This is truly a remarkable time in our field,” observed Dr. Lipton, professor and vice chair of the department of neurology at Albert Einstein College of Medicine in New York.
In addition to new studies of erenumab-aooe, which has been approved as Aimovig, the first-in-class calcitonin gene-related peptide (CGRP) inhibitor for the preventive treatment of migraine, the headache meeting also featured new positive phase 3 results for three other anti-CGRP monoclonal antibodies – galcanezumab, fremanezumab, and eptinezumab – as migraine-preventive therapy, with galcanezumab also demonstrating efficacy in episodic cluster headache; the oral small-molecule CGRP antagonists rimegepant and ubrogepant for acute treatment of migraine attacks; and the selective serotonin 5-HT 1F agonist lasmiditan, also for acute treatment of migraine.
Although the mechanisms of action and therapeutic purposes of the novel agents differ, they share in common what appears to be far better safety and tolerability than the current market leaders, topiramate (Topamax) for migraine prevention and the triptans for acute treatment.
Here are study highlights for the three potential new treatments for acute migraine attacks:
Rimegepant
Dr. Lipton presented the results of two virtually identical phase-3, double-blind, randomized trials in which a total of 2,162 patients with episodic migraine self-administered a 75-mg oral tablet of rimegepant or placebo to treat a single migraine attack when their headache pain reached moderate or severe intensity. The clinical trials, which lacked the customary snazzy acronyms, were simply called Study 301 and Study 302.
The two co-primary endpoints now required by the Food and Drug Administration for candidate agents for acute treatment of migraine attacks are freedom from pain and absence of the most bothersome symptom, both as assessed 2 hours post dose. The oral CGRP receptor antagonist met both endpoints, as well as key secondary endpoints.
In Study 302, for example, the pain-free rate 2 hours post dose was 19.6% in the rimegepant group, significantly higher than the 12% rate in placebo-treated controls. The rate of freedom from the most bothersome symptom, which was photophobia in the majority of patients, was 37.6% in the rimegepant group and 25.2% with placebo.
Dr. Lipton characterized the benefits seen with a single dose of rimegepant as “broad and clinically important.”
“The majority of patients achieved pain relief, durability of benefit at 24 and 48 hours, lower use of rescue medications, and a greater proportion of patients achieved normal function,” the neurologist reported.
The safety and tolerability profiles of rimegepant mirrored those of placebo, he added.
Ubrogepant
Dr. Lipton also presented the results of ACHIEVE II, a multicenter, double-blind, phase 3, placebo-controlled study of the oral CGRP receptor antagonist ubrogepant at 25 or 50 mg versus placebo in 1,355 patients with episodic migraine. Like rimegepant, it met both FDA-required primary endpoints. The pain freedom rate 2 hours post dose was 20.7% with ubrogepant at 25 mg, 21.8% with 50 mg, and 14.3% with placebo. The most bothersome symptom was gone at 2 hours in 34.1% of patients who received the CGRP receptor antagonist at 25 mg, 38.9% of those who got the 50-mg dose, and 27.4% of controls.
David W. Dodick, MD, explained the rationale for CGRP inhibition: CGRP and its receptors are highly expressed in pain-sensitive trigeminal sensory neurons, which innervate the dura and meningeal blood vessels. During the headache phase of migraine, the peptide is released in excess, making CGRP a key player in the pathophysiology of migraine.
Dr. Dodick presented an update focused on secondary endpoints in the phase 3, double-blind ACHIEVE I trial, whose positive co-primary outcomes have previously been reported. The analysis included 1,327 episodic migraine patients who were randomized to ubrogepant at 50 or 100 mg or placebo. Among the notable secondary outcomes was the clinically important rate of pain relief at 2 hours: 61% in both ubrogepant groups, significantly better than the 49% rate with placebo. Also, in terms of pain freedom, the 2-hour rate underestimated the true efficacy patients would experience in clinical practice: the maximum pain freedom rate occurred at 3 hours and was sustained to 8 hours post dose.
At the time study participants took their pill, only 30% indicated they were capable of functioning normally. Two hours later, this was still the case in 29.8% of placebo-treated controls, as compared with 40.6% on ubrogepant at 50 mg and 42.9% who took 100 mg of the drug. The proportion of patients who said they were satisfied or extremely satisfied with their treatment at the 2-hour mark was 24.1% in the placebo arm and 36.3% and 35.8% in the lower- and higher-dose ubrogepant arms, reported Dr. Dodick, professor of neurology at the Mayo Clinic in Scottsdale, Ariz.
Lasmiditan
Sheena K. Aurora, MD, presented the results of SAMURAI and SPARTAN, two randomized, double-blind, phase 3 clinical trials comparing lasmiditan versus placebo for the treatment of acute migraine in a collective 3,701 patients with longstanding episodic migraine, one-third of whom had a history of aura.
Lasmiditan is a novel oral serotonin receptor agonist that penetrates the CNS and selectively targets the 5-HT 1F receptor. The drug doesn’t cause the vasoconstrictive effects that make triptans, which target 5-HT 1B/1D receptors, contraindicated in patients with cardiovascular disease.
Indeed, SPARTAN included patients with known cardiovascular disease. SAMURAI did not; however, migraine is now recognized as an independent cardiovascular risk factor, and 80% of SAMURAI participants had one additional standard cardiovascular risk factor, such as diabetes, smoking, or hypertension.
SAMURAI randomized patients to lasmiditan at 100 or 200 mg or placebo to be taken within 4 hours of migraine onset, when the pain was of at least moderate severity. SPARTAN randomized patients to lasmiditan at 50, 100, or 200 mg or placebo.
A dose-response effect was noted. At 2 hours post dose of lasmiditan at 200 mg, 32.2% of patients in SAMURAI and 38.8% in SPARTAN were pain-free, compared with 15.3% and 21.3% on placebo, respectively. At the top dose of lasmiditan, 40.7% of patients in SAMURAI were free of their most bothersome baseline symptom, as were 48.7% in SPARTAN, with placebo response rates of 29.5% and 33.5%, respectively, for this endpoint. A significant separation from placebo was noted in 1 hour for the pain freedom endpoint, and in about 30 minutes for freedom from the most bothersome symptom, reported Dr. Aurora of Eli Lilly, which sponsored the trials.
Lasmiditan at 50 and 100 mg also significantly outperformed placebo for the co-primary endpoints.
As in the phase 3 trials of the two investigational oral CGRP antagonists, a secondary endpoint in SPARTAN and SAMURAI was pain relief at 2 hours, a lower bar than pain freedom. The rates in the lasmiditan 200 mg arms were 60%-65%, compared with about 40% with placebo.
Treatment-emergent adverse event rates were 11%-15% with placebo and in the 40% range for lasmiditan. Because the drug penetrates the CNS, centrally acting side effects were an issue. Dizziness was the most common, followed by paresthesia, somnolence, then fatigue. The dizziness was dose dependent: In SPARTAN, the complaint was noted in 2.5% of placebo-treated controls, 25.4% of patients on 50 mg of lasmiditan, 36.1% with 100 mg, and 39% at 200 mg.
Chest tightness, a common side effect with triptans, did not occur.
A large multicenter, open-label safety assessment study, called GLADIATOR, is ongoing.
Triptans, what have you done for me lately?
A recurring theme at the headache meeting was the vast unmet need for better treatments for acute migraine attacks.
“You all know very well that triptans have been the most widely prescribed acute treatments for migraine in North America now for decades, but there are people with unmet treatment needs,” Dr. Lipton said. “Depending on how you define it, perhaps 34% of patients do not respond, 30%-40% have attack recurrence, and 3.5 million people have absolute or relative contraindications to triptans among the 40 million people who have migraine in the United States.”
This was underscored by an analysis presented by Aftab Alam, MD, from the MAST (Migraine in America Symptoms and Treatment) study, a nationally representative cohort of 15,133 American adults with migraine and a mean monthly headache frequency of 3.3 days per month. Even though triptans are considered the gold standard acute migraine therapy, only 37% of participants in the detailed 30- to 40-minute survey had ever used a triptan, and just 15.9% of the overall study population were current users. Current triptan users averaged 7.3 headache days per month. A total of 85% of current users took oral formulations, 17% used nasal spray, and 8% utilized injectable triptans.
Among ever-users of triptans, 56.7% had discontinued them. The No.1 reason cited was lack of efficacy, named by 38% of those who stopped oral agents, 40% with the nasal spray, and 26% who discontinued injectables.
The second most common reason for triptan discontinuation was side effects, the most common of which was dizziness, followed by nausea and fatigue. Lack of insurance coverage was cited by only 6% of patients as a reason they discontinued triptans.
These MAST results suggest “there is a lot of unmet need in this area,” commented Dr. Alam, director of clinical development and medical affairs at Dr. Reddy’s Laboratories, Princeton, N.J. The MAST study was funded by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories.
Dr. Lipton reported serving as a consultant to more than a dozen pharmaceutical and medical device companies and holding stock options for Biohaven Pharmaceuticals, which is developing rimegepant.
Dr. Dodick reported serving as a consultant to Allergan, which sponsored the ubrogepant studies, as well as numerous other companies.
SOURCES: AHS Annual Meeting Abstracts. Alam A et al. Headache. 2018;58(Suppl 2):68. Abstract OR11; Wietecha L et al. Headache. 2018;58(Suppl 2):73. Abstract IOR02; Dodick D et al. AHS 2018 Abstract IOR01LB; Lipton R et al. AHS 2018 Abstract IOR02LB.
SAN FRANCISCO – After a lengthy drought in the development of major new headache medications, it was finally raining successful phase 3 clinical trials for novel drugs at the annual meeting of the American Headache Society.
From the podium, as a prelude to presenting one of many positive trials, Richard B. Lipton, MD, was moved to paraphrase Charles Dickens: “ ‘It was the best of times’ ... and these are truly the best of times,” the neurologist observed.
“This morning we’ve heard about seven new molecular entities that are effective in the acute and/or preventive treatment of migraine, a couple of novel ways of delivering older drugs, and some interesting comparative effectiveness research. I have this compulsion to say over and over again – because I also work in Alzheimer’s disease – it just isn’t like this in other fields. This is truly a remarkable time in our field,” observed Dr. Lipton, professor and vice chair of the department of neurology at Albert Einstein College of Medicine in New York.
In addition to new studies of erenumab-aooe, which has been approved as Aimovig, the first-in-class calcitonin gene-related peptide (CGRP) inhibitor for the preventive treatment of migraine, the headache meeting also featured new positive phase 3 results for three other anti-CGRP monoclonal antibodies – galcanezumab, fremanezumab, and eptinezumab – as migraine-preventive therapy, with galcanezumab also demonstrating efficacy in episodic cluster headache; the oral small-molecule CGRP antagonists rimegepant and ubrogepant for acute treatment of migraine attacks; and the selective serotonin 5-HT 1F agonist lasmiditan, also for acute treatment of migraine.
Although the mechanisms of action and therapeutic purposes of the novel agents differ, they share in common what appears to be far better safety and tolerability than the current market leaders, topiramate (Topamax) for migraine prevention and the triptans for acute treatment.
Here are study highlights for the three potential new treatments for acute migraine attacks:
Rimegepant
Dr. Lipton presented the results of two virtually identical phase-3, double-blind, randomized trials in which a total of 2,162 patients with episodic migraine self-administered a 75-mg oral tablet of rimegepant or placebo to treat a single migraine attack when their headache pain reached moderate or severe intensity. The clinical trials, which lacked the customary snazzy acronyms, were simply called Study 301 and Study 302.
The two co-primary endpoints now required by the Food and Drug Administration for candidate agents for acute treatment of migraine attacks are freedom from pain and absence of the most bothersome symptom, both as assessed 2 hours post dose. The oral CGRP receptor antagonist met both endpoints, as well as key secondary endpoints.
In Study 302, for example, the pain-free rate 2 hours post dose was 19.6% in the rimegepant group, significantly higher than the 12% rate in placebo-treated controls. The rate of freedom from the most bothersome symptom, which was photophobia in the majority of patients, was 37.6% in the rimegepant group and 25.2% with placebo.
Dr. Lipton characterized the benefits seen with a single dose of rimegepant as “broad and clinically important.”
“The majority of patients achieved pain relief, durability of benefit at 24 and 48 hours, lower use of rescue medications, and a greater proportion of patients achieved normal function,” the neurologist reported.
The safety and tolerability profiles of rimegepant mirrored those of placebo, he added.
Ubrogepant
Dr. Lipton also presented the results of ACHIEVE II, a multicenter, double-blind, phase 3, placebo-controlled study of the oral CGRP receptor antagonist ubrogepant at 25 or 50 mg versus placebo in 1,355 patients with episodic migraine. Like rimegepant, it met both FDA-required primary endpoints. The pain freedom rate 2 hours post dose was 20.7% with ubrogepant at 25 mg, 21.8% with 50 mg, and 14.3% with placebo. The most bothersome symptom was gone at 2 hours in 34.1% of patients who received the CGRP receptor antagonist at 25 mg, 38.9% of those who got the 50-mg dose, and 27.4% of controls.
David W. Dodick, MD, explained the rationale for CGRP inhibition: CGRP and its receptors are highly expressed in pain-sensitive trigeminal sensory neurons, which innervate the dura and meningeal blood vessels. During the headache phase of migraine, the peptide is released in excess, making CGRP a key player in the pathophysiology of migraine.
Dr. Dodick presented an update focused on secondary endpoints in the phase 3, double-blind ACHIEVE I trial, whose positive co-primary outcomes have previously been reported. The analysis included 1,327 episodic migraine patients who were randomized to ubrogepant at 50 or 100 mg or placebo. Among the notable secondary outcomes was the clinically important rate of pain relief at 2 hours: 61% in both ubrogepant groups, significantly better than the 49% rate with placebo. Also, in terms of pain freedom, the 2-hour rate underestimated the true efficacy patients would experience in clinical practice: the maximum pain freedom rate occurred at 3 hours and was sustained to 8 hours post dose.
At the time study participants took their pill, only 30% indicated they were capable of functioning normally. Two hours later, this was still the case in 29.8% of placebo-treated controls, as compared with 40.6% on ubrogepant at 50 mg and 42.9% who took 100 mg of the drug. The proportion of patients who said they were satisfied or extremely satisfied with their treatment at the 2-hour mark was 24.1% in the placebo arm and 36.3% and 35.8% in the lower- and higher-dose ubrogepant arms, reported Dr. Dodick, professor of neurology at the Mayo Clinic in Scottsdale, Ariz.
Lasmiditan
Sheena K. Aurora, MD, presented the results of SAMURAI and SPARTAN, two randomized, double-blind, phase 3 clinical trials comparing lasmiditan versus placebo for the treatment of acute migraine in a collective 3,701 patients with longstanding episodic migraine, one-third of whom had a history of aura.
Lasmiditan is a novel oral serotonin receptor agonist that penetrates the CNS and selectively targets the 5-HT 1F receptor. The drug doesn’t cause the vasoconstrictive effects that make triptans, which target 5-HT 1B/1D receptors, contraindicated in patients with cardiovascular disease.
Indeed, SPARTAN included patients with known cardiovascular disease. SAMURAI did not; however, migraine is now recognized as an independent cardiovascular risk factor, and 80% of SAMURAI participants had one additional standard cardiovascular risk factor, such as diabetes, smoking, or hypertension.
SAMURAI randomized patients to lasmiditan at 100 or 200 mg or placebo to be taken within 4 hours of migraine onset, when the pain was of at least moderate severity. SPARTAN randomized patients to lasmiditan at 50, 100, or 200 mg or placebo.
A dose-response effect was noted. At 2 hours post dose of lasmiditan at 200 mg, 32.2% of patients in SAMURAI and 38.8% in SPARTAN were pain-free, compared with 15.3% and 21.3% on placebo, respectively. At the top dose of lasmiditan, 40.7% of patients in SAMURAI were free of their most bothersome baseline symptom, as were 48.7% in SPARTAN, with placebo response rates of 29.5% and 33.5%, respectively, for this endpoint. A significant separation from placebo was noted in 1 hour for the pain freedom endpoint, and in about 30 minutes for freedom from the most bothersome symptom, reported Dr. Aurora of Eli Lilly, which sponsored the trials.
Lasmiditan at 50 and 100 mg also significantly outperformed placebo for the co-primary endpoints.
As in the phase 3 trials of the two investigational oral CGRP antagonists, a secondary endpoint in SPARTAN and SAMURAI was pain relief at 2 hours, a lower bar than pain freedom. The rates in the lasmiditan 200 mg arms were 60%-65%, compared with about 40% with placebo.
Treatment-emergent adverse event rates were 11%-15% with placebo and in the 40% range for lasmiditan. Because the drug penetrates the CNS, centrally acting side effects were an issue. Dizziness was the most common, followed by paresthesia, somnolence, then fatigue. The dizziness was dose dependent: In SPARTAN, the complaint was noted in 2.5% of placebo-treated controls, 25.4% of patients on 50 mg of lasmiditan, 36.1% with 100 mg, and 39% at 200 mg.
Chest tightness, a common side effect with triptans, did not occur.
A large multicenter, open-label safety assessment study, called GLADIATOR, is ongoing.
Triptans, what have you done for me lately?
A recurring theme at the headache meeting was the vast unmet need for better treatments for acute migraine attacks.
“You all know very well that triptans have been the most widely prescribed acute treatments for migraine in North America now for decades, but there are people with unmet treatment needs,” Dr. Lipton said. “Depending on how you define it, perhaps 34% of patients do not respond, 30%-40% have attack recurrence, and 3.5 million people have absolute or relative contraindications to triptans among the 40 million people who have migraine in the United States.”
This was underscored by an analysis presented by Aftab Alam, MD, from the MAST (Migraine in America Symptoms and Treatment) study, a nationally representative cohort of 15,133 American adults with migraine and a mean monthly headache frequency of 3.3 days per month. Even though triptans are considered the gold standard acute migraine therapy, only 37% of participants in the detailed 30- to 40-minute survey had ever used a triptan, and just 15.9% of the overall study population were current users. Current triptan users averaged 7.3 headache days per month. A total of 85% of current users took oral formulations, 17% used nasal spray, and 8% utilized injectable triptans.
Among ever-users of triptans, 56.7% had discontinued them. The No.1 reason cited was lack of efficacy, named by 38% of those who stopped oral agents, 40% with the nasal spray, and 26% who discontinued injectables.
The second most common reason for triptan discontinuation was side effects, the most common of which was dizziness, followed by nausea and fatigue. Lack of insurance coverage was cited by only 6% of patients as a reason they discontinued triptans.
These MAST results suggest “there is a lot of unmet need in this area,” commented Dr. Alam, director of clinical development and medical affairs at Dr. Reddy’s Laboratories, Princeton, N.J. The MAST study was funded by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories.
Dr. Lipton reported serving as a consultant to more than a dozen pharmaceutical and medical device companies and holding stock options for Biohaven Pharmaceuticals, which is developing rimegepant.
Dr. Dodick reported serving as a consultant to Allergan, which sponsored the ubrogepant studies, as well as numerous other companies.
SOURCES: AHS Annual Meeting Abstracts. Alam A et al. Headache. 2018;58(Suppl 2):68. Abstract OR11; Wietecha L et al. Headache. 2018;58(Suppl 2):73. Abstract IOR02; Dodick D et al. AHS 2018 Abstract IOR01LB; Lipton R et al. AHS 2018 Abstract IOR02LB.
REPORTING FROM THE AHS ANNUAL MEETING
Skip ultrasound in acute UTI in small children
MALMO, SWEDEN – Ultrasound of the kidneys and urinary tract in the acute phase of a first urinary tract infection in young children has an unacceptably high false-positive rate, Magdalena Okarska-Napierala, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
“Sonography performed 2 weeks after treatment initiation seems to be more reliable,” said Dr. Okarska-Napierala, a pediatrician at the Medical University of Warsaw Children’s Hospital.
Broad agreement exists that imaging is warranted in all children with a first urinary tract infection (UTI), because this infection can be the first signal of a structural abnormality of the kidneys or urinary tract. Abdominal ultrasound is the first-choice imaging modality in this setting because it is noninvasive, widely available, and inexpensive. But there remains controversy – and guidelines differ – regarding when to perform the ultrasound in children with UTI who respond well to therapy. This was the impetus for Dr. Okarska-Napierala and her coinvestigators to launch a prospective, single-center study examining the issue.
“The theory beneath it is the possibility that diffuse inflammation affects the ultrasound picture of the kidneys and urinary tract and may give us false-positive results, so we shouldn’t base our decisions on those results,” she explained.
This theory has been provisionally confirmed by the preliminary results of the study, which is continuing to enroll patients.
To date, the study includes 48 children, mean age 10.4 months, hospitalized for their first UTI. Participation was restricted to patients with no known congenital abnormalities of the kidneys or urinary tract and who were not on antibiotics at enrollment. Of the 48 children, 44 had an Escherichia coli infection. The predominant treatment was a second-generation cephalosporin for a median of 10 days.
On day 1 of treatment all patients underwent an ultrasound exam evaluating kidney size, anterior-posterior renal pelvis diameter, and the urinary tract based upon a grading system for urinary tract dilation developed by multidisciplinary consensus (J Pediatr Urol. 2014 Dec;10[6]:982-98). The ultrasound exam was repeated 2 weeks later, and again 2 weeks after that.
The most striking findings were a significantly increased kidney size and more prevalent urinary tract dilation on the day 1 ultrasound exam than on repeat ultrasound 2 weeks later. The average length of the left and right kidneys was 67.0 and 64.5 mm, respectively, on day 1, dropping off to 64.3 and 62.0 mm at 2 weeks, with a smaller and statistically nonsignificant further drop-off to 61.9 and 60.0 mm on the week 4 ultrasound.
“We saw a strong correlation between initial kidney size and CRP [C-reactive protein] value: The higher the CRP you have initially, the bigger the kidneys. It’s an interesting finding, but not so very practical. The only practical conclusion is that if we perform ultrasound at this stage and the child has big kidneys, it doesn’t mean anything. We have to check it again later,” she said.
Also, the number of renal units with urinary tract dilation went from 29 on day 1 ultrasound to 20 at 2 weeks and 19 at 4 weeks. Of the 48 children, 28 had urinary tract dilation on day 1, compared with 18 at 2 weeks and 16 at 4 weeks.
“If we look at this practically, if we base our decision on the day 1 ultrasound we would qualify half of all children for voiding cystourethrography, which is harmful, but if we wait 2 weeks to do the ultrasound we would reduce this number by six children. So I think we can call this a clinically significant difference,” she continued.
Of the 48 children, 11 have undergone voiding cystourethrography, revealing 2 mild cases of vesicoureteral reflux, which is the most common congenital abnormality of the urinary tract.
“I would like to emphasize that there is no real benefit in performing an ultrasound exam in children in this acute phase of infection. And there is harm in that we have to repeat the exam later, the parents are worried, the doctor is worried,” Dr. Okarska-Napierala concluded.
She reported having no relevant financial conflicts, and the study was conducted free of commercial support.
MALMO, SWEDEN – Ultrasound of the kidneys and urinary tract in the acute phase of a first urinary tract infection in young children has an unacceptably high false-positive rate, Magdalena Okarska-Napierala, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
“Sonography performed 2 weeks after treatment initiation seems to be more reliable,” said Dr. Okarska-Napierala, a pediatrician at the Medical University of Warsaw Children’s Hospital.
Broad agreement exists that imaging is warranted in all children with a first urinary tract infection (UTI), because this infection can be the first signal of a structural abnormality of the kidneys or urinary tract. Abdominal ultrasound is the first-choice imaging modality in this setting because it is noninvasive, widely available, and inexpensive. But there remains controversy – and guidelines differ – regarding when to perform the ultrasound in children with UTI who respond well to therapy. This was the impetus for Dr. Okarska-Napierala and her coinvestigators to launch a prospective, single-center study examining the issue.
“The theory beneath it is the possibility that diffuse inflammation affects the ultrasound picture of the kidneys and urinary tract and may give us false-positive results, so we shouldn’t base our decisions on those results,” she explained.
This theory has been provisionally confirmed by the preliminary results of the study, which is continuing to enroll patients.
To date, the study includes 48 children, mean age 10.4 months, hospitalized for their first UTI. Participation was restricted to patients with no known congenital abnormalities of the kidneys or urinary tract and who were not on antibiotics at enrollment. Of the 48 children, 44 had an Escherichia coli infection. The predominant treatment was a second-generation cephalosporin for a median of 10 days.
On day 1 of treatment all patients underwent an ultrasound exam evaluating kidney size, anterior-posterior renal pelvis diameter, and the urinary tract based upon a grading system for urinary tract dilation developed by multidisciplinary consensus (J Pediatr Urol. 2014 Dec;10[6]:982-98). The ultrasound exam was repeated 2 weeks later, and again 2 weeks after that.
The most striking findings were a significantly increased kidney size and more prevalent urinary tract dilation on the day 1 ultrasound exam than on repeat ultrasound 2 weeks later. The average length of the left and right kidneys was 67.0 and 64.5 mm, respectively, on day 1, dropping off to 64.3 and 62.0 mm at 2 weeks, with a smaller and statistically nonsignificant further drop-off to 61.9 and 60.0 mm on the week 4 ultrasound.
“We saw a strong correlation between initial kidney size and CRP [C-reactive protein] value: The higher the CRP you have initially, the bigger the kidneys. It’s an interesting finding, but not so very practical. The only practical conclusion is that if we perform ultrasound at this stage and the child has big kidneys, it doesn’t mean anything. We have to check it again later,” she said.
Also, the number of renal units with urinary tract dilation went from 29 on day 1 ultrasound to 20 at 2 weeks and 19 at 4 weeks. Of the 48 children, 28 had urinary tract dilation on day 1, compared with 18 at 2 weeks and 16 at 4 weeks.
“If we look at this practically, if we base our decision on the day 1 ultrasound we would qualify half of all children for voiding cystourethrography, which is harmful, but if we wait 2 weeks to do the ultrasound we would reduce this number by six children. So I think we can call this a clinically significant difference,” she continued.
Of the 48 children, 11 have undergone voiding cystourethrography, revealing 2 mild cases of vesicoureteral reflux, which is the most common congenital abnormality of the urinary tract.
“I would like to emphasize that there is no real benefit in performing an ultrasound exam in children in this acute phase of infection. And there is harm in that we have to repeat the exam later, the parents are worried, the doctor is worried,” Dr. Okarska-Napierala concluded.
She reported having no relevant financial conflicts, and the study was conducted free of commercial support.
MALMO, SWEDEN – Ultrasound of the kidneys and urinary tract in the acute phase of a first urinary tract infection in young children has an unacceptably high false-positive rate, Magdalena Okarska-Napierala, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
“Sonography performed 2 weeks after treatment initiation seems to be more reliable,” said Dr. Okarska-Napierala, a pediatrician at the Medical University of Warsaw Children’s Hospital.
Broad agreement exists that imaging is warranted in all children with a first urinary tract infection (UTI), because this infection can be the first signal of a structural abnormality of the kidneys or urinary tract. Abdominal ultrasound is the first-choice imaging modality in this setting because it is noninvasive, widely available, and inexpensive. But there remains controversy – and guidelines differ – regarding when to perform the ultrasound in children with UTI who respond well to therapy. This was the impetus for Dr. Okarska-Napierala and her coinvestigators to launch a prospective, single-center study examining the issue.
“The theory beneath it is the possibility that diffuse inflammation affects the ultrasound picture of the kidneys and urinary tract and may give us false-positive results, so we shouldn’t base our decisions on those results,” she explained.
This theory has been provisionally confirmed by the preliminary results of the study, which is continuing to enroll patients.
To date, the study includes 48 children, mean age 10.4 months, hospitalized for their first UTI. Participation was restricted to patients with no known congenital abnormalities of the kidneys or urinary tract and who were not on antibiotics at enrollment. Of the 48 children, 44 had an Escherichia coli infection. The predominant treatment was a second-generation cephalosporin for a median of 10 days.
On day 1 of treatment all patients underwent an ultrasound exam evaluating kidney size, anterior-posterior renal pelvis diameter, and the urinary tract based upon a grading system for urinary tract dilation developed by multidisciplinary consensus (J Pediatr Urol. 2014 Dec;10[6]:982-98). The ultrasound exam was repeated 2 weeks later, and again 2 weeks after that.
The most striking findings were a significantly increased kidney size and more prevalent urinary tract dilation on the day 1 ultrasound exam than on repeat ultrasound 2 weeks later. The average length of the left and right kidneys was 67.0 and 64.5 mm, respectively, on day 1, dropping off to 64.3 and 62.0 mm at 2 weeks, with a smaller and statistically nonsignificant further drop-off to 61.9 and 60.0 mm on the week 4 ultrasound.
“We saw a strong correlation between initial kidney size and CRP [C-reactive protein] value: The higher the CRP you have initially, the bigger the kidneys. It’s an interesting finding, but not so very practical. The only practical conclusion is that if we perform ultrasound at this stage and the child has big kidneys, it doesn’t mean anything. We have to check it again later,” she said.
Also, the number of renal units with urinary tract dilation went from 29 on day 1 ultrasound to 20 at 2 weeks and 19 at 4 weeks. Of the 48 children, 28 had urinary tract dilation on day 1, compared with 18 at 2 weeks and 16 at 4 weeks.
“If we look at this practically, if we base our decision on the day 1 ultrasound we would qualify half of all children for voiding cystourethrography, which is harmful, but if we wait 2 weeks to do the ultrasound we would reduce this number by six children. So I think we can call this a clinically significant difference,” she continued.
Of the 48 children, 11 have undergone voiding cystourethrography, revealing 2 mild cases of vesicoureteral reflux, which is the most common congenital abnormality of the urinary tract.
“I would like to emphasize that there is no real benefit in performing an ultrasound exam in children in this acute phase of infection. And there is harm in that we have to repeat the exam later, the parents are worried, the doctor is worried,” Dr. Okarska-Napierala concluded.
She reported having no relevant financial conflicts, and the study was conducted free of commercial support.
REPORTING FROM ESPID 2018
Key clinical point:
Major finding: Average left kidney length dropped from 67.0 mm on treatment day 1 to 64.3 mm 2 weeks later.
Study details: This interim report from an ongoing, prospective, single-center study included 48 children up to age 3 years who were hospitalized for their first urinary tract infection.
Disclosures: The presenter reported no relevant financial conflicts.
Reducing risk of febrile convulsion after first dose of MMRV
MALMO, SWEDEN – Giving a combined MMR vaccine and a varicella vaccine separately on the same day in children with personal or family history of febrile convulsions while utilizing the more convenient MMRV vaccine in those without such a history showed promise as a means of reducing the overall risk of febrile convulsions attributable to vaccination, Corinne Willame said at the annual meeting of the European Society for Paediatric Infectious Diseases.
She presented a post hoc analysis of an enormous, German observational study that demonstrated an increased risk of hospitalization for febrile convulsions 5-12 days after receiving the first dose of the Priorix-Tetra MMRV vaccine, with no alternative plausible cause of the convulsions (Vaccine. 2014 Feb 3;32[6]:645-50).
The original study was conducted in more than 180,000 children under the age of 5 years, 90% of whom were 11- 23 months. The increased risk associated with MMRV, compared with MMR alone or MMR plus V separately on the same day, was similar in magnitude to what had previously been reported for the ProQuad MMRV vaccine, suggesting a class effect for the quadrivalent vaccines.
Because genetic predisposition is known to be associated with increased risk of febrile convulsions, Ms. Willame of GlaxoSmithKline in Wavre, Belgium, and her coinvestigators conducted an exploratory analysis investigating whether the presence of a personal or first-degree family history of febrile convulsions impacted the risk of developing febrile convulsions following a first dose of MMRV, compared with MMR alone or MMR and V administered separately on the same day. They found that indeed it did, according to Ms. Willame.
They analyzed the data in multiple ways. The first scenario compared the risk of febrile convulsions in 74,631 children 5-12 days after receiving the MMRV vaccine with a roughly equal number of children who received the MMR vaccine. Study subjects were matched for age, sex, month of vaccination, and insurance provider. The febrile convulsion incidence rate was 6.03 cases per 10,000 children in MMRV recipients and 2.55 per 10,000 in those who got MMR. Then they reanalyzed the data after subtracting all children with a baseline personal history of febrile convulsions from the pool of MMRV recipients: The febrile convulsion rate in the MMRV group dropped to 5.27 cases per 10,000.
Next, they did the same analysis in more than 64,000 matched children who got either MMRV or MMR plus V separately. For the whole cohort of MMRV recipients, the febrile convulsion rate was 6.53 cases per 10,000 vaccine recipients, dropping to 5.95 per 10,000 if children with a personal history of febrile convulsions were removed. The relative risk of febrile convulsions was 150% greater in the overall MMRV group than with MMR plus V, but only 58% greater when the children with a personal history of febrile seizures were excluded from the MMRV population.
Unfortunately, the parent study didn’t record whether a history of febrile convulsions was present in first-degree family members. The investigators therefore turned to the published literature on the subject and constructed conditional probability analyses based upon a 20%-40% likelihood of a positive family history in children with a personal history, and a 5% likelihood in those children without such a history. In this scenario, when children with a personal or hypothetical family history of febrile convulsions were subtracted from the MMRV group, the result was a febrile convulsion incidence rate of 3.27-4.41 cases per 10,000 MMRV recipients in the comparison with MMR and 3.63-4.95 per 10,000 in the comparison with MMR plus V.
Ms. Willame emphasized that her analysis must be considered hypothesis generating because it’s post hoc and relies upon published estimates of the prevalence of a positive family history of febrile convulsions. The febrile convulsion risk differences she found with the different vaccination strategies should be confirmed in studies that collect family history data of febrile seizures at an individual level.
Her study was funded by her employer, GlaxoSmithKline.
MALMO, SWEDEN – Giving a combined MMR vaccine and a varicella vaccine separately on the same day in children with personal or family history of febrile convulsions while utilizing the more convenient MMRV vaccine in those without such a history showed promise as a means of reducing the overall risk of febrile convulsions attributable to vaccination, Corinne Willame said at the annual meeting of the European Society for Paediatric Infectious Diseases.
She presented a post hoc analysis of an enormous, German observational study that demonstrated an increased risk of hospitalization for febrile convulsions 5-12 days after receiving the first dose of the Priorix-Tetra MMRV vaccine, with no alternative plausible cause of the convulsions (Vaccine. 2014 Feb 3;32[6]:645-50).
The original study was conducted in more than 180,000 children under the age of 5 years, 90% of whom were 11- 23 months. The increased risk associated with MMRV, compared with MMR alone or MMR plus V separately on the same day, was similar in magnitude to what had previously been reported for the ProQuad MMRV vaccine, suggesting a class effect for the quadrivalent vaccines.
Because genetic predisposition is known to be associated with increased risk of febrile convulsions, Ms. Willame of GlaxoSmithKline in Wavre, Belgium, and her coinvestigators conducted an exploratory analysis investigating whether the presence of a personal or first-degree family history of febrile convulsions impacted the risk of developing febrile convulsions following a first dose of MMRV, compared with MMR alone or MMR and V administered separately on the same day. They found that indeed it did, according to Ms. Willame.
They analyzed the data in multiple ways. The first scenario compared the risk of febrile convulsions in 74,631 children 5-12 days after receiving the MMRV vaccine with a roughly equal number of children who received the MMR vaccine. Study subjects were matched for age, sex, month of vaccination, and insurance provider. The febrile convulsion incidence rate was 6.03 cases per 10,000 children in MMRV recipients and 2.55 per 10,000 in those who got MMR. Then they reanalyzed the data after subtracting all children with a baseline personal history of febrile convulsions from the pool of MMRV recipients: The febrile convulsion rate in the MMRV group dropped to 5.27 cases per 10,000.
Next, they did the same analysis in more than 64,000 matched children who got either MMRV or MMR plus V separately. For the whole cohort of MMRV recipients, the febrile convulsion rate was 6.53 cases per 10,000 vaccine recipients, dropping to 5.95 per 10,000 if children with a personal history of febrile convulsions were removed. The relative risk of febrile convulsions was 150% greater in the overall MMRV group than with MMR plus V, but only 58% greater when the children with a personal history of febrile seizures were excluded from the MMRV population.
Unfortunately, the parent study didn’t record whether a history of febrile convulsions was present in first-degree family members. The investigators therefore turned to the published literature on the subject and constructed conditional probability analyses based upon a 20%-40% likelihood of a positive family history in children with a personal history, and a 5% likelihood in those children without such a history. In this scenario, when children with a personal or hypothetical family history of febrile convulsions were subtracted from the MMRV group, the result was a febrile convulsion incidence rate of 3.27-4.41 cases per 10,000 MMRV recipients in the comparison with MMR and 3.63-4.95 per 10,000 in the comparison with MMR plus V.
Ms. Willame emphasized that her analysis must be considered hypothesis generating because it’s post hoc and relies upon published estimates of the prevalence of a positive family history of febrile convulsions. The febrile convulsion risk differences she found with the different vaccination strategies should be confirmed in studies that collect family history data of febrile seizures at an individual level.
Her study was funded by her employer, GlaxoSmithKline.
MALMO, SWEDEN – Giving a combined MMR vaccine and a varicella vaccine separately on the same day in children with personal or family history of febrile convulsions while utilizing the more convenient MMRV vaccine in those without such a history showed promise as a means of reducing the overall risk of febrile convulsions attributable to vaccination, Corinne Willame said at the annual meeting of the European Society for Paediatric Infectious Diseases.
She presented a post hoc analysis of an enormous, German observational study that demonstrated an increased risk of hospitalization for febrile convulsions 5-12 days after receiving the first dose of the Priorix-Tetra MMRV vaccine, with no alternative plausible cause of the convulsions (Vaccine. 2014 Feb 3;32[6]:645-50).
The original study was conducted in more than 180,000 children under the age of 5 years, 90% of whom were 11- 23 months. The increased risk associated with MMRV, compared with MMR alone or MMR plus V separately on the same day, was similar in magnitude to what had previously been reported for the ProQuad MMRV vaccine, suggesting a class effect for the quadrivalent vaccines.
Because genetic predisposition is known to be associated with increased risk of febrile convulsions, Ms. Willame of GlaxoSmithKline in Wavre, Belgium, and her coinvestigators conducted an exploratory analysis investigating whether the presence of a personal or first-degree family history of febrile convulsions impacted the risk of developing febrile convulsions following a first dose of MMRV, compared with MMR alone or MMR and V administered separately on the same day. They found that indeed it did, according to Ms. Willame.
They analyzed the data in multiple ways. The first scenario compared the risk of febrile convulsions in 74,631 children 5-12 days after receiving the MMRV vaccine with a roughly equal number of children who received the MMR vaccine. Study subjects were matched for age, sex, month of vaccination, and insurance provider. The febrile convulsion incidence rate was 6.03 cases per 10,000 children in MMRV recipients and 2.55 per 10,000 in those who got MMR. Then they reanalyzed the data after subtracting all children with a baseline personal history of febrile convulsions from the pool of MMRV recipients: The febrile convulsion rate in the MMRV group dropped to 5.27 cases per 10,000.
Next, they did the same analysis in more than 64,000 matched children who got either MMRV or MMR plus V separately. For the whole cohort of MMRV recipients, the febrile convulsion rate was 6.53 cases per 10,000 vaccine recipients, dropping to 5.95 per 10,000 if children with a personal history of febrile convulsions were removed. The relative risk of febrile convulsions was 150% greater in the overall MMRV group than with MMR plus V, but only 58% greater when the children with a personal history of febrile seizures were excluded from the MMRV population.
Unfortunately, the parent study didn’t record whether a history of febrile convulsions was present in first-degree family members. The investigators therefore turned to the published literature on the subject and constructed conditional probability analyses based upon a 20%-40% likelihood of a positive family history in children with a personal history, and a 5% likelihood in those children without such a history. In this scenario, when children with a personal or hypothetical family history of febrile convulsions were subtracted from the MMRV group, the result was a febrile convulsion incidence rate of 3.27-4.41 cases per 10,000 MMRV recipients in the comparison with MMR and 3.63-4.95 per 10,000 in the comparison with MMR plus V.
Ms. Willame emphasized that her analysis must be considered hypothesis generating because it’s post hoc and relies upon published estimates of the prevalence of a positive family history of febrile convulsions. The febrile convulsion risk differences she found with the different vaccination strategies should be confirmed in studies that collect family history data of febrile seizures at an individual level.
Her study was funded by her employer, GlaxoSmithKline.
REPORTING FROM ESPID 2018
Key clinical point: The increased risk of febrile seizures associated with MMRV vaccine can probably be reduced by administering the MMR and varicella vaccines separately on the same day in children with a personal or family history of febrile seizures.
Major finding: The incidence rate of febrile seizures 5-12 days post MMRV vaccination was reduced from 6.53 to 3.63-4.95 cases per 10,000 vaccine recipients.
Study details: This was a post hoc analysis of an observational study of more than 180,000 German children.
Disclosures: The study was sponsored by GlaxoSmithKline and presented by a company employee.
Weather changes trigger migraine
SAN FRANCISCO – Many migraineurs claim that changes in the weather can trigger their headache attacks. It took a headache specialist together with a meteorologist poring over surface weather maps to prove they are right.
“When patients tell you they can predict a headache from the weather, they really can,” Vincent T. Martin, MD, declared in presenting the evidence at the annual meeting of the American Headache Society.
Many physicians have been skeptical of patient self-reports of a weather/migraine connection because of mixed results in prior studies examining the impact of a single meteorologic factor at a time, such as barometric pressure, temperature, humidity, or wind speed.
“These studies, however, fail to account for the fact that weather events represent a confluence of meteorologic factors that occur in a specific temporal sequence. It may be necessary to model several variables together to achieve the optimal weather models,” explained Dr. Martin, a general internist, professor of medicine, and director of the Headache and Facial Pain Center at the University of Cincinnati.
He presented a retrospective cohort study of 218 patients with episodic migraine with a mean of 8.9 headache days per month who kept a daily electronic headache diary during two prior studies conducted in the St. Louis area. Their diary data were matched with hourly measurements of barometric pressure, temperature, relative humidity, and wind speed recorded at five St. Louis–area weather stations and archived at the National Climatic Data Center. Dr. Martin and his coinvestigators then created a series of models that predicted the weather conditions that were associated with each individual patient being in the top tertile for the presence of headache on a given day with no headache on the day before.
Preliminary analysis indicated that the most important predictor of new-onset headache in winter, spring, and fall was the barometric pressure differential between 2 consecutive days. These differentials were much smaller in the summer, so a separate model was created for that season. Multiple models were developed to identify binary cutpoints for each weather variable.
From fall through spring, during periods when barometric pressure was in the top tertile – that is, a high-pressure system was in play – a day-to-day difference in mean daily barometric pressure greater than 0.1 mm Hg was associated with a 4.9-fold increased risk of being in the top tertile for new-onset headache, and less than a 25% difference in minimal daily relative humidity was associated with a 4.6-fold increased risk.
In contrast, when barometric pressure was in the lowest tertile, a drop in mean daily barometric pressure of 0.05 mm Hg or less from one day to the next was associated with a 3.17-fold increased risk of entering the top tertile for new-onset headache, and a day-to-day increase in maximal wind speed of 7 mph or more was associated with a 2.64-fold increased risk.
In middle-tertile periods of barometric pressure, a drop in mean pressure of 0.05 mm Hg or less was associated with a 2.21-fold increase in new-onset headache, and a mean daily relative humidity of 79% or greater conferred a 4.43-fold relative risk.
“It’s very rare in epidemiologic studies to get magnitudes of association to those degrees,” Dr. Martin observed. “Our results provide strong evidence that weather is associated with days with a high probability of new-onset headache in persons with migraine.”
The mechanisms underlying this association aren’t known. Possibilities worthy of investigation include stimulation of hyperactivity of the sympathetic nervous system, increases in airborne environmental allergens or pollutants, or direct activation of trigeminal afferent nerve fibers, he said.
Dr. Martin reported having no financial conflicts of interest.
SAN FRANCISCO – Many migraineurs claim that changes in the weather can trigger their headache attacks. It took a headache specialist together with a meteorologist poring over surface weather maps to prove they are right.
“When patients tell you they can predict a headache from the weather, they really can,” Vincent T. Martin, MD, declared in presenting the evidence at the annual meeting of the American Headache Society.
Many physicians have been skeptical of patient self-reports of a weather/migraine connection because of mixed results in prior studies examining the impact of a single meteorologic factor at a time, such as barometric pressure, temperature, humidity, or wind speed.
“These studies, however, fail to account for the fact that weather events represent a confluence of meteorologic factors that occur in a specific temporal sequence. It may be necessary to model several variables together to achieve the optimal weather models,” explained Dr. Martin, a general internist, professor of medicine, and director of the Headache and Facial Pain Center at the University of Cincinnati.
He presented a retrospective cohort study of 218 patients with episodic migraine with a mean of 8.9 headache days per month who kept a daily electronic headache diary during two prior studies conducted in the St. Louis area. Their diary data were matched with hourly measurements of barometric pressure, temperature, relative humidity, and wind speed recorded at five St. Louis–area weather stations and archived at the National Climatic Data Center. Dr. Martin and his coinvestigators then created a series of models that predicted the weather conditions that were associated with each individual patient being in the top tertile for the presence of headache on a given day with no headache on the day before.
Preliminary analysis indicated that the most important predictor of new-onset headache in winter, spring, and fall was the barometric pressure differential between 2 consecutive days. These differentials were much smaller in the summer, so a separate model was created for that season. Multiple models were developed to identify binary cutpoints for each weather variable.
From fall through spring, during periods when barometric pressure was in the top tertile – that is, a high-pressure system was in play – a day-to-day difference in mean daily barometric pressure greater than 0.1 mm Hg was associated with a 4.9-fold increased risk of being in the top tertile for new-onset headache, and less than a 25% difference in minimal daily relative humidity was associated with a 4.6-fold increased risk.
In contrast, when barometric pressure was in the lowest tertile, a drop in mean daily barometric pressure of 0.05 mm Hg or less from one day to the next was associated with a 3.17-fold increased risk of entering the top tertile for new-onset headache, and a day-to-day increase in maximal wind speed of 7 mph or more was associated with a 2.64-fold increased risk.
In middle-tertile periods of barometric pressure, a drop in mean pressure of 0.05 mm Hg or less was associated with a 2.21-fold increase in new-onset headache, and a mean daily relative humidity of 79% or greater conferred a 4.43-fold relative risk.
“It’s very rare in epidemiologic studies to get magnitudes of association to those degrees,” Dr. Martin observed. “Our results provide strong evidence that weather is associated with days with a high probability of new-onset headache in persons with migraine.”
The mechanisms underlying this association aren’t known. Possibilities worthy of investigation include stimulation of hyperactivity of the sympathetic nervous system, increases in airborne environmental allergens or pollutants, or direct activation of trigeminal afferent nerve fibers, he said.
Dr. Martin reported having no financial conflicts of interest.
SAN FRANCISCO – Many migraineurs claim that changes in the weather can trigger their headache attacks. It took a headache specialist together with a meteorologist poring over surface weather maps to prove they are right.
“When patients tell you they can predict a headache from the weather, they really can,” Vincent T. Martin, MD, declared in presenting the evidence at the annual meeting of the American Headache Society.
Many physicians have been skeptical of patient self-reports of a weather/migraine connection because of mixed results in prior studies examining the impact of a single meteorologic factor at a time, such as barometric pressure, temperature, humidity, or wind speed.
“These studies, however, fail to account for the fact that weather events represent a confluence of meteorologic factors that occur in a specific temporal sequence. It may be necessary to model several variables together to achieve the optimal weather models,” explained Dr. Martin, a general internist, professor of medicine, and director of the Headache and Facial Pain Center at the University of Cincinnati.
He presented a retrospective cohort study of 218 patients with episodic migraine with a mean of 8.9 headache days per month who kept a daily electronic headache diary during two prior studies conducted in the St. Louis area. Their diary data were matched with hourly measurements of barometric pressure, temperature, relative humidity, and wind speed recorded at five St. Louis–area weather stations and archived at the National Climatic Data Center. Dr. Martin and his coinvestigators then created a series of models that predicted the weather conditions that were associated with each individual patient being in the top tertile for the presence of headache on a given day with no headache on the day before.
Preliminary analysis indicated that the most important predictor of new-onset headache in winter, spring, and fall was the barometric pressure differential between 2 consecutive days. These differentials were much smaller in the summer, so a separate model was created for that season. Multiple models were developed to identify binary cutpoints for each weather variable.
From fall through spring, during periods when barometric pressure was in the top tertile – that is, a high-pressure system was in play – a day-to-day difference in mean daily barometric pressure greater than 0.1 mm Hg was associated with a 4.9-fold increased risk of being in the top tertile for new-onset headache, and less than a 25% difference in minimal daily relative humidity was associated with a 4.6-fold increased risk.
In contrast, when barometric pressure was in the lowest tertile, a drop in mean daily barometric pressure of 0.05 mm Hg or less from one day to the next was associated with a 3.17-fold increased risk of entering the top tertile for new-onset headache, and a day-to-day increase in maximal wind speed of 7 mph or more was associated with a 2.64-fold increased risk.
In middle-tertile periods of barometric pressure, a drop in mean pressure of 0.05 mm Hg or less was associated with a 2.21-fold increase in new-onset headache, and a mean daily relative humidity of 79% or greater conferred a 4.43-fold relative risk.
“It’s very rare in epidemiologic studies to get magnitudes of association to those degrees,” Dr. Martin observed. “Our results provide strong evidence that weather is associated with days with a high probability of new-onset headache in persons with migraine.”
The mechanisms underlying this association aren’t known. Possibilities worthy of investigation include stimulation of hyperactivity of the sympathetic nervous system, increases in airborne environmental allergens or pollutants, or direct activation of trigeminal afferent nerve fibers, he said.
Dr. Martin reported having no financial conflicts of interest.
REPORTING FROM THE AHS ANNUAL MEETING
Key clinical point: Specific weather patterns can trigger migraine.
Major finding: During a low pressure front, a maximum wind speed of 7 mph or more on a given day was associated with a 2.6-fold increased relative risk of new-onset headache the next day.
Study details: This retrospective study of 218 episodic migraine patients linked their daily headache diary data to hourly measurements from local weather stations.
Disclosures: The presenter reported having no financial conflicts of interest.
How to prescribe effectively for opioid use disorder
NEW ORLEANS – Physicians committed to fighting the national opioid epidemic really need to take the 8-hour training course on addiction treatment required to obtain a Drug Enforcement Administration ‘X’ number, because it will enable them to prescribe buprenorphine, a drug with unique advantages for many affected patients, Ellie Grossman, MD, asserted at the annual meeting of the American College of Physicians.
Buprenorphine (Subutex) is one of the three medications approved for treatment of opioid use disorder (OUD), along with methadone and naltrexone (Revia). And for certain patients, it’s clearly the best choice, according to Dr. Grossman, a general internist at Harvard Medical School, Boston, and the primary care lead for behavioral health integration at the Cambridge (Mass.) Health Alliance.
The DEA X number certification process, which entails obtaining a waiver through SAMHSA – the Substance Abuse and Mental Health Services Administration – is bureaucratic. It’s unpopular with many physicians. But it’s well worth 8 hours of an internist’s time to get the waiver and gain the ability to prescribe buprenorphine.
“The requirement is admittedly clunky, and many people have strong feelings about whether this is a regulation that should exist,” according to Dr. Grossman. “I myself didn’t need to have special training to prescribe methadone, a full opioid agonist that my patients could easily die from. But I did have to undergo an 8-hour training to prescribe buprenorphine, and it’s much harder to die from that drug.”
She addressed which of the three medications for OUD is the best fit in a given patient, the appropriate treatment duration, and the role of adjunctive counseling, which – spoiler alert – has been cast into question by the results of a major government-funded randomized trial.
Dr. Grossman’s overriding message: “You are saving lives by getting people on medication.”
Indeed, studies have shown that patients with OUD who receive no treatment have a sixfold increase in the standardized mortality ratio, compared with the general population. Contrast that with the less than 2-fold increased risk with medication-assisted treatment and roughly a 2.5-fold increased risk when medication is given short term to cover withdrawal and then tapered and discontinued.
Other documented benefits of long-term medication-assisted treatment of patients with OUD as described in a 2014 Cochrane review include reductions in injection drug use, crime days, HIV-related risk behaviors and seroconversion, and improved health and social functioning.
Of note, those well-documented benefits apply only to methadone, a full opioid agonist, and buprenorphine, a partial agonist, because those two drugs have been around long enough to generate long-term outcome data. Naltrexone, which has a completely different mechanism of action – it’s a full opioid antagonist – has not as of yet.
Individualizing medical therapy for OUD
Physicians can’t write a prescription for methadone. The drug must be administered at a certified opioid treatment program, or OTP, otherwise known as a methadone clinic. Those clinics are highly regulated at both the federal and state levels, with lots of minutia involved. Patient counseling and drug screening are required.
In contrast, a physician with a DEA X number can write a prescription for buprenorphine and have a patient fill it at a pharmacy. There is inherently less structure surrounding buprenorphine therapy than that of methadone, Dr. Grossman noted. There are no hard and fast rules about how often a physician has to see the patient or do drug screens or counseling. Buprenorphine is available as once-daily oral sublingual therapy and, more recently, in long-acting injectable and implantable formulations, although Dr. Grossman believes the jury is still out about how these nonoral agents are best utilized.
“I’m often asked, ‘Which is better, methadone or buprenorphine?’ Really, the answer is they’re both pretty darn good,” according to Dr. Grossman.
The Cochrane review concluded that, in the studies that have used real-world dosing – that is, higher doses than in the initial studies – high-dose buprenorphine and high-dose methadone have similar rates of retention in treatment.
“What I tell patients is that a lot hinges on the structure of the treatment delivery system,” Dr. Grossman said. “If it’s methadone, they’re going to the OTP every day. Some people need more structure; they need a set of eyes on them every day. Or if they are at high risk for medication diversion – for example, someone else in their household might want to steal their medications – going to a methadone program gets around that. Also, when somebody has been on methadone in the past and did well on it and wants to go on it again, I’m likely to say, ‘That sounds like a good fit.’”
Buprenorphine is a good option for patients who don’t require close, structured supervision. It has fewer drug interactions than does methadone and is less prone to cause QTc prolongation. Also, it’s a more realistic option for patients who live so far from an OTP that daily attendance is impractical. And ob.gyns increasingly favor buprenorphine, because the problem of neonatal abstinence syndrome is less severe than when mothers are on methadone.
As for extended-release naltrexone (Vivitrol), the pivotal double-blind Russian trial that won FDA approval for treatment of OUD showed a dramatic improvement in opioid-free weeks (Lancet. 2011 Apr 30;377[9776]:1506-13).
More recently, the 24-week, multicenter, open-label X:BOT trial randomized 570 U.S. patients with OUD to once-monthly extended-release naltrexone or daily sublingual buprenorphine-naloxone (Suboxone). The dropout rate was higher in the extended-release naltrexone arm because patients had to be opioid free for 2 weeks before starting on the opioid antagonist. As a practical matter, that can be difficult to achieve unless a patient has just been released from jail or prison. But the per-protocol relapse rates were similar (Lancet. 2018 Jan 27;391[10118]:309-18).
“Many people interpret this study as saying, with the right patient who can get into an opioid-free state or, if you inherit an opioid-free state, the choice between extended-release naltrexone and buprenorphine-naloxone may be a bit of a wash in terms of clinical effectiveness, as best we can detect,” Dr. Grossman explained. “That said, they’re very different experiences: One is a shot in your butt once a month, the other is something you put in your mouth once a day. Patients typically have a strong point of view regarding what they’re up for.”
Extended-release naltrexone doesn’t require a DEA waiver or attendance at an OTP. But it costs roughly $800 per injection, although many insurers do cover it after additional paperwork is completed. While Dr. Grossman does use extended-release naltrexone in her own practice, it comes with some baggage. The drug comes in a powder, which is mixed with a diluent in the office, creating a thick, frothy substance that’s slow to inject. It has to be kept refrigerated, then warmed up in time for the patient visit.
“If you live somewhere where there’s no OTP and you don’t have a DEA X number, and you have a patient with OUD who’s interested in extended-release naltrexone, it’s not crazy to think about,” she noted.
Duration of medical therapy
Study after study demonstrates that, when treatment stops, the risk of relapse goes up.
“We as health care providers are used to the mentality of chronic diseases, like diabetes, where you’re probably on medicine for the rest of your life,” Dr. Grossman said. “OUD is another chronic disease where you might have a patient on medication for the rest of their life, although you may not want to drum that into their head right up front. It’s kind of scary. I don’t usually talk that way with my diabetic patients when I give them their diagnosis. So, I don’t push it.
“But the reality is, to give them the best chance of health, they should be on medication for a good long time,” she added. “And that’s true for all of the OUD medications.”
The role of counseling
The best evidence of the utility of adjunctive counseling in the treatment of OUD comes from the landmark Prescription Opioid Addiction Treatment Study (POATS), a 653-patient multicenter trial conducted by the National Drug Abuse Treatment Network and funded by the National Institute on Drug Abuse. Participants were randomized to standard medical management including medication and a meeting with a physician every 1-2 weeks, or to standard therapy plus individual counseling with a trained substance use counselor.
To the surprise of many, given that SAMHSA guidance strongly recommends counseling and other forms of behavioral therapy, there was no difference in outcomes between the two groups (Drug Alcohol Depend. 2015 May 1;150:112-9).
Subsequent parsing of the POATS data showed that the subgroup of people who were using heroin rather than prescription pills and who actually attended at least 60% of their counseling sessions did better than if they were randomized to no counseling.
“There’s still room for quibbling about the study, but many people would say, ‘You know, it’s not a slam dunk that everybody needs counseling,’ ” the internist commented.
“So, how do we pick the right treatment for our patients with OUD? It’s what feels right for them,” Dr. Grossman cautioned. “This gets back to what we do every day in managing chronic diseases: We nudge, we encourage, we use our motivational interviewing skills to help people figure out how they can change their lives and get healthier. There’s a long list of things going on in our patients’ lives that are going to help guide that decision.
“The message here: Medication is better than no medication, but it’s not a slam dunk which medication or how,” she concluded.
NEW ORLEANS – Physicians committed to fighting the national opioid epidemic really need to take the 8-hour training course on addiction treatment required to obtain a Drug Enforcement Administration ‘X’ number, because it will enable them to prescribe buprenorphine, a drug with unique advantages for many affected patients, Ellie Grossman, MD, asserted at the annual meeting of the American College of Physicians.
Buprenorphine (Subutex) is one of the three medications approved for treatment of opioid use disorder (OUD), along with methadone and naltrexone (Revia). And for certain patients, it’s clearly the best choice, according to Dr. Grossman, a general internist at Harvard Medical School, Boston, and the primary care lead for behavioral health integration at the Cambridge (Mass.) Health Alliance.
The DEA X number certification process, which entails obtaining a waiver through SAMHSA – the Substance Abuse and Mental Health Services Administration – is bureaucratic. It’s unpopular with many physicians. But it’s well worth 8 hours of an internist’s time to get the waiver and gain the ability to prescribe buprenorphine.
“The requirement is admittedly clunky, and many people have strong feelings about whether this is a regulation that should exist,” according to Dr. Grossman. “I myself didn’t need to have special training to prescribe methadone, a full opioid agonist that my patients could easily die from. But I did have to undergo an 8-hour training to prescribe buprenorphine, and it’s much harder to die from that drug.”
She addressed which of the three medications for OUD is the best fit in a given patient, the appropriate treatment duration, and the role of adjunctive counseling, which – spoiler alert – has been cast into question by the results of a major government-funded randomized trial.
Dr. Grossman’s overriding message: “You are saving lives by getting people on medication.”
Indeed, studies have shown that patients with OUD who receive no treatment have a sixfold increase in the standardized mortality ratio, compared with the general population. Contrast that with the less than 2-fold increased risk with medication-assisted treatment and roughly a 2.5-fold increased risk when medication is given short term to cover withdrawal and then tapered and discontinued.
Other documented benefits of long-term medication-assisted treatment of patients with OUD as described in a 2014 Cochrane review include reductions in injection drug use, crime days, HIV-related risk behaviors and seroconversion, and improved health and social functioning.
Of note, those well-documented benefits apply only to methadone, a full opioid agonist, and buprenorphine, a partial agonist, because those two drugs have been around long enough to generate long-term outcome data. Naltrexone, which has a completely different mechanism of action – it’s a full opioid antagonist – has not as of yet.
Individualizing medical therapy for OUD
Physicians can’t write a prescription for methadone. The drug must be administered at a certified opioid treatment program, or OTP, otherwise known as a methadone clinic. Those clinics are highly regulated at both the federal and state levels, with lots of minutia involved. Patient counseling and drug screening are required.
In contrast, a physician with a DEA X number can write a prescription for buprenorphine and have a patient fill it at a pharmacy. There is inherently less structure surrounding buprenorphine therapy than that of methadone, Dr. Grossman noted. There are no hard and fast rules about how often a physician has to see the patient or do drug screens or counseling. Buprenorphine is available as once-daily oral sublingual therapy and, more recently, in long-acting injectable and implantable formulations, although Dr. Grossman believes the jury is still out about how these nonoral agents are best utilized.
“I’m often asked, ‘Which is better, methadone or buprenorphine?’ Really, the answer is they’re both pretty darn good,” according to Dr. Grossman.
The Cochrane review concluded that, in the studies that have used real-world dosing – that is, higher doses than in the initial studies – high-dose buprenorphine and high-dose methadone have similar rates of retention in treatment.
“What I tell patients is that a lot hinges on the structure of the treatment delivery system,” Dr. Grossman said. “If it’s methadone, they’re going to the OTP every day. Some people need more structure; they need a set of eyes on them every day. Or if they are at high risk for medication diversion – for example, someone else in their household might want to steal their medications – going to a methadone program gets around that. Also, when somebody has been on methadone in the past and did well on it and wants to go on it again, I’m likely to say, ‘That sounds like a good fit.’”
Buprenorphine is a good option for patients who don’t require close, structured supervision. It has fewer drug interactions than does methadone and is less prone to cause QTc prolongation. Also, it’s a more realistic option for patients who live so far from an OTP that daily attendance is impractical. And ob.gyns increasingly favor buprenorphine, because the problem of neonatal abstinence syndrome is less severe than when mothers are on methadone.
As for extended-release naltrexone (Vivitrol), the pivotal double-blind Russian trial that won FDA approval for treatment of OUD showed a dramatic improvement in opioid-free weeks (Lancet. 2011 Apr 30;377[9776]:1506-13).
More recently, the 24-week, multicenter, open-label X:BOT trial randomized 570 U.S. patients with OUD to once-monthly extended-release naltrexone or daily sublingual buprenorphine-naloxone (Suboxone). The dropout rate was higher in the extended-release naltrexone arm because patients had to be opioid free for 2 weeks before starting on the opioid antagonist. As a practical matter, that can be difficult to achieve unless a patient has just been released from jail or prison. But the per-protocol relapse rates were similar (Lancet. 2018 Jan 27;391[10118]:309-18).
“Many people interpret this study as saying, with the right patient who can get into an opioid-free state or, if you inherit an opioid-free state, the choice between extended-release naltrexone and buprenorphine-naloxone may be a bit of a wash in terms of clinical effectiveness, as best we can detect,” Dr. Grossman explained. “That said, they’re very different experiences: One is a shot in your butt once a month, the other is something you put in your mouth once a day. Patients typically have a strong point of view regarding what they’re up for.”
Extended-release naltrexone doesn’t require a DEA waiver or attendance at an OTP. But it costs roughly $800 per injection, although many insurers do cover it after additional paperwork is completed. While Dr. Grossman does use extended-release naltrexone in her own practice, it comes with some baggage. The drug comes in a powder, which is mixed with a diluent in the office, creating a thick, frothy substance that’s slow to inject. It has to be kept refrigerated, then warmed up in time for the patient visit.
“If you live somewhere where there’s no OTP and you don’t have a DEA X number, and you have a patient with OUD who’s interested in extended-release naltrexone, it’s not crazy to think about,” she noted.
Duration of medical therapy
Study after study demonstrates that, when treatment stops, the risk of relapse goes up.
“We as health care providers are used to the mentality of chronic diseases, like diabetes, where you’re probably on medicine for the rest of your life,” Dr. Grossman said. “OUD is another chronic disease where you might have a patient on medication for the rest of their life, although you may not want to drum that into their head right up front. It’s kind of scary. I don’t usually talk that way with my diabetic patients when I give them their diagnosis. So, I don’t push it.
“But the reality is, to give them the best chance of health, they should be on medication for a good long time,” she added. “And that’s true for all of the OUD medications.”
The role of counseling
The best evidence of the utility of adjunctive counseling in the treatment of OUD comes from the landmark Prescription Opioid Addiction Treatment Study (POATS), a 653-patient multicenter trial conducted by the National Drug Abuse Treatment Network and funded by the National Institute on Drug Abuse. Participants were randomized to standard medical management including medication and a meeting with a physician every 1-2 weeks, or to standard therapy plus individual counseling with a trained substance use counselor.
To the surprise of many, given that SAMHSA guidance strongly recommends counseling and other forms of behavioral therapy, there was no difference in outcomes between the two groups (Drug Alcohol Depend. 2015 May 1;150:112-9).
Subsequent parsing of the POATS data showed that the subgroup of people who were using heroin rather than prescription pills and who actually attended at least 60% of their counseling sessions did better than if they were randomized to no counseling.
“There’s still room for quibbling about the study, but many people would say, ‘You know, it’s not a slam dunk that everybody needs counseling,’ ” the internist commented.
“So, how do we pick the right treatment for our patients with OUD? It’s what feels right for them,” Dr. Grossman cautioned. “This gets back to what we do every day in managing chronic diseases: We nudge, we encourage, we use our motivational interviewing skills to help people figure out how they can change their lives and get healthier. There’s a long list of things going on in our patients’ lives that are going to help guide that decision.
“The message here: Medication is better than no medication, but it’s not a slam dunk which medication or how,” she concluded.
NEW ORLEANS – Physicians committed to fighting the national opioid epidemic really need to take the 8-hour training course on addiction treatment required to obtain a Drug Enforcement Administration ‘X’ number, because it will enable them to prescribe buprenorphine, a drug with unique advantages for many affected patients, Ellie Grossman, MD, asserted at the annual meeting of the American College of Physicians.
Buprenorphine (Subutex) is one of the three medications approved for treatment of opioid use disorder (OUD), along with methadone and naltrexone (Revia). And for certain patients, it’s clearly the best choice, according to Dr. Grossman, a general internist at Harvard Medical School, Boston, and the primary care lead for behavioral health integration at the Cambridge (Mass.) Health Alliance.
The DEA X number certification process, which entails obtaining a waiver through SAMHSA – the Substance Abuse and Mental Health Services Administration – is bureaucratic. It’s unpopular with many physicians. But it’s well worth 8 hours of an internist’s time to get the waiver and gain the ability to prescribe buprenorphine.
“The requirement is admittedly clunky, and many people have strong feelings about whether this is a regulation that should exist,” according to Dr. Grossman. “I myself didn’t need to have special training to prescribe methadone, a full opioid agonist that my patients could easily die from. But I did have to undergo an 8-hour training to prescribe buprenorphine, and it’s much harder to die from that drug.”
She addressed which of the three medications for OUD is the best fit in a given patient, the appropriate treatment duration, and the role of adjunctive counseling, which – spoiler alert – has been cast into question by the results of a major government-funded randomized trial.
Dr. Grossman’s overriding message: “You are saving lives by getting people on medication.”
Indeed, studies have shown that patients with OUD who receive no treatment have a sixfold increase in the standardized mortality ratio, compared with the general population. Contrast that with the less than 2-fold increased risk with medication-assisted treatment and roughly a 2.5-fold increased risk when medication is given short term to cover withdrawal and then tapered and discontinued.
Other documented benefits of long-term medication-assisted treatment of patients with OUD as described in a 2014 Cochrane review include reductions in injection drug use, crime days, HIV-related risk behaviors and seroconversion, and improved health and social functioning.
Of note, those well-documented benefits apply only to methadone, a full opioid agonist, and buprenorphine, a partial agonist, because those two drugs have been around long enough to generate long-term outcome data. Naltrexone, which has a completely different mechanism of action – it’s a full opioid antagonist – has not as of yet.
Individualizing medical therapy for OUD
Physicians can’t write a prescription for methadone. The drug must be administered at a certified opioid treatment program, or OTP, otherwise known as a methadone clinic. Those clinics are highly regulated at both the federal and state levels, with lots of minutia involved. Patient counseling and drug screening are required.
In contrast, a physician with a DEA X number can write a prescription for buprenorphine and have a patient fill it at a pharmacy. There is inherently less structure surrounding buprenorphine therapy than that of methadone, Dr. Grossman noted. There are no hard and fast rules about how often a physician has to see the patient or do drug screens or counseling. Buprenorphine is available as once-daily oral sublingual therapy and, more recently, in long-acting injectable and implantable formulations, although Dr. Grossman believes the jury is still out about how these nonoral agents are best utilized.
“I’m often asked, ‘Which is better, methadone or buprenorphine?’ Really, the answer is they’re both pretty darn good,” according to Dr. Grossman.
The Cochrane review concluded that, in the studies that have used real-world dosing – that is, higher doses than in the initial studies – high-dose buprenorphine and high-dose methadone have similar rates of retention in treatment.
“What I tell patients is that a lot hinges on the structure of the treatment delivery system,” Dr. Grossman said. “If it’s methadone, they’re going to the OTP every day. Some people need more structure; they need a set of eyes on them every day. Or if they are at high risk for medication diversion – for example, someone else in their household might want to steal their medications – going to a methadone program gets around that. Also, when somebody has been on methadone in the past and did well on it and wants to go on it again, I’m likely to say, ‘That sounds like a good fit.’”
Buprenorphine is a good option for patients who don’t require close, structured supervision. It has fewer drug interactions than does methadone and is less prone to cause QTc prolongation. Also, it’s a more realistic option for patients who live so far from an OTP that daily attendance is impractical. And ob.gyns increasingly favor buprenorphine, because the problem of neonatal abstinence syndrome is less severe than when mothers are on methadone.
As for extended-release naltrexone (Vivitrol), the pivotal double-blind Russian trial that won FDA approval for treatment of OUD showed a dramatic improvement in opioid-free weeks (Lancet. 2011 Apr 30;377[9776]:1506-13).
More recently, the 24-week, multicenter, open-label X:BOT trial randomized 570 U.S. patients with OUD to once-monthly extended-release naltrexone or daily sublingual buprenorphine-naloxone (Suboxone). The dropout rate was higher in the extended-release naltrexone arm because patients had to be opioid free for 2 weeks before starting on the opioid antagonist. As a practical matter, that can be difficult to achieve unless a patient has just been released from jail or prison. But the per-protocol relapse rates were similar (Lancet. 2018 Jan 27;391[10118]:309-18).
“Many people interpret this study as saying, with the right patient who can get into an opioid-free state or, if you inherit an opioid-free state, the choice between extended-release naltrexone and buprenorphine-naloxone may be a bit of a wash in terms of clinical effectiveness, as best we can detect,” Dr. Grossman explained. “That said, they’re very different experiences: One is a shot in your butt once a month, the other is something you put in your mouth once a day. Patients typically have a strong point of view regarding what they’re up for.”
Extended-release naltrexone doesn’t require a DEA waiver or attendance at an OTP. But it costs roughly $800 per injection, although many insurers do cover it after additional paperwork is completed. While Dr. Grossman does use extended-release naltrexone in her own practice, it comes with some baggage. The drug comes in a powder, which is mixed with a diluent in the office, creating a thick, frothy substance that’s slow to inject. It has to be kept refrigerated, then warmed up in time for the patient visit.
“If you live somewhere where there’s no OTP and you don’t have a DEA X number, and you have a patient with OUD who’s interested in extended-release naltrexone, it’s not crazy to think about,” she noted.
Duration of medical therapy
Study after study demonstrates that, when treatment stops, the risk of relapse goes up.
“We as health care providers are used to the mentality of chronic diseases, like diabetes, where you’re probably on medicine for the rest of your life,” Dr. Grossman said. “OUD is another chronic disease where you might have a patient on medication for the rest of their life, although you may not want to drum that into their head right up front. It’s kind of scary. I don’t usually talk that way with my diabetic patients when I give them their diagnosis. So, I don’t push it.
“But the reality is, to give them the best chance of health, they should be on medication for a good long time,” she added. “And that’s true for all of the OUD medications.”
The role of counseling
The best evidence of the utility of adjunctive counseling in the treatment of OUD comes from the landmark Prescription Opioid Addiction Treatment Study (POATS), a 653-patient multicenter trial conducted by the National Drug Abuse Treatment Network and funded by the National Institute on Drug Abuse. Participants were randomized to standard medical management including medication and a meeting with a physician every 1-2 weeks, or to standard therapy plus individual counseling with a trained substance use counselor.
To the surprise of many, given that SAMHSA guidance strongly recommends counseling and other forms of behavioral therapy, there was no difference in outcomes between the two groups (Drug Alcohol Depend. 2015 May 1;150:112-9).
Subsequent parsing of the POATS data showed that the subgroup of people who were using heroin rather than prescription pills and who actually attended at least 60% of their counseling sessions did better than if they were randomized to no counseling.
“There’s still room for quibbling about the study, but many people would say, ‘You know, it’s not a slam dunk that everybody needs counseling,’ ” the internist commented.
“So, how do we pick the right treatment for our patients with OUD? It’s what feels right for them,” Dr. Grossman cautioned. “This gets back to what we do every day in managing chronic diseases: We nudge, we encourage, we use our motivational interviewing skills to help people figure out how they can change their lives and get healthier. There’s a long list of things going on in our patients’ lives that are going to help guide that decision.
“The message here: Medication is better than no medication, but it’s not a slam dunk which medication or how,” she concluded.
REPORTING FROM ACP INTERNAL MEDICINE
New studies expand on Aimovig for migraine
SAN FRANCISCO – Now that erenumab has won approval as the first-in-class calcitonin gene-related peptide inhibitor for prevention of episodic and chronic migraine, a flurry of new studies shedding light on how the drug might best be used in clinical practice emerged as a highlight of the annual meeting of the American Headache Society.
Erenumab (Aimovig) is a fully human monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor. It was approved by the Food and Drug Administration at 140 and 70 mg monthly by subcutaneous injection on the strength of the required 12-week, double-blind, placebo-controlled clinical trial data. Among the fresh data presented at the headache meeting was reassuring evidence of the monoclonal antibody’s continued high degree of safety and tolerability for episodic migraine after more than 3 years of therapy, as well as a suggestion that the biologic’s efficacy for chronic migraine was not only sustained but actually increased over the course of a 1-year study.
Also, erenumab appears to be a novel treatment option for patients who have previously failed adequate trials of two to four standard preventive therapies. In addition, it has now demonstrated efficacy in reducing overuse of acute migraine drugs such as triptans, ergots, and opioids.
Here are the highlights:
One-year safety and efficacy for chronic migraine
Stewart J. Tepper, MD, presented results of a 1-year, open-label extension study that began after participants completed a pivotal 12-week, placebo-controlled, double-blind, randomized trial whose findings have been published (Lancet Neurol. 2017 Jun;16[6]:425-34). At the end of the 12-week, double-blind period, the mean number of monthly migraine days (MMD) in the erenumab group had dropped by 6.6 days from 18.1 at baseline. Subsequently, after 52 weeks of open-label erenumab at 140 mg monthly, that figure had further improved to 10.5 fewer MMDs than at baseline.
“That’s encouraging for our patients in that we will be able to tell them that if you’re a responder, you’re likely to show some continued improvement over time,” observed Dr. Tepper, professor of neurology and director of the headache clinic at Dartmouth University in Hanover, N.H.
During 527 patient-years of open-label therapy, at least a 50% reduction in MMDs was achieved by 67% of patients in the 140-mg group and 53% in the 70-mg group.
“I think it’s also important to look at the rate of 75% or greater reduction in MMDs, which is the responder rate most closely linked to a drop in disability. That rate at 52 weeks was 42% at 140 mg and 27% at 70 mg,” the neurologist continued.
At week 52, 12.7% of patients on erenumab at 140 mg monthly had no migraines at all during the previous month.
The mean number of acute migraine-specific medication days per month decreased by about 4 days in the erenumab group during the 12-week, double-blind trial and continued to fall during the open-label extension study, with a mean reduction from baseline of 6.7 days at week 52.
“That’s clearly sustained efficacy, and it looks like some accumulating efficacy,” Dr. Tepper said.
Safety and tolerability continued to be excellent, as in the parent 12-week study.
“One of the very interesting findings we saw which differentiates erenumab from, say, onabotulinumtoxinA, is that if you looked at the patients who were on placebo during the 12 weeks of the double-blind study and then looked at the first month they went on erenumab, they caught up immediately to the patients who’d been receiving the monoclonal antibody from the beginning. That’s unlike onabotulinumtoxinA in the regulatory trials, where the patients who initially received placebo never quite caught up to those who received active therapy from the beginning,” he said.
Dr. Tepper emphasized that a clear-eyed view of an open-label study needs to recognize that only responders would have stayed in the erenumab study for a full 52 weeks, so the results paint an overly rosy picture of overall efficacy. Even so, he found the results impressive. Of 609 patients who enrolled in the study, 74% completed it.
“It’s a very encouraging 1-year study for erenumab,” he concluded.
Safety and tolerability for episodic migraine at 3-plus years
Among 383 episodic migraine patients who enrolled in an ongoing 5-year, open-label extension study of erenumab after completing a 12-week, placebo-controlled, double-blind clinical trial, there have been no new safety signals at a mean 3.2 years of follow-up. The incidence rates and types of adverse events remain indistinguishable from placebo as noted in the parent 12-week double-blind trial, with the exception of an increased rate of mild injection site reactions, reported Daniel D. Mikol, MD, PhD, executive medical director for global neuroscience development at Amgen in Thousand Oaks, Calif.
Erenumab proves effective in patients who have failed multiple preventive therapies
Jan Klatt, MD, presented the results of the 12-week, double-blind portion of the phase 3b LIBERTY study, the first clinical trial specifically designed to assess the effects of CGRP-directed therapy in patients who have previously failed to respond to and/or tolerate two to four currently available preventive medications at adequate doses for at least 2-3 months.
The rationale for the trial was straightforward: “There is a particularly high unmet need in patients who have failed currently available preventive therapies, and who are usually considered difficult to treat,” explained Dr. Klatt of Novartis in Basel, Switzerland.
LIBERTY included 246 such patients with episodic migraine who were randomized to 12 weeks of erenumab at 140 mg monthly or placebo. The primary endpoint – the proportion of patients with at least a 50% reduction in MMDs during weeks 9-12 from the baseline of 9.3 – occurred in 30.3% of the erenumab group, significantly better than the 13.7% rate with placebo, with an adjusted odds ratio of 2.73 for success with erenumab. An open-label extension study is ongoing.
A clear separation was already evident at week 4 of the randomized trial, a prespecified secondary endpoint. A 50% or greater reduction in MMDs was seen at that point in 23.5% of the erenumab group versus 4.8% in placebo-treated controls, for a response odds ratio of 6.16. A 75% or greater reduction in MMDs during weeks 9-12 occurred in 11.8% of the erenumab group and 4% of controls. A 100% response rate – that is, no migraines during weeks 9-12 – occurred in 5.9% of the active treatment arm and none of the controls. Outcomes on two novel patient-reported outcomes – the Migraine Physical Function Impact Diary–physical impairment and –everyday activities subscales – were also significantly better in the active treatment arm.
Treatment outcomes with erenumab were similar regardless of which drug classes patients had previously failed on, the three most common of which were beta-blockers, topiramate, and amitriptyline, which is approved for migraine prevention in Europe, where the LIBERTY trial was conducted.
One audience member observed that the 13.7% primary endpoint placebo response rate was far lower than typically seen in double-blind migraine trials.
“This is something we see quite consistently,” Dr. Klatt replied. “Once you proceed to this kind of more difficult-to-treat population, your placebo response rates drop to really low levels. It’s probably due to the fact that those patients have low expectations for any new therapy.”
Erenumab quells acute migraine medication overuse
Dr. Tepper presented a separate analysis of the 52-week, open-label extension study of erenumab, this time comparing outcomes in 252 chronic migraine patients who met criteria for acute medication overuse (AMO) at baseline and 357 who did not. Overuse was defined via International Headache Society criteria: The use of triptans, ergots, or combination analgesics on 10 or more days per month, or simple analgesics on at least 15 days monthly. Combination analgesics feature a simple analgesic plus opiates or butalbital.
“The bottom line here is that the drug worked about the same and in a very encouraging way in the AMO and nonoveruse patients,” he said. “This is obviously something that’s very, very important to us because we’d like to take our patients who are overusing acute migraine medications and use the monoclonal antibody as a way of getting them off overuse and into episodic migraine.”
After 52 weeks of open-label erenumab, 61% of the non-AMO group and 56% of those with baseline AMO had at least a 50% reduction from baseline in MMDs. The use of acute migraine-specific medications fell by 3.7 days in the non-AMO group and by 6.7 days in those with AMO at baseline.
Safety in patients with stable angina
Although no signal of any cardiovascular issues arose in four randomized, double-blind clinical trials or in the long-term extension studies, it was appropriate to take a more focused look at erenumab’s effects in a high-risk population with stable angina and proven ischemic coronary artery disease. That’s because CGRP is a neuropeptide that not only affects migraine, it also acts as a cytoprotective mediator released by cardiac nerve fibers during myocardial ischemia. Thus, erenumab posed a theoretic cardiovascular risk, explained Christophe Depre, MD, PhD, of Amgen.
He presented a 12-week, randomized, double-blind study in which 89 patients with stable angina were assigned to a single IV infusion of 140 mg of erenumab or placebo followed by an exercise treadmill test. Reassuringly, the CGRP inhibitor had no adverse effect on exercise time, time to onset of at least 1 mm of ST segment depression. Nor did it affect heart rate or blood pressure during or after exercise.
Dr. Tepper reported serving as a consultant to numerous pharmaceutical and medical device companies, including Amgen and Novartis, which sponsored the erenumab studies. Dr. Depre and Dr. Mikol are Amgen employees, while Dr. Klatt is employed by Novartis.
SAN FRANCISCO – Now that erenumab has won approval as the first-in-class calcitonin gene-related peptide inhibitor for prevention of episodic and chronic migraine, a flurry of new studies shedding light on how the drug might best be used in clinical practice emerged as a highlight of the annual meeting of the American Headache Society.
Erenumab (Aimovig) is a fully human monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor. It was approved by the Food and Drug Administration at 140 and 70 mg monthly by subcutaneous injection on the strength of the required 12-week, double-blind, placebo-controlled clinical trial data. Among the fresh data presented at the headache meeting was reassuring evidence of the monoclonal antibody’s continued high degree of safety and tolerability for episodic migraine after more than 3 years of therapy, as well as a suggestion that the biologic’s efficacy for chronic migraine was not only sustained but actually increased over the course of a 1-year study.
Also, erenumab appears to be a novel treatment option for patients who have previously failed adequate trials of two to four standard preventive therapies. In addition, it has now demonstrated efficacy in reducing overuse of acute migraine drugs such as triptans, ergots, and opioids.
Here are the highlights:
One-year safety and efficacy for chronic migraine
Stewart J. Tepper, MD, presented results of a 1-year, open-label extension study that began after participants completed a pivotal 12-week, placebo-controlled, double-blind, randomized trial whose findings have been published (Lancet Neurol. 2017 Jun;16[6]:425-34). At the end of the 12-week, double-blind period, the mean number of monthly migraine days (MMD) in the erenumab group had dropped by 6.6 days from 18.1 at baseline. Subsequently, after 52 weeks of open-label erenumab at 140 mg monthly, that figure had further improved to 10.5 fewer MMDs than at baseline.
“That’s encouraging for our patients in that we will be able to tell them that if you’re a responder, you’re likely to show some continued improvement over time,” observed Dr. Tepper, professor of neurology and director of the headache clinic at Dartmouth University in Hanover, N.H.
During 527 patient-years of open-label therapy, at least a 50% reduction in MMDs was achieved by 67% of patients in the 140-mg group and 53% in the 70-mg group.
“I think it’s also important to look at the rate of 75% or greater reduction in MMDs, which is the responder rate most closely linked to a drop in disability. That rate at 52 weeks was 42% at 140 mg and 27% at 70 mg,” the neurologist continued.
At week 52, 12.7% of patients on erenumab at 140 mg monthly had no migraines at all during the previous month.
The mean number of acute migraine-specific medication days per month decreased by about 4 days in the erenumab group during the 12-week, double-blind trial and continued to fall during the open-label extension study, with a mean reduction from baseline of 6.7 days at week 52.
“That’s clearly sustained efficacy, and it looks like some accumulating efficacy,” Dr. Tepper said.
Safety and tolerability continued to be excellent, as in the parent 12-week study.
“One of the very interesting findings we saw which differentiates erenumab from, say, onabotulinumtoxinA, is that if you looked at the patients who were on placebo during the 12 weeks of the double-blind study and then looked at the first month they went on erenumab, they caught up immediately to the patients who’d been receiving the monoclonal antibody from the beginning. That’s unlike onabotulinumtoxinA in the regulatory trials, where the patients who initially received placebo never quite caught up to those who received active therapy from the beginning,” he said.
Dr. Tepper emphasized that a clear-eyed view of an open-label study needs to recognize that only responders would have stayed in the erenumab study for a full 52 weeks, so the results paint an overly rosy picture of overall efficacy. Even so, he found the results impressive. Of 609 patients who enrolled in the study, 74% completed it.
“It’s a very encouraging 1-year study for erenumab,” he concluded.
Safety and tolerability for episodic migraine at 3-plus years
Among 383 episodic migraine patients who enrolled in an ongoing 5-year, open-label extension study of erenumab after completing a 12-week, placebo-controlled, double-blind clinical trial, there have been no new safety signals at a mean 3.2 years of follow-up. The incidence rates and types of adverse events remain indistinguishable from placebo as noted in the parent 12-week double-blind trial, with the exception of an increased rate of mild injection site reactions, reported Daniel D. Mikol, MD, PhD, executive medical director for global neuroscience development at Amgen in Thousand Oaks, Calif.
Erenumab proves effective in patients who have failed multiple preventive therapies
Jan Klatt, MD, presented the results of the 12-week, double-blind portion of the phase 3b LIBERTY study, the first clinical trial specifically designed to assess the effects of CGRP-directed therapy in patients who have previously failed to respond to and/or tolerate two to four currently available preventive medications at adequate doses for at least 2-3 months.
The rationale for the trial was straightforward: “There is a particularly high unmet need in patients who have failed currently available preventive therapies, and who are usually considered difficult to treat,” explained Dr. Klatt of Novartis in Basel, Switzerland.
LIBERTY included 246 such patients with episodic migraine who were randomized to 12 weeks of erenumab at 140 mg monthly or placebo. The primary endpoint – the proportion of patients with at least a 50% reduction in MMDs during weeks 9-12 from the baseline of 9.3 – occurred in 30.3% of the erenumab group, significantly better than the 13.7% rate with placebo, with an adjusted odds ratio of 2.73 for success with erenumab. An open-label extension study is ongoing.
A clear separation was already evident at week 4 of the randomized trial, a prespecified secondary endpoint. A 50% or greater reduction in MMDs was seen at that point in 23.5% of the erenumab group versus 4.8% in placebo-treated controls, for a response odds ratio of 6.16. A 75% or greater reduction in MMDs during weeks 9-12 occurred in 11.8% of the erenumab group and 4% of controls. A 100% response rate – that is, no migraines during weeks 9-12 – occurred in 5.9% of the active treatment arm and none of the controls. Outcomes on two novel patient-reported outcomes – the Migraine Physical Function Impact Diary–physical impairment and –everyday activities subscales – were also significantly better in the active treatment arm.
Treatment outcomes with erenumab were similar regardless of which drug classes patients had previously failed on, the three most common of which were beta-blockers, topiramate, and amitriptyline, which is approved for migraine prevention in Europe, where the LIBERTY trial was conducted.
One audience member observed that the 13.7% primary endpoint placebo response rate was far lower than typically seen in double-blind migraine trials.
“This is something we see quite consistently,” Dr. Klatt replied. “Once you proceed to this kind of more difficult-to-treat population, your placebo response rates drop to really low levels. It’s probably due to the fact that those patients have low expectations for any new therapy.”
Erenumab quells acute migraine medication overuse
Dr. Tepper presented a separate analysis of the 52-week, open-label extension study of erenumab, this time comparing outcomes in 252 chronic migraine patients who met criteria for acute medication overuse (AMO) at baseline and 357 who did not. Overuse was defined via International Headache Society criteria: The use of triptans, ergots, or combination analgesics on 10 or more days per month, or simple analgesics on at least 15 days monthly. Combination analgesics feature a simple analgesic plus opiates or butalbital.
“The bottom line here is that the drug worked about the same and in a very encouraging way in the AMO and nonoveruse patients,” he said. “This is obviously something that’s very, very important to us because we’d like to take our patients who are overusing acute migraine medications and use the monoclonal antibody as a way of getting them off overuse and into episodic migraine.”
After 52 weeks of open-label erenumab, 61% of the non-AMO group and 56% of those with baseline AMO had at least a 50% reduction from baseline in MMDs. The use of acute migraine-specific medications fell by 3.7 days in the non-AMO group and by 6.7 days in those with AMO at baseline.
Safety in patients with stable angina
Although no signal of any cardiovascular issues arose in four randomized, double-blind clinical trials or in the long-term extension studies, it was appropriate to take a more focused look at erenumab’s effects in a high-risk population with stable angina and proven ischemic coronary artery disease. That’s because CGRP is a neuropeptide that not only affects migraine, it also acts as a cytoprotective mediator released by cardiac nerve fibers during myocardial ischemia. Thus, erenumab posed a theoretic cardiovascular risk, explained Christophe Depre, MD, PhD, of Amgen.
He presented a 12-week, randomized, double-blind study in which 89 patients with stable angina were assigned to a single IV infusion of 140 mg of erenumab or placebo followed by an exercise treadmill test. Reassuringly, the CGRP inhibitor had no adverse effect on exercise time, time to onset of at least 1 mm of ST segment depression. Nor did it affect heart rate or blood pressure during or after exercise.
Dr. Tepper reported serving as a consultant to numerous pharmaceutical and medical device companies, including Amgen and Novartis, which sponsored the erenumab studies. Dr. Depre and Dr. Mikol are Amgen employees, while Dr. Klatt is employed by Novartis.
SAN FRANCISCO – Now that erenumab has won approval as the first-in-class calcitonin gene-related peptide inhibitor for prevention of episodic and chronic migraine, a flurry of new studies shedding light on how the drug might best be used in clinical practice emerged as a highlight of the annual meeting of the American Headache Society.
Erenumab (Aimovig) is a fully human monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor. It was approved by the Food and Drug Administration at 140 and 70 mg monthly by subcutaneous injection on the strength of the required 12-week, double-blind, placebo-controlled clinical trial data. Among the fresh data presented at the headache meeting was reassuring evidence of the monoclonal antibody’s continued high degree of safety and tolerability for episodic migraine after more than 3 years of therapy, as well as a suggestion that the biologic’s efficacy for chronic migraine was not only sustained but actually increased over the course of a 1-year study.
Also, erenumab appears to be a novel treatment option for patients who have previously failed adequate trials of two to four standard preventive therapies. In addition, it has now demonstrated efficacy in reducing overuse of acute migraine drugs such as triptans, ergots, and opioids.
Here are the highlights:
One-year safety and efficacy for chronic migraine
Stewart J. Tepper, MD, presented results of a 1-year, open-label extension study that began after participants completed a pivotal 12-week, placebo-controlled, double-blind, randomized trial whose findings have been published (Lancet Neurol. 2017 Jun;16[6]:425-34). At the end of the 12-week, double-blind period, the mean number of monthly migraine days (MMD) in the erenumab group had dropped by 6.6 days from 18.1 at baseline. Subsequently, after 52 weeks of open-label erenumab at 140 mg monthly, that figure had further improved to 10.5 fewer MMDs than at baseline.
“That’s encouraging for our patients in that we will be able to tell them that if you’re a responder, you’re likely to show some continued improvement over time,” observed Dr. Tepper, professor of neurology and director of the headache clinic at Dartmouth University in Hanover, N.H.
During 527 patient-years of open-label therapy, at least a 50% reduction in MMDs was achieved by 67% of patients in the 140-mg group and 53% in the 70-mg group.
“I think it’s also important to look at the rate of 75% or greater reduction in MMDs, which is the responder rate most closely linked to a drop in disability. That rate at 52 weeks was 42% at 140 mg and 27% at 70 mg,” the neurologist continued.
At week 52, 12.7% of patients on erenumab at 140 mg monthly had no migraines at all during the previous month.
The mean number of acute migraine-specific medication days per month decreased by about 4 days in the erenumab group during the 12-week, double-blind trial and continued to fall during the open-label extension study, with a mean reduction from baseline of 6.7 days at week 52.
“That’s clearly sustained efficacy, and it looks like some accumulating efficacy,” Dr. Tepper said.
Safety and tolerability continued to be excellent, as in the parent 12-week study.
“One of the very interesting findings we saw which differentiates erenumab from, say, onabotulinumtoxinA, is that if you looked at the patients who were on placebo during the 12 weeks of the double-blind study and then looked at the first month they went on erenumab, they caught up immediately to the patients who’d been receiving the monoclonal antibody from the beginning. That’s unlike onabotulinumtoxinA in the regulatory trials, where the patients who initially received placebo never quite caught up to those who received active therapy from the beginning,” he said.
Dr. Tepper emphasized that a clear-eyed view of an open-label study needs to recognize that only responders would have stayed in the erenumab study for a full 52 weeks, so the results paint an overly rosy picture of overall efficacy. Even so, he found the results impressive. Of 609 patients who enrolled in the study, 74% completed it.
“It’s a very encouraging 1-year study for erenumab,” he concluded.
Safety and tolerability for episodic migraine at 3-plus years
Among 383 episodic migraine patients who enrolled in an ongoing 5-year, open-label extension study of erenumab after completing a 12-week, placebo-controlled, double-blind clinical trial, there have been no new safety signals at a mean 3.2 years of follow-up. The incidence rates and types of adverse events remain indistinguishable from placebo as noted in the parent 12-week double-blind trial, with the exception of an increased rate of mild injection site reactions, reported Daniel D. Mikol, MD, PhD, executive medical director for global neuroscience development at Amgen in Thousand Oaks, Calif.
Erenumab proves effective in patients who have failed multiple preventive therapies
Jan Klatt, MD, presented the results of the 12-week, double-blind portion of the phase 3b LIBERTY study, the first clinical trial specifically designed to assess the effects of CGRP-directed therapy in patients who have previously failed to respond to and/or tolerate two to four currently available preventive medications at adequate doses for at least 2-3 months.
The rationale for the trial was straightforward: “There is a particularly high unmet need in patients who have failed currently available preventive therapies, and who are usually considered difficult to treat,” explained Dr. Klatt of Novartis in Basel, Switzerland.
LIBERTY included 246 such patients with episodic migraine who were randomized to 12 weeks of erenumab at 140 mg monthly or placebo. The primary endpoint – the proportion of patients with at least a 50% reduction in MMDs during weeks 9-12 from the baseline of 9.3 – occurred in 30.3% of the erenumab group, significantly better than the 13.7% rate with placebo, with an adjusted odds ratio of 2.73 for success with erenumab. An open-label extension study is ongoing.
A clear separation was already evident at week 4 of the randomized trial, a prespecified secondary endpoint. A 50% or greater reduction in MMDs was seen at that point in 23.5% of the erenumab group versus 4.8% in placebo-treated controls, for a response odds ratio of 6.16. A 75% or greater reduction in MMDs during weeks 9-12 occurred in 11.8% of the erenumab group and 4% of controls. A 100% response rate – that is, no migraines during weeks 9-12 – occurred in 5.9% of the active treatment arm and none of the controls. Outcomes on two novel patient-reported outcomes – the Migraine Physical Function Impact Diary–physical impairment and –everyday activities subscales – were also significantly better in the active treatment arm.
Treatment outcomes with erenumab were similar regardless of which drug classes patients had previously failed on, the three most common of which were beta-blockers, topiramate, and amitriptyline, which is approved for migraine prevention in Europe, where the LIBERTY trial was conducted.
One audience member observed that the 13.7% primary endpoint placebo response rate was far lower than typically seen in double-blind migraine trials.
“This is something we see quite consistently,” Dr. Klatt replied. “Once you proceed to this kind of more difficult-to-treat population, your placebo response rates drop to really low levels. It’s probably due to the fact that those patients have low expectations for any new therapy.”
Erenumab quells acute migraine medication overuse
Dr. Tepper presented a separate analysis of the 52-week, open-label extension study of erenumab, this time comparing outcomes in 252 chronic migraine patients who met criteria for acute medication overuse (AMO) at baseline and 357 who did not. Overuse was defined via International Headache Society criteria: The use of triptans, ergots, or combination analgesics on 10 or more days per month, or simple analgesics on at least 15 days monthly. Combination analgesics feature a simple analgesic plus opiates or butalbital.
“The bottom line here is that the drug worked about the same and in a very encouraging way in the AMO and nonoveruse patients,” he said. “This is obviously something that’s very, very important to us because we’d like to take our patients who are overusing acute migraine medications and use the monoclonal antibody as a way of getting them off overuse and into episodic migraine.”
After 52 weeks of open-label erenumab, 61% of the non-AMO group and 56% of those with baseline AMO had at least a 50% reduction from baseline in MMDs. The use of acute migraine-specific medications fell by 3.7 days in the non-AMO group and by 6.7 days in those with AMO at baseline.
Safety in patients with stable angina
Although no signal of any cardiovascular issues arose in four randomized, double-blind clinical trials or in the long-term extension studies, it was appropriate to take a more focused look at erenumab’s effects in a high-risk population with stable angina and proven ischemic coronary artery disease. That’s because CGRP is a neuropeptide that not only affects migraine, it also acts as a cytoprotective mediator released by cardiac nerve fibers during myocardial ischemia. Thus, erenumab posed a theoretic cardiovascular risk, explained Christophe Depre, MD, PhD, of Amgen.
He presented a 12-week, randomized, double-blind study in which 89 patients with stable angina were assigned to a single IV infusion of 140 mg of erenumab or placebo followed by an exercise treadmill test. Reassuringly, the CGRP inhibitor had no adverse effect on exercise time, time to onset of at least 1 mm of ST segment depression. Nor did it affect heart rate or blood pressure during or after exercise.
Dr. Tepper reported serving as a consultant to numerous pharmaceutical and medical device companies, including Amgen and Novartis, which sponsored the erenumab studies. Dr. Depre and Dr. Mikol are Amgen employees, while Dr. Klatt is employed by Novartis.
REPORTING FROM THE AHS ANNUAL MEETING
European experts envy U.S. pediatric flu vaccination approach
MALMO, SWEDEN – When American physicians think about health care in Europe, what typically comes to mind are government-funded, single-payer national health services with cradle-to-grave coverage of essential services, a strong public health bent, and perhaps some queuing.
“It’s complicated. There is no common strategic approach,” Hanna Nohynek, MD, PhD, observed at a session on childhood immunization against flu held during the annual meeting of the European Society for Paediatric Infectious Diseases.
“In real life, influenza coverage among [European] children is either not known or quite low. Impact assessments in children are done in only a few countries,” said Dr. Nohynek, chief physician in the infectious diseases control and vaccinations unit of the National Institute for Health and Welfare in Helsinki, Finland.
“The only country doing as well coverage-wise as the U.S. is the U.K., with rates of 50%-65%. In Finland it’s less than 40%,” according to Dr. Nohynek.
“We have 28 countries today in the E.U. [European Union], and we have 28 different recommendations in Europe. So where do we go from here? It’s really not easy,” observed session cochair Alberticus Osterhaus, DVM, PhD, emeritus professor of virology at Erasmus University in Rotterdam, the Netherlands.
For all the oft-cited shortcomings of health care in the United States, That’s why Jon S. Abramson, MD, a former chair of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP), was invited to explain how the U.S. strategy was accomplished.
The U.S. approach
The current U.S. policy, implemented in 2010, is to recommend an annual flu shot for all persons older than 6 months of age.
Influenza vaccination has been part of the U.S. public health program since 1960. Children aged 6-23 months, as well as their household contacts and women who will be pregnant during flu season, were added in 2004. In 2006, the flu vaccine recommendation was expanded to include children aged 6-59 months as a result of persuasive data showing that the rate of flu-associated hospitalizations and deaths in children up to 4 years old was second only to the rate in the elderly population.
The rationale for expanding the recommendation to include all school-age children and adolescents stemmed from evidence that the highest average flu-related illness rate in the United States was in that age group, which confirmed that schools are a powerful vector for the spread of influenza. Vaccinating this age-group also was seen as having an indirect benefit for their household contacts.
The current policy of recommending vaccination of everyone over age 6 months was adopted because it checked off a lot of boxes: “It’s a single recommendation, easy to apply; it eliminates the need to look for indications and risk factors; it increases vaccination coverage rates; annual vaccination is safe and effective; and flu-related morbidity and mortality occur in all age groups,” Dr. Abramson continued.
The rate of influenza vaccine coverage in pregnant women has improved over time from less than 15% to about 50%. To place that in perspective, however, the rate in Argentina is 95%, the pediatrician noted.
“We’re doing better in children than we are in adults in terms of seasonal coverage rates,” he added. “In 2015, it was 59%, versus 42% in adults.”
Dr. Abramson said there remains some skepticism in the United States regarding the effectiveness of flu vaccines in preventing flu-related illness. That’s because of the difficulty in communicating that vaccine effectiveness varies from year to year, sometimes substantially, depending upon two factors: the transmission characteristics of the circulating strains and how well the vaccines match up against those strains.
“I think we have to learn to live with that. I don’t think we’ll see a universal flu vaccine that we can give once every 10 years,” he said.
“The bottom line is, even if a vaccine is only 50% efficacious overall, we’re still impacting huge numbers,” the pediatrician added.
Dr. Abramson cited a CDC estimate that, for the 2012-2013 season, where the vaccine was 49% efficacious, the result of vaccination was 6.6 million fewer cases of influenza-associated illnesses nationally, 3.2 million fewer flu-associated medical visits, and 79,000 hospitalizations avoided.
“I think we have a fairly good program in the United States. We’re doing well in children. We certainly could be doing better. Not having FluMist for the past 2 seasons probably hurt us some,” according to Dr. Abramson.
The FluMist experience
The FluMist episode is viewed by many European pediatric infectious disease experts as a debacle. Europeans eager to develop a pan-European strategy for seasonal immunization against influenza in children and adolescents viewed the U.S. FluMist episode with dismay. For the 2016-2017 and 2017-2018 flu seasons, the ACIP recommended against FluMist, a previously approved intranasally administered quadrivalent live attenuated virus vaccine, on the basis of a single study showing subpar effectiveness against influenza A H1NI. Then at its October 2017 meeting, ACIP reversed itself and reinstated FluMist for the 2018-2019 season after viewing data from Finland and several other countries demonstrating that, in countries where it hadn’t been taken off the market, the vaccine had performed as well as injectable inactivated influenza vaccines in the 2016-2017 flu season.
“I think from the European side, it’s been a bit of a sorry spectacle,” commented Dr. Osterhaus, referring to the ACIP’s waffling. After all, authorities in Canada and European countries where FluMist was available had looked at the same data that caused ACIP to derecommend the vaccine but hadn’t found it convincing.
“We’re very happy to see ACIP has reinstated the vaccine,” Dr. Nohynek said.
Dr. Abramson declined to defend the ACIP decision to drop FluMist.
“From my standpoint, knowing that influenza B kills more children than A does, if I had been on the ACIP committee – and I’m not anymore – that would not have been my vote,” he said. “Whatever you want to say about the live attenuated influenza vaccine, about how good it is against some A strains or not, it’s better than other vaccines against influenza B. And the death rate is higher from B than A in children, although that is not true in adults.”
Plus, FluMist was an important option for people avoiding immunization because they dislike shots.
“The vast majority of deaths due to flu in children in 2010-2016 have been in kids who didn’t get vaccinated,” he noted.
Dr. Nohynek said the Finnish real-world experience recorded in comprehensive national registries for the 2017-2018 flu season – a bad year for vaccine/virus mismatch in Europe – confirmed Dr. Abramson’s comments about the superiority of quadrivalent live attenuated influenza vaccine against influenza B. Among 54,611 Finnish children aged 24-35 months, the laboratory-confirmed vaccine effectiveness of trivalent inactivated virus vaccine, with 9% coverage, was 4.5% for influenza A and 12.2% for influenza B. In contrast, the vaccine effectiveness for the intranasal quadrivalent live attenuated influenza vaccine was 32% for A and a whopping 80% for B.
“It’s quite amazing, at least to me, to see figures like this in real world data,” she commented.
Session cochair Adam Finn, MD, PhD, said he has found it instructive to take a closer look at the U.K. data for the past several flu seasons.
“We’ve seen greater control of the epidemic in Scotland and Northern Ireland, where coverage in primary school kids was higher, in the 60%-70% area, and lower in England and Wales, where it was more like 50%. So we’re beginning to think that’s the kind of level of annual coverage in children we might need to suppress an epidemic. I think that’s a really important message that people should understand: We’re not looking for 95% coverage,” observed Dr. Finn, aprofessor of pediatrics at the University of Bristol (England).
Vaccine effectiveness will improve
Dr. Osterhaus predicted better times are coming in terms of vaccine effectiveness. Vaccine production times will become shorter as recombinant technologies replace the traditional lengthy chicken egg-based vaccine production; as a result, there will be less drift-associated mismatch. Improved surveillance, including the ability to follow strain mobility patterns and population-based antibody landscapes, are another important advance.
“We’ve always been looking at one side of the coin: the virus. Once or twice a year eminent gray people sitting together in Geneva at WHO decide which strains should be selected for the next vaccine. But if you know what antibodies are present in the population, this can be quite important information as well,” he said.
Dr. Nohynek reported receiving research funding from GlaxoSmithKline and Pfizer. The other speakers reported having no relevant financial conflicts of interest.
MALMO, SWEDEN – When American physicians think about health care in Europe, what typically comes to mind are government-funded, single-payer national health services with cradle-to-grave coverage of essential services, a strong public health bent, and perhaps some queuing.
“It’s complicated. There is no common strategic approach,” Hanna Nohynek, MD, PhD, observed at a session on childhood immunization against flu held during the annual meeting of the European Society for Paediatric Infectious Diseases.
“In real life, influenza coverage among [European] children is either not known or quite low. Impact assessments in children are done in only a few countries,” said Dr. Nohynek, chief physician in the infectious diseases control and vaccinations unit of the National Institute for Health and Welfare in Helsinki, Finland.
“The only country doing as well coverage-wise as the U.S. is the U.K., with rates of 50%-65%. In Finland it’s less than 40%,” according to Dr. Nohynek.
“We have 28 countries today in the E.U. [European Union], and we have 28 different recommendations in Europe. So where do we go from here? It’s really not easy,” observed session cochair Alberticus Osterhaus, DVM, PhD, emeritus professor of virology at Erasmus University in Rotterdam, the Netherlands.
For all the oft-cited shortcomings of health care in the United States, That’s why Jon S. Abramson, MD, a former chair of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP), was invited to explain how the U.S. strategy was accomplished.
The U.S. approach
The current U.S. policy, implemented in 2010, is to recommend an annual flu shot for all persons older than 6 months of age.
Influenza vaccination has been part of the U.S. public health program since 1960. Children aged 6-23 months, as well as their household contacts and women who will be pregnant during flu season, were added in 2004. In 2006, the flu vaccine recommendation was expanded to include children aged 6-59 months as a result of persuasive data showing that the rate of flu-associated hospitalizations and deaths in children up to 4 years old was second only to the rate in the elderly population.
The rationale for expanding the recommendation to include all school-age children and adolescents stemmed from evidence that the highest average flu-related illness rate in the United States was in that age group, which confirmed that schools are a powerful vector for the spread of influenza. Vaccinating this age-group also was seen as having an indirect benefit for their household contacts.
The current policy of recommending vaccination of everyone over age 6 months was adopted because it checked off a lot of boxes: “It’s a single recommendation, easy to apply; it eliminates the need to look for indications and risk factors; it increases vaccination coverage rates; annual vaccination is safe and effective; and flu-related morbidity and mortality occur in all age groups,” Dr. Abramson continued.
The rate of influenza vaccine coverage in pregnant women has improved over time from less than 15% to about 50%. To place that in perspective, however, the rate in Argentina is 95%, the pediatrician noted.
“We’re doing better in children than we are in adults in terms of seasonal coverage rates,” he added. “In 2015, it was 59%, versus 42% in adults.”
Dr. Abramson said there remains some skepticism in the United States regarding the effectiveness of flu vaccines in preventing flu-related illness. That’s because of the difficulty in communicating that vaccine effectiveness varies from year to year, sometimes substantially, depending upon two factors: the transmission characteristics of the circulating strains and how well the vaccines match up against those strains.
“I think we have to learn to live with that. I don’t think we’ll see a universal flu vaccine that we can give once every 10 years,” he said.
“The bottom line is, even if a vaccine is only 50% efficacious overall, we’re still impacting huge numbers,” the pediatrician added.
Dr. Abramson cited a CDC estimate that, for the 2012-2013 season, where the vaccine was 49% efficacious, the result of vaccination was 6.6 million fewer cases of influenza-associated illnesses nationally, 3.2 million fewer flu-associated medical visits, and 79,000 hospitalizations avoided.
“I think we have a fairly good program in the United States. We’re doing well in children. We certainly could be doing better. Not having FluMist for the past 2 seasons probably hurt us some,” according to Dr. Abramson.
The FluMist experience
The FluMist episode is viewed by many European pediatric infectious disease experts as a debacle. Europeans eager to develop a pan-European strategy for seasonal immunization against influenza in children and adolescents viewed the U.S. FluMist episode with dismay. For the 2016-2017 and 2017-2018 flu seasons, the ACIP recommended against FluMist, a previously approved intranasally administered quadrivalent live attenuated virus vaccine, on the basis of a single study showing subpar effectiveness against influenza A H1NI. Then at its October 2017 meeting, ACIP reversed itself and reinstated FluMist for the 2018-2019 season after viewing data from Finland and several other countries demonstrating that, in countries where it hadn’t been taken off the market, the vaccine had performed as well as injectable inactivated influenza vaccines in the 2016-2017 flu season.
“I think from the European side, it’s been a bit of a sorry spectacle,” commented Dr. Osterhaus, referring to the ACIP’s waffling. After all, authorities in Canada and European countries where FluMist was available had looked at the same data that caused ACIP to derecommend the vaccine but hadn’t found it convincing.
“We’re very happy to see ACIP has reinstated the vaccine,” Dr. Nohynek said.
Dr. Abramson declined to defend the ACIP decision to drop FluMist.
“From my standpoint, knowing that influenza B kills more children than A does, if I had been on the ACIP committee – and I’m not anymore – that would not have been my vote,” he said. “Whatever you want to say about the live attenuated influenza vaccine, about how good it is against some A strains or not, it’s better than other vaccines against influenza B. And the death rate is higher from B than A in children, although that is not true in adults.”
Plus, FluMist was an important option for people avoiding immunization because they dislike shots.
“The vast majority of deaths due to flu in children in 2010-2016 have been in kids who didn’t get vaccinated,” he noted.
Dr. Nohynek said the Finnish real-world experience recorded in comprehensive national registries for the 2017-2018 flu season – a bad year for vaccine/virus mismatch in Europe – confirmed Dr. Abramson’s comments about the superiority of quadrivalent live attenuated influenza vaccine against influenza B. Among 54,611 Finnish children aged 24-35 months, the laboratory-confirmed vaccine effectiveness of trivalent inactivated virus vaccine, with 9% coverage, was 4.5% for influenza A and 12.2% for influenza B. In contrast, the vaccine effectiveness for the intranasal quadrivalent live attenuated influenza vaccine was 32% for A and a whopping 80% for B.
“It’s quite amazing, at least to me, to see figures like this in real world data,” she commented.
Session cochair Adam Finn, MD, PhD, said he has found it instructive to take a closer look at the U.K. data for the past several flu seasons.
“We’ve seen greater control of the epidemic in Scotland and Northern Ireland, where coverage in primary school kids was higher, in the 60%-70% area, and lower in England and Wales, where it was more like 50%. So we’re beginning to think that’s the kind of level of annual coverage in children we might need to suppress an epidemic. I think that’s a really important message that people should understand: We’re not looking for 95% coverage,” observed Dr. Finn, aprofessor of pediatrics at the University of Bristol (England).
Vaccine effectiveness will improve
Dr. Osterhaus predicted better times are coming in terms of vaccine effectiveness. Vaccine production times will become shorter as recombinant technologies replace the traditional lengthy chicken egg-based vaccine production; as a result, there will be less drift-associated mismatch. Improved surveillance, including the ability to follow strain mobility patterns and population-based antibody landscapes, are another important advance.
“We’ve always been looking at one side of the coin: the virus. Once or twice a year eminent gray people sitting together in Geneva at WHO decide which strains should be selected for the next vaccine. But if you know what antibodies are present in the population, this can be quite important information as well,” he said.
Dr. Nohynek reported receiving research funding from GlaxoSmithKline and Pfizer. The other speakers reported having no relevant financial conflicts of interest.
MALMO, SWEDEN – When American physicians think about health care in Europe, what typically comes to mind are government-funded, single-payer national health services with cradle-to-grave coverage of essential services, a strong public health bent, and perhaps some queuing.
“It’s complicated. There is no common strategic approach,” Hanna Nohynek, MD, PhD, observed at a session on childhood immunization against flu held during the annual meeting of the European Society for Paediatric Infectious Diseases.
“In real life, influenza coverage among [European] children is either not known or quite low. Impact assessments in children are done in only a few countries,” said Dr. Nohynek, chief physician in the infectious diseases control and vaccinations unit of the National Institute for Health and Welfare in Helsinki, Finland.
“The only country doing as well coverage-wise as the U.S. is the U.K., with rates of 50%-65%. In Finland it’s less than 40%,” according to Dr. Nohynek.
“We have 28 countries today in the E.U. [European Union], and we have 28 different recommendations in Europe. So where do we go from here? It’s really not easy,” observed session cochair Alberticus Osterhaus, DVM, PhD, emeritus professor of virology at Erasmus University in Rotterdam, the Netherlands.
For all the oft-cited shortcomings of health care in the United States, That’s why Jon S. Abramson, MD, a former chair of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP), was invited to explain how the U.S. strategy was accomplished.
The U.S. approach
The current U.S. policy, implemented in 2010, is to recommend an annual flu shot for all persons older than 6 months of age.
Influenza vaccination has been part of the U.S. public health program since 1960. Children aged 6-23 months, as well as their household contacts and women who will be pregnant during flu season, were added in 2004. In 2006, the flu vaccine recommendation was expanded to include children aged 6-59 months as a result of persuasive data showing that the rate of flu-associated hospitalizations and deaths in children up to 4 years old was second only to the rate in the elderly population.
The rationale for expanding the recommendation to include all school-age children and adolescents stemmed from evidence that the highest average flu-related illness rate in the United States was in that age group, which confirmed that schools are a powerful vector for the spread of influenza. Vaccinating this age-group also was seen as having an indirect benefit for their household contacts.
The current policy of recommending vaccination of everyone over age 6 months was adopted because it checked off a lot of boxes: “It’s a single recommendation, easy to apply; it eliminates the need to look for indications and risk factors; it increases vaccination coverage rates; annual vaccination is safe and effective; and flu-related morbidity and mortality occur in all age groups,” Dr. Abramson continued.
The rate of influenza vaccine coverage in pregnant women has improved over time from less than 15% to about 50%. To place that in perspective, however, the rate in Argentina is 95%, the pediatrician noted.
“We’re doing better in children than we are in adults in terms of seasonal coverage rates,” he added. “In 2015, it was 59%, versus 42% in adults.”
Dr. Abramson said there remains some skepticism in the United States regarding the effectiveness of flu vaccines in preventing flu-related illness. That’s because of the difficulty in communicating that vaccine effectiveness varies from year to year, sometimes substantially, depending upon two factors: the transmission characteristics of the circulating strains and how well the vaccines match up against those strains.
“I think we have to learn to live with that. I don’t think we’ll see a universal flu vaccine that we can give once every 10 years,” he said.
“The bottom line is, even if a vaccine is only 50% efficacious overall, we’re still impacting huge numbers,” the pediatrician added.
Dr. Abramson cited a CDC estimate that, for the 2012-2013 season, where the vaccine was 49% efficacious, the result of vaccination was 6.6 million fewer cases of influenza-associated illnesses nationally, 3.2 million fewer flu-associated medical visits, and 79,000 hospitalizations avoided.
“I think we have a fairly good program in the United States. We’re doing well in children. We certainly could be doing better. Not having FluMist for the past 2 seasons probably hurt us some,” according to Dr. Abramson.
The FluMist experience
The FluMist episode is viewed by many European pediatric infectious disease experts as a debacle. Europeans eager to develop a pan-European strategy for seasonal immunization against influenza in children and adolescents viewed the U.S. FluMist episode with dismay. For the 2016-2017 and 2017-2018 flu seasons, the ACIP recommended against FluMist, a previously approved intranasally administered quadrivalent live attenuated virus vaccine, on the basis of a single study showing subpar effectiveness against influenza A H1NI. Then at its October 2017 meeting, ACIP reversed itself and reinstated FluMist for the 2018-2019 season after viewing data from Finland and several other countries demonstrating that, in countries where it hadn’t been taken off the market, the vaccine had performed as well as injectable inactivated influenza vaccines in the 2016-2017 flu season.
“I think from the European side, it’s been a bit of a sorry spectacle,” commented Dr. Osterhaus, referring to the ACIP’s waffling. After all, authorities in Canada and European countries where FluMist was available had looked at the same data that caused ACIP to derecommend the vaccine but hadn’t found it convincing.
“We’re very happy to see ACIP has reinstated the vaccine,” Dr. Nohynek said.
Dr. Abramson declined to defend the ACIP decision to drop FluMist.
“From my standpoint, knowing that influenza B kills more children than A does, if I had been on the ACIP committee – and I’m not anymore – that would not have been my vote,” he said. “Whatever you want to say about the live attenuated influenza vaccine, about how good it is against some A strains or not, it’s better than other vaccines against influenza B. And the death rate is higher from B than A in children, although that is not true in adults.”
Plus, FluMist was an important option for people avoiding immunization because they dislike shots.
“The vast majority of deaths due to flu in children in 2010-2016 have been in kids who didn’t get vaccinated,” he noted.
Dr. Nohynek said the Finnish real-world experience recorded in comprehensive national registries for the 2017-2018 flu season – a bad year for vaccine/virus mismatch in Europe – confirmed Dr. Abramson’s comments about the superiority of quadrivalent live attenuated influenza vaccine against influenza B. Among 54,611 Finnish children aged 24-35 months, the laboratory-confirmed vaccine effectiveness of trivalent inactivated virus vaccine, with 9% coverage, was 4.5% for influenza A and 12.2% for influenza B. In contrast, the vaccine effectiveness for the intranasal quadrivalent live attenuated influenza vaccine was 32% for A and a whopping 80% for B.
“It’s quite amazing, at least to me, to see figures like this in real world data,” she commented.
Session cochair Adam Finn, MD, PhD, said he has found it instructive to take a closer look at the U.K. data for the past several flu seasons.
“We’ve seen greater control of the epidemic in Scotland and Northern Ireland, where coverage in primary school kids was higher, in the 60%-70% area, and lower in England and Wales, where it was more like 50%. So we’re beginning to think that’s the kind of level of annual coverage in children we might need to suppress an epidemic. I think that’s a really important message that people should understand: We’re not looking for 95% coverage,” observed Dr. Finn, aprofessor of pediatrics at the University of Bristol (England).
Vaccine effectiveness will improve
Dr. Osterhaus predicted better times are coming in terms of vaccine effectiveness. Vaccine production times will become shorter as recombinant technologies replace the traditional lengthy chicken egg-based vaccine production; as a result, there will be less drift-associated mismatch. Improved surveillance, including the ability to follow strain mobility patterns and population-based antibody landscapes, are another important advance.
“We’ve always been looking at one side of the coin: the virus. Once or twice a year eminent gray people sitting together in Geneva at WHO decide which strains should be selected for the next vaccine. But if you know what antibodies are present in the population, this can be quite important information as well,” he said.
Dr. Nohynek reported receiving research funding from GlaxoSmithKline and Pfizer. The other speakers reported having no relevant financial conflicts of interest.
EXPERT ANALYSIS FROM ESPID 2018