Among patients with a patent foramen ovale (PFO) who have had a cryptogenic stroke, closure of the PFO reduces the risk of recurrent stroke, compared with medical therapy alone, according to three studies published in the September 14 issue of the New England Journal of Medicine. PFO closure, however, entailed increased risk of atrial fibrillation and, in two of the studies, venous thromboembolism.

In prior trials, PFO closure did not have a statistically significant effect on stroke risk, although the results suggested potential benefit. In an editorial accompanying the new trial results, Allan H. Ropper, MD, said that various limitations of the prior studies, including inclusion of patients whose prior stroke would not benefit from PFO closure, could help explain the positive results of the current studies—the CLOSE and Gore REDUCE trials and extended follow-up from the RESPECT trial. Dr. Ropper is Professor of Neurology at Harvard Medical School and Raymond D. Adams Master Clinician and Executive Vice Chairman of the Department of Neurology at Brigham and Women’s Hospital in Boston.

Persuasive Effect

Together, the trials indicate the importance of considering the characteristics of a PFO when assessing whether a patient may be an appropriate candidate for the procedure, Dr. Ropper said. In the CLOSE trial, patients had to have a large interatrial shunt at rest or an atrial septal aneurysm. While rates of stroke in the PFO closure groups in all of the studies were low, “in the CLOSE trial, no patient in the PFO closure group had a stroke, whereas stroke occurred in 6% of the patients in the antiplatelet-only group.”

The Gore REDUCE trial represented a “middle ground” in that most patients (81%) had a moderate or large interatrial shunt. In that trial, PFO closure was associated with significantly reduced risk of recurrent stroke, compared with antiplatelet therapy alone (1.4% vs 5.4%).

The primary analysis of the RESPECT trial, published in 2013, suggested a potential benefit, but the primary result was not statistically significant. The trial nevertheless provided a reasonable assurance of safety and effectiveness, and the FDA approved the device studied in the trial, the Amplatzer PFO Occluder (St. Jude Medical, St. Paul), in October 2016. The primary analysis included a median of 2.1 years of follow-up, whereas the current analysis included a median of 5.9 years of follow-up. Through the extended follow-up, 3.6% of patients in the PFO closure group had recurrent ischemic stroke, compared with 5.8% of patients in the medical therapy group.

“Therefore, in patients who have had a stroke, are younger than 60 years of age, and have a PFO with characteristics that are highly likely to allow paradoxical embolism to occur, the effect of closure becomes persuasive,” Dr. Ropper said. “Restricting PFO closure entirely to patients with high-risk characteristics of the PFO may perhaps be too conservative, but the boundaries of the features that support the procedure are becoming clearer.”

CLOSE

In the CLOSE trial, Jean-Louis Mas, MD, Professor of Neurology at Paris Descartes University and Head of the Neurology Department at Sainte-Anne Hospital in Paris, and colleagues enrolled patients who had had a recent cryptogenic stroke attributed to a PFO with an associated atrial septal aneurysm or large interatrial shunt.

The investigators assigned in a 1:1:1 ratio patients age 16 to 60 to transcatheter PFO closure plus long-term antiplatelet therapy, antiplatelet therapy alone, or oral anticoagulation. The primary outcome was occurrence of stroke. In all, 663 patients were randomized and followed for a mean of 5.3 years.

“No stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03),” the researchers said. “Procedural complication from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs 0.9%). The number of serious adverse events did not differ significantly between the treatment groups.” The trial was underpowered to determine the effects of oral anticoagulant therapy versus antiplatelet therapy.

Unlike in prior studies, CLOSE “included only patients who had PFO features that have been associated with cryptogenic stroke” and researchers “used a standardized evaluation to define a previous cryptogenic stroke,” the authors noted.

REDUCE

In the Gore REDUCE trial, investigators enrolled patients with a PFO who had had a cryptogenic stroke. Lars Søndergaard, MD, of the Department of Cardiology at Rigshospitalet, University of Copenhagen, and colleagues randomly assigned patients 2:1 to undergo PFO closure (with the Helex Septal Occluder or Cardioform Septal Occluder; W.L. Gore and Associates, Newark, Delaware) plus antiplatelet therapy or to receive antiplatelet therapy alone. Patients underwent brain imaging at baseline and 24 months. Coprimary end points were freedom from clinical evidence of ischemic stroke through at least 24 months after randomization and the 24-month incidence of new brain infarction (ie, clinical ischemic stroke or silent brain infarction on imaging).

The investigators enrolled 664 patients (mean age, 45.2). During a median follow-up of 3.2 years, clinical ischemic stroke occurred in six of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23). The incidence of new brain infarctions was lower in the PFO closure group than in the antiplatelet-only group (5.7% vs 11.3%), but the incidence of silent brain infarction did not differ significantly between the study groups.

Serious adverse events occurred in 23.1% of the patients in the PFO closure group and 27.8% of the patients in the antiplatelet-only group. Serious device-related adverse events occurred in six patients (1.4%) in the PFO closure group. Atrial fibrillation or flutter occurred in significantly more patients in the PFO closure group than in the antiplatelet-only group (6.6% vs 0.4%). Most cases of atrial fibrillation or flutter were detected within 45 days after the procedure and resolved within two weeks after onset.

RESPECT

In RESPECT, among patients age 18 to 60 who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up.

Jeffrey L. Saver, MD, Director of the University of California, Los Angeles Comprehensive Stroke Center and Professor of Neurology at the David Geffen School of Medicine at UCLA, and colleagues randomly assigned patients who had a PFO and had had a cryptogenic ischemic stroke to undergo closure of the PFO with the Amplatzer PFO Occluder or to receive medical therapy alone (ie, aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole). After the device was implanted, patients in the PFO closure group received aspirin plus clopidogrel daily for one month, followed by aspirin monotherapy for five months. Subsequent antithrombotic therapy was at the site investigator’s discretion.

The investigators enrolled 980 patients (mean age, 45.9) at 69 sites and followed patients for a median of 5.9 years. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group (3.6%) and in 28 patients in the medical-therapy group (5.8%), resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs medical therapy, 0.55).

“The relative difference in the rate of recurrent ischemic stroke between PFO closure and medical therapy alone was large (45% lower with PFO closure), but the absolute difference was small (0.49 fewer events per 100 patient-years with PFO closure),” the authors said. “Nonetheless, the cumulative absolute benefit had clinical relevance, since patients in this trial were younger … than the general population of patients who have stroke and thus faced a longer period of risk for recurrent stroke.”

Venous thromboembolism (ie, pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group. Among patients in the PFO closure group, those with a history of overt deep-vein thrombosis had a higher incidence of venous thromboembolic events. A lower intensity of antithrombotic therapy, including less common use of anticoagulant agents, in the PFO closure group, compared with the medical therapy group, “may have contributed to the higher rate of venous thromboembolism in the PFO closure group,” the researchers said. “These findings provide indirect support for the recent revision in the national management guidelines that endorsed lifelong anticoagulation therapy in patients with overt deep-vein thrombosis.”

In addition, seven periprocedural events of atrial fibrillation occurred in the PFO closure group, all of which resolved before the patients’ discharge from the hospital.

Assessment by Neurologist and Cardiologist Is Key

“The key to appropriate device use is comprehensive clinical assessment by both a neurologist and a cardiologist to confirm the diagnosis of ischemic stroke and exclude other possible causes,” said Andrew Farb, MD, of the FDA’s Center for Devices and Radiological Health in Silver Spring, Maryland, and colleagues, in a perspective accompanying the RESPECT trial results. The Amplatzer PFO Occluder’s labeled directions for use outline the recommended evaluation, which includes brain MRI or CT, transesophageal echocardiography, prolonged cardiac rhythm monitoring, intracranial and extracranial arterial imaging, and assessment for a hypercoagulable state. “Clearly, a deliberate, systematic assessment of the patient’s underlying conditions and the risks associated with ischemic stroke is needed before closure of a PFO can be recommended,” Dr. Farb and his coauthors said. The published results of the REDUCE and CLOSE trials “appear to support the general conclusions reached by the FDA in the evaluation of the Amplatzer PFO Occluder,” they said.

—Jake Remaly

Suggested Reading

Farb A, Ibrahim NG, Zuckerman BD. Patent foramen ovale after cryptogenic stroke - assessing the evidence for closure. N Engl J Med. 2017;377(11):1006-1009.

Mas JL, Derumeaux G, Guillon B, et al; CLOSE Investigators. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med. 2017;377(11):1011-1021.

Ropper AH. Tipping point for patent foramen ovale closure. N Engl J Med. 2017;377(11):1093-1095.

Saver JL, Carroll JD, Thaler DE, et al; RESPECT Investigators. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med. 2017;377(11):1022-1032.

Søndergaard L, Kasner SE, Rhodes JF, et al; Gore REDUCE Clinical Study Investigators. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017;377(11):1033-1042.

Among patients with a patent foramen ovale (PFO) who have had a cryptogenic stroke, closure of the PFO reduces the risk of recurrent stroke, compared with medical therapy alone, according to three studies published in the September 14 issue of the New England Journal of Medicine. PFO closure, however, entailed increased risk of atrial fibrillation and, in two of the studies, venous thromboembolism.

In prior trials, PFO closure did not have a statistically significant effect on stroke risk, although the results suggested potential benefit. In an editorial accompanying the new trial results, Allan H. Ropper, MD, said that various limitations of the prior studies, including inclusion of patients whose prior stroke would not benefit from PFO closure, could help explain the positive results of the current studies—the CLOSE and Gore REDUCE trials and extended follow-up from the RESPECT trial. Dr. Ropper is Professor of Neurology at Harvard Medical School and Raymond D. Adams Master Clinician and Executive Vice Chairman of the Department of Neurology at Brigham and Women’s Hospital in Boston.

Persuasive Effect

Together, the trials indicate the importance of considering the characteristics of a PFO when assessing whether a patient may be an appropriate candidate for the procedure, Dr. Ropper said. In the CLOSE trial, patients had to have a large interatrial shunt at rest or an atrial septal aneurysm. While rates of stroke in the PFO closure groups in all of the studies were low, “in the CLOSE trial, no patient in the PFO closure group had a stroke, whereas stroke occurred in 6% of the patients in the antiplatelet-only group.”

The Gore REDUCE trial represented a “middle ground” in that most patients (81%) had a moderate or large interatrial shunt. In that trial, PFO closure was associated with significantly reduced risk of recurrent stroke, compared with antiplatelet therapy alone (1.4% vs 5.4%).

The primary analysis of the RESPECT trial, published in 2013, suggested a potential benefit, but the primary result was not statistically significant. The trial nevertheless provided a reasonable assurance of safety and effectiveness, and the FDA approved the device studied in the trial, the Amplatzer PFO Occluder (St. Jude Medical, St. Paul), in October 2016. The primary analysis included a median of 2.1 years of follow-up, whereas the current analysis included a median of 5.9 years of follow-up. Through the extended follow-up, 3.6% of patients in the PFO closure group had recurrent ischemic stroke, compared with 5.8% of patients in the medical therapy group.

“Therefore, in patients who have had a stroke, are younger than 60 years of age, and have a PFO with characteristics that are highly likely to allow paradoxical embolism to occur, the effect of closure becomes persuasive,” Dr. Ropper said. “Restricting PFO closure entirely to patients with high-risk characteristics of the PFO may perhaps be too conservative, but the boundaries of the features that support the procedure are becoming clearer.”

CLOSE

In the CLOSE trial, Jean-Louis Mas, MD, Professor of Neurology at Paris Descartes University and Head of the Neurology Department at Sainte-Anne Hospital in Paris, and colleagues enrolled patients who had had a recent cryptogenic stroke attributed to a PFO with an associated atrial septal aneurysm or large interatrial shunt.

The investigators assigned in a 1:1:1 ratio patients age 16 to 60 to transcatheter PFO closure plus long-term antiplatelet therapy, antiplatelet therapy alone, or oral anticoagulation. The primary outcome was occurrence of stroke. In all, 663 patients were randomized and followed for a mean of 5.3 years.

“No stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03),” the researchers said. “Procedural complication from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs 0.9%). The number of serious adverse events did not differ significantly between the treatment groups.” The trial was underpowered to determine the effects of oral anticoagulant therapy versus antiplatelet therapy.

Unlike in prior studies, CLOSE “included only patients who had PFO features that have been associated with cryptogenic stroke” and researchers “used a standardized evaluation to define a previous cryptogenic stroke,” the authors noted.

REDUCE

In the Gore REDUCE trial, investigators enrolled patients with a PFO who had had a cryptogenic stroke. Lars Søndergaard, MD, of the Department of Cardiology at Rigshospitalet, University of Copenhagen, and colleagues randomly assigned patients 2:1 to undergo PFO closure (with the Helex Septal Occluder or Cardioform Septal Occluder; W.L. Gore and Associates, Newark, Delaware) plus antiplatelet therapy or to receive antiplatelet therapy alone. Patients underwent brain imaging at baseline and 24 months. Coprimary end points were freedom from clinical evidence of ischemic stroke through at least 24 months after randomization and the 24-month incidence of new brain infarction (ie, clinical ischemic stroke or silent brain infarction on imaging).

The investigators enrolled 664 patients (mean age, 45.2). During a median follow-up of 3.2 years, clinical ischemic stroke occurred in six of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23). The incidence of new brain infarctions was lower in the PFO closure group than in the antiplatelet-only group (5.7% vs 11.3%), but the incidence of silent brain infarction did not differ significantly between the study groups.

Serious adverse events occurred in 23.1% of the patients in the PFO closure group and 27.8% of the patients in the antiplatelet-only group. Serious device-related adverse events occurred in six patients (1.4%) in the PFO closure group. Atrial fibrillation or flutter occurred in significantly more patients in the PFO closure group than in the antiplatelet-only group (6.6% vs 0.4%). Most cases of atrial fibrillation or flutter were detected within 45 days after the procedure and resolved within two weeks after onset.

RESPECT

In RESPECT, among patients age 18 to 60 who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up.

Jeffrey L. Saver, MD, Director of the University of California, Los Angeles Comprehensive Stroke Center and Professor of Neurology at the David Geffen School of Medicine at UCLA, and colleagues randomly assigned patients who had a PFO and had had a cryptogenic ischemic stroke to undergo closure of the PFO with the Amplatzer PFO Occluder or to receive medical therapy alone (ie, aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole). After the device was implanted, patients in the PFO closure group received aspirin plus clopidogrel daily for one month, followed by aspirin monotherapy for five months. Subsequent antithrombotic therapy was at the site investigator’s discretion.

The investigators enrolled 980 patients (mean age, 45.9) at 69 sites and followed patients for a median of 5.9 years. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group (3.6%) and in 28 patients in the medical-therapy group (5.8%), resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs medical therapy, 0.55).

“The relative difference in the rate of recurrent ischemic stroke between PFO closure and medical therapy alone was large (45% lower with PFO closure), but the absolute difference was small (0.49 fewer events per 100 patient-years with PFO closure),” the authors said. “Nonetheless, the cumulative absolute benefit had clinical relevance, since patients in this trial were younger … than the general population of patients who have stroke and thus faced a longer period of risk for recurrent stroke.”

Venous thromboembolism (ie, pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group. Among patients in the PFO closure group, those with a history of overt deep-vein thrombosis had a higher incidence of venous thromboembolic events. A lower intensity of antithrombotic therapy, including less common use of anticoagulant agents, in the PFO closure group, compared with the medical therapy group, “may have contributed to the higher rate of venous thromboembolism in the PFO closure group,” the researchers said. “These findings provide indirect support for the recent revision in the national management guidelines that endorsed lifelong anticoagulation therapy in patients with overt deep-vein thrombosis.”

In addition, seven periprocedural events of atrial fibrillation occurred in the PFO closure group, all of which resolved before the patients’ discharge from the hospital.

Assessment by Neurologist and Cardiologist Is Key

“The key to appropriate device use is comprehensive clinical assessment by both a neurologist and a cardiologist to confirm the diagnosis of ischemic stroke and exclude other possible causes,” said Andrew Farb, MD, of the FDA’s Center for Devices and Radiological Health in Silver Spring, Maryland, and colleagues, in a perspective accompanying the RESPECT trial results. The Amplatzer PFO Occluder’s labeled directions for use outline the recommended evaluation, which includes brain MRI or CT, transesophageal echocardiography, prolonged cardiac rhythm monitoring, intracranial and extracranial arterial imaging, and assessment for a hypercoagulable state. “Clearly, a deliberate, systematic assessment of the patient’s underlying conditions and the risks associated with ischemic stroke is needed before closure of a PFO can be recommended,” Dr. Farb and his coauthors said. The published results of the REDUCE and CLOSE trials “appear to support the general conclusions reached by the FDA in the evaluation of the Amplatzer PFO Occluder,” they said.

—Jake Remaly

Suggested Reading

Farb A, Ibrahim NG, Zuckerman BD. Patent foramen ovale after cryptogenic stroke - assessing the evidence for closure. N Engl J Med. 2017;377(11):1006-1009.

Mas JL, Derumeaux G, Guillon B, et al; CLOSE Investigators. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med. 2017;377(11):1011-1021.

Ropper AH. Tipping point for patent foramen ovale closure. N Engl J Med. 2017;377(11):1093-1095.

Saver JL, Carroll JD, Thaler DE, et al; RESPECT Investigators. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med. 2017;377(11):1022-1032.

Søndergaard L, Kasner SE, Rhodes JF, et al; Gore REDUCE Clinical Study Investigators. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017;377(11):1033-1042.

Among patients with a patent foramen ovale (PFO) who have had a cryptogenic stroke, closure of the PFO reduces the risk of recurrent stroke, compared with medical therapy alone, according to three studies published in the September 14 issue of the New England Journal of Medicine. PFO closure, however, entailed increased risk of atrial fibrillation and, in two of the studies, venous thromboembolism.

In prior trials, PFO closure did not have a statistically significant effect on stroke risk, although the results suggested potential benefit. In an editorial accompanying the new trial results, Allan H. Ropper, MD, said that various limitations of the prior studies, including inclusion of patients whose prior stroke would not benefit from PFO closure, could help explain the positive results of the current studies—the CLOSE and Gore REDUCE trials and extended follow-up from the RESPECT trial. Dr. Ropper is Professor of Neurology at Harvard Medical School and Raymond D. Adams Master Clinician and Executive Vice Chairman of the Department of Neurology at Brigham and Women’s Hospital in Boston.

Persuasive Effect

Together, the trials indicate the importance of considering the characteristics of a PFO when assessing whether a patient may be an appropriate candidate for the procedure, Dr. Ropper said. In the CLOSE trial, patients had to have a large interatrial shunt at rest or an atrial septal aneurysm. While rates of stroke in the PFO closure groups in all of the studies were low, “in the CLOSE trial, no patient in the PFO closure group had a stroke, whereas stroke occurred in 6% of the patients in the antiplatelet-only group.”

The Gore REDUCE trial represented a “middle ground” in that most patients (81%) had a moderate or large interatrial shunt. In that trial, PFO closure was associated with significantly reduced risk of recurrent stroke, compared with antiplatelet therapy alone (1.4% vs 5.4%).

The primary analysis of the RESPECT trial, published in 2013, suggested a potential benefit, but the primary result was not statistically significant. The trial nevertheless provided a reasonable assurance of safety and effectiveness, and the FDA approved the device studied in the trial, the Amplatzer PFO Occluder (St. Jude Medical, St. Paul), in October 2016. The primary analysis included a median of 2.1 years of follow-up, whereas the current analysis included a median of 5.9 years of follow-up. Through the extended follow-up, 3.6% of patients in the PFO closure group had recurrent ischemic stroke, compared with 5.8% of patients in the medical therapy group.

“Therefore, in patients who have had a stroke, are younger than 60 years of age, and have a PFO with characteristics that are highly likely to allow paradoxical embolism to occur, the effect of closure becomes persuasive,” Dr. Ropper said. “Restricting PFO closure entirely to patients with high-risk characteristics of the PFO may perhaps be too conservative, but the boundaries of the features that support the procedure are becoming clearer.”

CLOSE

In the CLOSE trial, Jean-Louis Mas, MD, Professor of Neurology at Paris Descartes University and Head of the Neurology Department at Sainte-Anne Hospital in Paris, and colleagues enrolled patients who had had a recent cryptogenic stroke attributed to a PFO with an associated atrial septal aneurysm or large interatrial shunt.

The investigators assigned in a 1:1:1 ratio patients age 16 to 60 to transcatheter PFO closure plus long-term antiplatelet therapy, antiplatelet therapy alone, or oral anticoagulation. The primary outcome was occurrence of stroke. In all, 663 patients were randomized and followed for a mean of 5.3 years.

“No stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03),” the researchers said. “Procedural complication from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs 0.9%). The number of serious adverse events did not differ significantly between the treatment groups.” The trial was underpowered to determine the effects of oral anticoagulant therapy versus antiplatelet therapy.

Unlike in prior studies, CLOSE “included only patients who had PFO features that have been associated with cryptogenic stroke” and researchers “used a standardized evaluation to define a previous cryptogenic stroke,” the authors noted.

REDUCE

In the Gore REDUCE trial, investigators enrolled patients with a PFO who had had a cryptogenic stroke. Lars Søndergaard, MD, of the Department of Cardiology at Rigshospitalet, University of Copenhagen, and colleagues randomly assigned patients 2:1 to undergo PFO closure (with the Helex Septal Occluder or Cardioform Septal Occluder; W.L. Gore and Associates, Newark, Delaware) plus antiplatelet therapy or to receive antiplatelet therapy alone. Patients underwent brain imaging at baseline and 24 months. Coprimary end points were freedom from clinical evidence of ischemic stroke through at least 24 months after randomization and the 24-month incidence of new brain infarction (ie, clinical ischemic stroke or silent brain infarction on imaging).

The investigators enrolled 664 patients (mean age, 45.2). During a median follow-up of 3.2 years, clinical ischemic stroke occurred in six of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23). The incidence of new brain infarctions was lower in the PFO closure group than in the antiplatelet-only group (5.7% vs 11.3%), but the incidence of silent brain infarction did not differ significantly between the study groups.

Serious adverse events occurred in 23.1% of the patients in the PFO closure group and 27.8% of the patients in the antiplatelet-only group. Serious device-related adverse events occurred in six patients (1.4%) in the PFO closure group. Atrial fibrillation or flutter occurred in significantly more patients in the PFO closure group than in the antiplatelet-only group (6.6% vs 0.4%). Most cases of atrial fibrillation or flutter were detected within 45 days after the procedure and resolved within two weeks after onset.

RESPECT

In RESPECT, among patients age 18 to 60 who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up.

Jeffrey L. Saver, MD, Director of the University of California, Los Angeles Comprehensive Stroke Center and Professor of Neurology at the David Geffen School of Medicine at UCLA, and colleagues randomly assigned patients who had a PFO and had had a cryptogenic ischemic stroke to undergo closure of the PFO with the Amplatzer PFO Occluder or to receive medical therapy alone (ie, aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole). After the device was implanted, patients in the PFO closure group received aspirin plus clopidogrel daily for one month, followed by aspirin monotherapy for five months. Subsequent antithrombotic therapy was at the site investigator’s discretion.

The investigators enrolled 980 patients (mean age, 45.9) at 69 sites and followed patients for a median of 5.9 years. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group (3.6%) and in 28 patients in the medical-therapy group (5.8%), resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs medical therapy, 0.55).

“The relative difference in the rate of recurrent ischemic stroke between PFO closure and medical therapy alone was large (45% lower with PFO closure), but the absolute difference was small (0.49 fewer events per 100 patient-years with PFO closure),” the authors said. “Nonetheless, the cumulative absolute benefit had clinical relevance, since patients in this trial were younger … than the general population of patients who have stroke and thus faced a longer period of risk for recurrent stroke.”

Venous thromboembolism (ie, pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group. Among patients in the PFO closure group, those with a history of overt deep-vein thrombosis had a higher incidence of venous thromboembolic events. A lower intensity of antithrombotic therapy, including less common use of anticoagulant agents, in the PFO closure group, compared with the medical therapy group, “may have contributed to the higher rate of venous thromboembolism in the PFO closure group,” the researchers said. “These findings provide indirect support for the recent revision in the national management guidelines that endorsed lifelong anticoagulation therapy in patients with overt deep-vein thrombosis.”

In addition, seven periprocedural events of atrial fibrillation occurred in the PFO closure group, all of which resolved before the patients’ discharge from the hospital.

Assessment by Neurologist and Cardiologist Is Key

“The key to appropriate device use is comprehensive clinical assessment by both a neurologist and a cardiologist to confirm the diagnosis of ischemic stroke and exclude other possible causes,” said Andrew Farb, MD, of the FDA’s Center for Devices and Radiological Health in Silver Spring, Maryland, and colleagues, in a perspective accompanying the RESPECT trial results. The Amplatzer PFO Occluder’s labeled directions for use outline the recommended evaluation, which includes brain MRI or CT, transesophageal echocardiography, prolonged cardiac rhythm monitoring, intracranial and extracranial arterial imaging, and assessment for a hypercoagulable state. “Clearly, a deliberate, systematic assessment of the patient’s underlying conditions and the risks associated with ischemic stroke is needed before closure of a PFO can be recommended,” Dr. Farb and his coauthors said. The published results of the REDUCE and CLOSE trials “appear to support the general conclusions reached by the FDA in the evaluation of the Amplatzer PFO Occluder,” they said.

—Jake Remaly

Suggested Reading

Farb A, Ibrahim NG, Zuckerman BD. Patent foramen ovale after cryptogenic stroke - assessing the evidence for closure. N Engl J Med. 2017;377(11):1006-1009.

Mas JL, Derumeaux G, Guillon B, et al; CLOSE Investigators. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med. 2017;377(11):1011-1021.

Ropper AH. Tipping point for patent foramen ovale closure. N Engl J Med. 2017;377(11):1093-1095.

Saver JL, Carroll JD, Thaler DE, et al; RESPECT Investigators. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med. 2017;377(11):1022-1032.

Søndergaard L, Kasner SE, Rhodes JF, et al; Gore REDUCE Clinical Study Investigators. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017;377(11):1033-1042.

Fentanyl analogues were involved in 14% of opioid overdose deaths in the second half of 2016, according to an analysis of 10 states reporting to the Enhanced State Opioid Overdose Surveillance program.

“Illicitly manufactured fentanyl is a key factor driving opioid overdose deaths and … fentanyl analogues [such as carfentanil, furanylfentanyl, and acetylfentanyl] are increasingly contributing to a complex illicit opioid market with significant public health implications,” investigators said in a report from the Centers for Disease Control and Prevention (MMWR 2017 Oct 27;66[early release]:1-6).

The overall rate of 14% represents 720 of the 5,152 total opioid deaths occurring in 10 states over the 6-month study period, they noted.

Of the 10 states in the analysis, Maine had the largest proportion (28.6%) of opioid overdose deaths involving fentanyl analogues, with Ohio second at 26% and West Virginia third at 20.1%. Ohio had the largest overall number of analogue-involved overdose deaths, however, at 531 during July-December 2016. At 1.6%, Massachusetts had the lowest rate of fentanyl analogue–involved deaths among the seven states for which separate figures were given, the published data show. (Three states – Missouri [22 counties], Oklahoma, and Rhode Island – were grouped together and had a combined rate of 1%.)

More than half of the overdose deaths involving fentanyl or a fentanyl analogue also involved heroin, cocaine, or methamphetamine, which means that almost half of the deaths “did not test positive for other illicit opioids, suggesting that fentanyl and fentanyl analogues might be emerging as unique illicit products,” the investigators wrote, adding that the fentanyl analogue situation “might mirror the rapidly rising trajectory of fentanyl overdose deaths that began in 2013 and become a major factor in opioid overdose deaths.”

[email protected]

Fentanyl analogues were involved in 14% of opioid overdose deaths in the second half of 2016, according to an analysis of 10 states reporting to the Enhanced State Opioid Overdose Surveillance program.

“Illicitly manufactured fentanyl is a key factor driving opioid overdose deaths and … fentanyl analogues [such as carfentanil, furanylfentanyl, and acetylfentanyl] are increasingly contributing to a complex illicit opioid market with significant public health implications,” investigators said in a report from the Centers for Disease Control and Prevention (MMWR 2017 Oct 27;66[early release]:1-6).

The overall rate of 14% represents 720 of the 5,152 total opioid deaths occurring in 10 states over the 6-month study period, they noted.

Of the 10 states in the analysis, Maine had the largest proportion (28.6%) of opioid overdose deaths involving fentanyl analogues, with Ohio second at 26% and West Virginia third at 20.1%. Ohio had the largest overall number of analogue-involved overdose deaths, however, at 531 during July-December 2016. At 1.6%, Massachusetts had the lowest rate of fentanyl analogue–involved deaths among the seven states for which separate figures were given, the published data show. (Three states – Missouri [22 counties], Oklahoma, and Rhode Island – were grouped together and had a combined rate of 1%.)

More than half of the overdose deaths involving fentanyl or a fentanyl analogue also involved heroin, cocaine, or methamphetamine, which means that almost half of the deaths “did not test positive for other illicit opioids, suggesting that fentanyl and fentanyl analogues might be emerging as unique illicit products,” the investigators wrote, adding that the fentanyl analogue situation “might mirror the rapidly rising trajectory of fentanyl overdose deaths that began in 2013 and become a major factor in opioid overdose deaths.”

[email protected]

Fentanyl analogues were involved in 14% of opioid overdose deaths in the second half of 2016, according to an analysis of 10 states reporting to the Enhanced State Opioid Overdose Surveillance program.

“Illicitly manufactured fentanyl is a key factor driving opioid overdose deaths and … fentanyl analogues [such as carfentanil, furanylfentanyl, and acetylfentanyl] are increasingly contributing to a complex illicit opioid market with significant public health implications,” investigators said in a report from the Centers for Disease Control and Prevention (MMWR 2017 Oct 27;66[early release]:1-6).

The overall rate of 14% represents 720 of the 5,152 total opioid deaths occurring in 10 states over the 6-month study period, they noted.

Of the 10 states in the analysis, Maine had the largest proportion (28.6%) of opioid overdose deaths involving fentanyl analogues, with Ohio second at 26% and West Virginia third at 20.1%. Ohio had the largest overall number of analogue-involved overdose deaths, however, at 531 during July-December 2016. At 1.6%, Massachusetts had the lowest rate of fentanyl analogue–involved deaths among the seven states for which separate figures were given, the published data show. (Three states – Missouri [22 counties], Oklahoma, and Rhode Island – were grouped together and had a combined rate of 1%.)

More than half of the overdose deaths involving fentanyl or a fentanyl analogue also involved heroin, cocaine, or methamphetamine, which means that almost half of the deaths “did not test positive for other illicit opioids, suggesting that fentanyl and fentanyl analogues might be emerging as unique illicit products,” the investigators wrote, adding that the fentanyl analogue situation “might mirror the rapidly rising trajectory of fentanyl overdose deaths that began in 2013 and become a major factor in opioid overdose deaths.”

[email protected]

Dual antithrombotic therapy with dabigatran and a P2Y12 inhibitor (eg, clopidogrel or ticagrelor) is associated with a lower risk of bleeding, compared with standard triple antithrombotic therapy, after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, according to research published online ahead of print August 27 in the New England Journal of Medicine. Dual therapy also is noninferior to triple therapy regarding the risk of thromboembolic events.

“Patients who received two anticlotting medications—including one of a newer class of drug—had fewer bleeding events without being more at risk for a stroke or other cardiac events,” said Christopher P. Cannon, MD, Professor of Medicine at Harvard Medical School and a cardiovascular medicine specialist at Brigham and Women’s Hospital in Boston, and colleagues.

Standard triple antithrombotic therapy (ie, warfarin plus two antiplatelet agents) has been associated with a high risk of bleeding, thus prompting researchers to seek a better approach to treatment. One emerging therapy omits aspirin from the standard regimen and uses a single P2Y₁₂ inhibitor in combination with an oral anticoagulant. A moderate-sized trial found that this form of dual-therapy lowered the risk of bleeding, compared with standard triple therapy. Another trial supported standard triple therapy for a shorter duration. Finally, a recent trial found that the risk of bleeding was lower with a regimen of reduced-dose rivaroxaban plus a P2Y₁₂ inhibitor than with standard triple therapy.

Dual Therapy Versus Triple Therapy

To compare two regimens of dual antithrombotic therapy that include dabigatran with a regimen of triple antithrombotic therapy that includes warfarin, Dr. Cannon and colleagues conducted the RE-DUAL PCI trial. Eligible participants were 18 or older, had nonvalvular atrial fibrillation, and had successfully undergone PCI with a bare-metal or drug-eluting stent within the previous 120 hours. Patients with bioprosthetic or mechanical heart valves, severe renal insufficiency, or other major coexisting conditions were excluded.

All patients in the United States and nonelderly patients in other countries were randomized 1:1:1 to receive triple therapy with warfarin plus a PSY₁₂ inhibitor and aspirin for one to three months, or to receive dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y₁₂ inhibitor and no aspirin. Outside the US, elderly patients (ie, 70 or older in Japan and 80 or older elsewhere) were randomized 1:1 to receive 110 mg of dual therapy or triple therapy.

The primary end point was the first major or clinically relevant nonmajor bleeding event. A major secondary end point was the composite of thromboembolic events (ie, myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization. Other secondary end points included a composite of thromboembolic events or death, as well as the individual thromboembolic events and definite stent thrombosis.

No Significant Difference in Serious Adverse Events Between Groups

Between July 21, 2014, and October 31, 2016, 2,725 participants underwent randomization at 414 sites in 41 countries. The mean age of participants was 70.8. The mean duration of treatment with the trial anticoagulant was 12.3 months, and the mean duration of follow-up was 14 months. Six patients were lost to follow-up. Most patients received clopidogrel as their P2Y₁₂ inhibitor, and 12% received ticagrelor.

The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group, compared with 26.9% in the triple-therapy group, and 20.2% in the 150-mg dual-therapy group, compared with 25.7% in the corresponding triple-therapy group. The incidence of the composite efficacy end point was 13.7% in both dual-therapy groups combined, compared with 13.4% in the triple-therapy group.

Researchers found no significant difference between groups in the rate of serious adverse events. Fatal serious adverse events occurred during treatment in 38 patients in the 100-mg dual-therapy group, 24 patients in the 150-mg dual-therapy group, and 41 patients in the triple-therapy group.

“We now have new information to help select the right treatment for individual patients,” said Dr. Cannon. “With respect to the results for both the bleeding and thromboembolic-event end points, we may only speculate on the relative contributions of the omission of aspirin and the type of oral anticoagulant in the dual-therapy groups and the triple-therapy group. A trial conducted with a formal two-by-two factorial design would be able to discern these contributions, and one such trial is ongoing.”

One limitation of this trial was that researchers enrolled a smaller number of patients than initially planned. The power of the trial to examine efficacy according to dabigatran dose consequently was limited, said the authors.

This study was supported by Boehringer Ingelheim.

—Erica Tricarico

Suggested Reading

Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017 Aug 27 [Epub ahead of print].

Dual antithrombotic therapy with dabigatran and a P2Y12 inhibitor (eg, clopidogrel or ticagrelor) is associated with a lower risk of bleeding, compared with standard triple antithrombotic therapy, after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, according to research published online ahead of print August 27 in the New England Journal of Medicine. Dual therapy also is noninferior to triple therapy regarding the risk of thromboembolic events.

“Patients who received two anticlotting medications—including one of a newer class of drug—had fewer bleeding events without being more at risk for a stroke or other cardiac events,” said Christopher P. Cannon, MD, Professor of Medicine at Harvard Medical School and a cardiovascular medicine specialist at Brigham and Women’s Hospital in Boston, and colleagues.

Standard triple antithrombotic therapy (ie, warfarin plus two antiplatelet agents) has been associated with a high risk of bleeding, thus prompting researchers to seek a better approach to treatment. One emerging therapy omits aspirin from the standard regimen and uses a single P2Y₁₂ inhibitor in combination with an oral anticoagulant. A moderate-sized trial found that this form of dual-therapy lowered the risk of bleeding, compared with standard triple therapy. Another trial supported standard triple therapy for a shorter duration. Finally, a recent trial found that the risk of bleeding was lower with a regimen of reduced-dose rivaroxaban plus a P2Y₁₂ inhibitor than with standard triple therapy.

Dual Therapy Versus Triple Therapy

To compare two regimens of dual antithrombotic therapy that include dabigatran with a regimen of triple antithrombotic therapy that includes warfarin, Dr. Cannon and colleagues conducted the RE-DUAL PCI trial. Eligible participants were 18 or older, had nonvalvular atrial fibrillation, and had successfully undergone PCI with a bare-metal or drug-eluting stent within the previous 120 hours. Patients with bioprosthetic or mechanical heart valves, severe renal insufficiency, or other major coexisting conditions were excluded.

All patients in the United States and nonelderly patients in other countries were randomized 1:1:1 to receive triple therapy with warfarin plus a PSY₁₂ inhibitor and aspirin for one to three months, or to receive dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y₁₂ inhibitor and no aspirin. Outside the US, elderly patients (ie, 70 or older in Japan and 80 or older elsewhere) were randomized 1:1 to receive 110 mg of dual therapy or triple therapy.

The primary end point was the first major or clinically relevant nonmajor bleeding event. A major secondary end point was the composite of thromboembolic events (ie, myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization. Other secondary end points included a composite of thromboembolic events or death, as well as the individual thromboembolic events and definite stent thrombosis.

No Significant Difference in Serious Adverse Events Between Groups

Between July 21, 2014, and October 31, 2016, 2,725 participants underwent randomization at 414 sites in 41 countries. The mean age of participants was 70.8. The mean duration of treatment with the trial anticoagulant was 12.3 months, and the mean duration of follow-up was 14 months. Six patients were lost to follow-up. Most patients received clopidogrel as their P2Y₁₂ inhibitor, and 12% received ticagrelor.

The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group, compared with 26.9% in the triple-therapy group, and 20.2% in the 150-mg dual-therapy group, compared with 25.7% in the corresponding triple-therapy group. The incidence of the composite efficacy end point was 13.7% in both dual-therapy groups combined, compared with 13.4% in the triple-therapy group.

Researchers found no significant difference between groups in the rate of serious adverse events. Fatal serious adverse events occurred during treatment in 38 patients in the 100-mg dual-therapy group, 24 patients in the 150-mg dual-therapy group, and 41 patients in the triple-therapy group.

“We now have new information to help select the right treatment for individual patients,” said Dr. Cannon. “With respect to the results for both the bleeding and thromboembolic-event end points, we may only speculate on the relative contributions of the omission of aspirin and the type of oral anticoagulant in the dual-therapy groups and the triple-therapy group. A trial conducted with a formal two-by-two factorial design would be able to discern these contributions, and one such trial is ongoing.”

One limitation of this trial was that researchers enrolled a smaller number of patients than initially planned. The power of the trial to examine efficacy according to dabigatran dose consequently was limited, said the authors.

This study was supported by Boehringer Ingelheim.

—Erica Tricarico

Suggested Reading

Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017 Aug 27 [Epub ahead of print].

Dual antithrombotic therapy with dabigatran and a P2Y12 inhibitor (eg, clopidogrel or ticagrelor) is associated with a lower risk of bleeding, compared with standard triple antithrombotic therapy, after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, according to research published online ahead of print August 27 in the New England Journal of Medicine. Dual therapy also is noninferior to triple therapy regarding the risk of thromboembolic events.

“Patients who received two anticlotting medications—including one of a newer class of drug—had fewer bleeding events without being more at risk for a stroke or other cardiac events,” said Christopher P. Cannon, MD, Professor of Medicine at Harvard Medical School and a cardiovascular medicine specialist at Brigham and Women’s Hospital in Boston, and colleagues.

Standard triple antithrombotic therapy (ie, warfarin plus two antiplatelet agents) has been associated with a high risk of bleeding, thus prompting researchers to seek a better approach to treatment. One emerging therapy omits aspirin from the standard regimen and uses a single P2Y₁₂ inhibitor in combination with an oral anticoagulant. A moderate-sized trial found that this form of dual-therapy lowered the risk of bleeding, compared with standard triple therapy. Another trial supported standard triple therapy for a shorter duration. Finally, a recent trial found that the risk of bleeding was lower with a regimen of reduced-dose rivaroxaban plus a P2Y₁₂ inhibitor than with standard triple therapy.

Dual Therapy Versus Triple Therapy

To compare two regimens of dual antithrombotic therapy that include dabigatran with a regimen of triple antithrombotic therapy that includes warfarin, Dr. Cannon and colleagues conducted the RE-DUAL PCI trial. Eligible participants were 18 or older, had nonvalvular atrial fibrillation, and had successfully undergone PCI with a bare-metal or drug-eluting stent within the previous 120 hours. Patients with bioprosthetic or mechanical heart valves, severe renal insufficiency, or other major coexisting conditions were excluded.

All patients in the United States and nonelderly patients in other countries were randomized 1:1:1 to receive triple therapy with warfarin plus a PSY₁₂ inhibitor and aspirin for one to three months, or to receive dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y₁₂ inhibitor and no aspirin. Outside the US, elderly patients (ie, 70 or older in Japan and 80 or older elsewhere) were randomized 1:1 to receive 110 mg of dual therapy or triple therapy.

The primary end point was the first major or clinically relevant nonmajor bleeding event. A major secondary end point was the composite of thromboembolic events (ie, myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization. Other secondary end points included a composite of thromboembolic events or death, as well as the individual thromboembolic events and definite stent thrombosis.

No Significant Difference in Serious Adverse Events Between Groups

Between July 21, 2014, and October 31, 2016, 2,725 participants underwent randomization at 414 sites in 41 countries. The mean age of participants was 70.8. The mean duration of treatment with the trial anticoagulant was 12.3 months, and the mean duration of follow-up was 14 months. Six patients were lost to follow-up. Most patients received clopidogrel as their P2Y₁₂ inhibitor, and 12% received ticagrelor.

The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group, compared with 26.9% in the triple-therapy group, and 20.2% in the 150-mg dual-therapy group, compared with 25.7% in the corresponding triple-therapy group. The incidence of the composite efficacy end point was 13.7% in both dual-therapy groups combined, compared with 13.4% in the triple-therapy group.

Researchers found no significant difference between groups in the rate of serious adverse events. Fatal serious adverse events occurred during treatment in 38 patients in the 100-mg dual-therapy group, 24 patients in the 150-mg dual-therapy group, and 41 patients in the triple-therapy group.

“We now have new information to help select the right treatment for individual patients,” said Dr. Cannon. “With respect to the results for both the bleeding and thromboembolic-event end points, we may only speculate on the relative contributions of the omission of aspirin and the type of oral anticoagulant in the dual-therapy groups and the triple-therapy group. A trial conducted with a formal two-by-two factorial design would be able to discern these contributions, and one such trial is ongoing.”

One limitation of this trial was that researchers enrolled a smaller number of patients than initially planned. The power of the trial to examine efficacy according to dabigatran dose consequently was limited, said the authors.

This study was supported by Boehringer Ingelheim.

—Erica Tricarico

Suggested Reading

Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017 Aug 27 [Epub ahead of print].

Visual hallucinations in Parkinson’s disease may arise from a global loss of network efficiency in the brain that disturbs visual attention and visual processing, according to research published online ahead of print September 27 in Radiology. A specific pattern of brain disconnection on fMRI may therefore help predict the development of visual hallucinations in patients with Parkinson’s disease.

An imperfect understanding of the pathophysiology behind visual hallucinations in Parkinson’s disease has hindered the development of effective treatments. Previous fMRI studies of these symptoms focused on task-based imaging, but visual hallucinations are associated with the development of cognitive decline, which could have influenced participants’ ability to perform specific tasks in the imager.

Dagmar H. Hepp, MD, of the Department of Neurology at VU University Medical Center in Amsterdam, and colleagues retrospectively examined resting-state fMRI data for 55 patients with Parkinson’s disease and 15 healthy controls who participated in a prospective cohort study. Of the participants with Parkinson’s disease, 15 had visual hallucinations. Dr. Hepp’s team calculated functional connectivity between 47 brain regions of interest. They compared whole-brain and region-specific means of connectivity using a general linear model with false discovery rate control for multiple comparisons.

In eight regions in the occipital lobe and paracentral area, functional connectivity was lower in all patients with Parkinson’s disease, compared with controls. Compared with controls, patients with Parkinson’s disease and visual hallucinations—but not patients with Parkinson’s disease without visual hallucinations—had nine brain regions with reduced functional connectivity. These regions were in the frontal cortex (ie, the superior frontal gyrus), temporal cortex (eg, the superior temporal gyrus), rolandic operculum, occipital cortex, and striatum. Connectivity of the superior temporal gyrus was correlated with orientation, attention, praxis, perception, and intraextra dimensional set shifting. Loss of functional connectivity of the rolandic operculum correlated with lower cognitive test scores in the subdomains of praxis and perception.

The superior frontal gyrus contributes to the allocation and maintenance of visuospatial attention and inhibitory control. This region also may allow an individual to reflect on sensory experience and judge its possible significance in relation to the self. Investigators believe that the superior temporal gyrus influences visual attention and controls the dorsal and ventral visual streams. Disconnection of frontal and temporal areas may impair the discrimination of external perceptions from internally generated information.

“Our findings argue against the notion that a single specific functional brain region or network is the neural substrate of visual hallucinations in Parkinson’s disease, but rather supply further evidence for a more global loss of network efficiency, which could drive disturbed attentional and visual processing and thereby lead to visual hallucinations in Parkinson’s disease,” the authors concluded.

—Erik Greb

Suggested Reading

Hepp DH, Foncke EMJ, Olde Dubbelink KTE, et al. Loss of functional connectivity in patients with Parkinson disease and visual hallucinations. Radiology. 2017 Sep 27 [Epub ahead of print].

Visual hallucinations in Parkinson’s disease may arise from a global loss of network efficiency in the brain that disturbs visual attention and visual processing, according to research published online ahead of print September 27 in Radiology. A specific pattern of brain disconnection on fMRI may therefore help predict the development of visual hallucinations in patients with Parkinson’s disease.

An imperfect understanding of the pathophysiology behind visual hallucinations in Parkinson’s disease has hindered the development of effective treatments. Previous fMRI studies of these symptoms focused on task-based imaging, but visual hallucinations are associated with the development of cognitive decline, which could have influenced participants’ ability to perform specific tasks in the imager.

Dagmar H. Hepp, MD, of the Department of Neurology at VU University Medical Center in Amsterdam, and colleagues retrospectively examined resting-state fMRI data for 55 patients with Parkinson’s disease and 15 healthy controls who participated in a prospective cohort study. Of the participants with Parkinson’s disease, 15 had visual hallucinations. Dr. Hepp’s team calculated functional connectivity between 47 brain regions of interest. They compared whole-brain and region-specific means of connectivity using a general linear model with false discovery rate control for multiple comparisons.

In eight regions in the occipital lobe and paracentral area, functional connectivity was lower in all patients with Parkinson’s disease, compared with controls. Compared with controls, patients with Parkinson’s disease and visual hallucinations—but not patients with Parkinson’s disease without visual hallucinations—had nine brain regions with reduced functional connectivity. These regions were in the frontal cortex (ie, the superior frontal gyrus), temporal cortex (eg, the superior temporal gyrus), rolandic operculum, occipital cortex, and striatum. Connectivity of the superior temporal gyrus was correlated with orientation, attention, praxis, perception, and intraextra dimensional set shifting. Loss of functional connectivity of the rolandic operculum correlated with lower cognitive test scores in the subdomains of praxis and perception.

The superior frontal gyrus contributes to the allocation and maintenance of visuospatial attention and inhibitory control. This region also may allow an individual to reflect on sensory experience and judge its possible significance in relation to the self. Investigators believe that the superior temporal gyrus influences visual attention and controls the dorsal and ventral visual streams. Disconnection of frontal and temporal areas may impair the discrimination of external perceptions from internally generated information.

“Our findings argue against the notion that a single specific functional brain region or network is the neural substrate of visual hallucinations in Parkinson’s disease, but rather supply further evidence for a more global loss of network efficiency, which could drive disturbed attentional and visual processing and thereby lead to visual hallucinations in Parkinson’s disease,” the authors concluded.

—Erik Greb

Suggested Reading

Hepp DH, Foncke EMJ, Olde Dubbelink KTE, et al. Loss of functional connectivity in patients with Parkinson disease and visual hallucinations. Radiology. 2017 Sep 27 [Epub ahead of print].

Visual hallucinations in Parkinson’s disease may arise from a global loss of network efficiency in the brain that disturbs visual attention and visual processing, according to research published online ahead of print September 27 in Radiology. A specific pattern of brain disconnection on fMRI may therefore help predict the development of visual hallucinations in patients with Parkinson’s disease.

An imperfect understanding of the pathophysiology behind visual hallucinations in Parkinson’s disease has hindered the development of effective treatments. Previous fMRI studies of these symptoms focused on task-based imaging, but visual hallucinations are associated with the development of cognitive decline, which could have influenced participants’ ability to perform specific tasks in the imager.

Dagmar H. Hepp, MD, of the Department of Neurology at VU University Medical Center in Amsterdam, and colleagues retrospectively examined resting-state fMRI data for 55 patients with Parkinson’s disease and 15 healthy controls who participated in a prospective cohort study. Of the participants with Parkinson’s disease, 15 had visual hallucinations. Dr. Hepp’s team calculated functional connectivity between 47 brain regions of interest. They compared whole-brain and region-specific means of connectivity using a general linear model with false discovery rate control for multiple comparisons.

In eight regions in the occipital lobe and paracentral area, functional connectivity was lower in all patients with Parkinson’s disease, compared with controls. Compared with controls, patients with Parkinson’s disease and visual hallucinations—but not patients with Parkinson’s disease without visual hallucinations—had nine brain regions with reduced functional connectivity. These regions were in the frontal cortex (ie, the superior frontal gyrus), temporal cortex (eg, the superior temporal gyrus), rolandic operculum, occipital cortex, and striatum. Connectivity of the superior temporal gyrus was correlated with orientation, attention, praxis, perception, and intraextra dimensional set shifting. Loss of functional connectivity of the rolandic operculum correlated with lower cognitive test scores in the subdomains of praxis and perception.

The superior frontal gyrus contributes to the allocation and maintenance of visuospatial attention and inhibitory control. This region also may allow an individual to reflect on sensory experience and judge its possible significance in relation to the self. Investigators believe that the superior temporal gyrus influences visual attention and controls the dorsal and ventral visual streams. Disconnection of frontal and temporal areas may impair the discrimination of external perceptions from internally generated information.

“Our findings argue against the notion that a single specific functional brain region or network is the neural substrate of visual hallucinations in Parkinson’s disease, but rather supply further evidence for a more global loss of network efficiency, which could drive disturbed attentional and visual processing and thereby lead to visual hallucinations in Parkinson’s disease,” the authors concluded.

—Erik Greb

Suggested Reading

Hepp DH, Foncke EMJ, Olde Dubbelink KTE, et al. Loss of functional connectivity in patients with Parkinson disease and visual hallucinations. Radiology. 2017 Sep 27 [Epub ahead of print].

The diagnosis

Answer: Hepatic foregut duplication cyst and concurrent acute gangrenous cholecystitis

AGA Institute

AGA Institute

AGA Institute

References

1. Imamoglu K.H., Walt, A.J. Duplication of the duodenum extending into liver. Am J Surg. 1977;133:628-32.
2. Seidman J.D., Yale-Loehr A.J., Beaver B., et al. Alimentary duplication presenting as an hepatic cyst in a neonate. Am J Surg Pathol. 1991;15:695-8.
3. Vick D.J., Goodman Z.D., Deavers M.T., et al. Ciliated hepatic foregut cyst: A study of six cases and review of the literature. Am J Surg Pathol. 1999;23:671-7.

[email protected]

The diagnosis

Answer: Hepatic foregut duplication cyst and concurrent acute gangrenous cholecystitis

AGA Institute

AGA Institute

AGA Institute

References

1. Imamoglu K.H., Walt, A.J. Duplication of the duodenum extending into liver. Am J Surg. 1977;133:628-32.
2. Seidman J.D., Yale-Loehr A.J., Beaver B., et al. Alimentary duplication presenting as an hepatic cyst in a neonate. Am J Surg Pathol. 1991;15:695-8.
3. Vick D.J., Goodman Z.D., Deavers M.T., et al. Ciliated hepatic foregut cyst: A study of six cases and review of the literature. Am J Surg Pathol. 1999;23:671-7.

[email protected]

The diagnosis

Answer: Hepatic foregut duplication cyst and concurrent acute gangrenous cholecystitis

AGA Institute

AGA Institute

AGA Institute

References

1. Imamoglu K.H., Walt, A.J. Duplication of the duodenum extending into liver. Am J Surg. 1977;133:628-32.
2. Seidman J.D., Yale-Loehr A.J., Beaver B., et al. Alimentary duplication presenting as an hepatic cyst in a neonate. Am J Surg Pathol. 1991;15:695-8.
3. Vick D.J., Goodman Z.D., Deavers M.T., et al. Ciliated hepatic foregut cyst: A study of six cases and review of the literature. Am J Surg Pathol. 1999;23:671-7.

[email protected]

A smell test may identify people at increased risk of incident Parkinson’s disease as many as 10 years before diagnosis, according to research published in the October 3 issue of Neurology. The association between poor olfaction and incident Parkinson’s disease may be stronger among men than among women, and among whites than among blacks, and this possibility requires further investigation, said the authors.

“Earlier studies had shown prediction of Parkinson’s disease about four to five years after the smell test was taken,” said Honglei Chen, MD, PhD, Professor of Epidemiology and Biostatistics at the Michigan State University College of Human Medicine in East Lansing. “Our study shows that this test may be able to inform the risk much earlier than that.”

A Prospective Study of the Elderly

Dr. Chen and colleagues examined data for 1,510 white participants and 952 black participants in the Health, Aging, and Body Composition study. During clinical examinations in 1999 and 2000, the participants underwent the Brief Smell Identification Test (BSIT). The researchers followed the population until the date of Parkinson’s disease diagnosis, death, last contact, or August 31, 2012, whichever came first. Parkinson’s disease was diagnosed retrospectively using several data sources. Dr. Chen and colleagues used multivariable Cox models to estimate hazard ratios for Parkinson’s disease.

Participants’ mean age was 76. About 49% of participants were male, and approximately 39% of the population was black. During a mean follow-up duration of 9.8 years, the researchers identified 42 incident cases of Parkinson’s disease, including 30 white participants and 12 black participants.

Patients in the lowest tertile of BSIT scores (ie, those with the worst olfaction) were older and more likely to be male, black, and current smokers, compared with participants in the highest tertile of BSIT scores. Participants in the lowest BSIT tertile also were less likely to report education beyond high school or optimal health.

Olfaction Predicted Parkinson’s Disease

Overall, poor olfaction was associated with a higher risk of Parkinson’s disease. Compared with the highest BSIT tertile, the hazard ratio for Parkinson’s disease was 1.3 for the middle tertile and 4.8 for the lowest tertile. The association between olfaction and Parkinson’s disease was stronger among whites than among blacks, and stronger among men than among women.

Furthermore, the association between olfaction and Parkinson’s disease was significant for the first five years of follow-up, as well as for the period of follow-up after five years. In lagged analyses that excluded the first years of follow-up, the association remained similarly strong for the first six years of follow-up (hazard ratio, 4.1–5.0), after which point the hazard ratio decreased to 2.9.

“Previous studies have shown that black people are more likely to have a poor sense of smell than whites, and yet may be less likely to develop Parkinson’s disease,” said Dr. Chen. “We found no statistical significance for a link between poor sense of smell and Parkinson’s disease in blacks, but that may have been due to the small sample size. More research is needed to further investigate a possible link.”

Several Factors Could Explain Hyposmia

“The observation that black participants have higher prevalence of hyposmia yet lower incidence of Parkinson’s disease needs further clarification to determine whether this observation is simply methodologic … or if there is a true biologic explanation,” said Gene L. Bowman, ND, MPH, Adjunct Assistant Professor of Neurology at Oregon Health and Science University in Portland, in an accompanying editorial.

One of the study’s limitations is that other factors besides neurodegeneration could explain hyposmia. The cause of the olfactory dysfunction observed in the study could be a subject for further research. “More granularity on the specific aspects of the smell tests that are impaired (eg, detection, identification, intensity) would help time-constrained clinicians focus on the most relevant tests,” Dr. Bowman concluded.

—Erik Greb

Suggested Reading

Bowman GL. Biomarkers for early detection of Parkinson disease: a scent of consistency with olfactory dysfunction. Neurology. 2017;89(14):1432-1434.

Chen H, Shrestha S, Huang X, et al. Olfaction and incident Parkinson disease in US white and black older adults. Neurology. 2017;89(14):1441-1447.

A smell test may identify people at increased risk of incident Parkinson’s disease as many as 10 years before diagnosis, according to research published in the October 3 issue of Neurology. The association between poor olfaction and incident Parkinson’s disease may be stronger among men than among women, and among whites than among blacks, and this possibility requires further investigation, said the authors.

“Earlier studies had shown prediction of Parkinson’s disease about four to five years after the smell test was taken,” said Honglei Chen, MD, PhD, Professor of Epidemiology and Biostatistics at the Michigan State University College of Human Medicine in East Lansing. “Our study shows that this test may be able to inform the risk much earlier than that.”

A Prospective Study of the Elderly

Dr. Chen and colleagues examined data for 1,510 white participants and 952 black participants in the Health, Aging, and Body Composition study. During clinical examinations in 1999 and 2000, the participants underwent the Brief Smell Identification Test (BSIT). The researchers followed the population until the date of Parkinson’s disease diagnosis, death, last contact, or August 31, 2012, whichever came first. Parkinson’s disease was diagnosed retrospectively using several data sources. Dr. Chen and colleagues used multivariable Cox models to estimate hazard ratios for Parkinson’s disease.

Participants’ mean age was 76. About 49% of participants were male, and approximately 39% of the population was black. During a mean follow-up duration of 9.8 years, the researchers identified 42 incident cases of Parkinson’s disease, including 30 white participants and 12 black participants.

Patients in the lowest tertile of BSIT scores (ie, those with the worst olfaction) were older and more likely to be male, black, and current smokers, compared with participants in the highest tertile of BSIT scores. Participants in the lowest BSIT tertile also were less likely to report education beyond high school or optimal health.

Olfaction Predicted Parkinson’s Disease

Overall, poor olfaction was associated with a higher risk of Parkinson’s disease. Compared with the highest BSIT tertile, the hazard ratio for Parkinson’s disease was 1.3 for the middle tertile and 4.8 for the lowest tertile. The association between olfaction and Parkinson’s disease was stronger among whites than among blacks, and stronger among men than among women.

Furthermore, the association between olfaction and Parkinson’s disease was significant for the first five years of follow-up, as well as for the period of follow-up after five years. In lagged analyses that excluded the first years of follow-up, the association remained similarly strong for the first six years of follow-up (hazard ratio, 4.1–5.0), after which point the hazard ratio decreased to 2.9.

“Previous studies have shown that black people are more likely to have a poor sense of smell than whites, and yet may be less likely to develop Parkinson’s disease,” said Dr. Chen. “We found no statistical significance for a link between poor sense of smell and Parkinson’s disease in blacks, but that may have been due to the small sample size. More research is needed to further investigate a possible link.”

Several Factors Could Explain Hyposmia

“The observation that black participants have higher prevalence of hyposmia yet lower incidence of Parkinson’s disease needs further clarification to determine whether this observation is simply methodologic … or if there is a true biologic explanation,” said Gene L. Bowman, ND, MPH, Adjunct Assistant Professor of Neurology at Oregon Health and Science University in Portland, in an accompanying editorial.

One of the study’s limitations is that other factors besides neurodegeneration could explain hyposmia. The cause of the olfactory dysfunction observed in the study could be a subject for further research. “More granularity on the specific aspects of the smell tests that are impaired (eg, detection, identification, intensity) would help time-constrained clinicians focus on the most relevant tests,” Dr. Bowman concluded.

—Erik Greb

Suggested Reading

Bowman GL. Biomarkers for early detection of Parkinson disease: a scent of consistency with olfactory dysfunction. Neurology. 2017;89(14):1432-1434.

Chen H, Shrestha S, Huang X, et al. Olfaction and incident Parkinson disease in US white and black older adults. Neurology. 2017;89(14):1441-1447.

A smell test may identify people at increased risk of incident Parkinson’s disease as many as 10 years before diagnosis, according to research published in the October 3 issue of Neurology. The association between poor olfaction and incident Parkinson’s disease may be stronger among men than among women, and among whites than among blacks, and this possibility requires further investigation, said the authors.

“Earlier studies had shown prediction of Parkinson’s disease about four to five years after the smell test was taken,” said Honglei Chen, MD, PhD, Professor of Epidemiology and Biostatistics at the Michigan State University College of Human Medicine in East Lansing. “Our study shows that this test may be able to inform the risk much earlier than that.”

A Prospective Study of the Elderly

Dr. Chen and colleagues examined data for 1,510 white participants and 952 black participants in the Health, Aging, and Body Composition study. During clinical examinations in 1999 and 2000, the participants underwent the Brief Smell Identification Test (BSIT). The researchers followed the population until the date of Parkinson’s disease diagnosis, death, last contact, or August 31, 2012, whichever came first. Parkinson’s disease was diagnosed retrospectively using several data sources. Dr. Chen and colleagues used multivariable Cox models to estimate hazard ratios for Parkinson’s disease.

Participants’ mean age was 76. About 49% of participants were male, and approximately 39% of the population was black. During a mean follow-up duration of 9.8 years, the researchers identified 42 incident cases of Parkinson’s disease, including 30 white participants and 12 black participants.

Patients in the lowest tertile of BSIT scores (ie, those with the worst olfaction) were older and more likely to be male, black, and current smokers, compared with participants in the highest tertile of BSIT scores. Participants in the lowest BSIT tertile also were less likely to report education beyond high school or optimal health.

Olfaction Predicted Parkinson’s Disease

Overall, poor olfaction was associated with a higher risk of Parkinson’s disease. Compared with the highest BSIT tertile, the hazard ratio for Parkinson’s disease was 1.3 for the middle tertile and 4.8 for the lowest tertile. The association between olfaction and Parkinson’s disease was stronger among whites than among blacks, and stronger among men than among women.

Furthermore, the association between olfaction and Parkinson’s disease was significant for the first five years of follow-up, as well as for the period of follow-up after five years. In lagged analyses that excluded the first years of follow-up, the association remained similarly strong for the first six years of follow-up (hazard ratio, 4.1–5.0), after which point the hazard ratio decreased to 2.9.

“Previous studies have shown that black people are more likely to have a poor sense of smell than whites, and yet may be less likely to develop Parkinson’s disease,” said Dr. Chen. “We found no statistical significance for a link between poor sense of smell and Parkinson’s disease in blacks, but that may have been due to the small sample size. More research is needed to further investigate a possible link.”

Several Factors Could Explain Hyposmia

“The observation that black participants have higher prevalence of hyposmia yet lower incidence of Parkinson’s disease needs further clarification to determine whether this observation is simply methodologic … or if there is a true biologic explanation,” said Gene L. Bowman, ND, MPH, Adjunct Assistant Professor of Neurology at Oregon Health and Science University in Portland, in an accompanying editorial.

One of the study’s limitations is that other factors besides neurodegeneration could explain hyposmia. The cause of the olfactory dysfunction observed in the study could be a subject for further research. “More granularity on the specific aspects of the smell tests that are impaired (eg, detection, identification, intensity) would help time-constrained clinicians focus on the most relevant tests,” Dr. Bowman concluded.

—Erik Greb

Suggested Reading

Bowman GL. Biomarkers for early detection of Parkinson disease: a scent of consistency with olfactory dysfunction. Neurology. 2017;89(14):1432-1434.

Chen H, Shrestha S, Huang X, et al. Olfaction and incident Parkinson disease in US white and black older adults. Neurology. 2017;89(14):1441-1447.

ORLANDO – Endoscopic therapy is as effective in Barrett’s esophagus patients with early cancer as in those with high-grade dysplasia, according to findings from an international multicenter consortium.

The findings suggest that invasive surgery may be avoidable in many Barrett’s esophagus patients with early cancer, Rajesh Krishnamoorthi, MD, of Virginia Mason Medical Center, Seattle, reported at the World Congress of Gastroenterology at ACG 2017.

[email protected]

ORLANDO – Endoscopic therapy is as effective in Barrett’s esophagus patients with early cancer as in those with high-grade dysplasia, according to findings from an international multicenter consortium.

The findings suggest that invasive surgery may be avoidable in many Barrett’s esophagus patients with early cancer, Rajesh Krishnamoorthi, MD, of Virginia Mason Medical Center, Seattle, reported at the World Congress of Gastroenterology at ACG 2017.

[email protected]

ORLANDO – Endoscopic therapy is as effective in Barrett’s esophagus patients with early cancer as in those with high-grade dysplasia, according to findings from an international multicenter consortium.

The findings suggest that invasive surgery may be avoidable in many Barrett’s esophagus patients with early cancer, Rajesh Krishnamoorthi, MD, of Virginia Mason Medical Center, Seattle, reported at the World Congress of Gastroenterology at ACG 2017.

[email protected]

Telemental health visits are on the rise.

copyright Andrea Danti/Thinkstock

Reference

Mehrotra A, Huskamp HA, Souza J, et al. Rapid growth in mental health telemedicine use among rural Medicare beneficiaries, wide variation across states. Health Aff. 2017 May 1;36(5):909-17. Accessed May 24, 2017.

Telemental health visits are on the rise.

copyright Andrea Danti/Thinkstock

Reference

Mehrotra A, Huskamp HA, Souza J, et al. Rapid growth in mental health telemedicine use among rural Medicare beneficiaries, wide variation across states. Health Aff. 2017 May 1;36(5):909-17. Accessed May 24, 2017.

Telemental health visits are on the rise.

copyright Andrea Danti/Thinkstock

Reference

Mehrotra A, Huskamp HA, Souza J, et al. Rapid growth in mental health telemedicine use among rural Medicare beneficiaries, wide variation across states. Health Aff. 2017 May 1;36(5):909-17. Accessed May 24, 2017.

For many years I have counseled medical students and residents that half of what I was taught in medical school has since been proven obsolete or frankly wrong. I counsel them that I have no reason to believe that I am any better than my professors were. So I wish them luck sorting out what is true. Earlier in my career, that warning was mild hyperbole, but not anymore.

Upper respiratory infections (URIs) are the most common reason for an office visit during the winter. Bronchiolitis is the most frequent diagnosis for a winter admission of an infant to a community hospital. Pediatricians have nuanced assessments and many options when treating these diseases. Best practices have changed frequently over the past 3 decades, mostly by eliminating previously espoused treatments as ineffective. In infants and young children, those obsolete treatments include decongestants and cough suppressants for young children with common colds, inhaled beta-agonists and steroids for infants with bronchiolitis, and antibiotics for simple otitis media in older children. In other words, most of what I was originally taught.

copyright iStock/Thinkstock

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at [email protected].

For many years I have counseled medical students and residents that half of what I was taught in medical school has since been proven obsolete or frankly wrong. I counsel them that I have no reason to believe that I am any better than my professors were. So I wish them luck sorting out what is true. Earlier in my career, that warning was mild hyperbole, but not anymore.

Upper respiratory infections (URIs) are the most common reason for an office visit during the winter. Bronchiolitis is the most frequent diagnosis for a winter admission of an infant to a community hospital. Pediatricians have nuanced assessments and many options when treating these diseases. Best practices have changed frequently over the past 3 decades, mostly by eliminating previously espoused treatments as ineffective. In infants and young children, those obsolete treatments include decongestants and cough suppressants for young children with common colds, inhaled beta-agonists and steroids for infants with bronchiolitis, and antibiotics for simple otitis media in older children. In other words, most of what I was originally taught.

copyright iStock/Thinkstock

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at [email protected].

For many years I have counseled medical students and residents that half of what I was taught in medical school has since been proven obsolete or frankly wrong. I counsel them that I have no reason to believe that I am any better than my professors were. So I wish them luck sorting out what is true. Earlier in my career, that warning was mild hyperbole, but not anymore.

Upper respiratory infections (URIs) are the most common reason for an office visit during the winter. Bronchiolitis is the most frequent diagnosis for a winter admission of an infant to a community hospital. Pediatricians have nuanced assessments and many options when treating these diseases. Best practices have changed frequently over the past 3 decades, mostly by eliminating previously espoused treatments as ineffective. In infants and young children, those obsolete treatments include decongestants and cough suppressants for young children with common colds, inhaled beta-agonists and steroids for infants with bronchiolitis, and antibiotics for simple otitis media in older children. In other words, most of what I was originally taught.

copyright iStock/Thinkstock

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at [email protected].