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Delay predicting outcome in comatose cardiac arrest
ANAHEIM, CALIF. – Withdrawal of life-sustaining systemic therapies in comatose patients after out-of-hospital cardiac arrest as advised in current guidelines often occurs too early, resulting in the death of many patients who could potentially survive with good outcome, according to the results of NORCAST, the Norwegian Cardiorespiratory Arrest Study.
“The take-home message is to be patient and wait. Three days may be too early to make decisions on the patient,” Kjetil Sunde, MD, said in presenting the study findings at the Resuscitation Science Symposium held during the American Heart Association scientific sessions.
The European Resuscitation Council and European Society of Intensive Care Medicine have jointly recommended a prognostic algorithm in which a multimodal assessment is made on patients who are still comatose on day 3 after cardiac arrest. But this advice is based on expert opinion and has never been validated. This was the impetus for the prospective NORCAST study.
Current practice in the management of out-of-hospital cardiac arrest patients who are comatose upon hospital admission is to induce therapeutic hypothermia, with targeted temperature management to 33° C for 24 hours under deep sedation. The study hypothesis was that this strategy delays the time to awakening and that, as a consequence, the recommended prognostic tests that are usually done on day 3 after withdrawal of sedation are rendered insufficiently reliable. Thus, decisions to withdraw life-supporting therapies at that point will reduce the survival potential of this population, Dr. Sunde explained.
NORCAST was a prospective observational study that included 259 patients admitted to Oslo University Hospital in a comatose state after out-of-hospital cardiac arrest. In this unselected group, 81% had a cardiac cause for their arrest; the remainder had hypoxic arrest. All patients underwent therapeutic hypothermia, then a period of nonhypothermia followed by sedation withdrawal.
All of the widely used multimodal prognostic tests were ordered, including serial measurement of serum neuron-specific enolase; neurophysiologic testing using EEG and sensory-evoked potential readings obtained both during hypothermia and again at least 3 days after sedation withdrawal; a standardized clinical neurologic exam including assessment of brainstem reflexes and a Glasgow Coma Scale rating 3 days after sedation withdrawal; and a transcranial Doppler study and cerebral MRI on day 5-7. However, the treatment team was blinded to the results of these tests and was encouraged to delay withdrawal of life-supporting therapies as long as possible.
Key findings
Out of 259 patients who were comatose upon admission, 54% were alive at 6 months – and 91% of them had a CPC of 1 or 2.
The final tally at 6 months: 44% of patients were CPC 1, 5.5% were CPC 2, 4% were CPC 3, meaning severely disabled, and 46.5% were CPC 5, which is brain dead.
Withdrawal of life-supporting therapies occurred in 73 patients, or 28%, and 71% of those patients died, few of them in the early days.
Among patients with a CPC score of 1 or 2 at 6 months, only 20% were awake on day 1-3 following admission. Fifty-seven percent awoke on day 4-7, but importantly, 23% of patients with a good outcome at 6 months were not yet awake on day 8.
Three days after withdrawal of sedation, 49% of patients were rated as having a Glasgow Coma Scale score of 3-8, while 51% were Glasgow Coma Scale 9-15. Moreover, at that time 26% of patients with a good outcome as defined by a CPC of 1 or 2 at 6 months were still in a coma.
“So a lot of patients were still affected by their disease or by sedation at that point. That’s an important finding,” Dr. Sunde said.
Some prognostic tests were highly unreliable
A standout in poor performance was the widely utilized standard of a time to return of spontaneous circulation greater than 25 minutes as a predictor of poor cerebral outcome. In fact, it had a 34% false-positive rate.
“I think it’s really useless to use that. I would rather have return to spontaneous circulation after 40 minutes of good-quality CPR than not have it with 25 minutes of lesser-quality CPR,” he commented.
Similarly, a Glasgow Coma Scale score of 9 or less or a Glasgow Coma Scale-Motor score of 1-3 upon assessment 3 days after sedation withdrawal had false-positive rates of 30% and 34%, respectively.
During hypothermia, EEG abnormalities had a high false-positive rate, and sensory-evoked potential findings were difficult to interpret.
Predictors showing utility
Several clinical factors predicted poor cerebral outcome with low false-positive rates: Unwitnessed cardiac arrest had a false-positive rate of only 4%; initial presentation in asystole or with pulseless electrical activity had a false-positive rate of 6%; and no bystander CPR had a false-positive rate of 13%.
Abnormal sensory-evoked potential or EEG findings 3 days after sedation withdrawal had low false-positive rates as prognosticators of poor cerebral outcome. An EEG showing burst suppression or epileptiform activity had a “pretty good” false-positive rate of only 7%, Dr. Sunde noted. Bilaterally absent N20 sensory-evoked potential findings, while uncommon, had a false-positive rate of zero. A serum neuron-specific enolase level greater than 80 mcg/mL had a 3% false-positive rate, in sharp contrast to the previously recommended cutoff of more than 33 mcg/mL, which had an unacceptable 38% false-positive rate.
“We should avoid using single predictors in decision making and be patient, especially if we have a witnessed ventricular fibrillation with bystander CPR, independent of time to return of spontaneous circulation,” he concluded.
Dr. Sunde and his coinvestigators plan to present numerous further follow-up studies from NORCAST, including the results of comprehensive cognitive function testing 6-9 months after cardiac arrest in all survivors, coupled with interviews with their close relatives, as well as cognitive function and quality-of-life measurements 3-6 years after cardiac arrest along with interviews with relatives.
Several audience members rose to declare that they’ve been waiting for data such as this for a long time. Session chair Karl B. Kern, MD, professor of medicine at the University of Arizona, Tucson, and codirector of the University of Arizona Sarver Heart Center, commented, “We’ve been talking about whether 3 days is too early for a number of years, and clearly from your data it is. It was twice as long before most of them woke up.”
Dr. Sunde reported having no financial conflicts of interest regarding the NORCAST study, which was sponsored by Oslo University Hospital.
ANAHEIM, CALIF. – Withdrawal of life-sustaining systemic therapies in comatose patients after out-of-hospital cardiac arrest as advised in current guidelines often occurs too early, resulting in the death of many patients who could potentially survive with good outcome, according to the results of NORCAST, the Norwegian Cardiorespiratory Arrest Study.
“The take-home message is to be patient and wait. Three days may be too early to make decisions on the patient,” Kjetil Sunde, MD, said in presenting the study findings at the Resuscitation Science Symposium held during the American Heart Association scientific sessions.
The European Resuscitation Council and European Society of Intensive Care Medicine have jointly recommended a prognostic algorithm in which a multimodal assessment is made on patients who are still comatose on day 3 after cardiac arrest. But this advice is based on expert opinion and has never been validated. This was the impetus for the prospective NORCAST study.
Current practice in the management of out-of-hospital cardiac arrest patients who are comatose upon hospital admission is to induce therapeutic hypothermia, with targeted temperature management to 33° C for 24 hours under deep sedation. The study hypothesis was that this strategy delays the time to awakening and that, as a consequence, the recommended prognostic tests that are usually done on day 3 after withdrawal of sedation are rendered insufficiently reliable. Thus, decisions to withdraw life-supporting therapies at that point will reduce the survival potential of this population, Dr. Sunde explained.
NORCAST was a prospective observational study that included 259 patients admitted to Oslo University Hospital in a comatose state after out-of-hospital cardiac arrest. In this unselected group, 81% had a cardiac cause for their arrest; the remainder had hypoxic arrest. All patients underwent therapeutic hypothermia, then a period of nonhypothermia followed by sedation withdrawal.
All of the widely used multimodal prognostic tests were ordered, including serial measurement of serum neuron-specific enolase; neurophysiologic testing using EEG and sensory-evoked potential readings obtained both during hypothermia and again at least 3 days after sedation withdrawal; a standardized clinical neurologic exam including assessment of brainstem reflexes and a Glasgow Coma Scale rating 3 days after sedation withdrawal; and a transcranial Doppler study and cerebral MRI on day 5-7. However, the treatment team was blinded to the results of these tests and was encouraged to delay withdrawal of life-supporting therapies as long as possible.
Key findings
Out of 259 patients who were comatose upon admission, 54% were alive at 6 months – and 91% of them had a CPC of 1 or 2.
The final tally at 6 months: 44% of patients were CPC 1, 5.5% were CPC 2, 4% were CPC 3, meaning severely disabled, and 46.5% were CPC 5, which is brain dead.
Withdrawal of life-supporting therapies occurred in 73 patients, or 28%, and 71% of those patients died, few of them in the early days.
Among patients with a CPC score of 1 or 2 at 6 months, only 20% were awake on day 1-3 following admission. Fifty-seven percent awoke on day 4-7, but importantly, 23% of patients with a good outcome at 6 months were not yet awake on day 8.
Three days after withdrawal of sedation, 49% of patients were rated as having a Glasgow Coma Scale score of 3-8, while 51% were Glasgow Coma Scale 9-15. Moreover, at that time 26% of patients with a good outcome as defined by a CPC of 1 or 2 at 6 months were still in a coma.
“So a lot of patients were still affected by their disease or by sedation at that point. That’s an important finding,” Dr. Sunde said.
Some prognostic tests were highly unreliable
A standout in poor performance was the widely utilized standard of a time to return of spontaneous circulation greater than 25 minutes as a predictor of poor cerebral outcome. In fact, it had a 34% false-positive rate.
“I think it’s really useless to use that. I would rather have return to spontaneous circulation after 40 minutes of good-quality CPR than not have it with 25 minutes of lesser-quality CPR,” he commented.
Similarly, a Glasgow Coma Scale score of 9 or less or a Glasgow Coma Scale-Motor score of 1-3 upon assessment 3 days after sedation withdrawal had false-positive rates of 30% and 34%, respectively.
During hypothermia, EEG abnormalities had a high false-positive rate, and sensory-evoked potential findings were difficult to interpret.
Predictors showing utility
Several clinical factors predicted poor cerebral outcome with low false-positive rates: Unwitnessed cardiac arrest had a false-positive rate of only 4%; initial presentation in asystole or with pulseless electrical activity had a false-positive rate of 6%; and no bystander CPR had a false-positive rate of 13%.
Abnormal sensory-evoked potential or EEG findings 3 days after sedation withdrawal had low false-positive rates as prognosticators of poor cerebral outcome. An EEG showing burst suppression or epileptiform activity had a “pretty good” false-positive rate of only 7%, Dr. Sunde noted. Bilaterally absent N20 sensory-evoked potential findings, while uncommon, had a false-positive rate of zero. A serum neuron-specific enolase level greater than 80 mcg/mL had a 3% false-positive rate, in sharp contrast to the previously recommended cutoff of more than 33 mcg/mL, which had an unacceptable 38% false-positive rate.
“We should avoid using single predictors in decision making and be patient, especially if we have a witnessed ventricular fibrillation with bystander CPR, independent of time to return of spontaneous circulation,” he concluded.
Dr. Sunde and his coinvestigators plan to present numerous further follow-up studies from NORCAST, including the results of comprehensive cognitive function testing 6-9 months after cardiac arrest in all survivors, coupled with interviews with their close relatives, as well as cognitive function and quality-of-life measurements 3-6 years after cardiac arrest along with interviews with relatives.
Several audience members rose to declare that they’ve been waiting for data such as this for a long time. Session chair Karl B. Kern, MD, professor of medicine at the University of Arizona, Tucson, and codirector of the University of Arizona Sarver Heart Center, commented, “We’ve been talking about whether 3 days is too early for a number of years, and clearly from your data it is. It was twice as long before most of them woke up.”
Dr. Sunde reported having no financial conflicts of interest regarding the NORCAST study, which was sponsored by Oslo University Hospital.
ANAHEIM, CALIF. – Withdrawal of life-sustaining systemic therapies in comatose patients after out-of-hospital cardiac arrest as advised in current guidelines often occurs too early, resulting in the death of many patients who could potentially survive with good outcome, according to the results of NORCAST, the Norwegian Cardiorespiratory Arrest Study.
“The take-home message is to be patient and wait. Three days may be too early to make decisions on the patient,” Kjetil Sunde, MD, said in presenting the study findings at the Resuscitation Science Symposium held during the American Heart Association scientific sessions.
The European Resuscitation Council and European Society of Intensive Care Medicine have jointly recommended a prognostic algorithm in which a multimodal assessment is made on patients who are still comatose on day 3 after cardiac arrest. But this advice is based on expert opinion and has never been validated. This was the impetus for the prospective NORCAST study.
Current practice in the management of out-of-hospital cardiac arrest patients who are comatose upon hospital admission is to induce therapeutic hypothermia, with targeted temperature management to 33° C for 24 hours under deep sedation. The study hypothesis was that this strategy delays the time to awakening and that, as a consequence, the recommended prognostic tests that are usually done on day 3 after withdrawal of sedation are rendered insufficiently reliable. Thus, decisions to withdraw life-supporting therapies at that point will reduce the survival potential of this population, Dr. Sunde explained.
NORCAST was a prospective observational study that included 259 patients admitted to Oslo University Hospital in a comatose state after out-of-hospital cardiac arrest. In this unselected group, 81% had a cardiac cause for their arrest; the remainder had hypoxic arrest. All patients underwent therapeutic hypothermia, then a period of nonhypothermia followed by sedation withdrawal.
All of the widely used multimodal prognostic tests were ordered, including serial measurement of serum neuron-specific enolase; neurophysiologic testing using EEG and sensory-evoked potential readings obtained both during hypothermia and again at least 3 days after sedation withdrawal; a standardized clinical neurologic exam including assessment of brainstem reflexes and a Glasgow Coma Scale rating 3 days after sedation withdrawal; and a transcranial Doppler study and cerebral MRI on day 5-7. However, the treatment team was blinded to the results of these tests and was encouraged to delay withdrawal of life-supporting therapies as long as possible.
Key findings
Out of 259 patients who were comatose upon admission, 54% were alive at 6 months – and 91% of them had a CPC of 1 or 2.
The final tally at 6 months: 44% of patients were CPC 1, 5.5% were CPC 2, 4% were CPC 3, meaning severely disabled, and 46.5% were CPC 5, which is brain dead.
Withdrawal of life-supporting therapies occurred in 73 patients, or 28%, and 71% of those patients died, few of them in the early days.
Among patients with a CPC score of 1 or 2 at 6 months, only 20% were awake on day 1-3 following admission. Fifty-seven percent awoke on day 4-7, but importantly, 23% of patients with a good outcome at 6 months were not yet awake on day 8.
Three days after withdrawal of sedation, 49% of patients were rated as having a Glasgow Coma Scale score of 3-8, while 51% were Glasgow Coma Scale 9-15. Moreover, at that time 26% of patients with a good outcome as defined by a CPC of 1 or 2 at 6 months were still in a coma.
“So a lot of patients were still affected by their disease or by sedation at that point. That’s an important finding,” Dr. Sunde said.
Some prognostic tests were highly unreliable
A standout in poor performance was the widely utilized standard of a time to return of spontaneous circulation greater than 25 minutes as a predictor of poor cerebral outcome. In fact, it had a 34% false-positive rate.
“I think it’s really useless to use that. I would rather have return to spontaneous circulation after 40 minutes of good-quality CPR than not have it with 25 minutes of lesser-quality CPR,” he commented.
Similarly, a Glasgow Coma Scale score of 9 or less or a Glasgow Coma Scale-Motor score of 1-3 upon assessment 3 days after sedation withdrawal had false-positive rates of 30% and 34%, respectively.
During hypothermia, EEG abnormalities had a high false-positive rate, and sensory-evoked potential findings were difficult to interpret.
Predictors showing utility
Several clinical factors predicted poor cerebral outcome with low false-positive rates: Unwitnessed cardiac arrest had a false-positive rate of only 4%; initial presentation in asystole or with pulseless electrical activity had a false-positive rate of 6%; and no bystander CPR had a false-positive rate of 13%.
Abnormal sensory-evoked potential or EEG findings 3 days after sedation withdrawal had low false-positive rates as prognosticators of poor cerebral outcome. An EEG showing burst suppression or epileptiform activity had a “pretty good” false-positive rate of only 7%, Dr. Sunde noted. Bilaterally absent N20 sensory-evoked potential findings, while uncommon, had a false-positive rate of zero. A serum neuron-specific enolase level greater than 80 mcg/mL had a 3% false-positive rate, in sharp contrast to the previously recommended cutoff of more than 33 mcg/mL, which had an unacceptable 38% false-positive rate.
“We should avoid using single predictors in decision making and be patient, especially if we have a witnessed ventricular fibrillation with bystander CPR, independent of time to return of spontaneous circulation,” he concluded.
Dr. Sunde and his coinvestigators plan to present numerous further follow-up studies from NORCAST, including the results of comprehensive cognitive function testing 6-9 months after cardiac arrest in all survivors, coupled with interviews with their close relatives, as well as cognitive function and quality-of-life measurements 3-6 years after cardiac arrest along with interviews with relatives.
Several audience members rose to declare that they’ve been waiting for data such as this for a long time. Session chair Karl B. Kern, MD, professor of medicine at the University of Arizona, Tucson, and codirector of the University of Arizona Sarver Heart Center, commented, “We’ve been talking about whether 3 days is too early for a number of years, and clearly from your data it is. It was twice as long before most of them woke up.”
Dr. Sunde reported having no financial conflicts of interest regarding the NORCAST study, which was sponsored by Oslo University Hospital.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Patients with good cerebral function 6 months after admission in a comatose state stemming from out-of-hospital cardiac arrest awoke a mean of 6.2 days post cardiac arrest, far later than most prognostic assessments take place.
Data source: NORCAST, a prospective observational study, included 259 patients who were comatose upon hospital admission after out-of-hospital cardiac arrest.
Disclosures: NORCAST was sponsored by Oslo University Hospital. The presenter reported having no financial conflicts.
Topical tapinarof heads for phase 3 in atopic dermatitis and psoriasis
GENEVA – Tapinarof cream, a first-in-class topical nonsteroidal anti-inflammatory agent, successfully met its primary and secondary efficacy endpoints in a large international, phase 2, dose-ranging study and is moving on to a phase 3 trial for atopic dermatitis.
Tapinarof is a naturally derived compound whose therapeutic mechanism of action has recently been shown to involve activation of the aryl hydrocarbon receptor, Johnny Peppers, PhD, said at the annual congress of the European Academy of Dermatology and Venereology.
GlaxoSmithKline is also developing tapinarof cream for mild to moderate plaque psoriasis, a disease that hasn’t seen a novel nonsteroidal topical therapy approved in more than 25 years. After a strong showing in a phase 2 study, a phase 3 trial in psoriasis is now scheduled.
Dr. Peppers presented a phase 2, double-blind, vehicle-controlled randomized trial including 247 adolescent and adult patients with mild, moderate, or severe atopic dermatitis. The six study arms were tapinarof cream at 1% or 0.5% or vehicle, self-administered at a frequency of either once or twice daily. Participants had a mean baseline Investigator’s Global Assessment (IGA) score of 3.1 on a 5-point scale, an Eczema Area and Severity Index (EASI) score of 9.8-13.1 in the various study arms, and a 5.1-5.8 score on an 11-point self-rated itch severity score recorded weekly.
“The 1% tapinarof arm showed higher efficacy and had a quicker onset of action than the 0.5% arm or vehicle,” he reported.
Indeed, the 1% tapinarof cream groups separated from controls in terms of the efficacy endpoints as early as week 1, with the maximum treatment effect seen at weeks 8-12, Dr. Peppers added.
The primary endpoint was a composite requiring both an IGA of 0 or 1, meaning clear or almost clear, at 12 weeks, along with a minimum 2-point improvement on the IGA from baseline to week 12. This was achieved in 46% of patients on tapinarof cream 1% applied once daily, 53% of those on tapinarof cream 1% twice a day, and in about 25% of controls on vehicle.
Eighty percent of subjects who achieved the primary endpoint maintained that level of treatment effect 2 weeks post treatment, and 70% still held their treatment response 4 weeks after they stopped using the medication.
There were two secondary endpoints. One was achievement of a 75% improvement from baseline on EASI scores (EASI-75) response. This was seen in 51% of the tapinarof 1% once-daily group, 60% on twice a day therapy, and 26% and 25% of controls. Onset of action was fastest with tapinarof cream 1% once daily.
The other secondary endpoint was at least a 3-point improvement from baseline to week 4 on the 11-point self-rated itch scale. This was achieved by 37% and 33% of patients on tapinarof cream 1% once daily and twice daily, respectively, a success rate twice that seen in controls.
Four percent of patients on tapinarof cream and 7% on vehicle discontinued the trial because of treatment-emergent adverse events. There were no serious treatment-related adverse events. The most frequent adverse events associated with tapinarof were folliculitis and contact dermatitis. The phase 3 trial will incorporate patch testing for contact dermatitis.
“We are very excited about this program. This will be the first topical therapy – if we’re able to achieve treatment success and ultimately regulatory approval – that would be able to treat both psoriasis and atopic dermatitis since topical steroids,” Dr. Peppers said.
The study was funded by GlaxoSmithKline and presented by a company employee.
bjancin@frontlinemedcom.com
GENEVA – Tapinarof cream, a first-in-class topical nonsteroidal anti-inflammatory agent, successfully met its primary and secondary efficacy endpoints in a large international, phase 2, dose-ranging study and is moving on to a phase 3 trial for atopic dermatitis.
Tapinarof is a naturally derived compound whose therapeutic mechanism of action has recently been shown to involve activation of the aryl hydrocarbon receptor, Johnny Peppers, PhD, said at the annual congress of the European Academy of Dermatology and Venereology.
GlaxoSmithKline is also developing tapinarof cream for mild to moderate plaque psoriasis, a disease that hasn’t seen a novel nonsteroidal topical therapy approved in more than 25 years. After a strong showing in a phase 2 study, a phase 3 trial in psoriasis is now scheduled.
Dr. Peppers presented a phase 2, double-blind, vehicle-controlled randomized trial including 247 adolescent and adult patients with mild, moderate, or severe atopic dermatitis. The six study arms were tapinarof cream at 1% or 0.5% or vehicle, self-administered at a frequency of either once or twice daily. Participants had a mean baseline Investigator’s Global Assessment (IGA) score of 3.1 on a 5-point scale, an Eczema Area and Severity Index (EASI) score of 9.8-13.1 in the various study arms, and a 5.1-5.8 score on an 11-point self-rated itch severity score recorded weekly.
“The 1% tapinarof arm showed higher efficacy and had a quicker onset of action than the 0.5% arm or vehicle,” he reported.
Indeed, the 1% tapinarof cream groups separated from controls in terms of the efficacy endpoints as early as week 1, with the maximum treatment effect seen at weeks 8-12, Dr. Peppers added.
The primary endpoint was a composite requiring both an IGA of 0 or 1, meaning clear or almost clear, at 12 weeks, along with a minimum 2-point improvement on the IGA from baseline to week 12. This was achieved in 46% of patients on tapinarof cream 1% applied once daily, 53% of those on tapinarof cream 1% twice a day, and in about 25% of controls on vehicle.
Eighty percent of subjects who achieved the primary endpoint maintained that level of treatment effect 2 weeks post treatment, and 70% still held their treatment response 4 weeks after they stopped using the medication.
There were two secondary endpoints. One was achievement of a 75% improvement from baseline on EASI scores (EASI-75) response. This was seen in 51% of the tapinarof 1% once-daily group, 60% on twice a day therapy, and 26% and 25% of controls. Onset of action was fastest with tapinarof cream 1% once daily.
The other secondary endpoint was at least a 3-point improvement from baseline to week 4 on the 11-point self-rated itch scale. This was achieved by 37% and 33% of patients on tapinarof cream 1% once daily and twice daily, respectively, a success rate twice that seen in controls.
Four percent of patients on tapinarof cream and 7% on vehicle discontinued the trial because of treatment-emergent adverse events. There were no serious treatment-related adverse events. The most frequent adverse events associated with tapinarof were folliculitis and contact dermatitis. The phase 3 trial will incorporate patch testing for contact dermatitis.
“We are very excited about this program. This will be the first topical therapy – if we’re able to achieve treatment success and ultimately regulatory approval – that would be able to treat both psoriasis and atopic dermatitis since topical steroids,” Dr. Peppers said.
The study was funded by GlaxoSmithKline and presented by a company employee.
bjancin@frontlinemedcom.com
GENEVA – Tapinarof cream, a first-in-class topical nonsteroidal anti-inflammatory agent, successfully met its primary and secondary efficacy endpoints in a large international, phase 2, dose-ranging study and is moving on to a phase 3 trial for atopic dermatitis.
Tapinarof is a naturally derived compound whose therapeutic mechanism of action has recently been shown to involve activation of the aryl hydrocarbon receptor, Johnny Peppers, PhD, said at the annual congress of the European Academy of Dermatology and Venereology.
GlaxoSmithKline is also developing tapinarof cream for mild to moderate plaque psoriasis, a disease that hasn’t seen a novel nonsteroidal topical therapy approved in more than 25 years. After a strong showing in a phase 2 study, a phase 3 trial in psoriasis is now scheduled.
Dr. Peppers presented a phase 2, double-blind, vehicle-controlled randomized trial including 247 adolescent and adult patients with mild, moderate, or severe atopic dermatitis. The six study arms were tapinarof cream at 1% or 0.5% or vehicle, self-administered at a frequency of either once or twice daily. Participants had a mean baseline Investigator’s Global Assessment (IGA) score of 3.1 on a 5-point scale, an Eczema Area and Severity Index (EASI) score of 9.8-13.1 in the various study arms, and a 5.1-5.8 score on an 11-point self-rated itch severity score recorded weekly.
“The 1% tapinarof arm showed higher efficacy and had a quicker onset of action than the 0.5% arm or vehicle,” he reported.
Indeed, the 1% tapinarof cream groups separated from controls in terms of the efficacy endpoints as early as week 1, with the maximum treatment effect seen at weeks 8-12, Dr. Peppers added.
The primary endpoint was a composite requiring both an IGA of 0 or 1, meaning clear or almost clear, at 12 weeks, along with a minimum 2-point improvement on the IGA from baseline to week 12. This was achieved in 46% of patients on tapinarof cream 1% applied once daily, 53% of those on tapinarof cream 1% twice a day, and in about 25% of controls on vehicle.
Eighty percent of subjects who achieved the primary endpoint maintained that level of treatment effect 2 weeks post treatment, and 70% still held their treatment response 4 weeks after they stopped using the medication.
There were two secondary endpoints. One was achievement of a 75% improvement from baseline on EASI scores (EASI-75) response. This was seen in 51% of the tapinarof 1% once-daily group, 60% on twice a day therapy, and 26% and 25% of controls. Onset of action was fastest with tapinarof cream 1% once daily.
The other secondary endpoint was at least a 3-point improvement from baseline to week 4 on the 11-point self-rated itch scale. This was achieved by 37% and 33% of patients on tapinarof cream 1% once daily and twice daily, respectively, a success rate twice that seen in controls.
Four percent of patients on tapinarof cream and 7% on vehicle discontinued the trial because of treatment-emergent adverse events. There were no serious treatment-related adverse events. The most frequent adverse events associated with tapinarof were folliculitis and contact dermatitis. The phase 3 trial will incorporate patch testing for contact dermatitis.
“We are very excited about this program. This will be the first topical therapy – if we’re able to achieve treatment success and ultimately regulatory approval – that would be able to treat both psoriasis and atopic dermatitis since topical steroids,” Dr. Peppers said.
The study was funded by GlaxoSmithKline and presented by a company employee.
bjancin@frontlinemedcom.com
AT THE EADV CONGRESS
Key clinical point:
Major finding: Forty-six percent of atopic dermatitis patients on tapinarof cream 1% applied once daily, and 53% of atopic dermatitis patients on tapinarof cream applied twice daily, met the primary study endpoint, rates twice those in vehicle-treated controls.
Data source: A phase 2, double-blind, vehicle-controlled, international 12-week clinical trial in 247 adolescents and adults with moderate to severe atopic dermatitis.
Disclosures: The study was funded by GlaxoSmithKline and presented by a company employee.
Adjunctive minocycline for schizophrenia found beneficial
PARIS – A report that adjunctive minocycline was found safe and effective for treatment of schizophrenia must be considered one of the year’s highlights in the field of psychosis, Pascal Steullet, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
The report came in the form of a meta-analysis conducted by investigators in China and Australia. This was the largest meta-analysis looking at the topic to date, and the only one to include a search of the Chinese language database, which provided three of the eight randomized, placebo-controlled clinical trials that were examined. Seven of the eight randomized trials were double-blind and deemed high quality by widely used criteria, including the Jadad scale and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology, noted Dr. Steullet, a neuroscientist at the University of Lausanne (Switzerland).
The primary outcome was change in the PANSS (Positive and Negative Syndrome Scale) total psychopathology score, and the positive, negative, and general symptom subscale scores.
The biggest benefit was on PANSS negative symptoms. Minocycline brought significantly greater improvement in this domain than placebo, with a standard mean difference (SMD) of –0.69 and a P value of less than .00001 (Eur Psychopharmacol. 2017 Jan;27[1]:8-18).
“That’s quite a good effect size,” Dr. Steullet commented.
The benefit on PANSS positive symptoms, while statistically significant, was far less robust, with an SMD of –0.22 in favor of minocycline.
The PANSS total psychopathology score favored minocycline with an SMD of –0.64, which Dr. Steullet again deemed “a quite significant effect size.” The PANSS general symptom score also showed a significant benefit in favor of minocycline, with an SMD of –0.45.
Among various secondary endpoints that were evaluated: A significant benefit was found favoring minocycline on the Clinical Global Impressions scale (SMD of –0.53) and the Abnormal Involuntary Movement Scale (SMD of –0.56). However, no differences were found between the minocycline and control groups on the Global Assessment of Functioning Scale, the Extrapyramidal Symptom Rating Scale, or the Calgary Depression Scale for Schizophrenia.
Although the average dose of minocycline prescribed in the eight trials was 171.9 mg/day, dosing strategies varied widely from trial to trial, and the investigators concluded that future studies are needed in order to pin down the optimal dosing and duration.
There was no increase in adverse drug reactions in the minocycline-treated group.
Neurocognitive function as assessed by the MATRICS Consensus Cognitive Battery showed no differences between the minocycline and placebo groups in working memory, problem solving, attention/vigilance, or other elements.
Proposed mechanisms of minocycline’s benefit as adjunctive therapy alongside antipsychotics for schizophrenia include the antimicrobial’s good CNS penetration and its anti-inflammatory effects, which could reduce neuroinflammation, dampen activated microglia, and enhance glutamate neurotransmitters.
The meta-analysis was supported by the University of Macau. Its authors reported having no financial conflicts of interest. Dr. Steullet, who was not involved in the work, also reported having no financial conflicts of interest.
PARIS – A report that adjunctive minocycline was found safe and effective for treatment of schizophrenia must be considered one of the year’s highlights in the field of psychosis, Pascal Steullet, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
The report came in the form of a meta-analysis conducted by investigators in China and Australia. This was the largest meta-analysis looking at the topic to date, and the only one to include a search of the Chinese language database, which provided three of the eight randomized, placebo-controlled clinical trials that were examined. Seven of the eight randomized trials were double-blind and deemed high quality by widely used criteria, including the Jadad scale and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology, noted Dr. Steullet, a neuroscientist at the University of Lausanne (Switzerland).
The primary outcome was change in the PANSS (Positive and Negative Syndrome Scale) total psychopathology score, and the positive, negative, and general symptom subscale scores.
The biggest benefit was on PANSS negative symptoms. Minocycline brought significantly greater improvement in this domain than placebo, with a standard mean difference (SMD) of –0.69 and a P value of less than .00001 (Eur Psychopharmacol. 2017 Jan;27[1]:8-18).
“That’s quite a good effect size,” Dr. Steullet commented.
The benefit on PANSS positive symptoms, while statistically significant, was far less robust, with an SMD of –0.22 in favor of minocycline.
The PANSS total psychopathology score favored minocycline with an SMD of –0.64, which Dr. Steullet again deemed “a quite significant effect size.” The PANSS general symptom score also showed a significant benefit in favor of minocycline, with an SMD of –0.45.
Among various secondary endpoints that were evaluated: A significant benefit was found favoring minocycline on the Clinical Global Impressions scale (SMD of –0.53) and the Abnormal Involuntary Movement Scale (SMD of –0.56). However, no differences were found between the minocycline and control groups on the Global Assessment of Functioning Scale, the Extrapyramidal Symptom Rating Scale, or the Calgary Depression Scale for Schizophrenia.
Although the average dose of minocycline prescribed in the eight trials was 171.9 mg/day, dosing strategies varied widely from trial to trial, and the investigators concluded that future studies are needed in order to pin down the optimal dosing and duration.
There was no increase in adverse drug reactions in the minocycline-treated group.
Neurocognitive function as assessed by the MATRICS Consensus Cognitive Battery showed no differences between the minocycline and placebo groups in working memory, problem solving, attention/vigilance, or other elements.
Proposed mechanisms of minocycline’s benefit as adjunctive therapy alongside antipsychotics for schizophrenia include the antimicrobial’s good CNS penetration and its anti-inflammatory effects, which could reduce neuroinflammation, dampen activated microglia, and enhance glutamate neurotransmitters.
The meta-analysis was supported by the University of Macau. Its authors reported having no financial conflicts of interest. Dr. Steullet, who was not involved in the work, also reported having no financial conflicts of interest.
PARIS – A report that adjunctive minocycline was found safe and effective for treatment of schizophrenia must be considered one of the year’s highlights in the field of psychosis, Pascal Steullet, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
The report came in the form of a meta-analysis conducted by investigators in China and Australia. This was the largest meta-analysis looking at the topic to date, and the only one to include a search of the Chinese language database, which provided three of the eight randomized, placebo-controlled clinical trials that were examined. Seven of the eight randomized trials were double-blind and deemed high quality by widely used criteria, including the Jadad scale and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology, noted Dr. Steullet, a neuroscientist at the University of Lausanne (Switzerland).
The primary outcome was change in the PANSS (Positive and Negative Syndrome Scale) total psychopathology score, and the positive, negative, and general symptom subscale scores.
The biggest benefit was on PANSS negative symptoms. Minocycline brought significantly greater improvement in this domain than placebo, with a standard mean difference (SMD) of –0.69 and a P value of less than .00001 (Eur Psychopharmacol. 2017 Jan;27[1]:8-18).
“That’s quite a good effect size,” Dr. Steullet commented.
The benefit on PANSS positive symptoms, while statistically significant, was far less robust, with an SMD of –0.22 in favor of minocycline.
The PANSS total psychopathology score favored minocycline with an SMD of –0.64, which Dr. Steullet again deemed “a quite significant effect size.” The PANSS general symptom score also showed a significant benefit in favor of minocycline, with an SMD of –0.45.
Among various secondary endpoints that were evaluated: A significant benefit was found favoring minocycline on the Clinical Global Impressions scale (SMD of –0.53) and the Abnormal Involuntary Movement Scale (SMD of –0.56). However, no differences were found between the minocycline and control groups on the Global Assessment of Functioning Scale, the Extrapyramidal Symptom Rating Scale, or the Calgary Depression Scale for Schizophrenia.
Although the average dose of minocycline prescribed in the eight trials was 171.9 mg/day, dosing strategies varied widely from trial to trial, and the investigators concluded that future studies are needed in order to pin down the optimal dosing and duration.
There was no increase in adverse drug reactions in the minocycline-treated group.
Neurocognitive function as assessed by the MATRICS Consensus Cognitive Battery showed no differences between the minocycline and placebo groups in working memory, problem solving, attention/vigilance, or other elements.
Proposed mechanisms of minocycline’s benefit as adjunctive therapy alongside antipsychotics for schizophrenia include the antimicrobial’s good CNS penetration and its anti-inflammatory effects, which could reduce neuroinflammation, dampen activated microglia, and enhance glutamate neurotransmitters.
The meta-analysis was supported by the University of Macau. Its authors reported having no financial conflicts of interest. Dr. Steullet, who was not involved in the work, also reported having no financial conflicts of interest.
EXPERT ANALYSIS FROM THE ECNP CONGRESS
Ustekinumab may reduce risk of nonmelanoma skin cancer
GENEVA – Ustekinumab therapy appears to protect psoriasis patients against nonmelanoma skin cancer (NMSC), according to a new analysis from the PSOLAR registry.
Compared with psoriasis patients on methotrexate, the risk of developing on-treatment NMSC was lower among patients on the interleukin-12-/23 inhibitor ustekinumab (Stelara) and those on the three tumor necrosis factor (TNF) inhibitors included in the PSOLAR registry – infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). The lower risk was statistically significant only for ustekinumab, although there was a favorable trend with the TNF inhibitors showing a 19% relative risk reduction, Bhaskar Srivastava, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
PSOLAR (Psoriasis Longitudinal Assessment and Registry) is an ongoing international prospective observational study evaluating long-term safety and clinical outcomes in psoriasis patients eligible for systemic therapies. The study is now fully enrolled, with 12,090 psoriasis patients and 48,870 patient-years of follow-up and climbing, noted Dr. Srivastava, an employee of Janssen Scientific Affairs, Spring House, Pa.
This analysis focused on 6,782 PSOLAR participants with a mean 18-year history of psoriasis and no history of NMSC at enrollment: 2,623 patients on ustekinumab with 7,900 patient-years of prospective follow-up, 3,727 on a TNF inhibitor with 10,580 patient-years of follow-up, and 432 controls on methotrexate with 781 patient-years of follow-up.
Patients on a biologic were significantly younger, with a mean age of 46.7 years, versus 53.6 years for those on methotrexate. Rates of past or current smoking were similar, in the 55%-60% range, regardless of which systemic agent patients were using.
The crude unadjusted incidence rate for NMSC among all patients on a biologic was 0.33 cancers/100 patient-years, compared with 1.41/100 patient-years for psoriasis patients on methotrexate.
Patients on ustekinumab had an NMSC incidence rate of 0.19/100 patient-years, with a basal cell carcinoma rate of 0.13/100 patient-years and a squamous cell carcinoma rate of 0.06/100 patient-years. Psoriasis patients on a TNF inhibitor had an NMSC incidence rate of 0.43/100 patient-years, with a basal cell carcinoma rate of 0.26/100 patient-years and a squamous cell carcinoma rate of 0.17/100 patient-years.
In a multivariate analysis adjusted for age, sex, race, location, duration of psoriasis, smoking, prior malignancy, skin type, and history of treatment with cyclosporine, methotrexate, other systemic agents, or phototherapy, patients taking ustekinumab had a statistically significant 65% reduction in the risk of NMSC compared with patients on methotrexate and a 74% relative risk reduction for basal cell carcinoma; however, the squamous cell carcinoma risk in the two patient groups was similar.
Dr. Srivastava said the PSOLAR data shouldn’t be taken as the final word regarding NMSC risk and the use of biologics. He noted that psoriasis itself is associated with an increased risk of NMSC. And methotrexate, which was used as the reference standard in this analysis, may alter the risk of NMSC.
“Overall, these results require further validation in psoriasis populations with larger numbers of exposed patients,” he said.
The PSOLAR registry is funded by Janssen, where Dr. Srivastava is employed.
GENEVA – Ustekinumab therapy appears to protect psoriasis patients against nonmelanoma skin cancer (NMSC), according to a new analysis from the PSOLAR registry.
Compared with psoriasis patients on methotrexate, the risk of developing on-treatment NMSC was lower among patients on the interleukin-12-/23 inhibitor ustekinumab (Stelara) and those on the three tumor necrosis factor (TNF) inhibitors included in the PSOLAR registry – infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). The lower risk was statistically significant only for ustekinumab, although there was a favorable trend with the TNF inhibitors showing a 19% relative risk reduction, Bhaskar Srivastava, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
PSOLAR (Psoriasis Longitudinal Assessment and Registry) is an ongoing international prospective observational study evaluating long-term safety and clinical outcomes in psoriasis patients eligible for systemic therapies. The study is now fully enrolled, with 12,090 psoriasis patients and 48,870 patient-years of follow-up and climbing, noted Dr. Srivastava, an employee of Janssen Scientific Affairs, Spring House, Pa.
This analysis focused on 6,782 PSOLAR participants with a mean 18-year history of psoriasis and no history of NMSC at enrollment: 2,623 patients on ustekinumab with 7,900 patient-years of prospective follow-up, 3,727 on a TNF inhibitor with 10,580 patient-years of follow-up, and 432 controls on methotrexate with 781 patient-years of follow-up.
Patients on a biologic were significantly younger, with a mean age of 46.7 years, versus 53.6 years for those on methotrexate. Rates of past or current smoking were similar, in the 55%-60% range, regardless of which systemic agent patients were using.
The crude unadjusted incidence rate for NMSC among all patients on a biologic was 0.33 cancers/100 patient-years, compared with 1.41/100 patient-years for psoriasis patients on methotrexate.
Patients on ustekinumab had an NMSC incidence rate of 0.19/100 patient-years, with a basal cell carcinoma rate of 0.13/100 patient-years and a squamous cell carcinoma rate of 0.06/100 patient-years. Psoriasis patients on a TNF inhibitor had an NMSC incidence rate of 0.43/100 patient-years, with a basal cell carcinoma rate of 0.26/100 patient-years and a squamous cell carcinoma rate of 0.17/100 patient-years.
In a multivariate analysis adjusted for age, sex, race, location, duration of psoriasis, smoking, prior malignancy, skin type, and history of treatment with cyclosporine, methotrexate, other systemic agents, or phototherapy, patients taking ustekinumab had a statistically significant 65% reduction in the risk of NMSC compared with patients on methotrexate and a 74% relative risk reduction for basal cell carcinoma; however, the squamous cell carcinoma risk in the two patient groups was similar.
Dr. Srivastava said the PSOLAR data shouldn’t be taken as the final word regarding NMSC risk and the use of biologics. He noted that psoriasis itself is associated with an increased risk of NMSC. And methotrexate, which was used as the reference standard in this analysis, may alter the risk of NMSC.
“Overall, these results require further validation in psoriasis populations with larger numbers of exposed patients,” he said.
The PSOLAR registry is funded by Janssen, where Dr. Srivastava is employed.
GENEVA – Ustekinumab therapy appears to protect psoriasis patients against nonmelanoma skin cancer (NMSC), according to a new analysis from the PSOLAR registry.
Compared with psoriasis patients on methotrexate, the risk of developing on-treatment NMSC was lower among patients on the interleukin-12-/23 inhibitor ustekinumab (Stelara) and those on the three tumor necrosis factor (TNF) inhibitors included in the PSOLAR registry – infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). The lower risk was statistically significant only for ustekinumab, although there was a favorable trend with the TNF inhibitors showing a 19% relative risk reduction, Bhaskar Srivastava, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
PSOLAR (Psoriasis Longitudinal Assessment and Registry) is an ongoing international prospective observational study evaluating long-term safety and clinical outcomes in psoriasis patients eligible for systemic therapies. The study is now fully enrolled, with 12,090 psoriasis patients and 48,870 patient-years of follow-up and climbing, noted Dr. Srivastava, an employee of Janssen Scientific Affairs, Spring House, Pa.
This analysis focused on 6,782 PSOLAR participants with a mean 18-year history of psoriasis and no history of NMSC at enrollment: 2,623 patients on ustekinumab with 7,900 patient-years of prospective follow-up, 3,727 on a TNF inhibitor with 10,580 patient-years of follow-up, and 432 controls on methotrexate with 781 patient-years of follow-up.
Patients on a biologic were significantly younger, with a mean age of 46.7 years, versus 53.6 years for those on methotrexate. Rates of past or current smoking were similar, in the 55%-60% range, regardless of which systemic agent patients were using.
The crude unadjusted incidence rate for NMSC among all patients on a biologic was 0.33 cancers/100 patient-years, compared with 1.41/100 patient-years for psoriasis patients on methotrexate.
Patients on ustekinumab had an NMSC incidence rate of 0.19/100 patient-years, with a basal cell carcinoma rate of 0.13/100 patient-years and a squamous cell carcinoma rate of 0.06/100 patient-years. Psoriasis patients on a TNF inhibitor had an NMSC incidence rate of 0.43/100 patient-years, with a basal cell carcinoma rate of 0.26/100 patient-years and a squamous cell carcinoma rate of 0.17/100 patient-years.
In a multivariate analysis adjusted for age, sex, race, location, duration of psoriasis, smoking, prior malignancy, skin type, and history of treatment with cyclosporine, methotrexate, other systemic agents, or phototherapy, patients taking ustekinumab had a statistically significant 65% reduction in the risk of NMSC compared with patients on methotrexate and a 74% relative risk reduction for basal cell carcinoma; however, the squamous cell carcinoma risk in the two patient groups was similar.
Dr. Srivastava said the PSOLAR data shouldn’t be taken as the final word regarding NMSC risk and the use of biologics. He noted that psoriasis itself is associated with an increased risk of NMSC. And methotrexate, which was used as the reference standard in this analysis, may alter the risk of NMSC.
“Overall, these results require further validation in psoriasis populations with larger numbers of exposed patients,” he said.
The PSOLAR registry is funded by Janssen, where Dr. Srivastava is employed.
AT THE EADV CONGRESS
Key clinical point:
Major finding: Psoriasis patients on ustekinumab had an adjusted 65% reduction in the risk of developing nonmelanoma skin cancer compared with patients on methotrexate.
Data source: An analysis of 6,782 psoriasis patients participating in an international prospective observational registry evaluating the long-term safety and clinical outcomes of systemic therapies.
Disclosures: The PSOLAR registry is funded by ustekinumab manufacturer Janssen; the study presenter is a company employee.
Nemolizumab continues to crush itch in 64-week atopic dermatitis study
GENEVA – Nemolizumab, a humanized monoclonal antibody that inhibits interleukin-31 signaling, maintained its early dramatic antipruritic effect in patients with moderate to severe atopic dermatitis (AD) throughout a year-long unblinded extension of a large, high-profile, 12-week, phase 2 randomized trial, Thomas Ruzicka, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
In contrast, the 52-week extension study also showed the improvement in the dermatitis aspect of AD as measured by Eczema Area and Severity Index (EASI) scores was more gradual and less robust.
The study, 64 weeks in total, also demonstrated that what really matters to patients with moderate or severe AD is relief from the itch. Scores on the Dermatology Life Quality Index showed marked improvement even if their improvement in EASI scores was suboptimal.
“The dermatitis scores improved. But the most concerning symptom to patients is the pruritus; that’s what worsens their quality of life. And this improves dramatically very early in the course of the study,” Dr. Ruzicka explained. “If they drop their itch they are very happy. They don’t care about the redness of the skin so much as the pruritus. This is what really bothers them, as has been shown in epidemiologic studies.”
The original 12-week, phase 2, randomized, double-blind, dose-ranging trial drew extensive attention because it demonstrated convincingly for the first time that the inflammatory cytokine interleukin-31 plays a key role in the pathobiology of AD by promoting skin barrier dysfunction, pruritus, and the inflammatory response in AD – and that a biologic agent, nemolizumab, could inhibit those disease mechanisms (N Engl J Med. 2017 Mar 2;376[9]:826-35).
At a dose of 0.5 mg/kg administered by subcutaneous injection every 4 weeks, nemolizumab, a humanized monoclonal antibody directed against interleukin-31 receptor A, reduced scores on the pruritus visual-analogue scale by 60% as early as 4 weeks and maintained that effect through 12 weeks. At that point, the double-blind study ended and the 52-week extension began. Patients on nemolizumab in the double-blind phase stayed on the same dosage for the extension, while those who’d been on placebo were switched to nemolizumab at 0.1, 0.5, or 2.0 mg/kg every 4 weeks.
A total of 211 patients with moderate to severe AD inadequately controlled by topical therapies enrolled in the extension study. The combined 64-week experience convinced investigators and the sponsor, Chugai Pharmaceutical, that 0.5 mg/kg every 4 weeks is the optimal dose to take forward into planned advanced-stage clinical trials.
“At this dosage the IL-31 receptor is saturated, so higher dosages aren’t needed,” according to Dr. Ruzicka.
By week 64, patients in the 0.5-mg/kg arm of the study showed further gradual improvement in their pruritus visual-analogue score, from a 60% reduction from baseline at 12 weeks to close to an 80% reduction at week 64.
Roughly half of nemolizumab-treated patients achieved an EASI-50 response within the first 4 weeks of the double-blind phase of the study and stayed in that response zone throughout the extension study.
The EASI-75 and -90 responses followed a pattern different from EASI-50. Patients didn’t leap to those more robust levels of response early and then plateau. Instead, the EASI-75 and -90 responses were achieved via a gradual climb in efficacy throughout the study, such that by week 64 roughly 35%-40% of patients on the various nemolizumab dosages had reached EASI-75.
In the extension study, patients were permitted to use a mild topical steroid or topical calcineurin inhibitor as needed, and a potent or very potent topical steroid as rescue medication. Roughly half of participants resorted to any topical steroid at least once during the 64 months. An important new observation gleaned in the long-term study was that the patients who did use topical steroids were twice as likely to reach an EASI 75 response.
Roughly 20% of patients on the three highest dosages of nemolizumab achieved a static Investigator’s Global Assessment score of 0 or 1, meaning clear or almost clear, by week 64.
Scores on the Dermatology Life Quality Index fell steadily over the course of 64 weeks, from a baseline of about 16 to 5 at study’s close.
The side effect profile of nemolizumab was essentially the same as seen in the placebo arm during the double-blind phase. About one-quarter of patients experienced nasopharyngitis over the course of 64 weeks of treatment. A similar fraction reported exacerbations of their atopic dermatitis; however, these events were front-loaded in the first weeks of the initial double-blind study phase and appeared to have been triggered by the drug washout period prior to the patients’ receiving the first dose of nemolizumab, according to Dr. Ruzicka. No new safety signals emerged during the additional 52 weeks of treatment.
The study was funded by Chugai. Dr. Ruzicka reported serving as a paid company adviser.
GENEVA – Nemolizumab, a humanized monoclonal antibody that inhibits interleukin-31 signaling, maintained its early dramatic antipruritic effect in patients with moderate to severe atopic dermatitis (AD) throughout a year-long unblinded extension of a large, high-profile, 12-week, phase 2 randomized trial, Thomas Ruzicka, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
In contrast, the 52-week extension study also showed the improvement in the dermatitis aspect of AD as measured by Eczema Area and Severity Index (EASI) scores was more gradual and less robust.
The study, 64 weeks in total, also demonstrated that what really matters to patients with moderate or severe AD is relief from the itch. Scores on the Dermatology Life Quality Index showed marked improvement even if their improvement in EASI scores was suboptimal.
“The dermatitis scores improved. But the most concerning symptom to patients is the pruritus; that’s what worsens their quality of life. And this improves dramatically very early in the course of the study,” Dr. Ruzicka explained. “If they drop their itch they are very happy. They don’t care about the redness of the skin so much as the pruritus. This is what really bothers them, as has been shown in epidemiologic studies.”
The original 12-week, phase 2, randomized, double-blind, dose-ranging trial drew extensive attention because it demonstrated convincingly for the first time that the inflammatory cytokine interleukin-31 plays a key role in the pathobiology of AD by promoting skin barrier dysfunction, pruritus, and the inflammatory response in AD – and that a biologic agent, nemolizumab, could inhibit those disease mechanisms (N Engl J Med. 2017 Mar 2;376[9]:826-35).
At a dose of 0.5 mg/kg administered by subcutaneous injection every 4 weeks, nemolizumab, a humanized monoclonal antibody directed against interleukin-31 receptor A, reduced scores on the pruritus visual-analogue scale by 60% as early as 4 weeks and maintained that effect through 12 weeks. At that point, the double-blind study ended and the 52-week extension began. Patients on nemolizumab in the double-blind phase stayed on the same dosage for the extension, while those who’d been on placebo were switched to nemolizumab at 0.1, 0.5, or 2.0 mg/kg every 4 weeks.
A total of 211 patients with moderate to severe AD inadequately controlled by topical therapies enrolled in the extension study. The combined 64-week experience convinced investigators and the sponsor, Chugai Pharmaceutical, that 0.5 mg/kg every 4 weeks is the optimal dose to take forward into planned advanced-stage clinical trials.
“At this dosage the IL-31 receptor is saturated, so higher dosages aren’t needed,” according to Dr. Ruzicka.
By week 64, patients in the 0.5-mg/kg arm of the study showed further gradual improvement in their pruritus visual-analogue score, from a 60% reduction from baseline at 12 weeks to close to an 80% reduction at week 64.
Roughly half of nemolizumab-treated patients achieved an EASI-50 response within the first 4 weeks of the double-blind phase of the study and stayed in that response zone throughout the extension study.
The EASI-75 and -90 responses followed a pattern different from EASI-50. Patients didn’t leap to those more robust levels of response early and then plateau. Instead, the EASI-75 and -90 responses were achieved via a gradual climb in efficacy throughout the study, such that by week 64 roughly 35%-40% of patients on the various nemolizumab dosages had reached EASI-75.
In the extension study, patients were permitted to use a mild topical steroid or topical calcineurin inhibitor as needed, and a potent or very potent topical steroid as rescue medication. Roughly half of participants resorted to any topical steroid at least once during the 64 months. An important new observation gleaned in the long-term study was that the patients who did use topical steroids were twice as likely to reach an EASI 75 response.
Roughly 20% of patients on the three highest dosages of nemolizumab achieved a static Investigator’s Global Assessment score of 0 or 1, meaning clear or almost clear, by week 64.
Scores on the Dermatology Life Quality Index fell steadily over the course of 64 weeks, from a baseline of about 16 to 5 at study’s close.
The side effect profile of nemolizumab was essentially the same as seen in the placebo arm during the double-blind phase. About one-quarter of patients experienced nasopharyngitis over the course of 64 weeks of treatment. A similar fraction reported exacerbations of their atopic dermatitis; however, these events were front-loaded in the first weeks of the initial double-blind study phase and appeared to have been triggered by the drug washout period prior to the patients’ receiving the first dose of nemolizumab, according to Dr. Ruzicka. No new safety signals emerged during the additional 52 weeks of treatment.
The study was funded by Chugai. Dr. Ruzicka reported serving as a paid company adviser.
GENEVA – Nemolizumab, a humanized monoclonal antibody that inhibits interleukin-31 signaling, maintained its early dramatic antipruritic effect in patients with moderate to severe atopic dermatitis (AD) throughout a year-long unblinded extension of a large, high-profile, 12-week, phase 2 randomized trial, Thomas Ruzicka, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
In contrast, the 52-week extension study also showed the improvement in the dermatitis aspect of AD as measured by Eczema Area and Severity Index (EASI) scores was more gradual and less robust.
The study, 64 weeks in total, also demonstrated that what really matters to patients with moderate or severe AD is relief from the itch. Scores on the Dermatology Life Quality Index showed marked improvement even if their improvement in EASI scores was suboptimal.
“The dermatitis scores improved. But the most concerning symptom to patients is the pruritus; that’s what worsens their quality of life. And this improves dramatically very early in the course of the study,” Dr. Ruzicka explained. “If they drop their itch they are very happy. They don’t care about the redness of the skin so much as the pruritus. This is what really bothers them, as has been shown in epidemiologic studies.”
The original 12-week, phase 2, randomized, double-blind, dose-ranging trial drew extensive attention because it demonstrated convincingly for the first time that the inflammatory cytokine interleukin-31 plays a key role in the pathobiology of AD by promoting skin barrier dysfunction, pruritus, and the inflammatory response in AD – and that a biologic agent, nemolizumab, could inhibit those disease mechanisms (N Engl J Med. 2017 Mar 2;376[9]:826-35).
At a dose of 0.5 mg/kg administered by subcutaneous injection every 4 weeks, nemolizumab, a humanized monoclonal antibody directed against interleukin-31 receptor A, reduced scores on the pruritus visual-analogue scale by 60% as early as 4 weeks and maintained that effect through 12 weeks. At that point, the double-blind study ended and the 52-week extension began. Patients on nemolizumab in the double-blind phase stayed on the same dosage for the extension, while those who’d been on placebo were switched to nemolizumab at 0.1, 0.5, or 2.0 mg/kg every 4 weeks.
A total of 211 patients with moderate to severe AD inadequately controlled by topical therapies enrolled in the extension study. The combined 64-week experience convinced investigators and the sponsor, Chugai Pharmaceutical, that 0.5 mg/kg every 4 weeks is the optimal dose to take forward into planned advanced-stage clinical trials.
“At this dosage the IL-31 receptor is saturated, so higher dosages aren’t needed,” according to Dr. Ruzicka.
By week 64, patients in the 0.5-mg/kg arm of the study showed further gradual improvement in their pruritus visual-analogue score, from a 60% reduction from baseline at 12 weeks to close to an 80% reduction at week 64.
Roughly half of nemolizumab-treated patients achieved an EASI-50 response within the first 4 weeks of the double-blind phase of the study and stayed in that response zone throughout the extension study.
The EASI-75 and -90 responses followed a pattern different from EASI-50. Patients didn’t leap to those more robust levels of response early and then plateau. Instead, the EASI-75 and -90 responses were achieved via a gradual climb in efficacy throughout the study, such that by week 64 roughly 35%-40% of patients on the various nemolizumab dosages had reached EASI-75.
In the extension study, patients were permitted to use a mild topical steroid or topical calcineurin inhibitor as needed, and a potent or very potent topical steroid as rescue medication. Roughly half of participants resorted to any topical steroid at least once during the 64 months. An important new observation gleaned in the long-term study was that the patients who did use topical steroids were twice as likely to reach an EASI 75 response.
Roughly 20% of patients on the three highest dosages of nemolizumab achieved a static Investigator’s Global Assessment score of 0 or 1, meaning clear or almost clear, by week 64.
Scores on the Dermatology Life Quality Index fell steadily over the course of 64 weeks, from a baseline of about 16 to 5 at study’s close.
The side effect profile of nemolizumab was essentially the same as seen in the placebo arm during the double-blind phase. About one-quarter of patients experienced nasopharyngitis over the course of 64 weeks of treatment. A similar fraction reported exacerbations of their atopic dermatitis; however, these events were front-loaded in the first weeks of the initial double-blind study phase and appeared to have been triggered by the drug washout period prior to the patients’ receiving the first dose of nemolizumab, according to Dr. Ruzicka. No new safety signals emerged during the additional 52 weeks of treatment.
The study was funded by Chugai. Dr. Ruzicka reported serving as a paid company adviser.
AT THE EADV CONGRESS
Key clinical point:
Major finding: The early dramatic antipruritic effect demonstrated by nemolizumab for atopic dermatitis in a 12-week randomized trial was maintained throughout an additional 52 weeks in an extension study.
Data source: This analysis focused on 211 patients with moderate to severe atopic dermatitis who participated in a 52-week open-label extension study after completing a previously reported 12-week, double-blind, placebo-controlled phase.
Disclosures: The presenter is a paid medical adviser to Chugai Pharmaceutical, which funded the study.
Moderate psoriasis: the new frontier for systemic therapies
GENEVA – Apremilast showed substantial efficacy for patients with truly moderate psoriasis as defined by an involved body surface area of 5%-10% in the first-of-its-kind UNVEIL trial, Bruce Strober, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Patients with moderate psoriasis constitute a very large and underserved population, said Dr. Strober, professor and chair of the department of dermatology at the University of Connecticut, Farmington. “I would say the moderate psoriasis group defined by 5%-10% psoriasis-involved body surface area represents a gray area in our treatment. Often, people with this degree of psoriasis receive no treatment or are relegated to topical monotherapy, yet unfortunately do not respond to those treatments. Nevertheless, clinical trials for systemic therapies, including biologics, exclude this population solely because they’re under 10% involved body surface area,” he noted.
“A large percentage of my patients who are on biologic therapy have less than 10% involved body surface area and would have a PASI [Psoriasis Area Severity Index] score, if I were to measure it, of under 12. Therefore they couldn’t get into a typical registration study for moderate to severe psoriasis,” he continued.
The UNVEIL trial included a 16-week, double-blind, placebo-controlled phase in which 221 systemic therapy–naive patients with plaque psoriasis on 5%-10% of their body surface area (BSA) were randomized 2:1 to apremilast at 30 mg twice a day or placebo. Thereafter, the placebo group was switched over to apremilast and the trial continued in open-label fashion out to 52 weeks. Apremilast (Otezla) is approved only for use in moderate to severe psoriasis.
At baseline, participants had a mean 15-year duration of psoriasis, an involved BSA of 7.1%, a PASI score of 8.1, a static Physician’s Global Assessment (PGA) score of 3 on a 0-5 scale, and a Dermatology Life Quality Index (DLQI) score of 11.
UNVEIL not only targeted a new population for a modern systemic therapy, it also debuted as its primary endpoint a novel metric for disease severity. Because PASI score is a relatively crude measure of change in a population with moderate psoriasis, Dr. Strober and his coinvestigators developed and employed as the primary outcome measure PGA+BSA, which can range from 15 to 30.
The mean baseline PGA+BSA was 21.8. At week 16, the placebo group averaged a 10% decrease in this metric, while the apremilast group showed a 48% reduction. At week 52, the group switched from placebo to apremilast at 16 weeks had a 42% improvement in PGA+BSA and patients on apremilast for the full study had a 49% improvement.
“So you can assume about half of patients with moderate psoriasis will experience a 50% reduction in the product of PGA+BSA on apremilast,” Dr. Strober observed.
At week 52, a PGA score of 0 or 1, meaning clear or almost clear, was present in 36% of the switchover group and 29% of patients on apremilast for 52 weeks.
A 75% improvement in PGA+BSA, or a PGA+BSA–75 response, occurred at week 52 in 45% of the switchover group and 37% of those on apremilast for the entire study.
The mean improvement in the DLQI at week 16 was 2.4 points in the placebo arm and twice that amount with apremilast. At 52 weeks, the switchover group averaged a 5.1-point reduction in DLQI from baseline and the full-time apremilast group had a 4.3-point reduction.
The incidence of apremilast-related adverse events didn’t increase over time. The main issues were diarrhea, nausea, and headache, as is the case when the oral drug is prescribed for its approved indication in patients with moderate to severe psoriasis.
In an interview, Dr. Strober said that despite the encouraging results of UNVEIL, the study is not by itself sufficient evidence to win an expanded indication for apremilast from regulatory agencies and the drug’s manufacturer, Celgene, is not interested in pursuing that course.
UNVEIL, a phase 4 study, was funded by Celgene. Dr. Strober reported serving as a consultant to and/or receiving research funding from that company and more than a dozen others.
GENEVA – Apremilast showed substantial efficacy for patients with truly moderate psoriasis as defined by an involved body surface area of 5%-10% in the first-of-its-kind UNVEIL trial, Bruce Strober, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Patients with moderate psoriasis constitute a very large and underserved population, said Dr. Strober, professor and chair of the department of dermatology at the University of Connecticut, Farmington. “I would say the moderate psoriasis group defined by 5%-10% psoriasis-involved body surface area represents a gray area in our treatment. Often, people with this degree of psoriasis receive no treatment or are relegated to topical monotherapy, yet unfortunately do not respond to those treatments. Nevertheless, clinical trials for systemic therapies, including biologics, exclude this population solely because they’re under 10% involved body surface area,” he noted.
“A large percentage of my patients who are on biologic therapy have less than 10% involved body surface area and would have a PASI [Psoriasis Area Severity Index] score, if I were to measure it, of under 12. Therefore they couldn’t get into a typical registration study for moderate to severe psoriasis,” he continued.
The UNVEIL trial included a 16-week, double-blind, placebo-controlled phase in which 221 systemic therapy–naive patients with plaque psoriasis on 5%-10% of their body surface area (BSA) were randomized 2:1 to apremilast at 30 mg twice a day or placebo. Thereafter, the placebo group was switched over to apremilast and the trial continued in open-label fashion out to 52 weeks. Apremilast (Otezla) is approved only for use in moderate to severe psoriasis.
At baseline, participants had a mean 15-year duration of psoriasis, an involved BSA of 7.1%, a PASI score of 8.1, a static Physician’s Global Assessment (PGA) score of 3 on a 0-5 scale, and a Dermatology Life Quality Index (DLQI) score of 11.
UNVEIL not only targeted a new population for a modern systemic therapy, it also debuted as its primary endpoint a novel metric for disease severity. Because PASI score is a relatively crude measure of change in a population with moderate psoriasis, Dr. Strober and his coinvestigators developed and employed as the primary outcome measure PGA+BSA, which can range from 15 to 30.
The mean baseline PGA+BSA was 21.8. At week 16, the placebo group averaged a 10% decrease in this metric, while the apremilast group showed a 48% reduction. At week 52, the group switched from placebo to apremilast at 16 weeks had a 42% improvement in PGA+BSA and patients on apremilast for the full study had a 49% improvement.
“So you can assume about half of patients with moderate psoriasis will experience a 50% reduction in the product of PGA+BSA on apremilast,” Dr. Strober observed.
At week 52, a PGA score of 0 or 1, meaning clear or almost clear, was present in 36% of the switchover group and 29% of patients on apremilast for 52 weeks.
A 75% improvement in PGA+BSA, or a PGA+BSA–75 response, occurred at week 52 in 45% of the switchover group and 37% of those on apremilast for the entire study.
The mean improvement in the DLQI at week 16 was 2.4 points in the placebo arm and twice that amount with apremilast. At 52 weeks, the switchover group averaged a 5.1-point reduction in DLQI from baseline and the full-time apremilast group had a 4.3-point reduction.
The incidence of apremilast-related adverse events didn’t increase over time. The main issues were diarrhea, nausea, and headache, as is the case when the oral drug is prescribed for its approved indication in patients with moderate to severe psoriasis.
In an interview, Dr. Strober said that despite the encouraging results of UNVEIL, the study is not by itself sufficient evidence to win an expanded indication for apremilast from regulatory agencies and the drug’s manufacturer, Celgene, is not interested in pursuing that course.
UNVEIL, a phase 4 study, was funded by Celgene. Dr. Strober reported serving as a consultant to and/or receiving research funding from that company and more than a dozen others.
GENEVA – Apremilast showed substantial efficacy for patients with truly moderate psoriasis as defined by an involved body surface area of 5%-10% in the first-of-its-kind UNVEIL trial, Bruce Strober, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Patients with moderate psoriasis constitute a very large and underserved population, said Dr. Strober, professor and chair of the department of dermatology at the University of Connecticut, Farmington. “I would say the moderate psoriasis group defined by 5%-10% psoriasis-involved body surface area represents a gray area in our treatment. Often, people with this degree of psoriasis receive no treatment or are relegated to topical monotherapy, yet unfortunately do not respond to those treatments. Nevertheless, clinical trials for systemic therapies, including biologics, exclude this population solely because they’re under 10% involved body surface area,” he noted.
“A large percentage of my patients who are on biologic therapy have less than 10% involved body surface area and would have a PASI [Psoriasis Area Severity Index] score, if I were to measure it, of under 12. Therefore they couldn’t get into a typical registration study for moderate to severe psoriasis,” he continued.
The UNVEIL trial included a 16-week, double-blind, placebo-controlled phase in which 221 systemic therapy–naive patients with plaque psoriasis on 5%-10% of their body surface area (BSA) were randomized 2:1 to apremilast at 30 mg twice a day or placebo. Thereafter, the placebo group was switched over to apremilast and the trial continued in open-label fashion out to 52 weeks. Apremilast (Otezla) is approved only for use in moderate to severe psoriasis.
At baseline, participants had a mean 15-year duration of psoriasis, an involved BSA of 7.1%, a PASI score of 8.1, a static Physician’s Global Assessment (PGA) score of 3 on a 0-5 scale, and a Dermatology Life Quality Index (DLQI) score of 11.
UNVEIL not only targeted a new population for a modern systemic therapy, it also debuted as its primary endpoint a novel metric for disease severity. Because PASI score is a relatively crude measure of change in a population with moderate psoriasis, Dr. Strober and his coinvestigators developed and employed as the primary outcome measure PGA+BSA, which can range from 15 to 30.
The mean baseline PGA+BSA was 21.8. At week 16, the placebo group averaged a 10% decrease in this metric, while the apremilast group showed a 48% reduction. At week 52, the group switched from placebo to apremilast at 16 weeks had a 42% improvement in PGA+BSA and patients on apremilast for the full study had a 49% improvement.
“So you can assume about half of patients with moderate psoriasis will experience a 50% reduction in the product of PGA+BSA on apremilast,” Dr. Strober observed.
At week 52, a PGA score of 0 or 1, meaning clear or almost clear, was present in 36% of the switchover group and 29% of patients on apremilast for 52 weeks.
A 75% improvement in PGA+BSA, or a PGA+BSA–75 response, occurred at week 52 in 45% of the switchover group and 37% of those on apremilast for the entire study.
The mean improvement in the DLQI at week 16 was 2.4 points in the placebo arm and twice that amount with apremilast. At 52 weeks, the switchover group averaged a 5.1-point reduction in DLQI from baseline and the full-time apremilast group had a 4.3-point reduction.
The incidence of apremilast-related adverse events didn’t increase over time. The main issues were diarrhea, nausea, and headache, as is the case when the oral drug is prescribed for its approved indication in patients with moderate to severe psoriasis.
In an interview, Dr. Strober said that despite the encouraging results of UNVEIL, the study is not by itself sufficient evidence to win an expanded indication for apremilast from regulatory agencies and the drug’s manufacturer, Celgene, is not interested in pursuing that course.
UNVEIL, a phase 4 study, was funded by Celgene. Dr. Strober reported serving as a consultant to and/or receiving research funding from that company and more than a dozen others.
AT THE EADV CONGRESS
Key clinical point:
Major finding: Roughly half of apremilast-treated patients with moderate psoriasis as defined by an involved body surface area of 5%-10% experienced a 50% reduction in a novel outcome metric: the product of the Physician’s Global Assessment plus the involved body surface area.
Data source: This 52-week study of 221 patients with truly moderate psoriasis featured a 16-week, double-blind, placebo-controlled phase, after which everyone continued on open-label apremilast out to 51 weeks.
Disclosures: The UNVEIL study was sponsored by Celgene. The presenter reported receiving research funding from and serving as a consultant to that company and numerous others.
ORBITA: PCI no better than meds for stable angina
DENVER – The first-ever blinded, sham-controlled randomized trial of percutaneous coronary intervention for stable angina failed to show a significant improvement in exercise time for PCI, compared with placebo PCI, Rasha Al-Lamee, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
The blockbuster results of the ORBITA trial, published online in the Lancet simultaneously with Dr. Al-Lamee’s presentation in Denver, quickly went viral, with a story splashed across the front page of the New York Times under the headline “‘Unbelievable’: Heart Stents Fail to Ease Chest Pain.” Interventional cardiology thought leaders at TCT said the newspaper piece, and a Lancet editorial commentary entitled “Last nail in the coffin for PCI in stable angina?” that accompanied publication of ORBITA, failed to convey the study’s major limitations, drawbacks that Dr. Al-Lamee readily acknowledged.
What ORBITA did
ORBITA (Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina) included 200 patients referred to five U.K. cardiac catheterization labs for diagnostic angiography. Participants had to have stable angina, single-vessel disease, and at least one 70% or greater stenosis; in fact, their stenotic severity averaged 84.4% by quantitative coronary angiography.
The patients received 6 weeks of intensive medical therapy during which they were uptitrated to an average of three antianginal medications. They then underwent either real or sham PCI followed by 6 weeks of recovery, during which both the patients and care team remained blinded. Then the same assessments done before randomization were repeated, including exercise treadmill testing, the Seattle Angina Questionnaire, and dobutamine stress echocardiography, explained Dr. Al-Lamee of Imperial College London.
The primary outcome was achievement of at least a 30-second greater improvement in total exercise time following PCI, compared with sham PCI, an effect size chosen based on placebo-controlled studies of antianginal drugs. The PCI group improved by a mean of 28.4 seconds, the controls by 11.8 seconds, and the resultant 16.6-second difference made for a negative result (Lancet. 2017 Nov 2;doi: 10.1016/S0140-6736[17]32714-9).
PCI did, however, result in significant improvement in the secondary endpoint of ischemia reduction as assessed by blinded evaluation of dobutamine stress echocardiography results. The PCI group’s mean peak stress wall motion index score improved from 1.11 prerandomization to 1.03 – that is, normal – at follow-up 6 weeks post procedure while remaining unchanged in the sham PCI group, Dr. Al-Lamee noted at the meeting, sponsored by the Cardiovascular Research Foundation.
What the results mean
Dr. Al-Lamee said the ORBITA results should enable cardiologists to sit with patients similar to those in the trial and have a more informed, patient-centered discussion in which intensive medical management can be offered as an initial first-line option with an understanding that it will likely improve their symptoms to the same degree as angioplasty.
“There will be those patients who would rather avoid having to take high doses of antianginal medications with the side effects they involve, who may well prefer to have an upfront procedure with a small risk in order to reduce their pill count, and who also would rather have improved blood flow to the heart, which may have prognostic implications,” Dr. Al-Lamee said.
Carl L. Tommaso, MD, part of the panel of discussants at the late-breaking clinical trials session in which Dr. Al-Lamee presented the ORBITA findings, applauded the investigators for their ingenious study design, which included elaborate blinding techniques involving music played through headphones throughout the procedure, heavy sedation, separate angioplasty and clinical care teams, the same postprocedural instructions and discharge letter, and dual-antiplatelet therapy in both study arms.
“This is a great study. I don’t think any of us could get this study past an institutional review board in the United States,” commented Dr. Tommaso, director of the cardiac catheterization laboratory at Skokie (Ill.) Hospital.
He added, however, that he wouldn’t have performed PCI on the basis of angiographic findings alone in stable angina patients with a 9-minute treadmill exercise time.
Where OPTIMA fell short
Angiography vs. functional testing
“Twenty-nine percent of patients, we’d all agree, should not have had angioplasty because they had no ischemia,” said Dr. Stone, professor of medicine at Columbia University, New York, and director of the TCT conference.
All subjects in ORBITA did indeed undergo measurement of both FFR and instant Wave-Free Ratio (iFR) while on the table immediately before and after their real or sham PCI. The mean stenosis severity was 0.69 by FFR and 0.76 by iFR, readings indicative of significantly impaired flow. However, the operators were blinded as to those results. The rationale for withholding that information was that, even though it has been shown to be clinically useful, studies show that 80% of angioplasties are done based upon angiography alone, and the ORBITA investigators wanted the study to reflect routine clinical practice, Dr. Al-Lamee explained.
“I think one of the many lessons coming out of this trial is to see the discrepancy between the angiogram and functional testing. We cannot guide our therapy solely by the angiogram. We have to get physiologic data and consider that together with symptoms in the patient’s clinical context,” said panelist Allen Jeremias, MD, director of interventional cardiology research at St. Francis Hospital in Rosyln, N.Y.
Commentary goes too far
The “last-nail-in-the-coffin” Lancet commentary (2017 Nov 2. doi: 10.1016/S0140-6736[17]32757-5) penned by David L. Brown, MD, of Washington University in St. Louis and Rita F. Redberg, MD, of the University of California, San Francisco, emphatically declared that the ORBITA results mean all cardiology guidelines should be revised to downgrade the recommendation for PCI in patients with angina despite medical therapy. Dr. Al-Lamee was one of many at TCT 2017 who took strong exception to that.
“This is the first trial of its kind. I think it would be very easy to take the results of this trial and overextrapolate. To downgrade the guideline recommendations based on this study would be an incredibly large overreach,” she said.
Ajay J. Kirtane, MD, who chaired a press conference in which Dr. Al-Lamee presented the ORBITA results, had a further criticism of the editorial.
“Some of the risks of PCI as described in the editorial are just factually inaccurate. An MI rate of 15%, an acute kidney injury rate of 13% – those are simply factually incorrect,” said Dr. Kirtane, director of the cardiac catheterization laboratories at New York-Presbyterian/Columbia University Medical Center.
The ORBITA trial was sponsored by Imperial College London and funded by grants from the National Institute of Health Research Imperial Biomedical Research Center and charity organizations. Dr. Al-Lamee reported serving as a paid consultant to Philips Volcano, which supplied the coronary pressure wires for physiologic testing.
DENVER – The first-ever blinded, sham-controlled randomized trial of percutaneous coronary intervention for stable angina failed to show a significant improvement in exercise time for PCI, compared with placebo PCI, Rasha Al-Lamee, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
The blockbuster results of the ORBITA trial, published online in the Lancet simultaneously with Dr. Al-Lamee’s presentation in Denver, quickly went viral, with a story splashed across the front page of the New York Times under the headline “‘Unbelievable’: Heart Stents Fail to Ease Chest Pain.” Interventional cardiology thought leaders at TCT said the newspaper piece, and a Lancet editorial commentary entitled “Last nail in the coffin for PCI in stable angina?” that accompanied publication of ORBITA, failed to convey the study’s major limitations, drawbacks that Dr. Al-Lamee readily acknowledged.
What ORBITA did
ORBITA (Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina) included 200 patients referred to five U.K. cardiac catheterization labs for diagnostic angiography. Participants had to have stable angina, single-vessel disease, and at least one 70% or greater stenosis; in fact, their stenotic severity averaged 84.4% by quantitative coronary angiography.
The patients received 6 weeks of intensive medical therapy during which they were uptitrated to an average of three antianginal medications. They then underwent either real or sham PCI followed by 6 weeks of recovery, during which both the patients and care team remained blinded. Then the same assessments done before randomization were repeated, including exercise treadmill testing, the Seattle Angina Questionnaire, and dobutamine stress echocardiography, explained Dr. Al-Lamee of Imperial College London.
The primary outcome was achievement of at least a 30-second greater improvement in total exercise time following PCI, compared with sham PCI, an effect size chosen based on placebo-controlled studies of antianginal drugs. The PCI group improved by a mean of 28.4 seconds, the controls by 11.8 seconds, and the resultant 16.6-second difference made for a negative result (Lancet. 2017 Nov 2;doi: 10.1016/S0140-6736[17]32714-9).
PCI did, however, result in significant improvement in the secondary endpoint of ischemia reduction as assessed by blinded evaluation of dobutamine stress echocardiography results. The PCI group’s mean peak stress wall motion index score improved from 1.11 prerandomization to 1.03 – that is, normal – at follow-up 6 weeks post procedure while remaining unchanged in the sham PCI group, Dr. Al-Lamee noted at the meeting, sponsored by the Cardiovascular Research Foundation.
What the results mean
Dr. Al-Lamee said the ORBITA results should enable cardiologists to sit with patients similar to those in the trial and have a more informed, patient-centered discussion in which intensive medical management can be offered as an initial first-line option with an understanding that it will likely improve their symptoms to the same degree as angioplasty.
“There will be those patients who would rather avoid having to take high doses of antianginal medications with the side effects they involve, who may well prefer to have an upfront procedure with a small risk in order to reduce their pill count, and who also would rather have improved blood flow to the heart, which may have prognostic implications,” Dr. Al-Lamee said.
Carl L. Tommaso, MD, part of the panel of discussants at the late-breaking clinical trials session in which Dr. Al-Lamee presented the ORBITA findings, applauded the investigators for their ingenious study design, which included elaborate blinding techniques involving music played through headphones throughout the procedure, heavy sedation, separate angioplasty and clinical care teams, the same postprocedural instructions and discharge letter, and dual-antiplatelet therapy in both study arms.
“This is a great study. I don’t think any of us could get this study past an institutional review board in the United States,” commented Dr. Tommaso, director of the cardiac catheterization laboratory at Skokie (Ill.) Hospital.
He added, however, that he wouldn’t have performed PCI on the basis of angiographic findings alone in stable angina patients with a 9-minute treadmill exercise time.
Where OPTIMA fell short
Angiography vs. functional testing
“Twenty-nine percent of patients, we’d all agree, should not have had angioplasty because they had no ischemia,” said Dr. Stone, professor of medicine at Columbia University, New York, and director of the TCT conference.
All subjects in ORBITA did indeed undergo measurement of both FFR and instant Wave-Free Ratio (iFR) while on the table immediately before and after their real or sham PCI. The mean stenosis severity was 0.69 by FFR and 0.76 by iFR, readings indicative of significantly impaired flow. However, the operators were blinded as to those results. The rationale for withholding that information was that, even though it has been shown to be clinically useful, studies show that 80% of angioplasties are done based upon angiography alone, and the ORBITA investigators wanted the study to reflect routine clinical practice, Dr. Al-Lamee explained.
“I think one of the many lessons coming out of this trial is to see the discrepancy between the angiogram and functional testing. We cannot guide our therapy solely by the angiogram. We have to get physiologic data and consider that together with symptoms in the patient’s clinical context,” said panelist Allen Jeremias, MD, director of interventional cardiology research at St. Francis Hospital in Rosyln, N.Y.
Commentary goes too far
The “last-nail-in-the-coffin” Lancet commentary (2017 Nov 2. doi: 10.1016/S0140-6736[17]32757-5) penned by David L. Brown, MD, of Washington University in St. Louis and Rita F. Redberg, MD, of the University of California, San Francisco, emphatically declared that the ORBITA results mean all cardiology guidelines should be revised to downgrade the recommendation for PCI in patients with angina despite medical therapy. Dr. Al-Lamee was one of many at TCT 2017 who took strong exception to that.
“This is the first trial of its kind. I think it would be very easy to take the results of this trial and overextrapolate. To downgrade the guideline recommendations based on this study would be an incredibly large overreach,” she said.
Ajay J. Kirtane, MD, who chaired a press conference in which Dr. Al-Lamee presented the ORBITA results, had a further criticism of the editorial.
“Some of the risks of PCI as described in the editorial are just factually inaccurate. An MI rate of 15%, an acute kidney injury rate of 13% – those are simply factually incorrect,” said Dr. Kirtane, director of the cardiac catheterization laboratories at New York-Presbyterian/Columbia University Medical Center.
The ORBITA trial was sponsored by Imperial College London and funded by grants from the National Institute of Health Research Imperial Biomedical Research Center and charity organizations. Dr. Al-Lamee reported serving as a paid consultant to Philips Volcano, which supplied the coronary pressure wires for physiologic testing.
DENVER – The first-ever blinded, sham-controlled randomized trial of percutaneous coronary intervention for stable angina failed to show a significant improvement in exercise time for PCI, compared with placebo PCI, Rasha Al-Lamee, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
The blockbuster results of the ORBITA trial, published online in the Lancet simultaneously with Dr. Al-Lamee’s presentation in Denver, quickly went viral, with a story splashed across the front page of the New York Times under the headline “‘Unbelievable’: Heart Stents Fail to Ease Chest Pain.” Interventional cardiology thought leaders at TCT said the newspaper piece, and a Lancet editorial commentary entitled “Last nail in the coffin for PCI in stable angina?” that accompanied publication of ORBITA, failed to convey the study’s major limitations, drawbacks that Dr. Al-Lamee readily acknowledged.
What ORBITA did
ORBITA (Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina) included 200 patients referred to five U.K. cardiac catheterization labs for diagnostic angiography. Participants had to have stable angina, single-vessel disease, and at least one 70% or greater stenosis; in fact, their stenotic severity averaged 84.4% by quantitative coronary angiography.
The patients received 6 weeks of intensive medical therapy during which they were uptitrated to an average of three antianginal medications. They then underwent either real or sham PCI followed by 6 weeks of recovery, during which both the patients and care team remained blinded. Then the same assessments done before randomization were repeated, including exercise treadmill testing, the Seattle Angina Questionnaire, and dobutamine stress echocardiography, explained Dr. Al-Lamee of Imperial College London.
The primary outcome was achievement of at least a 30-second greater improvement in total exercise time following PCI, compared with sham PCI, an effect size chosen based on placebo-controlled studies of antianginal drugs. The PCI group improved by a mean of 28.4 seconds, the controls by 11.8 seconds, and the resultant 16.6-second difference made for a negative result (Lancet. 2017 Nov 2;doi: 10.1016/S0140-6736[17]32714-9).
PCI did, however, result in significant improvement in the secondary endpoint of ischemia reduction as assessed by blinded evaluation of dobutamine stress echocardiography results. The PCI group’s mean peak stress wall motion index score improved from 1.11 prerandomization to 1.03 – that is, normal – at follow-up 6 weeks post procedure while remaining unchanged in the sham PCI group, Dr. Al-Lamee noted at the meeting, sponsored by the Cardiovascular Research Foundation.
What the results mean
Dr. Al-Lamee said the ORBITA results should enable cardiologists to sit with patients similar to those in the trial and have a more informed, patient-centered discussion in which intensive medical management can be offered as an initial first-line option with an understanding that it will likely improve their symptoms to the same degree as angioplasty.
“There will be those patients who would rather avoid having to take high doses of antianginal medications with the side effects they involve, who may well prefer to have an upfront procedure with a small risk in order to reduce their pill count, and who also would rather have improved blood flow to the heart, which may have prognostic implications,” Dr. Al-Lamee said.
Carl L. Tommaso, MD, part of the panel of discussants at the late-breaking clinical trials session in which Dr. Al-Lamee presented the ORBITA findings, applauded the investigators for their ingenious study design, which included elaborate blinding techniques involving music played through headphones throughout the procedure, heavy sedation, separate angioplasty and clinical care teams, the same postprocedural instructions and discharge letter, and dual-antiplatelet therapy in both study arms.
“This is a great study. I don’t think any of us could get this study past an institutional review board in the United States,” commented Dr. Tommaso, director of the cardiac catheterization laboratory at Skokie (Ill.) Hospital.
He added, however, that he wouldn’t have performed PCI on the basis of angiographic findings alone in stable angina patients with a 9-minute treadmill exercise time.
Where OPTIMA fell short
Angiography vs. functional testing
“Twenty-nine percent of patients, we’d all agree, should not have had angioplasty because they had no ischemia,” said Dr. Stone, professor of medicine at Columbia University, New York, and director of the TCT conference.
All subjects in ORBITA did indeed undergo measurement of both FFR and instant Wave-Free Ratio (iFR) while on the table immediately before and after their real or sham PCI. The mean stenosis severity was 0.69 by FFR and 0.76 by iFR, readings indicative of significantly impaired flow. However, the operators were blinded as to those results. The rationale for withholding that information was that, even though it has been shown to be clinically useful, studies show that 80% of angioplasties are done based upon angiography alone, and the ORBITA investigators wanted the study to reflect routine clinical practice, Dr. Al-Lamee explained.
“I think one of the many lessons coming out of this trial is to see the discrepancy between the angiogram and functional testing. We cannot guide our therapy solely by the angiogram. We have to get physiologic data and consider that together with symptoms in the patient’s clinical context,” said panelist Allen Jeremias, MD, director of interventional cardiology research at St. Francis Hospital in Rosyln, N.Y.
Commentary goes too far
The “last-nail-in-the-coffin” Lancet commentary (2017 Nov 2. doi: 10.1016/S0140-6736[17]32757-5) penned by David L. Brown, MD, of Washington University in St. Louis and Rita F. Redberg, MD, of the University of California, San Francisco, emphatically declared that the ORBITA results mean all cardiology guidelines should be revised to downgrade the recommendation for PCI in patients with angina despite medical therapy. Dr. Al-Lamee was one of many at TCT 2017 who took strong exception to that.
“This is the first trial of its kind. I think it would be very easy to take the results of this trial and overextrapolate. To downgrade the guideline recommendations based on this study would be an incredibly large overreach,” she said.
Ajay J. Kirtane, MD, who chaired a press conference in which Dr. Al-Lamee presented the ORBITA results, had a further criticism of the editorial.
“Some of the risks of PCI as described in the editorial are just factually inaccurate. An MI rate of 15%, an acute kidney injury rate of 13% – those are simply factually incorrect,” said Dr. Kirtane, director of the cardiac catheterization laboratories at New York-Presbyterian/Columbia University Medical Center.
The ORBITA trial was sponsored by Imperial College London and funded by grants from the National Institute of Health Research Imperial Biomedical Research Center and charity organizations. Dr. Al-Lamee reported serving as a paid consultant to Philips Volcano, which supplied the coronary pressure wires for physiologic testing.
AT TCT 2017
Key clinical point:
Major finding: PCI on top of intensive antianginal medications was not significantly more effective at improving exercise tolerance than sham PCI.
Data source: ORBITA, a randomized, multicenter, blinded, sham-controlled study of 200 patients with mild angina and single-vessel CAD.
Disclosures: ORBITA was sponsored by Imperial College London and funded by grants from the National Institute of Health Research Imperial Biomedical Research Center and charity organizations. The presenter reported serving as a paid consultant to Philips Volcano, which supplied the coronary pressure wires for physiologic testing.
TAVR wallops SAVR in cost-effectiveness for intermediate-risk patients
DENVER – A formal cost-effectiveness analysis indicates that transcatheter aortic valve replacement (TAVR) is substantially more cost effective than surgical valve replacement in patients at intermediate surgical risk similar to those enrolled in the landmark PARTNER 2 trial.
The analysis demonstrated that over a 1- and 2-year follow-up period, as well as with projected lifetime follow-up, TAVR entails both lower long-term costs and greater quality-adjusted life expectancy, David J. Cohen, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
His two-part, patient-level economic analysis examined data from nearly 2,000 participants in the PARTNER 2A randomized trial comparing TAVR, using the Sapien XT valve, with surgical aortic valve replacement (SAVR), as well as the experience with the current-generation Sapien 3 TAVR valve in 1,077 intermediate–surgical risk TAVR patients in the S3i registry. The analysis utilized Medicare claims data on the costs of the index hospitalization and follow-up care.
In PARTNER 2A, the average total cost of the index hospitalization for valve replacement was $61,433 with TAVR. That was just $2,888 more than the SAVR hospitalization, despite the far higher acquisition cost of the Sapien 3 valve, which was roughly $32,500, compared with $5,000 for the surgical valve. Most of this additional cost of the TAVR valve was counterbalanced by TAVR’s 2-hour shorter procedural duration, the 6.4-day average length of stay, compared with 10.9 days for SAVR, and the fact that TAVR patients spent only 2.4 days in intensive care while SAVR patients averaged 4.6 days, Dr. Cohen explained at the meeting sponsored by the Cardiovascular Research Foundation.
During 24 months of postdischarge follow-up in the PARTNER 2A trial, SAVR patients racked up an average of $9,303 more in costs than TAVR patients. This was mainly because of their much higher rates of rehospitalization and time spent in skilled nursing facilities and rehabilitation centers, mainly during months 2-6 post discharge. The result was that 2-year total costs including the index hospitalization averaged $107,716 per TAVR patient and $114,132 per SAVR patient.
“One of the really remarkable findings of this study was what happened during follow-up,” the cardiologist observed.
Extrapolating to projected remaining lifetime years, TAVR using the Sapien XT valve resulted in a cost savings of $7,949 per patient and a 0.15-year increase in quality-adjusted life expectancy compared with SAVR.
But since the time of PARTNER 2A, the Sapien XT valve has been replaced by the updated Sapien 3 valve. The analysis of the S3i registry showed that the economic dominance of TAVR over SAVR was even greater owing to improved valve technology and contemporary care patterns. For this analysis, because there has been no randomized trial of TAVR with the Sapien 3 valve versus SAVR, patients in the SAVR of arm of PARTNER 2A served as the comparison group.
The cost of the index hospitalization was more than $4,000 less with TAVR in the S3i registry than with SAVR. The total cost of TAVR through 1 year of follow-up averaged $80,977, which was $15,511 less than the $96,489 for SAVR. The cost post discharge out to 1 year was more than $11,000 less per TAVR patient, driven by sharply lower rates of both cardiovascular and noncardiovascular hospitalizations as well as a greater than 50% reduction in days spent in rehab centers and skilled nursing facilities, compared with SAVR patients.
Projected over estimated remaining years of life, TAVR with the Sapien 3 valve yielded a cost savings of $9,692 per patient compared with SAVR, as well as a 0.27-year gain in quality-adjusted life-years.
Eighty-eight percent of patients in the S3i registry received their Sapien 3 valve via a transfemoral approach. When Dr. Cohen and his coinvestigators compared their costs and clinical outcomes to the subset of PARTNER 2A TAVR patients who got the Sapien XT valve transfemorally, the outcomes were “virtually identical,” he said.
“These findings are reassuring with regard to the S3i results and also suggest that the primary mechanism of benefit of the Sapien 3 valve over the XT valve is its lower profile, which allows roughly 90% of patients to be treated via a transfemoral approach,” according to Dr. Cohen.
He predicted the new cost-effectiveness findings will not substantially increase patient demand for TAVR, which is already high.
“By far what’s driving patients to TAVR today are the quality of life advantages. They love the idea of recovering quickly,” he said.
Michael Mack, MD, commented that this analysis probably underestimates the true cost advantage of TAVR by a fair amount, since the average hospital length of stay for TAVR patients in PARTNER 2A was 6.4 days.
“We now know that half of U.S. TAVR patients in many centers go home the day after the procedure, so you would expect that TAVR would look even more favorable based on current practice,” said Dr. Mack, medical director of cardiovascular surgery for the Baylor Health Care System and chairman of the Heart Hospital Baylor Plano (Tex.) Research Center.
Session moderator Patrick W. Serruys, MD, of Imperial College, London, observed that the cost differential between TAVR and SAVR will grow even larger once the sky-high cost of TAVR valves comes down. He predicted that’s likely to happen as a result of increased competition once a third valve receives marketing approval, just as occurred after a third drug-eluting stent hit the market.
Several physicians grumbled about the unfairness of current reimbursement for TAVR, which in effect penalizes hospitals. Dr. Cohen said that situation will change.
“I think the future of health care financing in the U.S. is bundled payment and accountable care organizations. In the setting of bundled payment for a 6-month period or even for 90 days, TAVR would look fantastic to a hospital or an health maintenance organization due to avoidance of rehospitalizations and rehabilitation and skilled nursing facility stays,” the cardiologist said.
The PARTNER 2A trial, the S3i registry, and the cost-effectiveness analysis were funded by Edwards Lifesciences. Dr. Cohen reported receiving research funding from and serving as a consultant to Edwards Lifesciences and other device companies.
DENVER – A formal cost-effectiveness analysis indicates that transcatheter aortic valve replacement (TAVR) is substantially more cost effective than surgical valve replacement in patients at intermediate surgical risk similar to those enrolled in the landmark PARTNER 2 trial.
The analysis demonstrated that over a 1- and 2-year follow-up period, as well as with projected lifetime follow-up, TAVR entails both lower long-term costs and greater quality-adjusted life expectancy, David J. Cohen, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
His two-part, patient-level economic analysis examined data from nearly 2,000 participants in the PARTNER 2A randomized trial comparing TAVR, using the Sapien XT valve, with surgical aortic valve replacement (SAVR), as well as the experience with the current-generation Sapien 3 TAVR valve in 1,077 intermediate–surgical risk TAVR patients in the S3i registry. The analysis utilized Medicare claims data on the costs of the index hospitalization and follow-up care.
In PARTNER 2A, the average total cost of the index hospitalization for valve replacement was $61,433 with TAVR. That was just $2,888 more than the SAVR hospitalization, despite the far higher acquisition cost of the Sapien 3 valve, which was roughly $32,500, compared with $5,000 for the surgical valve. Most of this additional cost of the TAVR valve was counterbalanced by TAVR’s 2-hour shorter procedural duration, the 6.4-day average length of stay, compared with 10.9 days for SAVR, and the fact that TAVR patients spent only 2.4 days in intensive care while SAVR patients averaged 4.6 days, Dr. Cohen explained at the meeting sponsored by the Cardiovascular Research Foundation.
During 24 months of postdischarge follow-up in the PARTNER 2A trial, SAVR patients racked up an average of $9,303 more in costs than TAVR patients. This was mainly because of their much higher rates of rehospitalization and time spent in skilled nursing facilities and rehabilitation centers, mainly during months 2-6 post discharge. The result was that 2-year total costs including the index hospitalization averaged $107,716 per TAVR patient and $114,132 per SAVR patient.
“One of the really remarkable findings of this study was what happened during follow-up,” the cardiologist observed.
Extrapolating to projected remaining lifetime years, TAVR using the Sapien XT valve resulted in a cost savings of $7,949 per patient and a 0.15-year increase in quality-adjusted life expectancy compared with SAVR.
But since the time of PARTNER 2A, the Sapien XT valve has been replaced by the updated Sapien 3 valve. The analysis of the S3i registry showed that the economic dominance of TAVR over SAVR was even greater owing to improved valve technology and contemporary care patterns. For this analysis, because there has been no randomized trial of TAVR with the Sapien 3 valve versus SAVR, patients in the SAVR of arm of PARTNER 2A served as the comparison group.
The cost of the index hospitalization was more than $4,000 less with TAVR in the S3i registry than with SAVR. The total cost of TAVR through 1 year of follow-up averaged $80,977, which was $15,511 less than the $96,489 for SAVR. The cost post discharge out to 1 year was more than $11,000 less per TAVR patient, driven by sharply lower rates of both cardiovascular and noncardiovascular hospitalizations as well as a greater than 50% reduction in days spent in rehab centers and skilled nursing facilities, compared with SAVR patients.
Projected over estimated remaining years of life, TAVR with the Sapien 3 valve yielded a cost savings of $9,692 per patient compared with SAVR, as well as a 0.27-year gain in quality-adjusted life-years.
Eighty-eight percent of patients in the S3i registry received their Sapien 3 valve via a transfemoral approach. When Dr. Cohen and his coinvestigators compared their costs and clinical outcomes to the subset of PARTNER 2A TAVR patients who got the Sapien XT valve transfemorally, the outcomes were “virtually identical,” he said.
“These findings are reassuring with regard to the S3i results and also suggest that the primary mechanism of benefit of the Sapien 3 valve over the XT valve is its lower profile, which allows roughly 90% of patients to be treated via a transfemoral approach,” according to Dr. Cohen.
He predicted the new cost-effectiveness findings will not substantially increase patient demand for TAVR, which is already high.
“By far what’s driving patients to TAVR today are the quality of life advantages. They love the idea of recovering quickly,” he said.
Michael Mack, MD, commented that this analysis probably underestimates the true cost advantage of TAVR by a fair amount, since the average hospital length of stay for TAVR patients in PARTNER 2A was 6.4 days.
“We now know that half of U.S. TAVR patients in many centers go home the day after the procedure, so you would expect that TAVR would look even more favorable based on current practice,” said Dr. Mack, medical director of cardiovascular surgery for the Baylor Health Care System and chairman of the Heart Hospital Baylor Plano (Tex.) Research Center.
Session moderator Patrick W. Serruys, MD, of Imperial College, London, observed that the cost differential between TAVR and SAVR will grow even larger once the sky-high cost of TAVR valves comes down. He predicted that’s likely to happen as a result of increased competition once a third valve receives marketing approval, just as occurred after a third drug-eluting stent hit the market.
Several physicians grumbled about the unfairness of current reimbursement for TAVR, which in effect penalizes hospitals. Dr. Cohen said that situation will change.
“I think the future of health care financing in the U.S. is bundled payment and accountable care organizations. In the setting of bundled payment for a 6-month period or even for 90 days, TAVR would look fantastic to a hospital or an health maintenance organization due to avoidance of rehospitalizations and rehabilitation and skilled nursing facility stays,” the cardiologist said.
The PARTNER 2A trial, the S3i registry, and the cost-effectiveness analysis were funded by Edwards Lifesciences. Dr. Cohen reported receiving research funding from and serving as a consultant to Edwards Lifesciences and other device companies.
DENVER – A formal cost-effectiveness analysis indicates that transcatheter aortic valve replacement (TAVR) is substantially more cost effective than surgical valve replacement in patients at intermediate surgical risk similar to those enrolled in the landmark PARTNER 2 trial.
The analysis demonstrated that over a 1- and 2-year follow-up period, as well as with projected lifetime follow-up, TAVR entails both lower long-term costs and greater quality-adjusted life expectancy, David J. Cohen, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
His two-part, patient-level economic analysis examined data from nearly 2,000 participants in the PARTNER 2A randomized trial comparing TAVR, using the Sapien XT valve, with surgical aortic valve replacement (SAVR), as well as the experience with the current-generation Sapien 3 TAVR valve in 1,077 intermediate–surgical risk TAVR patients in the S3i registry. The analysis utilized Medicare claims data on the costs of the index hospitalization and follow-up care.
In PARTNER 2A, the average total cost of the index hospitalization for valve replacement was $61,433 with TAVR. That was just $2,888 more than the SAVR hospitalization, despite the far higher acquisition cost of the Sapien 3 valve, which was roughly $32,500, compared with $5,000 for the surgical valve. Most of this additional cost of the TAVR valve was counterbalanced by TAVR’s 2-hour shorter procedural duration, the 6.4-day average length of stay, compared with 10.9 days for SAVR, and the fact that TAVR patients spent only 2.4 days in intensive care while SAVR patients averaged 4.6 days, Dr. Cohen explained at the meeting sponsored by the Cardiovascular Research Foundation.
During 24 months of postdischarge follow-up in the PARTNER 2A trial, SAVR patients racked up an average of $9,303 more in costs than TAVR patients. This was mainly because of their much higher rates of rehospitalization and time spent in skilled nursing facilities and rehabilitation centers, mainly during months 2-6 post discharge. The result was that 2-year total costs including the index hospitalization averaged $107,716 per TAVR patient and $114,132 per SAVR patient.
“One of the really remarkable findings of this study was what happened during follow-up,” the cardiologist observed.
Extrapolating to projected remaining lifetime years, TAVR using the Sapien XT valve resulted in a cost savings of $7,949 per patient and a 0.15-year increase in quality-adjusted life expectancy compared with SAVR.
But since the time of PARTNER 2A, the Sapien XT valve has been replaced by the updated Sapien 3 valve. The analysis of the S3i registry showed that the economic dominance of TAVR over SAVR was even greater owing to improved valve technology and contemporary care patterns. For this analysis, because there has been no randomized trial of TAVR with the Sapien 3 valve versus SAVR, patients in the SAVR of arm of PARTNER 2A served as the comparison group.
The cost of the index hospitalization was more than $4,000 less with TAVR in the S3i registry than with SAVR. The total cost of TAVR through 1 year of follow-up averaged $80,977, which was $15,511 less than the $96,489 for SAVR. The cost post discharge out to 1 year was more than $11,000 less per TAVR patient, driven by sharply lower rates of both cardiovascular and noncardiovascular hospitalizations as well as a greater than 50% reduction in days spent in rehab centers and skilled nursing facilities, compared with SAVR patients.
Projected over estimated remaining years of life, TAVR with the Sapien 3 valve yielded a cost savings of $9,692 per patient compared with SAVR, as well as a 0.27-year gain in quality-adjusted life-years.
Eighty-eight percent of patients in the S3i registry received their Sapien 3 valve via a transfemoral approach. When Dr. Cohen and his coinvestigators compared their costs and clinical outcomes to the subset of PARTNER 2A TAVR patients who got the Sapien XT valve transfemorally, the outcomes were “virtually identical,” he said.
“These findings are reassuring with regard to the S3i results and also suggest that the primary mechanism of benefit of the Sapien 3 valve over the XT valve is its lower profile, which allows roughly 90% of patients to be treated via a transfemoral approach,” according to Dr. Cohen.
He predicted the new cost-effectiveness findings will not substantially increase patient demand for TAVR, which is already high.
“By far what’s driving patients to TAVR today are the quality of life advantages. They love the idea of recovering quickly,” he said.
Michael Mack, MD, commented that this analysis probably underestimates the true cost advantage of TAVR by a fair amount, since the average hospital length of stay for TAVR patients in PARTNER 2A was 6.4 days.
“We now know that half of U.S. TAVR patients in many centers go home the day after the procedure, so you would expect that TAVR would look even more favorable based on current practice,” said Dr. Mack, medical director of cardiovascular surgery for the Baylor Health Care System and chairman of the Heart Hospital Baylor Plano (Tex.) Research Center.
Session moderator Patrick W. Serruys, MD, of Imperial College, London, observed that the cost differential between TAVR and SAVR will grow even larger once the sky-high cost of TAVR valves comes down. He predicted that’s likely to happen as a result of increased competition once a third valve receives marketing approval, just as occurred after a third drug-eluting stent hit the market.
Several physicians grumbled about the unfairness of current reimbursement for TAVR, which in effect penalizes hospitals. Dr. Cohen said that situation will change.
“I think the future of health care financing in the U.S. is bundled payment and accountable care organizations. In the setting of bundled payment for a 6-month period or even for 90 days, TAVR would look fantastic to a hospital or an health maintenance organization due to avoidance of rehospitalizations and rehabilitation and skilled nursing facility stays,” the cardiologist said.
The PARTNER 2A trial, the S3i registry, and the cost-effectiveness analysis were funded by Edwards Lifesciences. Dr. Cohen reported receiving research funding from and serving as a consultant to Edwards Lifesciences and other device companies.
AT TCT 2017
Key clinical point:
Major finding: The total cost of TAVR with the Sapien 3 valve in intermediate-risk patients, including the index hospitalization and costs incurred during the first year after, averaged $80,977, compared with $96,489 per SAVR patient.
Data source: This patient-level formal cost-effectiveness analysis included nearly 2,000 patients in the PARTNER 2A trial and more than 1,700 in a registry of recipients of the Sapien 3 TAVR valve.
Disclosures: The cost-effectiveness analysis was funded by Edwards Lifesciences. The presenter reported receiving research funding from and serving as a consultant to Edwards Lifesciences and other device companies.
Drug-eluting balloon is as good as drug-eluting stent for in-stent restenosis
DENVER – Treatment of coronary in-stent restenosis using a paclitaxel-eluting balloon proved noninferior to an everolimus-eluting stent in terms of minimal lumen diameter at 6 months in the DARE trial, Jose P.S. Henriques, MD, reported at the Transcatheter Cardiovascular Therapeutics annual meeting.
The two forms of device therapy also yielded similar rates of adverse clinical events, including target vessel revascularization, at 12 months, he said.
The DARE (Drug-Eluting Balloon for In-Stent Restenosis) trial included 278 patients with in-stent restenosis (ISR) randomized to the SeQuent Please paclitaxel-eluting balloon or Xience everolimus-eluting stent at high-volume Dutch percutaneous coronary intervention centers. The trial was unique in that it included a mix of patients with in-stent restenosis involving DES and bare-metal stents. Indeed, 44% of participants had ISR in a bare-metal stent. These older-model stents are still used in patients who require a shorter duration of dual-antiplatelet therapy, so the DARE population reflects real-world clinical practice better than do prior studies restricted to ISR in only one stent type or the other, according to the cardiologist.
The primary outcome in this noninferiority trial was the in-segment minimal lumen diameter at 6-month angiographic follow-up. The mean diameter was 1.71 mm in the drug-eluting balloon (DEB) group and closely similar at 1.74 mm in the DES group. There was greater acute gain with the drug-eluting stent, but it was canceled out by greater late loss by 6 months.
Moreover, the 12-month composite clinical event rate composed of death, target vessel MI, and target vessel revascularization was 10.9% in the DEB recipients and 9.2% with the DES, a nonsignificant difference. Of note, target vessel revascularization occurred in 8.8% of the DEB group and was similar at 7.1% in the DES recipients, although the DARE trial wasn’t powered to detect differences in clinical events.
These results confirm the European Society of Cardiology’s class 1A recommendation for DEB as well as DES for ISR, Dr. Henriques said at the meeting sponsored by the Cardiovascular Research Foundation.
U.S. guidelines don’t address DEB for the treatment of coronary ISR. That’s because the devices, which have long been available in Europe, aren’t approved for use in the coronary tree in the United States. They are available in the United States only for treatment of peripheral vascular disease. And no U.S. clinical trials of DEBs in the coronary tree are planned.
“I wish the U.S. Food and Drug Administration was listening to the DARE results because we really would like to see this technology in the U.S.,” said Roxana Mehran, MD, who moderated a press conference where the DARE findings were highlighted.
David J. Cohen, MD, director of cardiovascular research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., commented, “This type of device, obviously with it being similar in performance to drug-eluting stents, would be a very welcome addition to our armamentarium, because one of the things I don’t like to do as a coronary interventionalist is to line up multiple stents inside each other.”
“Making club sandwiches out of patients’ arteries with stent after stent is not a good idea. We know that,” added Dr. Mehran, professor of medicine and director of interventional cardiovascular research and clinical trials at Mount Sinai School of Medicine in New York.
Cindy L. Grines, MD, chair of cardiology at the Hofstra Northwell School of Medicine in Hempstead, N.Y., said DEBs “would absolutely be welcome” if they were available to cardiologists in the United States.
“When you have repeated episodes of in-stent restenosis, you can start with a vessel that’s 3 mm in diameter; then when it restenoses and you place a second stent inside there, all of a sudden – even if you have a great stent result – you can be down to 2.25 mm. And then the next time you need to treat it for restenosis, you’re down to a very tiny lumen. That’s the big problem with trying to treat in-stent restenosis with more stents,” she explained.
The DEBs are expensive, and ISR has become so uncommon with the use of the current generation of drug-eluting stents that the device companies have little incentive to do the studies required to be able to market DEBs in the United States.
“I think the FDA should consider in-stent restenosis as an orphan disease. We really should be able to get a drug-eluting balloon approved in this country based on the data over in Europe,” Dr. Grines said.
Dr. Henriques reported receiving research grants from B. Braun, which markets the paclitaxel-eluting stent in Europe, as well as from Abbott Vascular.
DENVER – Treatment of coronary in-stent restenosis using a paclitaxel-eluting balloon proved noninferior to an everolimus-eluting stent in terms of minimal lumen diameter at 6 months in the DARE trial, Jose P.S. Henriques, MD, reported at the Transcatheter Cardiovascular Therapeutics annual meeting.
The two forms of device therapy also yielded similar rates of adverse clinical events, including target vessel revascularization, at 12 months, he said.
The DARE (Drug-Eluting Balloon for In-Stent Restenosis) trial included 278 patients with in-stent restenosis (ISR) randomized to the SeQuent Please paclitaxel-eluting balloon or Xience everolimus-eluting stent at high-volume Dutch percutaneous coronary intervention centers. The trial was unique in that it included a mix of patients with in-stent restenosis involving DES and bare-metal stents. Indeed, 44% of participants had ISR in a bare-metal stent. These older-model stents are still used in patients who require a shorter duration of dual-antiplatelet therapy, so the DARE population reflects real-world clinical practice better than do prior studies restricted to ISR in only one stent type or the other, according to the cardiologist.
The primary outcome in this noninferiority trial was the in-segment minimal lumen diameter at 6-month angiographic follow-up. The mean diameter was 1.71 mm in the drug-eluting balloon (DEB) group and closely similar at 1.74 mm in the DES group. There was greater acute gain with the drug-eluting stent, but it was canceled out by greater late loss by 6 months.
Moreover, the 12-month composite clinical event rate composed of death, target vessel MI, and target vessel revascularization was 10.9% in the DEB recipients and 9.2% with the DES, a nonsignificant difference. Of note, target vessel revascularization occurred in 8.8% of the DEB group and was similar at 7.1% in the DES recipients, although the DARE trial wasn’t powered to detect differences in clinical events.
These results confirm the European Society of Cardiology’s class 1A recommendation for DEB as well as DES for ISR, Dr. Henriques said at the meeting sponsored by the Cardiovascular Research Foundation.
U.S. guidelines don’t address DEB for the treatment of coronary ISR. That’s because the devices, which have long been available in Europe, aren’t approved for use in the coronary tree in the United States. They are available in the United States only for treatment of peripheral vascular disease. And no U.S. clinical trials of DEBs in the coronary tree are planned.
“I wish the U.S. Food and Drug Administration was listening to the DARE results because we really would like to see this technology in the U.S.,” said Roxana Mehran, MD, who moderated a press conference where the DARE findings were highlighted.
David J. Cohen, MD, director of cardiovascular research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., commented, “This type of device, obviously with it being similar in performance to drug-eluting stents, would be a very welcome addition to our armamentarium, because one of the things I don’t like to do as a coronary interventionalist is to line up multiple stents inside each other.”
“Making club sandwiches out of patients’ arteries with stent after stent is not a good idea. We know that,” added Dr. Mehran, professor of medicine and director of interventional cardiovascular research and clinical trials at Mount Sinai School of Medicine in New York.
Cindy L. Grines, MD, chair of cardiology at the Hofstra Northwell School of Medicine in Hempstead, N.Y., said DEBs “would absolutely be welcome” if they were available to cardiologists in the United States.
“When you have repeated episodes of in-stent restenosis, you can start with a vessel that’s 3 mm in diameter; then when it restenoses and you place a second stent inside there, all of a sudden – even if you have a great stent result – you can be down to 2.25 mm. And then the next time you need to treat it for restenosis, you’re down to a very tiny lumen. That’s the big problem with trying to treat in-stent restenosis with more stents,” she explained.
The DEBs are expensive, and ISR has become so uncommon with the use of the current generation of drug-eluting stents that the device companies have little incentive to do the studies required to be able to market DEBs in the United States.
“I think the FDA should consider in-stent restenosis as an orphan disease. We really should be able to get a drug-eluting balloon approved in this country based on the data over in Europe,” Dr. Grines said.
Dr. Henriques reported receiving research grants from B. Braun, which markets the paclitaxel-eluting stent in Europe, as well as from Abbott Vascular.
DENVER – Treatment of coronary in-stent restenosis using a paclitaxel-eluting balloon proved noninferior to an everolimus-eluting stent in terms of minimal lumen diameter at 6 months in the DARE trial, Jose P.S. Henriques, MD, reported at the Transcatheter Cardiovascular Therapeutics annual meeting.
The two forms of device therapy also yielded similar rates of adverse clinical events, including target vessel revascularization, at 12 months, he said.
The DARE (Drug-Eluting Balloon for In-Stent Restenosis) trial included 278 patients with in-stent restenosis (ISR) randomized to the SeQuent Please paclitaxel-eluting balloon or Xience everolimus-eluting stent at high-volume Dutch percutaneous coronary intervention centers. The trial was unique in that it included a mix of patients with in-stent restenosis involving DES and bare-metal stents. Indeed, 44% of participants had ISR in a bare-metal stent. These older-model stents are still used in patients who require a shorter duration of dual-antiplatelet therapy, so the DARE population reflects real-world clinical practice better than do prior studies restricted to ISR in only one stent type or the other, according to the cardiologist.
The primary outcome in this noninferiority trial was the in-segment minimal lumen diameter at 6-month angiographic follow-up. The mean diameter was 1.71 mm in the drug-eluting balloon (DEB) group and closely similar at 1.74 mm in the DES group. There was greater acute gain with the drug-eluting stent, but it was canceled out by greater late loss by 6 months.
Moreover, the 12-month composite clinical event rate composed of death, target vessel MI, and target vessel revascularization was 10.9% in the DEB recipients and 9.2% with the DES, a nonsignificant difference. Of note, target vessel revascularization occurred in 8.8% of the DEB group and was similar at 7.1% in the DES recipients, although the DARE trial wasn’t powered to detect differences in clinical events.
These results confirm the European Society of Cardiology’s class 1A recommendation for DEB as well as DES for ISR, Dr. Henriques said at the meeting sponsored by the Cardiovascular Research Foundation.
U.S. guidelines don’t address DEB for the treatment of coronary ISR. That’s because the devices, which have long been available in Europe, aren’t approved for use in the coronary tree in the United States. They are available in the United States only for treatment of peripheral vascular disease. And no U.S. clinical trials of DEBs in the coronary tree are planned.
“I wish the U.S. Food and Drug Administration was listening to the DARE results because we really would like to see this technology in the U.S.,” said Roxana Mehran, MD, who moderated a press conference where the DARE findings were highlighted.
David J. Cohen, MD, director of cardiovascular research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., commented, “This type of device, obviously with it being similar in performance to drug-eluting stents, would be a very welcome addition to our armamentarium, because one of the things I don’t like to do as a coronary interventionalist is to line up multiple stents inside each other.”
“Making club sandwiches out of patients’ arteries with stent after stent is not a good idea. We know that,” added Dr. Mehran, professor of medicine and director of interventional cardiovascular research and clinical trials at Mount Sinai School of Medicine in New York.
Cindy L. Grines, MD, chair of cardiology at the Hofstra Northwell School of Medicine in Hempstead, N.Y., said DEBs “would absolutely be welcome” if they were available to cardiologists in the United States.
“When you have repeated episodes of in-stent restenosis, you can start with a vessel that’s 3 mm in diameter; then when it restenoses and you place a second stent inside there, all of a sudden – even if you have a great stent result – you can be down to 2.25 mm. And then the next time you need to treat it for restenosis, you’re down to a very tiny lumen. That’s the big problem with trying to treat in-stent restenosis with more stents,” she explained.
The DEBs are expensive, and ISR has become so uncommon with the use of the current generation of drug-eluting stents that the device companies have little incentive to do the studies required to be able to market DEBs in the United States.
“I think the FDA should consider in-stent restenosis as an orphan disease. We really should be able to get a drug-eluting balloon approved in this country based on the data over in Europe,” Dr. Grines said.
Dr. Henriques reported receiving research grants from B. Braun, which markets the paclitaxel-eluting stent in Europe, as well as from Abbott Vascular.
AT TCT 2017
Key clinical point:
Major finding: The mean 6-month in-segment minimal lumen diameter following treatment of in-stent restenosis with a paclitaxel-eluting balloon was 1.71 mm and was similar at 1.74 mm in patients treated using an everolimus-eluting stent.
Data source: A prospective, multicenter Dutch randomized trial including 278 patients with in-stent restenosis.
Disclosures: The study was sponsored by the University of Amsterdam and financially supported by a research grant from B. Braun. The presenter reported receiving research grants from that company and Abbott Vascular.
Left main distal bifurcation? Double kiss and crush it
DENVER – A planned two-stent, double-kissing crush PCI technique proved superior to the widely utilized provisional stenting strategy for treatment of unprotected distal left main bifurcation lesions in the randomized DKCRUSH-V trial, Shao-Liang Chen, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
The study randomized 482 patients with unprotected true distal left main bifurcation lesions to one of the two PCI strategies at 26 centers in five countries, including the United States. Roughly 80% of the left main lesions were categorized as Medina 1,1,1.
The primary outcome was the 1-year composite rate of target lesion failure (TLF), defined as cardiac death, target vessel MI, or clinically driven target lesion revascularization. The rate was 10.7% in patients assigned to provisional stenting and 5.0% with double kissing (DK) crush. This clinically and statistically significant difference was driven by a sharp reduction in target vessel MI in the DK crush group: 0.4%, compared with 2.9% in the provisional stenting group.
Moreover, the DK crush group’s 3.8% rate of clinically driven target lesion revascularization and 7.1% rate of angiographic restenosis within the left main complex were both less than half the rates in the provisional stenting group, he added at the meeting, which was sponsored by the Cardiovascular Research Foundation.
The absolute benefit for the DK crush strategy was greatest in the roughly 30% of patients with complex bifurcations, defined as those with an ostial side branch lesion length of at least 10 mm and 70% diameter stenosis while meeting at least two of six minor criteria. The 1-year TLF rate in such patients was 18.2% with provisional stenting versus 7% with DK crush. For simple bifurcations, the TLF rates were 8% versus 1.9%.
The results favored DK crush in all examined subgroups, including those based upon age, gender, SYNTAX score, distal angle, and diabetes status.
Forty-seven percent of patients in the provisional stenting arm received a second stent, typically needed as a bailout for the side branch. Most of the excess target vessel MIs and other TLF events in the provisional stenting group occurred in patients who got a second stent.
The DK crush is an advanced technique with numerous steps involving multiple vessel wirings, rewirings, and stent crushing. It can be challenging to perform. It took an average of 82 minutes, 16 minutes longer than provisional stenting – a difference in procedural time that interventional cardiologists don’t take lightly. It also entailed an average of 36 mL more contrast media than the 191 mL for provisional stenting.
In an earlier multicenter, randomized, prospective trial – DKCRUSH-III – Dr. Chen and his coinvestigators showed that the DK crush technique provides superior outcomes compared with culotte stenting, another widely used treatment strategy for distal left main bifurcation lesions (J Am Coll Cardiol. 2013 Apr 9;61[14]:1482-8).
“The take home message on the surface of the data would be that we should consider this particular two-stent bifurcation technique as perhaps the treatment of choice for true distal bifurcation lesions,” said Gregg W. Stone, MD, who was a coinvestigator in DKCRUSH-V and chaired the late-breaking clinical trial session where Dr. Chen presented the results.
“This technique theoretically gives you the largest amount of laminar flow both in the main vessel and the side branch,” added Dr. Stone, professor of medicine and director of cardiovascular research and education at Columbia University Medical Center in New York.
Simultaneously with Dr. Chen’s presentation at TCT 2017, the DKCRUSH-V results were published online (J Am Coll Cardiol. 2017 Oct 30. doi: 10.1016/j.jacc.2017.09.1066). In an accompanying editorial, Emmanouil S. Brilakis, MD, declared that DK crush should become the preferred strategy for treating unprotected left main bifurcation lesions.
It’s not a technique for the average interventionalist, though. It should be performed in high-volume centers of excellence accustomed to performing complex PCIs. Indeed, the DKCRUSH-V trial required the primary operators to have performed at least 300 PCIs per year for 5 years, including 20 left main PCIs per year or more. To put that in perspective, the median annual PCI volume in the United States is 59 cases, noted Dr. Brilakis of the Minneapolis Heart Institute (J Am Coll Cardiol. 2017 Oct. 30. doi: 10.1016/j.jacc.2017.09.1083).
At TCT 2017 in Denver, not everyone found the DKCRUSH-V findings persuasive.
“I’m quite surprised by the results,” said panel discussant David Hildick-Smith, MD.
“There’s something we have yet to understand about the divergence between the results that are coming out of China and the results coming out of Europe. Almost everything coming out of Europe tends to suggest that provisional stenting is better, while in Chinese hands the DK crush technique has proved to be an extremely successful strategy,” said Dr. Hildick-Smith, professor of interventional cardiology and director of the cardiac research unit at the Brighton and Sussex (England) Medical School.
He added that he intends to reserve judgment as to the preferred strategy until the results of the ongoing European Bifurcation Club Left Main Study (EBC MAIN) become available late in 2018. EBC MAIN is comparing the DK crush, culotte, and other strategies, with the choice of technique left to the operator’s discretion.
The DKCRUSH-V trial was supported by the National Science Foundation of China, the Nanjing Municipal Medical Development Project, Microport, Abbott Vascular, and Medtronic. Dr. Chen and Dr. Stone reported having no financial conflicts of interest regarding the study.
DENVER – A planned two-stent, double-kissing crush PCI technique proved superior to the widely utilized provisional stenting strategy for treatment of unprotected distal left main bifurcation lesions in the randomized DKCRUSH-V trial, Shao-Liang Chen, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
The study randomized 482 patients with unprotected true distal left main bifurcation lesions to one of the two PCI strategies at 26 centers in five countries, including the United States. Roughly 80% of the left main lesions were categorized as Medina 1,1,1.
The primary outcome was the 1-year composite rate of target lesion failure (TLF), defined as cardiac death, target vessel MI, or clinically driven target lesion revascularization. The rate was 10.7% in patients assigned to provisional stenting and 5.0% with double kissing (DK) crush. This clinically and statistically significant difference was driven by a sharp reduction in target vessel MI in the DK crush group: 0.4%, compared with 2.9% in the provisional stenting group.
Moreover, the DK crush group’s 3.8% rate of clinically driven target lesion revascularization and 7.1% rate of angiographic restenosis within the left main complex were both less than half the rates in the provisional stenting group, he added at the meeting, which was sponsored by the Cardiovascular Research Foundation.
The absolute benefit for the DK crush strategy was greatest in the roughly 30% of patients with complex bifurcations, defined as those with an ostial side branch lesion length of at least 10 mm and 70% diameter stenosis while meeting at least two of six minor criteria. The 1-year TLF rate in such patients was 18.2% with provisional stenting versus 7% with DK crush. For simple bifurcations, the TLF rates were 8% versus 1.9%.
The results favored DK crush in all examined subgroups, including those based upon age, gender, SYNTAX score, distal angle, and diabetes status.
Forty-seven percent of patients in the provisional stenting arm received a second stent, typically needed as a bailout for the side branch. Most of the excess target vessel MIs and other TLF events in the provisional stenting group occurred in patients who got a second stent.
The DK crush is an advanced technique with numerous steps involving multiple vessel wirings, rewirings, and stent crushing. It can be challenging to perform. It took an average of 82 minutes, 16 minutes longer than provisional stenting – a difference in procedural time that interventional cardiologists don’t take lightly. It also entailed an average of 36 mL more contrast media than the 191 mL for provisional stenting.
In an earlier multicenter, randomized, prospective trial – DKCRUSH-III – Dr. Chen and his coinvestigators showed that the DK crush technique provides superior outcomes compared with culotte stenting, another widely used treatment strategy for distal left main bifurcation lesions (J Am Coll Cardiol. 2013 Apr 9;61[14]:1482-8).
“The take home message on the surface of the data would be that we should consider this particular two-stent bifurcation technique as perhaps the treatment of choice for true distal bifurcation lesions,” said Gregg W. Stone, MD, who was a coinvestigator in DKCRUSH-V and chaired the late-breaking clinical trial session where Dr. Chen presented the results.
“This technique theoretically gives you the largest amount of laminar flow both in the main vessel and the side branch,” added Dr. Stone, professor of medicine and director of cardiovascular research and education at Columbia University Medical Center in New York.
Simultaneously with Dr. Chen’s presentation at TCT 2017, the DKCRUSH-V results were published online (J Am Coll Cardiol. 2017 Oct 30. doi: 10.1016/j.jacc.2017.09.1066). In an accompanying editorial, Emmanouil S. Brilakis, MD, declared that DK crush should become the preferred strategy for treating unprotected left main bifurcation lesions.
It’s not a technique for the average interventionalist, though. It should be performed in high-volume centers of excellence accustomed to performing complex PCIs. Indeed, the DKCRUSH-V trial required the primary operators to have performed at least 300 PCIs per year for 5 years, including 20 left main PCIs per year or more. To put that in perspective, the median annual PCI volume in the United States is 59 cases, noted Dr. Brilakis of the Minneapolis Heart Institute (J Am Coll Cardiol. 2017 Oct. 30. doi: 10.1016/j.jacc.2017.09.1083).
At TCT 2017 in Denver, not everyone found the DKCRUSH-V findings persuasive.
“I’m quite surprised by the results,” said panel discussant David Hildick-Smith, MD.
“There’s something we have yet to understand about the divergence between the results that are coming out of China and the results coming out of Europe. Almost everything coming out of Europe tends to suggest that provisional stenting is better, while in Chinese hands the DK crush technique has proved to be an extremely successful strategy,” said Dr. Hildick-Smith, professor of interventional cardiology and director of the cardiac research unit at the Brighton and Sussex (England) Medical School.
He added that he intends to reserve judgment as to the preferred strategy until the results of the ongoing European Bifurcation Club Left Main Study (EBC MAIN) become available late in 2018. EBC MAIN is comparing the DK crush, culotte, and other strategies, with the choice of technique left to the operator’s discretion.
The DKCRUSH-V trial was supported by the National Science Foundation of China, the Nanjing Municipal Medical Development Project, Microport, Abbott Vascular, and Medtronic. Dr. Chen and Dr. Stone reported having no financial conflicts of interest regarding the study.
DENVER – A planned two-stent, double-kissing crush PCI technique proved superior to the widely utilized provisional stenting strategy for treatment of unprotected distal left main bifurcation lesions in the randomized DKCRUSH-V trial, Shao-Liang Chen, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
The study randomized 482 patients with unprotected true distal left main bifurcation lesions to one of the two PCI strategies at 26 centers in five countries, including the United States. Roughly 80% of the left main lesions were categorized as Medina 1,1,1.
The primary outcome was the 1-year composite rate of target lesion failure (TLF), defined as cardiac death, target vessel MI, or clinically driven target lesion revascularization. The rate was 10.7% in patients assigned to provisional stenting and 5.0% with double kissing (DK) crush. This clinically and statistically significant difference was driven by a sharp reduction in target vessel MI in the DK crush group: 0.4%, compared with 2.9% in the provisional stenting group.
Moreover, the DK crush group’s 3.8% rate of clinically driven target lesion revascularization and 7.1% rate of angiographic restenosis within the left main complex were both less than half the rates in the provisional stenting group, he added at the meeting, which was sponsored by the Cardiovascular Research Foundation.
The absolute benefit for the DK crush strategy was greatest in the roughly 30% of patients with complex bifurcations, defined as those with an ostial side branch lesion length of at least 10 mm and 70% diameter stenosis while meeting at least two of six minor criteria. The 1-year TLF rate in such patients was 18.2% with provisional stenting versus 7% with DK crush. For simple bifurcations, the TLF rates were 8% versus 1.9%.
The results favored DK crush in all examined subgroups, including those based upon age, gender, SYNTAX score, distal angle, and diabetes status.
Forty-seven percent of patients in the provisional stenting arm received a second stent, typically needed as a bailout for the side branch. Most of the excess target vessel MIs and other TLF events in the provisional stenting group occurred in patients who got a second stent.
The DK crush is an advanced technique with numerous steps involving multiple vessel wirings, rewirings, and stent crushing. It can be challenging to perform. It took an average of 82 minutes, 16 minutes longer than provisional stenting – a difference in procedural time that interventional cardiologists don’t take lightly. It also entailed an average of 36 mL more contrast media than the 191 mL for provisional stenting.
In an earlier multicenter, randomized, prospective trial – DKCRUSH-III – Dr. Chen and his coinvestigators showed that the DK crush technique provides superior outcomes compared with culotte stenting, another widely used treatment strategy for distal left main bifurcation lesions (J Am Coll Cardiol. 2013 Apr 9;61[14]:1482-8).
“The take home message on the surface of the data would be that we should consider this particular two-stent bifurcation technique as perhaps the treatment of choice for true distal bifurcation lesions,” said Gregg W. Stone, MD, who was a coinvestigator in DKCRUSH-V and chaired the late-breaking clinical trial session where Dr. Chen presented the results.
“This technique theoretically gives you the largest amount of laminar flow both in the main vessel and the side branch,” added Dr. Stone, professor of medicine and director of cardiovascular research and education at Columbia University Medical Center in New York.
Simultaneously with Dr. Chen’s presentation at TCT 2017, the DKCRUSH-V results were published online (J Am Coll Cardiol. 2017 Oct 30. doi: 10.1016/j.jacc.2017.09.1066). In an accompanying editorial, Emmanouil S. Brilakis, MD, declared that DK crush should become the preferred strategy for treating unprotected left main bifurcation lesions.
It’s not a technique for the average interventionalist, though. It should be performed in high-volume centers of excellence accustomed to performing complex PCIs. Indeed, the DKCRUSH-V trial required the primary operators to have performed at least 300 PCIs per year for 5 years, including 20 left main PCIs per year or more. To put that in perspective, the median annual PCI volume in the United States is 59 cases, noted Dr. Brilakis of the Minneapolis Heart Institute (J Am Coll Cardiol. 2017 Oct. 30. doi: 10.1016/j.jacc.2017.09.1083).
At TCT 2017 in Denver, not everyone found the DKCRUSH-V findings persuasive.
“I’m quite surprised by the results,” said panel discussant David Hildick-Smith, MD.
“There’s something we have yet to understand about the divergence between the results that are coming out of China and the results coming out of Europe. Almost everything coming out of Europe tends to suggest that provisional stenting is better, while in Chinese hands the DK crush technique has proved to be an extremely successful strategy,” said Dr. Hildick-Smith, professor of interventional cardiology and director of the cardiac research unit at the Brighton and Sussex (England) Medical School.
He added that he intends to reserve judgment as to the preferred strategy until the results of the ongoing European Bifurcation Club Left Main Study (EBC MAIN) become available late in 2018. EBC MAIN is comparing the DK crush, culotte, and other strategies, with the choice of technique left to the operator’s discretion.
The DKCRUSH-V trial was supported by the National Science Foundation of China, the Nanjing Municipal Medical Development Project, Microport, Abbott Vascular, and Medtronic. Dr. Chen and Dr. Stone reported having no financial conflicts of interest regarding the study.
AT TCT 2017
Key clinical point:
Major finding: The 1-year composite rate of target lesion failure in patients treated with the planned two-stent double-kissing crush strategy was 5%, significantly less than the 10.7% rate with provisional stenting.
Data source: The DKCRUSH-V study randomized 482 patients with unprotected true distal left main bifurcation lesions to one of the two PCI strategies at 26 centers in five countries.
Disclosures: The study was supported by the National Science Foundation of China, the Nanjing Municipal Medical Development Project, Microport, Abbott Vascular, and Medtronic. The presenter reported having no financial conflicts of interest.