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Therapy, methylphenidate combo proves best treatment of adult ADHD
VIENNA – One-on-one counseling and manualized cognitive-behavioral therapy are equally effective as adjuncts to methylphenidate in the treatment of adult ADHD, Jan K. Buitelaar, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
He highlighted this finding from what he considers a well-conducted German randomized, double-blind, multicenter clinical trial in his discussion of recent major developments in the field of adult attention-deficit/hyperactivity disorder. He singled out the study because it provides clinicians with an evidence-based approach to treatment of this common disorder: namely, psychotherapy plus medication is better than either alone, and it doesn’t matter whether the psychotherapy takes the form of individual clinical behavioral counseling or a structured group cognitive-behavioral therapy (CBT) program tailored specifically for adult ADHD.
Investigators in the German COMPAS (Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study) Consortium randomized 419 18- to 58-year-old outpatients with ADHD to one of four treatment arms: group CBT plus methylphenidate or placebo, or nonspecific individual counseling plus methylphenidate or placebo. Psychotherapy sessions were conducted once weekly for the first 3 months and monthly for the next 9 months. The group CBT emphasized building self-esteem, coping skills, and acceptance. Methylphenidate was started at 10 mg per day and titrated over 6 weeks to 60 mg per day or a maximum of 1.2 mg/kg. The medication portion of the trial was conducted double-blind.
The primary outcome was the change in the ADHD Index of the Conners’ Adult ADHD Rating Scale as assessed by blinded observers from baseline to the end of the initial 3-month intensive treatment. The ADHD Index improved significantly from a mean baseline score of 20.6 to 17.6 in the group therapy arms and 16.5 with individual counseling, with no significant difference between the groups. Methylphenidate proved superior to placebo: those in the groups that received the medication in addition to their psychological intervention had a mean 3-month ADHD Index score that was 1.7 points lower than those on placebo (JAMA Psychiatry. 2015 Dec;72[12]:1199-210).
Regarding secondary outcomes, the ADHD Index results remained stable at the study’s conclusion at 12 months. However, there were no significant changes in self-rated depression scores over time. Blinded observers rated the group CBT patients as showing significantly greater improvement on the Clinical Global Impression Scale of Effectiveness.
The COMPAS trial was funded by the German Federal Ministry of Research and Education.
“This study provides real guidance for those of us who treat adult ADHD. The critical question here, of course, is what is the longer-term effect,” Dr. Buitelaar said.
He reported having no financial conflicts of interest regarding his presentation.
VIENNA – One-on-one counseling and manualized cognitive-behavioral therapy are equally effective as adjuncts to methylphenidate in the treatment of adult ADHD, Jan K. Buitelaar, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
He highlighted this finding from what he considers a well-conducted German randomized, double-blind, multicenter clinical trial in his discussion of recent major developments in the field of adult attention-deficit/hyperactivity disorder. He singled out the study because it provides clinicians with an evidence-based approach to treatment of this common disorder: namely, psychotherapy plus medication is better than either alone, and it doesn’t matter whether the psychotherapy takes the form of individual clinical behavioral counseling or a structured group cognitive-behavioral therapy (CBT) program tailored specifically for adult ADHD.
Investigators in the German COMPAS (Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study) Consortium randomized 419 18- to 58-year-old outpatients with ADHD to one of four treatment arms: group CBT plus methylphenidate or placebo, or nonspecific individual counseling plus methylphenidate or placebo. Psychotherapy sessions were conducted once weekly for the first 3 months and monthly for the next 9 months. The group CBT emphasized building self-esteem, coping skills, and acceptance. Methylphenidate was started at 10 mg per day and titrated over 6 weeks to 60 mg per day or a maximum of 1.2 mg/kg. The medication portion of the trial was conducted double-blind.
The primary outcome was the change in the ADHD Index of the Conners’ Adult ADHD Rating Scale as assessed by blinded observers from baseline to the end of the initial 3-month intensive treatment. The ADHD Index improved significantly from a mean baseline score of 20.6 to 17.6 in the group therapy arms and 16.5 with individual counseling, with no significant difference between the groups. Methylphenidate proved superior to placebo: those in the groups that received the medication in addition to their psychological intervention had a mean 3-month ADHD Index score that was 1.7 points lower than those on placebo (JAMA Psychiatry. 2015 Dec;72[12]:1199-210).
Regarding secondary outcomes, the ADHD Index results remained stable at the study’s conclusion at 12 months. However, there were no significant changes in self-rated depression scores over time. Blinded observers rated the group CBT patients as showing significantly greater improvement on the Clinical Global Impression Scale of Effectiveness.
The COMPAS trial was funded by the German Federal Ministry of Research and Education.
“This study provides real guidance for those of us who treat adult ADHD. The critical question here, of course, is what is the longer-term effect,” Dr. Buitelaar said.
He reported having no financial conflicts of interest regarding his presentation.
VIENNA – One-on-one counseling and manualized cognitive-behavioral therapy are equally effective as adjuncts to methylphenidate in the treatment of adult ADHD, Jan K. Buitelaar, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
He highlighted this finding from what he considers a well-conducted German randomized, double-blind, multicenter clinical trial in his discussion of recent major developments in the field of adult attention-deficit/hyperactivity disorder. He singled out the study because it provides clinicians with an evidence-based approach to treatment of this common disorder: namely, psychotherapy plus medication is better than either alone, and it doesn’t matter whether the psychotherapy takes the form of individual clinical behavioral counseling or a structured group cognitive-behavioral therapy (CBT) program tailored specifically for adult ADHD.
Investigators in the German COMPAS (Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study) Consortium randomized 419 18- to 58-year-old outpatients with ADHD to one of four treatment arms: group CBT plus methylphenidate or placebo, or nonspecific individual counseling plus methylphenidate or placebo. Psychotherapy sessions were conducted once weekly for the first 3 months and monthly for the next 9 months. The group CBT emphasized building self-esteem, coping skills, and acceptance. Methylphenidate was started at 10 mg per day and titrated over 6 weeks to 60 mg per day or a maximum of 1.2 mg/kg. The medication portion of the trial was conducted double-blind.
The primary outcome was the change in the ADHD Index of the Conners’ Adult ADHD Rating Scale as assessed by blinded observers from baseline to the end of the initial 3-month intensive treatment. The ADHD Index improved significantly from a mean baseline score of 20.6 to 17.6 in the group therapy arms and 16.5 with individual counseling, with no significant difference between the groups. Methylphenidate proved superior to placebo: those in the groups that received the medication in addition to their psychological intervention had a mean 3-month ADHD Index score that was 1.7 points lower than those on placebo (JAMA Psychiatry. 2015 Dec;72[12]:1199-210).
Regarding secondary outcomes, the ADHD Index results remained stable at the study’s conclusion at 12 months. However, there were no significant changes in self-rated depression scores over time. Blinded observers rated the group CBT patients as showing significantly greater improvement on the Clinical Global Impression Scale of Effectiveness.
The COMPAS trial was funded by the German Federal Ministry of Research and Education.
“This study provides real guidance for those of us who treat adult ADHD. The critical question here, of course, is what is the longer-term effect,” Dr. Buitelaar said.
He reported having no financial conflicts of interest regarding his presentation.
AT THE ECNP
Key clinical point:
Major finding: ADHD Index scores in patients with adult ADHD improved to a similar extent in response to methylphenidate plus either nonspecific individual counseling or structured group cognitive-behavioral therapy.
Data source: A randomized, multicenter, 12-month, four-arm clinical trial of 419 patients with adult ADHD.
Disclosures: The presenter reported having no financial conflicts of interest.
Joint European atrial fibrillation guidelines break new ground
ROME – The 2016 joint European guidelines on management of atrial fibrillation break new ground by declaring as a strong Class IA recommendation that the novel oral anticoagulants are now the drugs of choice – preferred over warfarin – for stroke prevention.
The joint guidelines from the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery recommend that warfarin’s use be reserved for the relatively small proportion of atrial fibrillation (AF) patients who are ineligible for the four commercially available novel oral anticoagulants (NOACs). That’s mainly patients with mechanical heart valves, moderate to severe mitral stenosis, or severe chronic kidney disease.
The ESC/EACTS guidelines, taken together with the American College of Chest Physicians guidelines on antithrombotic therapy for venous thromboembolic disease released earlier in the year, suggest that the old war horse warfarin is being eased out to pasture. The ACCP guidelines recommend any of the four NOACS – apixaban, dabigatran, edoxaban, or rivaroxaban – be used preferentially over warfarin in the treatment of venous thromboembolism (Chest 2016 Feb;149[2]:315-52). Both sets of guidelines cite compelling evidence that the NOACs are significantly safer than warfarin yet equally effective.
The ESC/EACTS guidelines are a full rewrite containing numerous departures from the previous 2012 AF management guidelines as well as from current ACC/AHA guidelines. The report includes more than 1,000 references. Eighty percent of the 154 recommendations provide Class I or IIa guidance. Two-thirds of the recommendations are Level of Evidence A or B, task force chairperson Paulus Kirchhof, MD, said at the annual congress of the European Society of Cardiology.
He and co-chairperson Stefano Benussi, MD, presented some of the highlights.
The guidelines issue a strong call for greater use of targeted ECG screening in populations at risk for silent AF, including stroke survivors and the elderly. And AF should always be documented before starting treatment, given that all of the treatments carry risk, said Dr. Kirchhof, professor of cardiovascular medicine at the University of Birmingham (England).
Once the diagnosis is established, it’s essential to address in a structured way five domains of management: acute rate and rhythm control; management of precipitating factors, including underlying cardiovascular conditions such as hypertension or valvular heart disease; assessment of stroke risk using the CHA2DS2-VASc scoring system; assessment of heart rate; and evaluation of the impact of AF symptoms on the patient’s life, including fatigue and breathlessness, using a structured instrument such as the modified European Heart Rhythm Association symptom scale.
Men with a CHA2DS2-VASc score of 1 and women with a score of 2 should be considered for anticoagulation. And the treatment should be recommended – not merely considered – for men with a score of 2 or more and women with a score of 3; that’s a Class Ia recommendation, Dr. Kirchhof continued.
The use of a specific bleeding risk score is no longer recommended in AF patients on oral anticoagulation. The emphasis has shifted to reduction of modifiable bleeding risk factors, including limiting alcohol intake to fewer than 8 drinks per week, control of hypertension, and discontinuing antiplatelet and anti-inflammatory agents.
Consideration of left atrial appendage occlusion devices should be reserved for the small percentage of patients who have clear contraindications to all forms of oral anticoagulation.
The task force concluded that patients who have bleeding on oral anticoagulation can often be managed with local therapy and discontinuation of anticoagulation therapy for a day or two before resumption. However, decisions regarding resumption of a NOAC or warfarin after an intracranial bleed should be handled by an interdisciplinary panel composed of a stroke neurologist, a cardiologist, a neuroradiologist, and a neurosurgeon.
Evidence-based treatment options in patients with symptomatic AF after failed catheter ablation include minimally invasive surgery with epicardial pulmonary vein isolation, more extensive catheter ablation, and hybrid procedures, according to Dr. Benussi, who is codirector of clinical cardiovascular surgery at University Hospital in Zurich.
The guidelines state that the data supporting catheter ablation to achieve long-term rhythm control are now sufficiently strong that this intervention should be considered as a first-line option alongside antiarrhythmic drugs as a matter of patient preference in the setting of symptomatic paroxysmal AF regardless of whether the patient has CAD, heart failure, valvular heart disease, or no structural heart disease.
Catheter ablation using radiofrequency energy or cryoablation should target complete isolation of the pulmonary veins.
“Additional ablation lines do not provide demonstrable clinical benefit and increase the risk of postablation left atrial arrhythmias,” the surgeon said.
Maze surgery, preferably biatrial, received a favorable Class IIa, Level of Evidence A recommendation as worthy of consideration in patients with symptomatic AF who are already undergoing cardiac surgery. This recommendation was based upon an external review by the Cochrane group which was commissioned by the guidelines task force. The Cochrane review of eight published studies concluded that Maze surgery under such circumstances was associated with a twofold increased freedom from AF, atrial flutter, and atrial tachycardia (Cochrane Database of Systematic Reviews 2016;8: CD012088. doi: 10.1002/14651858.CD012088.pub2).
The AF management guidelines are supported by the ESC Pocket Guidelines app, which includes an overall AF treatment manager developed by the European Union–funded CATCH ME (Characterizing Atrial Fibrillation by Translating its Causes Into Health Modifiers in the Elderly) project.
The multidisciplinary 17-member AF management task force was drawn from cardiology, stroke neurology, cardiac surgery, and specialist nursing. Dr. Kirchhof stressed that only recommendations supported by at least 75% of task force members made it into the guidelines (Eur Heart J. 2016 Aug 27. pii: ehw210. [Epub ahead of print] doi: 10.1093/eurheartj/ehw210).
ROME – The 2016 joint European guidelines on management of atrial fibrillation break new ground by declaring as a strong Class IA recommendation that the novel oral anticoagulants are now the drugs of choice – preferred over warfarin – for stroke prevention.
The joint guidelines from the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery recommend that warfarin’s use be reserved for the relatively small proportion of atrial fibrillation (AF) patients who are ineligible for the four commercially available novel oral anticoagulants (NOACs). That’s mainly patients with mechanical heart valves, moderate to severe mitral stenosis, or severe chronic kidney disease.
The ESC/EACTS guidelines, taken together with the American College of Chest Physicians guidelines on antithrombotic therapy for venous thromboembolic disease released earlier in the year, suggest that the old war horse warfarin is being eased out to pasture. The ACCP guidelines recommend any of the four NOACS – apixaban, dabigatran, edoxaban, or rivaroxaban – be used preferentially over warfarin in the treatment of venous thromboembolism (Chest 2016 Feb;149[2]:315-52). Both sets of guidelines cite compelling evidence that the NOACs are significantly safer than warfarin yet equally effective.
The ESC/EACTS guidelines are a full rewrite containing numerous departures from the previous 2012 AF management guidelines as well as from current ACC/AHA guidelines. The report includes more than 1,000 references. Eighty percent of the 154 recommendations provide Class I or IIa guidance. Two-thirds of the recommendations are Level of Evidence A or B, task force chairperson Paulus Kirchhof, MD, said at the annual congress of the European Society of Cardiology.
He and co-chairperson Stefano Benussi, MD, presented some of the highlights.
The guidelines issue a strong call for greater use of targeted ECG screening in populations at risk for silent AF, including stroke survivors and the elderly. And AF should always be documented before starting treatment, given that all of the treatments carry risk, said Dr. Kirchhof, professor of cardiovascular medicine at the University of Birmingham (England).
Once the diagnosis is established, it’s essential to address in a structured way five domains of management: acute rate and rhythm control; management of precipitating factors, including underlying cardiovascular conditions such as hypertension or valvular heart disease; assessment of stroke risk using the CHA2DS2-VASc scoring system; assessment of heart rate; and evaluation of the impact of AF symptoms on the patient’s life, including fatigue and breathlessness, using a structured instrument such as the modified European Heart Rhythm Association symptom scale.
Men with a CHA2DS2-VASc score of 1 and women with a score of 2 should be considered for anticoagulation. And the treatment should be recommended – not merely considered – for men with a score of 2 or more and women with a score of 3; that’s a Class Ia recommendation, Dr. Kirchhof continued.
The use of a specific bleeding risk score is no longer recommended in AF patients on oral anticoagulation. The emphasis has shifted to reduction of modifiable bleeding risk factors, including limiting alcohol intake to fewer than 8 drinks per week, control of hypertension, and discontinuing antiplatelet and anti-inflammatory agents.
Consideration of left atrial appendage occlusion devices should be reserved for the small percentage of patients who have clear contraindications to all forms of oral anticoagulation.
The task force concluded that patients who have bleeding on oral anticoagulation can often be managed with local therapy and discontinuation of anticoagulation therapy for a day or two before resumption. However, decisions regarding resumption of a NOAC or warfarin after an intracranial bleed should be handled by an interdisciplinary panel composed of a stroke neurologist, a cardiologist, a neuroradiologist, and a neurosurgeon.
Evidence-based treatment options in patients with symptomatic AF after failed catheter ablation include minimally invasive surgery with epicardial pulmonary vein isolation, more extensive catheter ablation, and hybrid procedures, according to Dr. Benussi, who is codirector of clinical cardiovascular surgery at University Hospital in Zurich.
The guidelines state that the data supporting catheter ablation to achieve long-term rhythm control are now sufficiently strong that this intervention should be considered as a first-line option alongside antiarrhythmic drugs as a matter of patient preference in the setting of symptomatic paroxysmal AF regardless of whether the patient has CAD, heart failure, valvular heart disease, or no structural heart disease.
Catheter ablation using radiofrequency energy or cryoablation should target complete isolation of the pulmonary veins.
“Additional ablation lines do not provide demonstrable clinical benefit and increase the risk of postablation left atrial arrhythmias,” the surgeon said.
Maze surgery, preferably biatrial, received a favorable Class IIa, Level of Evidence A recommendation as worthy of consideration in patients with symptomatic AF who are already undergoing cardiac surgery. This recommendation was based upon an external review by the Cochrane group which was commissioned by the guidelines task force. The Cochrane review of eight published studies concluded that Maze surgery under such circumstances was associated with a twofold increased freedom from AF, atrial flutter, and atrial tachycardia (Cochrane Database of Systematic Reviews 2016;8: CD012088. doi: 10.1002/14651858.CD012088.pub2).
The AF management guidelines are supported by the ESC Pocket Guidelines app, which includes an overall AF treatment manager developed by the European Union–funded CATCH ME (Characterizing Atrial Fibrillation by Translating its Causes Into Health Modifiers in the Elderly) project.
The multidisciplinary 17-member AF management task force was drawn from cardiology, stroke neurology, cardiac surgery, and specialist nursing. Dr. Kirchhof stressed that only recommendations supported by at least 75% of task force members made it into the guidelines (Eur Heart J. 2016 Aug 27. pii: ehw210. [Epub ahead of print] doi: 10.1093/eurheartj/ehw210).
ROME – The 2016 joint European guidelines on management of atrial fibrillation break new ground by declaring as a strong Class IA recommendation that the novel oral anticoagulants are now the drugs of choice – preferred over warfarin – for stroke prevention.
The joint guidelines from the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery recommend that warfarin’s use be reserved for the relatively small proportion of atrial fibrillation (AF) patients who are ineligible for the four commercially available novel oral anticoagulants (NOACs). That’s mainly patients with mechanical heart valves, moderate to severe mitral stenosis, or severe chronic kidney disease.
The ESC/EACTS guidelines, taken together with the American College of Chest Physicians guidelines on antithrombotic therapy for venous thromboembolic disease released earlier in the year, suggest that the old war horse warfarin is being eased out to pasture. The ACCP guidelines recommend any of the four NOACS – apixaban, dabigatran, edoxaban, or rivaroxaban – be used preferentially over warfarin in the treatment of venous thromboembolism (Chest 2016 Feb;149[2]:315-52). Both sets of guidelines cite compelling evidence that the NOACs are significantly safer than warfarin yet equally effective.
The ESC/EACTS guidelines are a full rewrite containing numerous departures from the previous 2012 AF management guidelines as well as from current ACC/AHA guidelines. The report includes more than 1,000 references. Eighty percent of the 154 recommendations provide Class I or IIa guidance. Two-thirds of the recommendations are Level of Evidence A or B, task force chairperson Paulus Kirchhof, MD, said at the annual congress of the European Society of Cardiology.
He and co-chairperson Stefano Benussi, MD, presented some of the highlights.
The guidelines issue a strong call for greater use of targeted ECG screening in populations at risk for silent AF, including stroke survivors and the elderly. And AF should always be documented before starting treatment, given that all of the treatments carry risk, said Dr. Kirchhof, professor of cardiovascular medicine at the University of Birmingham (England).
Once the diagnosis is established, it’s essential to address in a structured way five domains of management: acute rate and rhythm control; management of precipitating factors, including underlying cardiovascular conditions such as hypertension or valvular heart disease; assessment of stroke risk using the CHA2DS2-VASc scoring system; assessment of heart rate; and evaluation of the impact of AF symptoms on the patient’s life, including fatigue and breathlessness, using a structured instrument such as the modified European Heart Rhythm Association symptom scale.
Men with a CHA2DS2-VASc score of 1 and women with a score of 2 should be considered for anticoagulation. And the treatment should be recommended – not merely considered – for men with a score of 2 or more and women with a score of 3; that’s a Class Ia recommendation, Dr. Kirchhof continued.
The use of a specific bleeding risk score is no longer recommended in AF patients on oral anticoagulation. The emphasis has shifted to reduction of modifiable bleeding risk factors, including limiting alcohol intake to fewer than 8 drinks per week, control of hypertension, and discontinuing antiplatelet and anti-inflammatory agents.
Consideration of left atrial appendage occlusion devices should be reserved for the small percentage of patients who have clear contraindications to all forms of oral anticoagulation.
The task force concluded that patients who have bleeding on oral anticoagulation can often be managed with local therapy and discontinuation of anticoagulation therapy for a day or two before resumption. However, decisions regarding resumption of a NOAC or warfarin after an intracranial bleed should be handled by an interdisciplinary panel composed of a stroke neurologist, a cardiologist, a neuroradiologist, and a neurosurgeon.
Evidence-based treatment options in patients with symptomatic AF after failed catheter ablation include minimally invasive surgery with epicardial pulmonary vein isolation, more extensive catheter ablation, and hybrid procedures, according to Dr. Benussi, who is codirector of clinical cardiovascular surgery at University Hospital in Zurich.
The guidelines state that the data supporting catheter ablation to achieve long-term rhythm control are now sufficiently strong that this intervention should be considered as a first-line option alongside antiarrhythmic drugs as a matter of patient preference in the setting of symptomatic paroxysmal AF regardless of whether the patient has CAD, heart failure, valvular heart disease, or no structural heart disease.
Catheter ablation using radiofrequency energy or cryoablation should target complete isolation of the pulmonary veins.
“Additional ablation lines do not provide demonstrable clinical benefit and increase the risk of postablation left atrial arrhythmias,” the surgeon said.
Maze surgery, preferably biatrial, received a favorable Class IIa, Level of Evidence A recommendation as worthy of consideration in patients with symptomatic AF who are already undergoing cardiac surgery. This recommendation was based upon an external review by the Cochrane group which was commissioned by the guidelines task force. The Cochrane review of eight published studies concluded that Maze surgery under such circumstances was associated with a twofold increased freedom from AF, atrial flutter, and atrial tachycardia (Cochrane Database of Systematic Reviews 2016;8: CD012088. doi: 10.1002/14651858.CD012088.pub2).
The AF management guidelines are supported by the ESC Pocket Guidelines app, which includes an overall AF treatment manager developed by the European Union–funded CATCH ME (Characterizing Atrial Fibrillation by Translating its Causes Into Health Modifiers in the Elderly) project.
The multidisciplinary 17-member AF management task force was drawn from cardiology, stroke neurology, cardiac surgery, and specialist nursing. Dr. Kirchhof stressed that only recommendations supported by at least 75% of task force members made it into the guidelines (Eur Heart J. 2016 Aug 27. pii: ehw210. [Epub ahead of print] doi: 10.1093/eurheartj/ehw210).
Modafinil improves cognitive impairment in remitted depression
VIENNA – Modafinil shows potential for the treatment of episodic and working memory dysfunction in patients with remitted depression, Muzaffer Kaser, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
He presented a randomized, double-blind, placebo-controlled proof-of-concept study in which 60 patients with remitted depression undertook a battery of cognitive tests before and 2 hours after either a single 200-mg dose of modafinil or placebo.
“For episodic memory we saw a medium-to-large effect size for modafinil’s effects over placebo, and a medium effect size for working memory. So for administration of a single dose we think these results are quite promising,” said Dr. Kaser, a psychiatrist and PhD candidate at the University of Cambridge, England.
Longer-term studies of modafinil are planned in light of the major unmet need for treatments to address cognitive dysfunction in depression, he added in an interview. Currently, there are none. Yet it is now recognized that cognitive dysfunction in the domains of memory, attention, and planning are a core feature of depression, and they tend to persist after mood symptoms have recovered.
“Because of the cognitive dysfunction, people have difficulty getting back to work at the same pre-illness level, which creates more stress and increases the potential for future relapse. So cognitive dysfunction in depression should be a target for treatment,” the psychiatrist said.
Modafinil’s well-established safety profile makes it an attractive candidate, he continued. In placebo-controlled studies of the drug as augmentation therapy for depression, modafinil’s side effects were at the placebo level.
In this proof-of-concept study, the payoff with a single dose of modafinil was confined to the domain of memory, where the effects were most evident at the most difficult stages of the tests. Most impressively, the modafinil group made half as many errors on the episodic memory test. However, the drug did not improve performance on tests of planning accuracy or sustained attention.
Study participants had a mean of 3.2 prior depressive episodes and were in their current remission for 8.2 months.
The tests were drawn from the Cambridge Neuropsychological Test Automated Battery. They included the Paired Associates Learning measure of episodic memory, Spatial Working Memory, the Stockings of Cambridge measure of planning and executive function, and the Rapid Visual Information Processing measure of sustained attention.
The study was funded by the U.K. Medical Research Council and the Wellcome Trust. Dr. Kaser reported having no financial conflicts of interest.
Correction, 12/15/16: An earlier version of this article misstated Dr. Kaser's name in the photo caption.
VIENNA – Modafinil shows potential for the treatment of episodic and working memory dysfunction in patients with remitted depression, Muzaffer Kaser, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
He presented a randomized, double-blind, placebo-controlled proof-of-concept study in which 60 patients with remitted depression undertook a battery of cognitive tests before and 2 hours after either a single 200-mg dose of modafinil or placebo.
“For episodic memory we saw a medium-to-large effect size for modafinil’s effects over placebo, and a medium effect size for working memory. So for administration of a single dose we think these results are quite promising,” said Dr. Kaser, a psychiatrist and PhD candidate at the University of Cambridge, England.
Longer-term studies of modafinil are planned in light of the major unmet need for treatments to address cognitive dysfunction in depression, he added in an interview. Currently, there are none. Yet it is now recognized that cognitive dysfunction in the domains of memory, attention, and planning are a core feature of depression, and they tend to persist after mood symptoms have recovered.
“Because of the cognitive dysfunction, people have difficulty getting back to work at the same pre-illness level, which creates more stress and increases the potential for future relapse. So cognitive dysfunction in depression should be a target for treatment,” the psychiatrist said.
Modafinil’s well-established safety profile makes it an attractive candidate, he continued. In placebo-controlled studies of the drug as augmentation therapy for depression, modafinil’s side effects were at the placebo level.
In this proof-of-concept study, the payoff with a single dose of modafinil was confined to the domain of memory, where the effects were most evident at the most difficult stages of the tests. Most impressively, the modafinil group made half as many errors on the episodic memory test. However, the drug did not improve performance on tests of planning accuracy or sustained attention.
Study participants had a mean of 3.2 prior depressive episodes and were in their current remission for 8.2 months.
The tests were drawn from the Cambridge Neuropsychological Test Automated Battery. They included the Paired Associates Learning measure of episodic memory, Spatial Working Memory, the Stockings of Cambridge measure of planning and executive function, and the Rapid Visual Information Processing measure of sustained attention.
The study was funded by the U.K. Medical Research Council and the Wellcome Trust. Dr. Kaser reported having no financial conflicts of interest.
Correction, 12/15/16: An earlier version of this article misstated Dr. Kaser's name in the photo caption.
VIENNA – Modafinil shows potential for the treatment of episodic and working memory dysfunction in patients with remitted depression, Muzaffer Kaser, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
He presented a randomized, double-blind, placebo-controlled proof-of-concept study in which 60 patients with remitted depression undertook a battery of cognitive tests before and 2 hours after either a single 200-mg dose of modafinil or placebo.
“For episodic memory we saw a medium-to-large effect size for modafinil’s effects over placebo, and a medium effect size for working memory. So for administration of a single dose we think these results are quite promising,” said Dr. Kaser, a psychiatrist and PhD candidate at the University of Cambridge, England.
Longer-term studies of modafinil are planned in light of the major unmet need for treatments to address cognitive dysfunction in depression, he added in an interview. Currently, there are none. Yet it is now recognized that cognitive dysfunction in the domains of memory, attention, and planning are a core feature of depression, and they tend to persist after mood symptoms have recovered.
“Because of the cognitive dysfunction, people have difficulty getting back to work at the same pre-illness level, which creates more stress and increases the potential for future relapse. So cognitive dysfunction in depression should be a target for treatment,” the psychiatrist said.
Modafinil’s well-established safety profile makes it an attractive candidate, he continued. In placebo-controlled studies of the drug as augmentation therapy for depression, modafinil’s side effects were at the placebo level.
In this proof-of-concept study, the payoff with a single dose of modafinil was confined to the domain of memory, where the effects were most evident at the most difficult stages of the tests. Most impressively, the modafinil group made half as many errors on the episodic memory test. However, the drug did not improve performance on tests of planning accuracy or sustained attention.
Study participants had a mean of 3.2 prior depressive episodes and were in their current remission for 8.2 months.
The tests were drawn from the Cambridge Neuropsychological Test Automated Battery. They included the Paired Associates Learning measure of episodic memory, Spatial Working Memory, the Stockings of Cambridge measure of planning and executive function, and the Rapid Visual Information Processing measure of sustained attention.
The study was funded by the U.K. Medical Research Council and the Wellcome Trust. Dr. Kaser reported having no financial conflicts of interest.
Correction, 12/15/16: An earlier version of this article misstated Dr. Kaser's name in the photo caption.
Key clinical point:
Major finding: Patients with remitted depression made half as many errors on a well-established measure of episodic memory 2 hours after taking a single dose of modafinil, compared with placebo.
Data source: This double-blind, randomized, placebo-controlled study included 60 adults with remitted depression who underwent cognitive testing before and 2 hours after taking a single 200-mg dose of modafinil or placebo.
Disclosures: The study was funded by the UK Medical Research Council and the Wellcome Trust. The presenter reported having no financial conflicts of interest.
Ketamine augmentation doesn’t boost ECT outcomes
VIENNA – Low-dose ketamine provided no benefit as adjunctive anesthesia for severely depressed patients undergoing electroconvulsive therapy in the randomized, multicenter U.K. Ketamine-ECT Study, Ian Anderson, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
The hope was that ketamine would lessen the cognitive impairment that is a prominent side effect of ECT. It’s thought that this cognitive impairment results from treatment-induced excessive stimulation of glutamate receptors, and ketamine is a glutamate antagonist, explained Dr. Anderson of the University of Manchester (England).
He and his coinvestigators had also hypothesized that ketamine might result in more rapid improvement in depression in patients undergoing ECT, since a single intravenous infusion of the drug has been shown to produce an extremely rapid, albeit temporary, antidepressant effect. But this was not borne out in the Ketamine-ECT Study.
Dr. Anderson reported on 70 severely depressed patients who were randomized to ketamine at 0.5 mg/kg or saline as an adjunct to standard propofol anesthesia for their course of weekly ECT sessions at seven U.K. mental health centers.
The primary study endpoint was the delayed verbal recall score on the Hopkins Verbal Learning Test–Revised after four ECT sessions, which was midway through the full course of treatment. Blinded assessors found no significant difference between the ketamine and placebo groups then. Nor were significant differences evident at prespecified further assessments 1 and 4 months after conclusion of the treatment program.
Secondary outcomes comprised of cognitive measures of verbal fluency, and autobiographical, working, and visual memory also proved similar in the two study arms, as did assessments of quality of life, safety, and tolerability.
At the end of the full course of ECT, 39% of the ketamine group were categorized as being in remission based upon at least a 50% drop from their baseline score on the Montgomery-Åsberg Depression Rating Scale (MADRS) with a final score of 10 or less, as were 35% of controls. Forty-nine percent of the ketamine group and 60% of controls were categorized as treatment responders, meaning their MADRS score dropped by at least 50% but their final score was greater than 10.
No serious adverse reactions to ketamine occurred.
The study was funded by the United Kingdom's National Institute for Health Research and the Medical Research Council. Dr. Anderson reported having no relevant financial conflicts.
VIENNA – Low-dose ketamine provided no benefit as adjunctive anesthesia for severely depressed patients undergoing electroconvulsive therapy in the randomized, multicenter U.K. Ketamine-ECT Study, Ian Anderson, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
The hope was that ketamine would lessen the cognitive impairment that is a prominent side effect of ECT. It’s thought that this cognitive impairment results from treatment-induced excessive stimulation of glutamate receptors, and ketamine is a glutamate antagonist, explained Dr. Anderson of the University of Manchester (England).
He and his coinvestigators had also hypothesized that ketamine might result in more rapid improvement in depression in patients undergoing ECT, since a single intravenous infusion of the drug has been shown to produce an extremely rapid, albeit temporary, antidepressant effect. But this was not borne out in the Ketamine-ECT Study.
Dr. Anderson reported on 70 severely depressed patients who were randomized to ketamine at 0.5 mg/kg or saline as an adjunct to standard propofol anesthesia for their course of weekly ECT sessions at seven U.K. mental health centers.
The primary study endpoint was the delayed verbal recall score on the Hopkins Verbal Learning Test–Revised after four ECT sessions, which was midway through the full course of treatment. Blinded assessors found no significant difference between the ketamine and placebo groups then. Nor were significant differences evident at prespecified further assessments 1 and 4 months after conclusion of the treatment program.
Secondary outcomes comprised of cognitive measures of verbal fluency, and autobiographical, working, and visual memory also proved similar in the two study arms, as did assessments of quality of life, safety, and tolerability.
At the end of the full course of ECT, 39% of the ketamine group were categorized as being in remission based upon at least a 50% drop from their baseline score on the Montgomery-Åsberg Depression Rating Scale (MADRS) with a final score of 10 or less, as were 35% of controls. Forty-nine percent of the ketamine group and 60% of controls were categorized as treatment responders, meaning their MADRS score dropped by at least 50% but their final score was greater than 10.
No serious adverse reactions to ketamine occurred.
The study was funded by the United Kingdom's National Institute for Health Research and the Medical Research Council. Dr. Anderson reported having no relevant financial conflicts.
VIENNA – Low-dose ketamine provided no benefit as adjunctive anesthesia for severely depressed patients undergoing electroconvulsive therapy in the randomized, multicenter U.K. Ketamine-ECT Study, Ian Anderson, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
The hope was that ketamine would lessen the cognitive impairment that is a prominent side effect of ECT. It’s thought that this cognitive impairment results from treatment-induced excessive stimulation of glutamate receptors, and ketamine is a glutamate antagonist, explained Dr. Anderson of the University of Manchester (England).
He and his coinvestigators had also hypothesized that ketamine might result in more rapid improvement in depression in patients undergoing ECT, since a single intravenous infusion of the drug has been shown to produce an extremely rapid, albeit temporary, antidepressant effect. But this was not borne out in the Ketamine-ECT Study.
Dr. Anderson reported on 70 severely depressed patients who were randomized to ketamine at 0.5 mg/kg or saline as an adjunct to standard propofol anesthesia for their course of weekly ECT sessions at seven U.K. mental health centers.
The primary study endpoint was the delayed verbal recall score on the Hopkins Verbal Learning Test–Revised after four ECT sessions, which was midway through the full course of treatment. Blinded assessors found no significant difference between the ketamine and placebo groups then. Nor were significant differences evident at prespecified further assessments 1 and 4 months after conclusion of the treatment program.
Secondary outcomes comprised of cognitive measures of verbal fluency, and autobiographical, working, and visual memory also proved similar in the two study arms, as did assessments of quality of life, safety, and tolerability.
At the end of the full course of ECT, 39% of the ketamine group were categorized as being in remission based upon at least a 50% drop from their baseline score on the Montgomery-Åsberg Depression Rating Scale (MADRS) with a final score of 10 or less, as were 35% of controls. Forty-nine percent of the ketamine group and 60% of controls were categorized as treatment responders, meaning their MADRS score dropped by at least 50% but their final score was greater than 10.
No serious adverse reactions to ketamine occurred.
The study was funded by the United Kingdom's National Institute for Health Research and the Medical Research Council. Dr. Anderson reported having no relevant financial conflicts.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: Cognitive impairment as measured by delayed verbal recall on the Hopkins Verbal Learning Task–Revised was not reduced by the use of ketamine as an adjunctive anesthetic agent for ECT.
Data source: This randomized, multicenter trial featuring blinded assessments included 70 severely depressed patients who received either ketamine or saline in addition to standard anesthesia during their ECT sessions.
Disclosures: The Ketamine-ECT Study was funded by the U.K. National Institute for Health Research and the Medical Research Council. The presenter reported having no conflicts of interest.
SAVR for radiation-induced aortic stenosis has high late mortality
ROME – Radiation-induced aortic stenosis is associated with markedly worse long-term outcome after surgical aortic valve replacement than when the operation is performed in patients without a history of radiotherapy, Milind Y. Desai, MD, reported at the annual congress of the European Society of Cardiology.
Moreover, the Society of Thoracic Surgeons (STS) score isn’t good at risk-stratifying patients with radiation-induced aortic stenosis who are under consideration for surgical aortic valve replacement (SAVR).
Radiation-induced heart disease is a late complication of thoracic radiotherapy. It’s particularly common in patients who got radiation for lymphomas or breast cancer. It can affect any cardiac structure, including the myocardium, pericardium, valves, coronary arteries, and the conduction system.
Aortic stenosis is the most common valvular manifestation, present in roughly 80% of patients with radiation-induced heart disease. At the Cleveland Clinic, the average time from radiotherapy to development of radiation-induced aortic stenosis (RIAS) is about 20 years. The condition is characterized by thickening of the junction between the base of the anterior mitral leaflet and aortic root, known as the aortomitral curtain, Dr. Desai explained.
He presented a retrospective observational cohort study involving 172 patients who underwent SAVR for RIAS and an equal number of SAVR patients with no such history. The groups were matched by age, sex, aortic valve area, and type and timing of SAVR. Of note, the group with RIAS had a mean preoperative STS score of 11, and the control group averaged a similar score of 10.
The key finding: During a mean follow-up of 6 years, the all-cause mortality rate was a hefty 48% in patients with RIAS, compared with just 7% in matched controls. Only about 5% of deaths in the group with RIAS were from recurrent malignancy. The low figure is not surprising given the average 20-year lag between radiotherapy and development of radiation-induced heart disease.
“In our experience, most of these patients develop a recurrent pleural effusion and nasty cardiopulmonary issues that result in their death,” according to Dr. Desai.
In a multivariate Cox proportional hazards analysis, a history of chest radiation therapy was by far the strongest predictor of all-cause mortality, conferring an 8.5-fold increase in risk.
The only other statistically significant predictor of mortality during follow-up in multivariate analysis was a high STS score, with an associated weak albeit statistically significant 1.15-fold increased risk. A total of 30 of 78 (39%) RIAS patients with an STS score below 4 died during follow-up, compared with none of 91 controls.
Thirty-four of 92 (37%) RIAS patients under age 65 died during follow-up, whereas none of 83 control SAVR patients did so.
Having coronary artery bypass surgery or other cardiac surgery at the time of SAVR was not associated with significantly increased risk of mortality compared with solo SAVR.
In-hospital outcomes were consistently worse after SAVR in the RIAS group. Half of the RIAS patients experienced in-hospital atrial fibrillation and 29% developed persistent atrial fibrillation, compared with 30% and 24% of controls. About 22% of RIAS patients were readmitted within 3 months after surgery, as were only 8% of controls. In-hospital mortality occurred in 2% of SAVR patients with RIAS; none of the matched controls did.
Dr. Desai reported having no financial interests relative to this study.
ROME – Radiation-induced aortic stenosis is associated with markedly worse long-term outcome after surgical aortic valve replacement than when the operation is performed in patients without a history of radiotherapy, Milind Y. Desai, MD, reported at the annual congress of the European Society of Cardiology.
Moreover, the Society of Thoracic Surgeons (STS) score isn’t good at risk-stratifying patients with radiation-induced aortic stenosis who are under consideration for surgical aortic valve replacement (SAVR).
Radiation-induced heart disease is a late complication of thoracic radiotherapy. It’s particularly common in patients who got radiation for lymphomas or breast cancer. It can affect any cardiac structure, including the myocardium, pericardium, valves, coronary arteries, and the conduction system.
Aortic stenosis is the most common valvular manifestation, present in roughly 80% of patients with radiation-induced heart disease. At the Cleveland Clinic, the average time from radiotherapy to development of radiation-induced aortic stenosis (RIAS) is about 20 years. The condition is characterized by thickening of the junction between the base of the anterior mitral leaflet and aortic root, known as the aortomitral curtain, Dr. Desai explained.
He presented a retrospective observational cohort study involving 172 patients who underwent SAVR for RIAS and an equal number of SAVR patients with no such history. The groups were matched by age, sex, aortic valve area, and type and timing of SAVR. Of note, the group with RIAS had a mean preoperative STS score of 11, and the control group averaged a similar score of 10.
The key finding: During a mean follow-up of 6 years, the all-cause mortality rate was a hefty 48% in patients with RIAS, compared with just 7% in matched controls. Only about 5% of deaths in the group with RIAS were from recurrent malignancy. The low figure is not surprising given the average 20-year lag between radiotherapy and development of radiation-induced heart disease.
“In our experience, most of these patients develop a recurrent pleural effusion and nasty cardiopulmonary issues that result in their death,” according to Dr. Desai.
In a multivariate Cox proportional hazards analysis, a history of chest radiation therapy was by far the strongest predictor of all-cause mortality, conferring an 8.5-fold increase in risk.
The only other statistically significant predictor of mortality during follow-up in multivariate analysis was a high STS score, with an associated weak albeit statistically significant 1.15-fold increased risk. A total of 30 of 78 (39%) RIAS patients with an STS score below 4 died during follow-up, compared with none of 91 controls.
Thirty-four of 92 (37%) RIAS patients under age 65 died during follow-up, whereas none of 83 control SAVR patients did so.
Having coronary artery bypass surgery or other cardiac surgery at the time of SAVR was not associated with significantly increased risk of mortality compared with solo SAVR.
In-hospital outcomes were consistently worse after SAVR in the RIAS group. Half of the RIAS patients experienced in-hospital atrial fibrillation and 29% developed persistent atrial fibrillation, compared with 30% and 24% of controls. About 22% of RIAS patients were readmitted within 3 months after surgery, as were only 8% of controls. In-hospital mortality occurred in 2% of SAVR patients with RIAS; none of the matched controls did.
Dr. Desai reported having no financial interests relative to this study.
ROME – Radiation-induced aortic stenosis is associated with markedly worse long-term outcome after surgical aortic valve replacement than when the operation is performed in patients without a history of radiotherapy, Milind Y. Desai, MD, reported at the annual congress of the European Society of Cardiology.
Moreover, the Society of Thoracic Surgeons (STS) score isn’t good at risk-stratifying patients with radiation-induced aortic stenosis who are under consideration for surgical aortic valve replacement (SAVR).
Radiation-induced heart disease is a late complication of thoracic radiotherapy. It’s particularly common in patients who got radiation for lymphomas or breast cancer. It can affect any cardiac structure, including the myocardium, pericardium, valves, coronary arteries, and the conduction system.
Aortic stenosis is the most common valvular manifestation, present in roughly 80% of patients with radiation-induced heart disease. At the Cleveland Clinic, the average time from radiotherapy to development of radiation-induced aortic stenosis (RIAS) is about 20 years. The condition is characterized by thickening of the junction between the base of the anterior mitral leaflet and aortic root, known as the aortomitral curtain, Dr. Desai explained.
He presented a retrospective observational cohort study involving 172 patients who underwent SAVR for RIAS and an equal number of SAVR patients with no such history. The groups were matched by age, sex, aortic valve area, and type and timing of SAVR. Of note, the group with RIAS had a mean preoperative STS score of 11, and the control group averaged a similar score of 10.
The key finding: During a mean follow-up of 6 years, the all-cause mortality rate was a hefty 48% in patients with RIAS, compared with just 7% in matched controls. Only about 5% of deaths in the group with RIAS were from recurrent malignancy. The low figure is not surprising given the average 20-year lag between radiotherapy and development of radiation-induced heart disease.
“In our experience, most of these patients develop a recurrent pleural effusion and nasty cardiopulmonary issues that result in their death,” according to Dr. Desai.
In a multivariate Cox proportional hazards analysis, a history of chest radiation therapy was by far the strongest predictor of all-cause mortality, conferring an 8.5-fold increase in risk.
The only other statistically significant predictor of mortality during follow-up in multivariate analysis was a high STS score, with an associated weak albeit statistically significant 1.15-fold increased risk. A total of 30 of 78 (39%) RIAS patients with an STS score below 4 died during follow-up, compared with none of 91 controls.
Thirty-four of 92 (37%) RIAS patients under age 65 died during follow-up, whereas none of 83 control SAVR patients did so.
Having coronary artery bypass surgery or other cardiac surgery at the time of SAVR was not associated with significantly increased risk of mortality compared with solo SAVR.
In-hospital outcomes were consistently worse after SAVR in the RIAS group. Half of the RIAS patients experienced in-hospital atrial fibrillation and 29% developed persistent atrial fibrillation, compared with 30% and 24% of controls. About 22% of RIAS patients were readmitted within 3 months after surgery, as were only 8% of controls. In-hospital mortality occurred in 2% of SAVR patients with RIAS; none of the matched controls did.
Dr. Desai reported having no financial interests relative to this study.
AT THE ESC CONGRESS 2016
Key clinical point:
Major finding: All-cause mortality occurred in 48% of 172 patients with radiation-induced severe aortic stenosis during a mean follow-up of 6 years after surgical aortic valve replacement, compared with just 7% of matched controls.
Data source: This was a retrospective observational study involving 172 closely matched pairs of surgical aortic valve replacement patients.
Disclosures: The presenter reported having no financial conflicts of interest regarding this study.
Tildrakizumab for psoriasis scores high marks in phase III
VIENNA – The investigational interleukin-23 p-19 subunit inhibitor tildrakizumab achieved PASI 90 improvement rates approaching 60% in patients with moderate to severe plaque psoriasis at week 28 of the pivotal phase III reSURFACE 1 and reSURFACE 2 trials, Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Moreover, the PASI 100 rate at week 28 in the two clinical trials was 24% with tildrakizumab, a humanized monoclonal antibody, at the 100-mg dose and 30% at 200 mg.
It was at these highest efficacy thresholds that the p-19 inhibitor really separated itself from etanercept (Enbrel) in reSURFACE 2, where the two biologics went head-to-head in randomized fashion. Patients on etanercept had a PASI 90 rate at week 28 of 31%, roughly only half that of tildrakizumab at the higher dose.
Guselkumab was the other IL-23 p-19 inhibitor that was a featured attraction at the EADV congress, with 48-week outcomes presented from the 837-patient, pivotal phase III VOYAGE 1 trial. Although caution is always warranted in comparing results across clinical trials because of differences in study populations, guselkumab achieved better top-end efficacy numbers than did tildrakizumab: a PASI 90 of 73.3% at 16 weeks and 80.2% at 24 weeks, along with PASI 100 responses of 34.4% at 16 weeks and 44.4% at 24 weeks.
“I believe there will be characteristics of the new drugs beyond efficacy that will come into play when making treatment decisions: Is dosing every 8 weeks or every 12 weeks? What is the price? What is the outcome after 1 year? I think it’s too early to close the book in trying to understand what these different drugs do, but these phase III results do give us the insight that IL-23 p-19 is actually the sweet spot in psoriasis. By targeting it we are able to keep the disease under control with drugs that are very convenient to use,” Dr. Reich said.
He added that his psoriasis patients really appreciate the convenience of quarterly as opposed to more frequent dosing of biologics, and he does, too.
reSURFACE 1 is a 64-week, randomized, phase III trial conducted in the United States, Canada, and Europe in which 772 patients were randomized 2:2:1 to tildrakizumab at 100 mg or 200 mg or to placebo. reSURFACE 2 is a 64-week trial in which 1,090 patients were randomized 2:2:1:2 to tildrakizumab at 100 mg or 200 mg, placebo, or etanercept at 50 mg twice weekly for the first 12 weeks and once weekly thereafter. At week 12 in both trials, patients on placebo were rerandomized to tildrakizumab at 100 or 200 mg for the duration. Participants averaged a baseline Psoriasis Area and Severity index score of 20, a body weight of 88 kg, and disease involvement over 31% of their body surface area.
Tildrakizumab was dosed in a regimen that’s the same as for ustekinumab (Stelara), which inhibits IL-12 as well as IL-23: one subcutaneous injection at baseline, another 1 month later, and every 12 weeks thereafter.
Dr. Reich presented results of the two pivotal trials through week 28. The coprimary efficacy endpoints in both studies were the PASI 75 response and proportion of subjects with a Physician’s Global Assessment (PGA) score of 0 or 1, meaning clear or minimal disease, compared with placebo at week 12. In hindsight, he said, those were not the best endpoints to have employed.
“We have here a drug that takes a little while to get to full throttle. The primary endpoint selected here at week 12 does not show efficacy data that really separates tildrakizumab from a drug like Stelara. But at week 28 you move toward levels of PASI 90 and PASI 100 response that we really want to see,” the dermatologist said.
Combining the results of reSURFACE 1 and 2, the PASI 75 response rate at week 12 – after only two doses – was 63% in the 100-mg arm and 64% at 200 mg. But the rates kept climbing thereafter such that by week 28 the PASI 75 rates were 77% and 78%.
Fifty-seven percent of patients on tildrakizumab at 100 mg had a PGA score of 0 or 1 at week 12, as did 6% of placebo-treated controls. By week 28, 66% of patients on the lower dose of the p-19 inhibitor had a PGA of 0 or 1. Rates in patients on tildrakizumab at 200 mg were 57% and 66% at 12 and 28 weeks, respectively.
Rates of adverse events of special interest in new biologic agents, including severe infections, malignancies, and major cardiovascular events, were similarly low across all study arms.
“My feeling is that looking at week 12 and week 28 safety data is of limited value. All I can say here is that through week 28 in these two studies I don’t see a safety signal. But for me, the real insight will have to come from larger studies with longer follow-up,” Dr. Reich said.
Asked why he thinks tildrakizumab is a slow starter, with only middling efficacy at the 12-week mark before subsequently picking up steam, he said it’s probably not a matter of the wrong doses being selected for reSURFACE 1 and 2, since the outcomes with 100 and 200 mg are fairly similar. More likely, the monoclonal antibody takes a bit longer to bind to its target and neutralize it than do some of the other biologics.
“It could be that if you dosed tildrakizumab at weeks 0, 2, and 8 as induction therapy you’d hit the mark at 12 weeks,” he added.
The reSURFACE trials are funded by Sun Pharma and Merck. Dr. Reich reported having received research grants from and serving as a consultant to Merck and numerous other pharmaceutical companies interested in new treatments for inflammatory skin diseases.
VIENNA – The investigational interleukin-23 p-19 subunit inhibitor tildrakizumab achieved PASI 90 improvement rates approaching 60% in patients with moderate to severe plaque psoriasis at week 28 of the pivotal phase III reSURFACE 1 and reSURFACE 2 trials, Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Moreover, the PASI 100 rate at week 28 in the two clinical trials was 24% with tildrakizumab, a humanized monoclonal antibody, at the 100-mg dose and 30% at 200 mg.
It was at these highest efficacy thresholds that the p-19 inhibitor really separated itself from etanercept (Enbrel) in reSURFACE 2, where the two biologics went head-to-head in randomized fashion. Patients on etanercept had a PASI 90 rate at week 28 of 31%, roughly only half that of tildrakizumab at the higher dose.
Guselkumab was the other IL-23 p-19 inhibitor that was a featured attraction at the EADV congress, with 48-week outcomes presented from the 837-patient, pivotal phase III VOYAGE 1 trial. Although caution is always warranted in comparing results across clinical trials because of differences in study populations, guselkumab achieved better top-end efficacy numbers than did tildrakizumab: a PASI 90 of 73.3% at 16 weeks and 80.2% at 24 weeks, along with PASI 100 responses of 34.4% at 16 weeks and 44.4% at 24 weeks.
“I believe there will be characteristics of the new drugs beyond efficacy that will come into play when making treatment decisions: Is dosing every 8 weeks or every 12 weeks? What is the price? What is the outcome after 1 year? I think it’s too early to close the book in trying to understand what these different drugs do, but these phase III results do give us the insight that IL-23 p-19 is actually the sweet spot in psoriasis. By targeting it we are able to keep the disease under control with drugs that are very convenient to use,” Dr. Reich said.
He added that his psoriasis patients really appreciate the convenience of quarterly as opposed to more frequent dosing of biologics, and he does, too.
reSURFACE 1 is a 64-week, randomized, phase III trial conducted in the United States, Canada, and Europe in which 772 patients were randomized 2:2:1 to tildrakizumab at 100 mg or 200 mg or to placebo. reSURFACE 2 is a 64-week trial in which 1,090 patients were randomized 2:2:1:2 to tildrakizumab at 100 mg or 200 mg, placebo, or etanercept at 50 mg twice weekly for the first 12 weeks and once weekly thereafter. At week 12 in both trials, patients on placebo were rerandomized to tildrakizumab at 100 or 200 mg for the duration. Participants averaged a baseline Psoriasis Area and Severity index score of 20, a body weight of 88 kg, and disease involvement over 31% of their body surface area.
Tildrakizumab was dosed in a regimen that’s the same as for ustekinumab (Stelara), which inhibits IL-12 as well as IL-23: one subcutaneous injection at baseline, another 1 month later, and every 12 weeks thereafter.
Dr. Reich presented results of the two pivotal trials through week 28. The coprimary efficacy endpoints in both studies were the PASI 75 response and proportion of subjects with a Physician’s Global Assessment (PGA) score of 0 or 1, meaning clear or minimal disease, compared with placebo at week 12. In hindsight, he said, those were not the best endpoints to have employed.
“We have here a drug that takes a little while to get to full throttle. The primary endpoint selected here at week 12 does not show efficacy data that really separates tildrakizumab from a drug like Stelara. But at week 28 you move toward levels of PASI 90 and PASI 100 response that we really want to see,” the dermatologist said.
Combining the results of reSURFACE 1 and 2, the PASI 75 response rate at week 12 – after only two doses – was 63% in the 100-mg arm and 64% at 200 mg. But the rates kept climbing thereafter such that by week 28 the PASI 75 rates were 77% and 78%.
Fifty-seven percent of patients on tildrakizumab at 100 mg had a PGA score of 0 or 1 at week 12, as did 6% of placebo-treated controls. By week 28, 66% of patients on the lower dose of the p-19 inhibitor had a PGA of 0 or 1. Rates in patients on tildrakizumab at 200 mg were 57% and 66% at 12 and 28 weeks, respectively.
Rates of adverse events of special interest in new biologic agents, including severe infections, malignancies, and major cardiovascular events, were similarly low across all study arms.
“My feeling is that looking at week 12 and week 28 safety data is of limited value. All I can say here is that through week 28 in these two studies I don’t see a safety signal. But for me, the real insight will have to come from larger studies with longer follow-up,” Dr. Reich said.
Asked why he thinks tildrakizumab is a slow starter, with only middling efficacy at the 12-week mark before subsequently picking up steam, he said it’s probably not a matter of the wrong doses being selected for reSURFACE 1 and 2, since the outcomes with 100 and 200 mg are fairly similar. More likely, the monoclonal antibody takes a bit longer to bind to its target and neutralize it than do some of the other biologics.
“It could be that if you dosed tildrakizumab at weeks 0, 2, and 8 as induction therapy you’d hit the mark at 12 weeks,” he added.
The reSURFACE trials are funded by Sun Pharma and Merck. Dr. Reich reported having received research grants from and serving as a consultant to Merck and numerous other pharmaceutical companies interested in new treatments for inflammatory skin diseases.
VIENNA – The investigational interleukin-23 p-19 subunit inhibitor tildrakizumab achieved PASI 90 improvement rates approaching 60% in patients with moderate to severe plaque psoriasis at week 28 of the pivotal phase III reSURFACE 1 and reSURFACE 2 trials, Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Moreover, the PASI 100 rate at week 28 in the two clinical trials was 24% with tildrakizumab, a humanized monoclonal antibody, at the 100-mg dose and 30% at 200 mg.
It was at these highest efficacy thresholds that the p-19 inhibitor really separated itself from etanercept (Enbrel) in reSURFACE 2, where the two biologics went head-to-head in randomized fashion. Patients on etanercept had a PASI 90 rate at week 28 of 31%, roughly only half that of tildrakizumab at the higher dose.
Guselkumab was the other IL-23 p-19 inhibitor that was a featured attraction at the EADV congress, with 48-week outcomes presented from the 837-patient, pivotal phase III VOYAGE 1 trial. Although caution is always warranted in comparing results across clinical trials because of differences in study populations, guselkumab achieved better top-end efficacy numbers than did tildrakizumab: a PASI 90 of 73.3% at 16 weeks and 80.2% at 24 weeks, along with PASI 100 responses of 34.4% at 16 weeks and 44.4% at 24 weeks.
“I believe there will be characteristics of the new drugs beyond efficacy that will come into play when making treatment decisions: Is dosing every 8 weeks or every 12 weeks? What is the price? What is the outcome after 1 year? I think it’s too early to close the book in trying to understand what these different drugs do, but these phase III results do give us the insight that IL-23 p-19 is actually the sweet spot in psoriasis. By targeting it we are able to keep the disease under control with drugs that are very convenient to use,” Dr. Reich said.
He added that his psoriasis patients really appreciate the convenience of quarterly as opposed to more frequent dosing of biologics, and he does, too.
reSURFACE 1 is a 64-week, randomized, phase III trial conducted in the United States, Canada, and Europe in which 772 patients were randomized 2:2:1 to tildrakizumab at 100 mg or 200 mg or to placebo. reSURFACE 2 is a 64-week trial in which 1,090 patients were randomized 2:2:1:2 to tildrakizumab at 100 mg or 200 mg, placebo, or etanercept at 50 mg twice weekly for the first 12 weeks and once weekly thereafter. At week 12 in both trials, patients on placebo were rerandomized to tildrakizumab at 100 or 200 mg for the duration. Participants averaged a baseline Psoriasis Area and Severity index score of 20, a body weight of 88 kg, and disease involvement over 31% of their body surface area.
Tildrakizumab was dosed in a regimen that’s the same as for ustekinumab (Stelara), which inhibits IL-12 as well as IL-23: one subcutaneous injection at baseline, another 1 month later, and every 12 weeks thereafter.
Dr. Reich presented results of the two pivotal trials through week 28. The coprimary efficacy endpoints in both studies were the PASI 75 response and proportion of subjects with a Physician’s Global Assessment (PGA) score of 0 or 1, meaning clear or minimal disease, compared with placebo at week 12. In hindsight, he said, those were not the best endpoints to have employed.
“We have here a drug that takes a little while to get to full throttle. The primary endpoint selected here at week 12 does not show efficacy data that really separates tildrakizumab from a drug like Stelara. But at week 28 you move toward levels of PASI 90 and PASI 100 response that we really want to see,” the dermatologist said.
Combining the results of reSURFACE 1 and 2, the PASI 75 response rate at week 12 – after only two doses – was 63% in the 100-mg arm and 64% at 200 mg. But the rates kept climbing thereafter such that by week 28 the PASI 75 rates were 77% and 78%.
Fifty-seven percent of patients on tildrakizumab at 100 mg had a PGA score of 0 or 1 at week 12, as did 6% of placebo-treated controls. By week 28, 66% of patients on the lower dose of the p-19 inhibitor had a PGA of 0 or 1. Rates in patients on tildrakizumab at 200 mg were 57% and 66% at 12 and 28 weeks, respectively.
Rates of adverse events of special interest in new biologic agents, including severe infections, malignancies, and major cardiovascular events, were similarly low across all study arms.
“My feeling is that looking at week 12 and week 28 safety data is of limited value. All I can say here is that through week 28 in these two studies I don’t see a safety signal. But for me, the real insight will have to come from larger studies with longer follow-up,” Dr. Reich said.
Asked why he thinks tildrakizumab is a slow starter, with only middling efficacy at the 12-week mark before subsequently picking up steam, he said it’s probably not a matter of the wrong doses being selected for reSURFACE 1 and 2, since the outcomes with 100 and 200 mg are fairly similar. More likely, the monoclonal antibody takes a bit longer to bind to its target and neutralize it than do some of the other biologics.
“It could be that if you dosed tildrakizumab at weeks 0, 2, and 8 as induction therapy you’d hit the mark at 12 weeks,” he added.
The reSURFACE trials are funded by Sun Pharma and Merck. Dr. Reich reported having received research grants from and serving as a consultant to Merck and numerous other pharmaceutical companies interested in new treatments for inflammatory skin diseases.
AT THE EADV CONGRESS
Key clinical point:
Major finding: Tildrakizumab dosed quarterly at 100 or 200 mg achieved PASI 75 response rates of 63%-64% at week 12 and 77%-78% at week 28.
Data source: reSURFACE 1 and 2: two pivotal, phase III, randomized clinical trials comprising 1,862 patients with moderate to severe plaque psoriasis.
Disclosures: The reSURFACE trials are funded by Sun Pharma and Merck. The presenter reported having received research grants from and serving as a consultant to Merck and numerous other pharmaceutical companies developing treatments for inflammatory skin diseases.
Secukinumab for psoriasis at 4 years: undiminished efficacy and safety
VIENNA – Four-year follow-up of patients on secukinumab for psoriasis shows sustained very high efficacy, with almost 100% of patients who had a Psoriasis Area and Severity Index (PASI) 90 or 100 response at 1 year maintaining it through 4 years, Robert Bissonnette, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“I must warn you that my presentation will be very boring as compared to what I’ve seen earlier at this meeting, the very cutting edge phase II and phase III data being presented. My presentation doesn’t contain any surprises. However, as a clinician who is using interleukin-17A inhibition in my practice to treat psoriasis patients, that’s probably what I want,” said Dr. Bissonnette, president of Innovaderm Research in Montreal.
“This is the longest-term safety and efficacy data available to date for patients treated with an IL-17 antagonist using an approved dose,” he noted.
Dr. Bissonnette presented 4-year results in the 165 participants who took the approved regimen from the start of the study. These were patients at the serious end of the disease severity spectrum. Their mean baseline PASI score was 23.5, with 33% of their body surface area being affected. Their mean Dermatology Life Quality Index (DLQI) score was 13.1. The mean body mass index was 28.7 kg/m2. A total of 71% of subjects had previously been on systemic therapy. One-third of participants had been on other biologics.
At 1 year, 88.9% of subjects had a PASI 75 response; at 4 years, the PASI 75 rate was 88.5%. Similarly, the PASI 90 rate was 68.5% at 1 year and 66.4% after 4 years. The PASI 100 rate was 43.8% at 1 year and 43.5% at year 4.
After 1 year on secukinumab, patients showed a mean 91.1% improvement, compared with their baseline PASI score. At 4 years, the figure was 90.8%.
Bearing in mind that the average baseline DLQI score at baseline was 13.1, it’s noteworthy that after 1 year on secukinumab, 72.7% of patients had a DLQI of 0 or 1, indicating psoriasis had no impact on their life. At year 4, the rate was 70.8%, Dr. Bissonnette continued.
As an audience member observed, however, the study population decreased from 165 patients to 131 over the course of 4 years. And since this was an “as observed” analysis, outcomes were counted only in those patients still in the study. It’s accepted as a legitimate statistical method, but it casts outcomes in a particularly favorable light.
“The main reason for dropouts was for personal reasons,” Dr. Bissonnette explained in response. “Number two was lack of or loss of efficacy. Loss of efficacy over time occurred at an absolute rate of 4%-8% per year.”
Overall, adverse event rates declined over the course of 4 years of follow-up.
“This is reassuring, but I don’t think it’s evidence that adverse events actually decrease over time because of longer use of secukinumab. I think it’s probably due to something we usually see in long-term clinical trials: a phenomenon of underreporting. When patients are treated with a new agent they tend to be very, very conscientious about what’s going on with their well-being. They will report a slight sore throat, a slight congestion. But once they’ve been on treatment for a longer time they’re less likely to report those very minor adverse events,” according to the dermatologist.
The Food and Drug Administration requires clinical trialists to keep careful track of selected adverse events in studies of biologic agents. In 4 years on secukinumab, there were no cases of tuberculosis, neutropenia, major adverse cardiovascular events, or Crohn’s disease. There were two cases of ulcerative colitis in year 2; however, one involved an exacerbation of preexisting disease. Also, two patients developed cancer other than nonmelanoma skin cancer in year 2. The incidence of vulvovaginal candidiasis was 1.8% during years 1 and 2, 0.6% in year 3, and zero in year 4.
Thus, the safety profile was favorable, with no pattern of increasing adverse events with longer medication use, Dr. Bissonnette concluded.
The study was sponsored by Novartis. Dr. Bissonnette reported serving as an investigator for and consultant to Novartis and 16 other pharmaceutical companies.
VIENNA – Four-year follow-up of patients on secukinumab for psoriasis shows sustained very high efficacy, with almost 100% of patients who had a Psoriasis Area and Severity Index (PASI) 90 or 100 response at 1 year maintaining it through 4 years, Robert Bissonnette, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“I must warn you that my presentation will be very boring as compared to what I’ve seen earlier at this meeting, the very cutting edge phase II and phase III data being presented. My presentation doesn’t contain any surprises. However, as a clinician who is using interleukin-17A inhibition in my practice to treat psoriasis patients, that’s probably what I want,” said Dr. Bissonnette, president of Innovaderm Research in Montreal.
“This is the longest-term safety and efficacy data available to date for patients treated with an IL-17 antagonist using an approved dose,” he noted.
Dr. Bissonnette presented 4-year results in the 165 participants who took the approved regimen from the start of the study. These were patients at the serious end of the disease severity spectrum. Their mean baseline PASI score was 23.5, with 33% of their body surface area being affected. Their mean Dermatology Life Quality Index (DLQI) score was 13.1. The mean body mass index was 28.7 kg/m2. A total of 71% of subjects had previously been on systemic therapy. One-third of participants had been on other biologics.
At 1 year, 88.9% of subjects had a PASI 75 response; at 4 years, the PASI 75 rate was 88.5%. Similarly, the PASI 90 rate was 68.5% at 1 year and 66.4% after 4 years. The PASI 100 rate was 43.8% at 1 year and 43.5% at year 4.
After 1 year on secukinumab, patients showed a mean 91.1% improvement, compared with their baseline PASI score. At 4 years, the figure was 90.8%.
Bearing in mind that the average baseline DLQI score at baseline was 13.1, it’s noteworthy that after 1 year on secukinumab, 72.7% of patients had a DLQI of 0 or 1, indicating psoriasis had no impact on their life. At year 4, the rate was 70.8%, Dr. Bissonnette continued.
As an audience member observed, however, the study population decreased from 165 patients to 131 over the course of 4 years. And since this was an “as observed” analysis, outcomes were counted only in those patients still in the study. It’s accepted as a legitimate statistical method, but it casts outcomes in a particularly favorable light.
“The main reason for dropouts was for personal reasons,” Dr. Bissonnette explained in response. “Number two was lack of or loss of efficacy. Loss of efficacy over time occurred at an absolute rate of 4%-8% per year.”
Overall, adverse event rates declined over the course of 4 years of follow-up.
“This is reassuring, but I don’t think it’s evidence that adverse events actually decrease over time because of longer use of secukinumab. I think it’s probably due to something we usually see in long-term clinical trials: a phenomenon of underreporting. When patients are treated with a new agent they tend to be very, very conscientious about what’s going on with their well-being. They will report a slight sore throat, a slight congestion. But once they’ve been on treatment for a longer time they’re less likely to report those very minor adverse events,” according to the dermatologist.
The Food and Drug Administration requires clinical trialists to keep careful track of selected adverse events in studies of biologic agents. In 4 years on secukinumab, there were no cases of tuberculosis, neutropenia, major adverse cardiovascular events, or Crohn’s disease. There were two cases of ulcerative colitis in year 2; however, one involved an exacerbation of preexisting disease. Also, two patients developed cancer other than nonmelanoma skin cancer in year 2. The incidence of vulvovaginal candidiasis was 1.8% during years 1 and 2, 0.6% in year 3, and zero in year 4.
Thus, the safety profile was favorable, with no pattern of increasing adverse events with longer medication use, Dr. Bissonnette concluded.
The study was sponsored by Novartis. Dr. Bissonnette reported serving as an investigator for and consultant to Novartis and 16 other pharmaceutical companies.
VIENNA – Four-year follow-up of patients on secukinumab for psoriasis shows sustained very high efficacy, with almost 100% of patients who had a Psoriasis Area and Severity Index (PASI) 90 or 100 response at 1 year maintaining it through 4 years, Robert Bissonnette, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“I must warn you that my presentation will be very boring as compared to what I’ve seen earlier at this meeting, the very cutting edge phase II and phase III data being presented. My presentation doesn’t contain any surprises. However, as a clinician who is using interleukin-17A inhibition in my practice to treat psoriasis patients, that’s probably what I want,” said Dr. Bissonnette, president of Innovaderm Research in Montreal.
“This is the longest-term safety and efficacy data available to date for patients treated with an IL-17 antagonist using an approved dose,” he noted.
Dr. Bissonnette presented 4-year results in the 165 participants who took the approved regimen from the start of the study. These were patients at the serious end of the disease severity spectrum. Their mean baseline PASI score was 23.5, with 33% of their body surface area being affected. Their mean Dermatology Life Quality Index (DLQI) score was 13.1. The mean body mass index was 28.7 kg/m2. A total of 71% of subjects had previously been on systemic therapy. One-third of participants had been on other biologics.
At 1 year, 88.9% of subjects had a PASI 75 response; at 4 years, the PASI 75 rate was 88.5%. Similarly, the PASI 90 rate was 68.5% at 1 year and 66.4% after 4 years. The PASI 100 rate was 43.8% at 1 year and 43.5% at year 4.
After 1 year on secukinumab, patients showed a mean 91.1% improvement, compared with their baseline PASI score. At 4 years, the figure was 90.8%.
Bearing in mind that the average baseline DLQI score at baseline was 13.1, it’s noteworthy that after 1 year on secukinumab, 72.7% of patients had a DLQI of 0 or 1, indicating psoriasis had no impact on their life. At year 4, the rate was 70.8%, Dr. Bissonnette continued.
As an audience member observed, however, the study population decreased from 165 patients to 131 over the course of 4 years. And since this was an “as observed” analysis, outcomes were counted only in those patients still in the study. It’s accepted as a legitimate statistical method, but it casts outcomes in a particularly favorable light.
“The main reason for dropouts was for personal reasons,” Dr. Bissonnette explained in response. “Number two was lack of or loss of efficacy. Loss of efficacy over time occurred at an absolute rate of 4%-8% per year.”
Overall, adverse event rates declined over the course of 4 years of follow-up.
“This is reassuring, but I don’t think it’s evidence that adverse events actually decrease over time because of longer use of secukinumab. I think it’s probably due to something we usually see in long-term clinical trials: a phenomenon of underreporting. When patients are treated with a new agent they tend to be very, very conscientious about what’s going on with their well-being. They will report a slight sore throat, a slight congestion. But once they’ve been on treatment for a longer time they’re less likely to report those very minor adverse events,” according to the dermatologist.
The Food and Drug Administration requires clinical trialists to keep careful track of selected adverse events in studies of biologic agents. In 4 years on secukinumab, there were no cases of tuberculosis, neutropenia, major adverse cardiovascular events, or Crohn’s disease. There were two cases of ulcerative colitis in year 2; however, one involved an exacerbation of preexisting disease. Also, two patients developed cancer other than nonmelanoma skin cancer in year 2. The incidence of vulvovaginal candidiasis was 1.8% during years 1 and 2, 0.6% in year 3, and zero in year 4.
Thus, the safety profile was favorable, with no pattern of increasing adverse events with longer medication use, Dr. Bissonnette concluded.
The study was sponsored by Novartis. Dr. Bissonnette reported serving as an investigator for and consultant to Novartis and 16 other pharmaceutical companies.
AT THE EADV CONGRESS
Key clinical point:
Major finding: After 1 year on secukinumab, 43.8% of psoriasis patients had a PASI 100 response. After 3 additional years on the interleukin-17A inhibitor, the rate was virtually unchanged at 43.5%.
Data source: This was analysis of 165 psoriasis patients on secukinumab at the approved dose prospectively followed for 4 years in an extension of a phase III clinical trial.
Disclosures: Novartis sponsored the study. The presenter reported serving as an investigator for and consultant to Novartis and 16 other pharmaceutical companies.
Beta-blockers curb death risk in patients with primary prevention ICD
ROME – Beta-blocker therapy reduces the risks of all-cause mortality as well as cardiac death in patients with a left ventricular ejection fraction below 35% who get an implantable cardioverter-defibrillator for primary prevention, Laurent Fauchier, MD, PhD, reported at the annual congress of the European Society of Cardiology.
Some physicians have recently urged reconsideration of current guidelines recommending routine use of beta-blockers for prevention of cardiovascular events in certain groups of patients with coronary artery disease, including those with chronic heart failure who have received an ICD for primary prevention of sudden death. And indeed it’s true that the now–relatively old randomized trials of ICDs for primary prevention in patients with chronic heart failure don’t provide any real evidence that beta-blockers reduce mortality in this setting. In fact, the guideline recommendation for beta-blockade has been based upon expert opinion. This was the impetus for Dr. Fauchier and coinvestigators to conduct a large retrospective observational study in a contemporary cohort of heart failure patients who received an ICD for primary prevention during a recent 10-year period at the 12 largest centers in France.
Fifteen percent of the 3,975 French ICD recipients did not receive a beta-blocker. They differed from those who did in that they were on average 2 years older, had an absolute 5% lower ejection fraction, and were more likely to also receive cardiac resynchronization therapy. Propensity score matching based on these and 19 other baseline characteristics enabled investigators to assemble a cohort of 541 closely matched patient pairs, explained Dr. Fauchier, professor of cardiology at Francois Rabelais University in Tours, France.
During a mean follow-up of 3.2 years, the risk of all-cause mortality in ICD recipients not on a beta-blocker was 34% higher than in those who were. Moreover, their risk of cardiac death was 50% greater.
In contrast, beta-blocker therapy had no effect on the risks of sudden death or of appropriate or inappropriate shocks.
The finding that beta-blocker therapy doesn’t prevent sudden death in patients with an ICD for primary prevention has not previously been reported. However, it makes sense. The device prevents such events so effectively that a beta-blocker adds nothing further in that regard, according to Dr. Fauchier.
“Beta-blockers should continue to be used widely, as currently recommended, for heart failure in the specific setting of patients with prophylactic ICD implantation. You do not have the benefit for prevention of sudden death, but you still have all the benefit from preventing cardiac death,” the electrophysiologist concluded.
This study was supported by French governmental research grants. Dr. Fauchier reported serving as a consultant to Bayer, Pfizer, Boehringer Ingelheim, Medtronic, and Novartis.
ROME – Beta-blocker therapy reduces the risks of all-cause mortality as well as cardiac death in patients with a left ventricular ejection fraction below 35% who get an implantable cardioverter-defibrillator for primary prevention, Laurent Fauchier, MD, PhD, reported at the annual congress of the European Society of Cardiology.
Some physicians have recently urged reconsideration of current guidelines recommending routine use of beta-blockers for prevention of cardiovascular events in certain groups of patients with coronary artery disease, including those with chronic heart failure who have received an ICD for primary prevention of sudden death. And indeed it’s true that the now–relatively old randomized trials of ICDs for primary prevention in patients with chronic heart failure don’t provide any real evidence that beta-blockers reduce mortality in this setting. In fact, the guideline recommendation for beta-blockade has been based upon expert opinion. This was the impetus for Dr. Fauchier and coinvestigators to conduct a large retrospective observational study in a contemporary cohort of heart failure patients who received an ICD for primary prevention during a recent 10-year period at the 12 largest centers in France.
Fifteen percent of the 3,975 French ICD recipients did not receive a beta-blocker. They differed from those who did in that they were on average 2 years older, had an absolute 5% lower ejection fraction, and were more likely to also receive cardiac resynchronization therapy. Propensity score matching based on these and 19 other baseline characteristics enabled investigators to assemble a cohort of 541 closely matched patient pairs, explained Dr. Fauchier, professor of cardiology at Francois Rabelais University in Tours, France.
During a mean follow-up of 3.2 years, the risk of all-cause mortality in ICD recipients not on a beta-blocker was 34% higher than in those who were. Moreover, their risk of cardiac death was 50% greater.
In contrast, beta-blocker therapy had no effect on the risks of sudden death or of appropriate or inappropriate shocks.
The finding that beta-blocker therapy doesn’t prevent sudden death in patients with an ICD for primary prevention has not previously been reported. However, it makes sense. The device prevents such events so effectively that a beta-blocker adds nothing further in that regard, according to Dr. Fauchier.
“Beta-blockers should continue to be used widely, as currently recommended, for heart failure in the specific setting of patients with prophylactic ICD implantation. You do not have the benefit for prevention of sudden death, but you still have all the benefit from preventing cardiac death,” the electrophysiologist concluded.
This study was supported by French governmental research grants. Dr. Fauchier reported serving as a consultant to Bayer, Pfizer, Boehringer Ingelheim, Medtronic, and Novartis.
ROME – Beta-blocker therapy reduces the risks of all-cause mortality as well as cardiac death in patients with a left ventricular ejection fraction below 35% who get an implantable cardioverter-defibrillator for primary prevention, Laurent Fauchier, MD, PhD, reported at the annual congress of the European Society of Cardiology.
Some physicians have recently urged reconsideration of current guidelines recommending routine use of beta-blockers for prevention of cardiovascular events in certain groups of patients with coronary artery disease, including those with chronic heart failure who have received an ICD for primary prevention of sudden death. And indeed it’s true that the now–relatively old randomized trials of ICDs for primary prevention in patients with chronic heart failure don’t provide any real evidence that beta-blockers reduce mortality in this setting. In fact, the guideline recommendation for beta-blockade has been based upon expert opinion. This was the impetus for Dr. Fauchier and coinvestigators to conduct a large retrospective observational study in a contemporary cohort of heart failure patients who received an ICD for primary prevention during a recent 10-year period at the 12 largest centers in France.
Fifteen percent of the 3,975 French ICD recipients did not receive a beta-blocker. They differed from those who did in that they were on average 2 years older, had an absolute 5% lower ejection fraction, and were more likely to also receive cardiac resynchronization therapy. Propensity score matching based on these and 19 other baseline characteristics enabled investigators to assemble a cohort of 541 closely matched patient pairs, explained Dr. Fauchier, professor of cardiology at Francois Rabelais University in Tours, France.
During a mean follow-up of 3.2 years, the risk of all-cause mortality in ICD recipients not on a beta-blocker was 34% higher than in those who were. Moreover, their risk of cardiac death was 50% greater.
In contrast, beta-blocker therapy had no effect on the risks of sudden death or of appropriate or inappropriate shocks.
The finding that beta-blocker therapy doesn’t prevent sudden death in patients with an ICD for primary prevention has not previously been reported. However, it makes sense. The device prevents such events so effectively that a beta-blocker adds nothing further in that regard, according to Dr. Fauchier.
“Beta-blockers should continue to be used widely, as currently recommended, for heart failure in the specific setting of patients with prophylactic ICD implantation. You do not have the benefit for prevention of sudden death, but you still have all the benefit from preventing cardiac death,” the electrophysiologist concluded.
This study was supported by French governmental research grants. Dr. Fauchier reported serving as a consultant to Bayer, Pfizer, Boehringer Ingelheim, Medtronic, and Novartis.
AT THE ESC CONGRESS 2016
Key clinical point:
Major finding: Patients with heart failure with reduced ejection fraction who received an ICD for primary prevention and were not on a beta-blocker were at an adjusted 50% increased risk for cardiac death and 34% increased risk for all-cause mortality during 3.2 years of follow-up, but they were at no increased risk for sudden death.
Data source: A retrospective observational study of all of the nearly 4,000 patients who received a primary prevention ICD at the 12 largest French centers during a recent 10-year period.
Disclosures: This study was supported by French governmental research funds. The presenter reported serving as a consultant to Bayer, Pfizer, Boehringer Ingelheim, Medtronic, and Novartis.
NOACs show benefit in calciphylaxis
VIENNA – The novel oral anticoagulants may provide effective adjunctive therapy in patients with calciphylaxis, Brian J. King, MD, said at the annual congress of the European Academy of Dermatology and Venereology.
He presented a retrospective case series of 16 patients with a confirmed diagnosis of calciphylaxis who were treated with NOACs at the Mayo Clinic in Rochester, Minn., where he is a dermatology resident. The results were impressive, particularly given that the estimated 1-year survival following diagnosis of calciphylaxis is only 45%.
At a mean followup of 418 days, 9 of 16 patients were still alive. More remarkably, five of those nine experienced complete resolution of their clinical lesions and remained alive at a mean followup of 775 days.
Calciphylaxis is a cutaneous manifestation of arteriolar thrombosis. It is classically associated with end-stage renal disease, hyperparathyroidism, a variety of hypercoagulable states, diabetes, and/or obesity. Fifteen of the 16 patients in the Mayo series were women. Fourteen patients had proximal involvement. The lesions occurred most often in fatty tissue on the hips, abdomen, thighs, breasts, and buttocks.
“It’s important to know that this is a deep, incredibly painful process and should not be confused with superficial crusted ulcerations,” Dr. King said.
A variety of treatments have been utilized for calciphylaxis, including sodium thiosulfate, debridement, advanced wound care, hyperbaric oxygen, and parathyroidectomy. But they are often ineffective.
Why not simply use warfarin instead of a costlier NOAC in addressing the problem? Because warfarin has actually been implicated as a cause of the vascular calcification that leads to thrombosis of dermal and pannicular arterioles. Indeed, 12 of the 16 patients in this series were on warfarin at the time of diagnosis of calciphylaxis, either for deep venous thrombosis, pulmonary embolism, or stroke prevention in atrial fibrillation. All were transitioned to a NOAC.
One group of Belgian investigators has provided evidence that strongly suggests the mechanism by which warfarin causes vascular calcification is via inhibition of vitamin K-dependent activation of matrix GLA 1, an enzyme which prevents calcification of vascular endothelial cells (BMC Nephrol. 2014 Sep 4;15:145).
“It is possible and even likely that the vessel calcification we see in patients on warfarin predisposes to thrombosis,” according to Dr. King.
The pathologic diagnostic criteria for calciphylaxis utilized at the Mayo Clinic require skin biopsy evidence of medial calcification and intimal fibroplasia of pannicular arterioles with cutaneous necrosis. Extravascular calcium deposition or thrombosis of pannicular or dermal arterioles is also typically present.
The major clinical criteria are necrotic cutaneous ulcers over indurated plaques, or indurated plaques without ulceration in adipose-rich tissue. The minor criteria are livedo racemosa, hemorrhagic bullae, or hemorrhagic plaques.
Asked if the NOACs can be used interchangeably for treatment of calciphylaxis, Dr. King said the direct factor Xa inhibitor apixaban is the NOAC of choice for this condition at the Mayo Clinic because unlike rivaroxaban (Xarelto) it doesn’t require dosing adjustment in the setting of renal impairment, which is extremely common in patients with calciphylaxis. The direct thrombin inhibitor dabigatran (Pradaxa) is contraindicated in chronic renal failure. Edoxaban (Savaysa) is not on the Mayo Clinic’s formulary, but it is contraindicated in patients with a creatinine clearance of 95 mL/min or more.
Dr. King said he and his coinvestigators recognize that a retrospective case series such as this must be considered hypothesis-generating and nondefinitive. They have already begun a larger prospective comparative outcomes study.
Dr. King reported having no financial conflicts of interest.
VIENNA – The novel oral anticoagulants may provide effective adjunctive therapy in patients with calciphylaxis, Brian J. King, MD, said at the annual congress of the European Academy of Dermatology and Venereology.
He presented a retrospective case series of 16 patients with a confirmed diagnosis of calciphylaxis who were treated with NOACs at the Mayo Clinic in Rochester, Minn., where he is a dermatology resident. The results were impressive, particularly given that the estimated 1-year survival following diagnosis of calciphylaxis is only 45%.
At a mean followup of 418 days, 9 of 16 patients were still alive. More remarkably, five of those nine experienced complete resolution of their clinical lesions and remained alive at a mean followup of 775 days.
Calciphylaxis is a cutaneous manifestation of arteriolar thrombosis. It is classically associated with end-stage renal disease, hyperparathyroidism, a variety of hypercoagulable states, diabetes, and/or obesity. Fifteen of the 16 patients in the Mayo series were women. Fourteen patients had proximal involvement. The lesions occurred most often in fatty tissue on the hips, abdomen, thighs, breasts, and buttocks.
“It’s important to know that this is a deep, incredibly painful process and should not be confused with superficial crusted ulcerations,” Dr. King said.
A variety of treatments have been utilized for calciphylaxis, including sodium thiosulfate, debridement, advanced wound care, hyperbaric oxygen, and parathyroidectomy. But they are often ineffective.
Why not simply use warfarin instead of a costlier NOAC in addressing the problem? Because warfarin has actually been implicated as a cause of the vascular calcification that leads to thrombosis of dermal and pannicular arterioles. Indeed, 12 of the 16 patients in this series were on warfarin at the time of diagnosis of calciphylaxis, either for deep venous thrombosis, pulmonary embolism, or stroke prevention in atrial fibrillation. All were transitioned to a NOAC.
One group of Belgian investigators has provided evidence that strongly suggests the mechanism by which warfarin causes vascular calcification is via inhibition of vitamin K-dependent activation of matrix GLA 1, an enzyme which prevents calcification of vascular endothelial cells (BMC Nephrol. 2014 Sep 4;15:145).
“It is possible and even likely that the vessel calcification we see in patients on warfarin predisposes to thrombosis,” according to Dr. King.
The pathologic diagnostic criteria for calciphylaxis utilized at the Mayo Clinic require skin biopsy evidence of medial calcification and intimal fibroplasia of pannicular arterioles with cutaneous necrosis. Extravascular calcium deposition or thrombosis of pannicular or dermal arterioles is also typically present.
The major clinical criteria are necrotic cutaneous ulcers over indurated plaques, or indurated plaques without ulceration in adipose-rich tissue. The minor criteria are livedo racemosa, hemorrhagic bullae, or hemorrhagic plaques.
Asked if the NOACs can be used interchangeably for treatment of calciphylaxis, Dr. King said the direct factor Xa inhibitor apixaban is the NOAC of choice for this condition at the Mayo Clinic because unlike rivaroxaban (Xarelto) it doesn’t require dosing adjustment in the setting of renal impairment, which is extremely common in patients with calciphylaxis. The direct thrombin inhibitor dabigatran (Pradaxa) is contraindicated in chronic renal failure. Edoxaban (Savaysa) is not on the Mayo Clinic’s formulary, but it is contraindicated in patients with a creatinine clearance of 95 mL/min or more.
Dr. King said he and his coinvestigators recognize that a retrospective case series such as this must be considered hypothesis-generating and nondefinitive. They have already begun a larger prospective comparative outcomes study.
Dr. King reported having no financial conflicts of interest.
VIENNA – The novel oral anticoagulants may provide effective adjunctive therapy in patients with calciphylaxis, Brian J. King, MD, said at the annual congress of the European Academy of Dermatology and Venereology.
He presented a retrospective case series of 16 patients with a confirmed diagnosis of calciphylaxis who were treated with NOACs at the Mayo Clinic in Rochester, Minn., where he is a dermatology resident. The results were impressive, particularly given that the estimated 1-year survival following diagnosis of calciphylaxis is only 45%.
At a mean followup of 418 days, 9 of 16 patients were still alive. More remarkably, five of those nine experienced complete resolution of their clinical lesions and remained alive at a mean followup of 775 days.
Calciphylaxis is a cutaneous manifestation of arteriolar thrombosis. It is classically associated with end-stage renal disease, hyperparathyroidism, a variety of hypercoagulable states, diabetes, and/or obesity. Fifteen of the 16 patients in the Mayo series were women. Fourteen patients had proximal involvement. The lesions occurred most often in fatty tissue on the hips, abdomen, thighs, breasts, and buttocks.
“It’s important to know that this is a deep, incredibly painful process and should not be confused with superficial crusted ulcerations,” Dr. King said.
A variety of treatments have been utilized for calciphylaxis, including sodium thiosulfate, debridement, advanced wound care, hyperbaric oxygen, and parathyroidectomy. But they are often ineffective.
Why not simply use warfarin instead of a costlier NOAC in addressing the problem? Because warfarin has actually been implicated as a cause of the vascular calcification that leads to thrombosis of dermal and pannicular arterioles. Indeed, 12 of the 16 patients in this series were on warfarin at the time of diagnosis of calciphylaxis, either for deep venous thrombosis, pulmonary embolism, or stroke prevention in atrial fibrillation. All were transitioned to a NOAC.
One group of Belgian investigators has provided evidence that strongly suggests the mechanism by which warfarin causes vascular calcification is via inhibition of vitamin K-dependent activation of matrix GLA 1, an enzyme which prevents calcification of vascular endothelial cells (BMC Nephrol. 2014 Sep 4;15:145).
“It is possible and even likely that the vessel calcification we see in patients on warfarin predisposes to thrombosis,” according to Dr. King.
The pathologic diagnostic criteria for calciphylaxis utilized at the Mayo Clinic require skin biopsy evidence of medial calcification and intimal fibroplasia of pannicular arterioles with cutaneous necrosis. Extravascular calcium deposition or thrombosis of pannicular or dermal arterioles is also typically present.
The major clinical criteria are necrotic cutaneous ulcers over indurated plaques, or indurated plaques without ulceration in adipose-rich tissue. The minor criteria are livedo racemosa, hemorrhagic bullae, or hemorrhagic plaques.
Asked if the NOACs can be used interchangeably for treatment of calciphylaxis, Dr. King said the direct factor Xa inhibitor apixaban is the NOAC of choice for this condition at the Mayo Clinic because unlike rivaroxaban (Xarelto) it doesn’t require dosing adjustment in the setting of renal impairment, which is extremely common in patients with calciphylaxis. The direct thrombin inhibitor dabigatran (Pradaxa) is contraindicated in chronic renal failure. Edoxaban (Savaysa) is not on the Mayo Clinic’s formulary, but it is contraindicated in patients with a creatinine clearance of 95 mL/min or more.
Dr. King said he and his coinvestigators recognize that a retrospective case series such as this must be considered hypothesis-generating and nondefinitive. They have already begun a larger prospective comparative outcomes study.
Dr. King reported having no financial conflicts of interest.
AT THE EADV CONGRESS
Key clinical point:
Major finding: Nine of 16 patients with calciphylaxis who were placed on adjunctive therapy with a novel oral anticoagulant responded with significant improvement in their cutaneous disease, four experienced disease stabilization, and three had progressive disease.
Data source: This was a retrospective case study of 16 patients with biopsy-confirmed calciphylaxis.
Disclosures: The study presenter reported having no financial conflicts of interest.
Atopic dermatitis prevention strategies under study
VIENNA – Diverse strategies aimed at preventing childhood atopic dermatitis (AD) now under study include installation of home water softeners, daily use of emollients starting at birth, and maternal consumption of probiotics beginning late in pregnancy, Carsten Flohr, PhD, said at a joint program of the International Eczema Council and the International Psoriasis Council held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.
To date there is no effective method for preventing AD. Preventive strategies are needed sorely because the prevalence of pediatric AD worldwide is expected to increase substantially. It appears to have stabilized at roughly 20% in many affluent countries, but the global burden of the disease will climb as low-income countries – where AD is historically uncommon – become more developed and urbanized. This trend has been well documented via the International Study of Asthma and Allergies in Childhood (ISAAC), which in several phases has studied nearly 2 million children in more than 100 countries, noted Dr. Flohr of St. John’s Institute of Dermatology at King’s College London.
Dr. Flohr and coinvestigators in the Enquiring About Tolerance (EAT) study recently documented a significant association between water hardness and the risk of infant-onset AD. The investigators took advantage of the considerable variation in the amount of bedrock limestone across England, which enabled them to study the relationship between domestic water calcium carbonate concentrations and the presence of AD in 1,303 babies at 3 monthd of age drawn from the general population across the country. Filaggrin skin barrier gene mutation status was determined in all infants.
Infants whose water supply contained a calcium carbonate level above the median value were at an adjusted 46% greater risk of having visible AD at age 3 months than those whose household water calcium carbonate level was below the median. The AD risk rose by 1% for each 1 mg/L increase in calcium carbonate concentration above the median. This increased risk was confined to infants with a filaggrin skin barrier gene mutation; hard water didn’t increase early AD risk in children with the normal, wild-type version of the filaggrin gene (J Allergy Clin Immunol. 2016 Aug;138[2]:509-16).
As a result of these findings, a UK prevention trial is underway in which home water softeners are provided to families at high risk of having a baby with AD in water districts with high calcium carbonate concentrations. An earlier UK study found that installation of home water softeners didn’t reduce AD severity in children with established disease (PLoS Med. 2011 Feb 15;8[2]:e1000395), but disease prevention may be another story.
The role of the gut microbiota in development of childhood AD is an active area of investigation. Dr. Flohr said “there is a signal” that maternal intake of probiotics including lactobacilli and bifidobacteria in the third trimester and postnatally may reduce a child’s risk of developing AD by encouraging establishment of a more diverse gut microflora. He cited a meta-analysis of 14 published studies of probiotics which provided evidence of a 21% reduction in the incidence of AD in young children (Epidemiology 2012 May;23[3]:402-14). The studies have methodologic shortcomings, so multiple research groups are continuing to pursue the signal of an AD preventive effect.
Dr. Flor reported having no financial conflicts of interest regarding his presentation.
VIENNA – Diverse strategies aimed at preventing childhood atopic dermatitis (AD) now under study include installation of home water softeners, daily use of emollients starting at birth, and maternal consumption of probiotics beginning late in pregnancy, Carsten Flohr, PhD, said at a joint program of the International Eczema Council and the International Psoriasis Council held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.
To date there is no effective method for preventing AD. Preventive strategies are needed sorely because the prevalence of pediatric AD worldwide is expected to increase substantially. It appears to have stabilized at roughly 20% in many affluent countries, but the global burden of the disease will climb as low-income countries – where AD is historically uncommon – become more developed and urbanized. This trend has been well documented via the International Study of Asthma and Allergies in Childhood (ISAAC), which in several phases has studied nearly 2 million children in more than 100 countries, noted Dr. Flohr of St. John’s Institute of Dermatology at King’s College London.
Dr. Flohr and coinvestigators in the Enquiring About Tolerance (EAT) study recently documented a significant association between water hardness and the risk of infant-onset AD. The investigators took advantage of the considerable variation in the amount of bedrock limestone across England, which enabled them to study the relationship between domestic water calcium carbonate concentrations and the presence of AD in 1,303 babies at 3 monthd of age drawn from the general population across the country. Filaggrin skin barrier gene mutation status was determined in all infants.
Infants whose water supply contained a calcium carbonate level above the median value were at an adjusted 46% greater risk of having visible AD at age 3 months than those whose household water calcium carbonate level was below the median. The AD risk rose by 1% for each 1 mg/L increase in calcium carbonate concentration above the median. This increased risk was confined to infants with a filaggrin skin barrier gene mutation; hard water didn’t increase early AD risk in children with the normal, wild-type version of the filaggrin gene (J Allergy Clin Immunol. 2016 Aug;138[2]:509-16).
As a result of these findings, a UK prevention trial is underway in which home water softeners are provided to families at high risk of having a baby with AD in water districts with high calcium carbonate concentrations. An earlier UK study found that installation of home water softeners didn’t reduce AD severity in children with established disease (PLoS Med. 2011 Feb 15;8[2]:e1000395), but disease prevention may be another story.
The role of the gut microbiota in development of childhood AD is an active area of investigation. Dr. Flohr said “there is a signal” that maternal intake of probiotics including lactobacilli and bifidobacteria in the third trimester and postnatally may reduce a child’s risk of developing AD by encouraging establishment of a more diverse gut microflora. He cited a meta-analysis of 14 published studies of probiotics which provided evidence of a 21% reduction in the incidence of AD in young children (Epidemiology 2012 May;23[3]:402-14). The studies have methodologic shortcomings, so multiple research groups are continuing to pursue the signal of an AD preventive effect.
Dr. Flor reported having no financial conflicts of interest regarding his presentation.
VIENNA – Diverse strategies aimed at preventing childhood atopic dermatitis (AD) now under study include installation of home water softeners, daily use of emollients starting at birth, and maternal consumption of probiotics beginning late in pregnancy, Carsten Flohr, PhD, said at a joint program of the International Eczema Council and the International Psoriasis Council held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.
To date there is no effective method for preventing AD. Preventive strategies are needed sorely because the prevalence of pediatric AD worldwide is expected to increase substantially. It appears to have stabilized at roughly 20% in many affluent countries, but the global burden of the disease will climb as low-income countries – where AD is historically uncommon – become more developed and urbanized. This trend has been well documented via the International Study of Asthma and Allergies in Childhood (ISAAC), which in several phases has studied nearly 2 million children in more than 100 countries, noted Dr. Flohr of St. John’s Institute of Dermatology at King’s College London.
Dr. Flohr and coinvestigators in the Enquiring About Tolerance (EAT) study recently documented a significant association between water hardness and the risk of infant-onset AD. The investigators took advantage of the considerable variation in the amount of bedrock limestone across England, which enabled them to study the relationship between domestic water calcium carbonate concentrations and the presence of AD in 1,303 babies at 3 monthd of age drawn from the general population across the country. Filaggrin skin barrier gene mutation status was determined in all infants.
Infants whose water supply contained a calcium carbonate level above the median value were at an adjusted 46% greater risk of having visible AD at age 3 months than those whose household water calcium carbonate level was below the median. The AD risk rose by 1% for each 1 mg/L increase in calcium carbonate concentration above the median. This increased risk was confined to infants with a filaggrin skin barrier gene mutation; hard water didn’t increase early AD risk in children with the normal, wild-type version of the filaggrin gene (J Allergy Clin Immunol. 2016 Aug;138[2]:509-16).
As a result of these findings, a UK prevention trial is underway in which home water softeners are provided to families at high risk of having a baby with AD in water districts with high calcium carbonate concentrations. An earlier UK study found that installation of home water softeners didn’t reduce AD severity in children with established disease (PLoS Med. 2011 Feb 15;8[2]:e1000395), but disease prevention may be another story.
The role of the gut microbiota in development of childhood AD is an active area of investigation. Dr. Flohr said “there is a signal” that maternal intake of probiotics including lactobacilli and bifidobacteria in the third trimester and postnatally may reduce a child’s risk of developing AD by encouraging establishment of a more diverse gut microflora. He cited a meta-analysis of 14 published studies of probiotics which provided evidence of a 21% reduction in the incidence of AD in young children (Epidemiology 2012 May;23[3]:402-14). The studies have methodologic shortcomings, so multiple research groups are continuing to pursue the signal of an AD preventive effect.
Dr. Flor reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE EADV CONGRESS