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Metronidazole clears PID anaerobes with no drop in antibiotic compliance
PARK CITY, UTAH – Adding metronidazole to ceftriaxone/doxycycline for acute pelvic inflammatory disease (PID) improved clearance of endometrial anaerobes and reduced the frequency of pelvic tenderness at 30 days, without reducing overall antibiotic compliance, in a randomized, placebo-controlled trial conducted at the University of Pittsburgh.
Anaerobic organisms are associated with endometritis, but guidelines from the Centers for Disease Control and Prevention have been equivocal about adding metronidazole to standard antibiotic regimens, citing a lack of data. CDC currently recommends treatment “with or without metronidazole.”
“Finally, we have data. This work has been needed to be done for over a decade. This is a huge contribution to the literature,” said Cheryl Walker, MD, of the department of obstetrics and gynecology at the University of California, Davis; she moderated the study presentation.
All 233 women in the study received ceftriaxone 250 mg (intramuscular) once and doxycycline 100 mg orally twice a day for 14 days; 116 were randomized to metronidazole 500 mg orally twice a day for 14 days, and 117 to matching placebo.
At 30 days, just 8% in the metronidazole group had pelvic tenderness, compared with 22.3% in the placebo arm (P = .006); clinical outcomes were otherwise similar.
Meanwhile, all of the women taking metronidazole cleared Atopobium vaginae, anaerobic gram-negative rods, and anaerobic gram-positive cocci, while one-third of women in the placebo group did not (P = .02).
Many clinicians hesitate to give metronidazole for PID out of concern that the drug’s gastrointestinal side effects will cause women to quit their antibiotic regimens early, but that wasn’t a problem in the Pittsburgh study. Compliance and adverse events were similar in both groups; 53.8% of the women taking metronidazole, for instance, versus 47.1% of women in the placebo arm, reported gastrointestinal side effects (P = .57).
“When we unmasked the treatment arms and showed there was really no difference, it was very surprising. When we looked at compliance at a level of 75% of drugs taken – we used blister packs and self-report – 90% of women in each arm took at least 75% of the medication,” Dr. Wiesenfeld said. Metronidazole side effects didn’t have much of an impact in the study, he added.
The women were a mean age of 23 years old; 59% were black, 28% were white, and 15% had private insurance. The groups were well balanced, with similar clinical presentations and prevalence of chlamydia (15%), gonorrhea (7%), Mycoplasma genitalium (18%), bacterial vaginosis (55%) and Trichomonas vaginalis (8.9%). Pregnant women and those requiring hospitalization were among those excluded from the study.
The work was funded by the National Institutes of Health. Hologic donated laboratory reagents. Dr. Wiesenfeld reported having no relevant disclosures.
PARK CITY, UTAH – Adding metronidazole to ceftriaxone/doxycycline for acute pelvic inflammatory disease (PID) improved clearance of endometrial anaerobes and reduced the frequency of pelvic tenderness at 30 days, without reducing overall antibiotic compliance, in a randomized, placebo-controlled trial conducted at the University of Pittsburgh.
Anaerobic organisms are associated with endometritis, but guidelines from the Centers for Disease Control and Prevention have been equivocal about adding metronidazole to standard antibiotic regimens, citing a lack of data. CDC currently recommends treatment “with or without metronidazole.”
“Finally, we have data. This work has been needed to be done for over a decade. This is a huge contribution to the literature,” said Cheryl Walker, MD, of the department of obstetrics and gynecology at the University of California, Davis; she moderated the study presentation.
All 233 women in the study received ceftriaxone 250 mg (intramuscular) once and doxycycline 100 mg orally twice a day for 14 days; 116 were randomized to metronidazole 500 mg orally twice a day for 14 days, and 117 to matching placebo.
At 30 days, just 8% in the metronidazole group had pelvic tenderness, compared with 22.3% in the placebo arm (P = .006); clinical outcomes were otherwise similar.
Meanwhile, all of the women taking metronidazole cleared Atopobium vaginae, anaerobic gram-negative rods, and anaerobic gram-positive cocci, while one-third of women in the placebo group did not (P = .02).
Many clinicians hesitate to give metronidazole for PID out of concern that the drug’s gastrointestinal side effects will cause women to quit their antibiotic regimens early, but that wasn’t a problem in the Pittsburgh study. Compliance and adverse events were similar in both groups; 53.8% of the women taking metronidazole, for instance, versus 47.1% of women in the placebo arm, reported gastrointestinal side effects (P = .57).
“When we unmasked the treatment arms and showed there was really no difference, it was very surprising. When we looked at compliance at a level of 75% of drugs taken – we used blister packs and self-report – 90% of women in each arm took at least 75% of the medication,” Dr. Wiesenfeld said. Metronidazole side effects didn’t have much of an impact in the study, he added.
The women were a mean age of 23 years old; 59% were black, 28% were white, and 15% had private insurance. The groups were well balanced, with similar clinical presentations and prevalence of chlamydia (15%), gonorrhea (7%), Mycoplasma genitalium (18%), bacterial vaginosis (55%) and Trichomonas vaginalis (8.9%). Pregnant women and those requiring hospitalization were among those excluded from the study.
The work was funded by the National Institutes of Health. Hologic donated laboratory reagents. Dr. Wiesenfeld reported having no relevant disclosures.
PARK CITY, UTAH – Adding metronidazole to ceftriaxone/doxycycline for acute pelvic inflammatory disease (PID) improved clearance of endometrial anaerobes and reduced the frequency of pelvic tenderness at 30 days, without reducing overall antibiotic compliance, in a randomized, placebo-controlled trial conducted at the University of Pittsburgh.
Anaerobic organisms are associated with endometritis, but guidelines from the Centers for Disease Control and Prevention have been equivocal about adding metronidazole to standard antibiotic regimens, citing a lack of data. CDC currently recommends treatment “with or without metronidazole.”
“Finally, we have data. This work has been needed to be done for over a decade. This is a huge contribution to the literature,” said Cheryl Walker, MD, of the department of obstetrics and gynecology at the University of California, Davis; she moderated the study presentation.
All 233 women in the study received ceftriaxone 250 mg (intramuscular) once and doxycycline 100 mg orally twice a day for 14 days; 116 were randomized to metronidazole 500 mg orally twice a day for 14 days, and 117 to matching placebo.
At 30 days, just 8% in the metronidazole group had pelvic tenderness, compared with 22.3% in the placebo arm (P = .006); clinical outcomes were otherwise similar.
Meanwhile, all of the women taking metronidazole cleared Atopobium vaginae, anaerobic gram-negative rods, and anaerobic gram-positive cocci, while one-third of women in the placebo group did not (P = .02).
Many clinicians hesitate to give metronidazole for PID out of concern that the drug’s gastrointestinal side effects will cause women to quit their antibiotic regimens early, but that wasn’t a problem in the Pittsburgh study. Compliance and adverse events were similar in both groups; 53.8% of the women taking metronidazole, for instance, versus 47.1% of women in the placebo arm, reported gastrointestinal side effects (P = .57).
“When we unmasked the treatment arms and showed there was really no difference, it was very surprising. When we looked at compliance at a level of 75% of drugs taken – we used blister packs and self-report – 90% of women in each arm took at least 75% of the medication,” Dr. Wiesenfeld said. Metronidazole side effects didn’t have much of an impact in the study, he added.
The women were a mean age of 23 years old; 59% were black, 28% were white, and 15% had private insurance. The groups were well balanced, with similar clinical presentations and prevalence of chlamydia (15%), gonorrhea (7%), Mycoplasma genitalium (18%), bacterial vaginosis (55%) and Trichomonas vaginalis (8.9%). Pregnant women and those requiring hospitalization were among those excluded from the study.
The work was funded by the National Institutes of Health. Hologic donated laboratory reagents. Dr. Wiesenfeld reported having no relevant disclosures.
AT IDSOG
Key clinical point:
Major finding: At 30 days, just 8% in the metronidazole group had pelvic tenderness, compared with 22.3% in the placebo arm (P = .006); clinical outcomes were otherwise similar. All of the women taking metronidazole also completely cleared Atopobium vaginae, anaerobic gram-negative rods, and anaerobic gram-positive cocci, but one-third of women on placebo did not (P = .02).
Data source: Randomized, placebo-controlled trial with 233 women.
Disclosures: The work was funded by the National Institutes of Health. Hologic donated laboratory reagents. The lead investigator reported having no relevant disclosures.
Multimodal approach is state of the art for ulcerated infantile hemangiomas
CHICAGO –
About 16% of infantile hemangiomas become ulcerated at some point during their proliferative phase, said Kate Puttgen, MD, during a talk at the World Congress of Pediatric Dermatology.
One clinical clue to picking up an infantile hemangioma (IH) that’s destined to ulcerate is an early grayish to white discoloration of the lesion, said Dr. Puttgen, chief of the division of pediatric dermatology at Johns Hopkins Medicine, Baltimore.
“Multimodal therapy is an absolute necessity” in treating an ulcerated IH, said Dr. Puttgen. Using an “all hands on deck” approach – a combination of topical and systemic modalities – can help bring the lesion under control.
Beta-blockers are first-line therapy to manage complicated IHs, with propranolol yielding a 98% response rate for all complicated IHs in the literature, said Dr. Puttgen.
Propranolol can decrease the volume and color of IHs and speed involution, in part by its ability to continue working after the proliferative growth phase of an IH. It’s also been shown to reduce the need for surgery in nasal IH, and it’s well tolerated, she added.
Evidence-based therapies for ulcerated hemangiomas include systemic propranolol at 1-3 mg/kg per day. That protocol will result in a healed ulcer within 2-6 weeks in most of the published case series, Dr. Puttgen noted.
Topical timolol also has evidence supporting its use for an ulcerated IH, and it has been found generally safe. In one study of 30 patients with IH, she said, three had mild adverse events consisting of sleep disturbance, diarrhea, and acrocyanosis. Another study reported success when brimonidine 0.2% and timolol 0.5% were used together. It’s possible, said Dr. Puttgen, that there’s a synergistic effect when combining the selective alpha-2 adrenergic agonist effect of brimonidine with timolol, which provides nonselective beta adrenergic blockade. However, she said, there has been an isolated report of brimonidine toxicity.
The ulcerated IHs need wound care, Dr. Puttgen added, with barrier creams and dressings. Pain management should be considered, because an ulcerated IH may have a large, friable, bleeding area. Pulsed-dye laser can also be a useful treatment modality for an ulcerating IH.
Going beyond the treatments for which the evidence is strongest and moving into more “state-of-the-art” treatments, “there may be a niche role for oral corticosteroids” as combination systemic therapy with propranolol, Dr. Puttgen said.
She shared images from a recently published report, in which she’s the senior author, showing the progression of an ulcerated IH. The hemangioma had received wound care and pulsed-dye laser treatment, and the infant was started on systemic propranolol. After 2 weeks, the IH had decreased significantly in volume, but the ulcerated area had actually increased. With the addition of oral corticosteroids, there was a reduction in ulceration after 2 weeks; and after 5 weeks of prednisolone, “the ulceration resolved without rebound,” said Dr. Puttgen. The corticosteroid was then tapered and propranolol was continued for an additional 2 months, then tapered. By 10 months, the IH had almost completely resolved (Br J Dermatol. 2017 Apr;176[4]:1064-7).
If a corticosteroid is added to propranolol, there may be benefit to a slower propranolol dose, Dr. Puttgen said. She suggests an altered dosing schedule, beginning with 1 mg/kg per day in two or three divided doses. Then, over a period of 2-7 days, the total daily dose can be increased to 1.5 mg/kg per day. Bumping the dose up to 2 mg/kg per day or higher should not happen until after 2 weeks at the reduced dosing schedule, she explained.
Dr. Puttgen disclosed that she is on the advisory board and has received honoraria from Pierre Fabre Dermatologie.
[email protected]
On Twitter @karioakes
CHICAGO –
About 16% of infantile hemangiomas become ulcerated at some point during their proliferative phase, said Kate Puttgen, MD, during a talk at the World Congress of Pediatric Dermatology.
One clinical clue to picking up an infantile hemangioma (IH) that’s destined to ulcerate is an early grayish to white discoloration of the lesion, said Dr. Puttgen, chief of the division of pediatric dermatology at Johns Hopkins Medicine, Baltimore.
“Multimodal therapy is an absolute necessity” in treating an ulcerated IH, said Dr. Puttgen. Using an “all hands on deck” approach – a combination of topical and systemic modalities – can help bring the lesion under control.
Beta-blockers are first-line therapy to manage complicated IHs, with propranolol yielding a 98% response rate for all complicated IHs in the literature, said Dr. Puttgen.
Propranolol can decrease the volume and color of IHs and speed involution, in part by its ability to continue working after the proliferative growth phase of an IH. It’s also been shown to reduce the need for surgery in nasal IH, and it’s well tolerated, she added.
Evidence-based therapies for ulcerated hemangiomas include systemic propranolol at 1-3 mg/kg per day. That protocol will result in a healed ulcer within 2-6 weeks in most of the published case series, Dr. Puttgen noted.
Topical timolol also has evidence supporting its use for an ulcerated IH, and it has been found generally safe. In one study of 30 patients with IH, she said, three had mild adverse events consisting of sleep disturbance, diarrhea, and acrocyanosis. Another study reported success when brimonidine 0.2% and timolol 0.5% were used together. It’s possible, said Dr. Puttgen, that there’s a synergistic effect when combining the selective alpha-2 adrenergic agonist effect of brimonidine with timolol, which provides nonselective beta adrenergic blockade. However, she said, there has been an isolated report of brimonidine toxicity.
The ulcerated IHs need wound care, Dr. Puttgen added, with barrier creams and dressings. Pain management should be considered, because an ulcerated IH may have a large, friable, bleeding area. Pulsed-dye laser can also be a useful treatment modality for an ulcerating IH.
Going beyond the treatments for which the evidence is strongest and moving into more “state-of-the-art” treatments, “there may be a niche role for oral corticosteroids” as combination systemic therapy with propranolol, Dr. Puttgen said.
She shared images from a recently published report, in which she’s the senior author, showing the progression of an ulcerated IH. The hemangioma had received wound care and pulsed-dye laser treatment, and the infant was started on systemic propranolol. After 2 weeks, the IH had decreased significantly in volume, but the ulcerated area had actually increased. With the addition of oral corticosteroids, there was a reduction in ulceration after 2 weeks; and after 5 weeks of prednisolone, “the ulceration resolved without rebound,” said Dr. Puttgen. The corticosteroid was then tapered and propranolol was continued for an additional 2 months, then tapered. By 10 months, the IH had almost completely resolved (Br J Dermatol. 2017 Apr;176[4]:1064-7).
If a corticosteroid is added to propranolol, there may be benefit to a slower propranolol dose, Dr. Puttgen said. She suggests an altered dosing schedule, beginning with 1 mg/kg per day in two or three divided doses. Then, over a period of 2-7 days, the total daily dose can be increased to 1.5 mg/kg per day. Bumping the dose up to 2 mg/kg per day or higher should not happen until after 2 weeks at the reduced dosing schedule, she explained.
Dr. Puttgen disclosed that she is on the advisory board and has received honoraria from Pierre Fabre Dermatologie.
[email protected]
On Twitter @karioakes
CHICAGO –
About 16% of infantile hemangiomas become ulcerated at some point during their proliferative phase, said Kate Puttgen, MD, during a talk at the World Congress of Pediatric Dermatology.
One clinical clue to picking up an infantile hemangioma (IH) that’s destined to ulcerate is an early grayish to white discoloration of the lesion, said Dr. Puttgen, chief of the division of pediatric dermatology at Johns Hopkins Medicine, Baltimore.
“Multimodal therapy is an absolute necessity” in treating an ulcerated IH, said Dr. Puttgen. Using an “all hands on deck” approach – a combination of topical and systemic modalities – can help bring the lesion under control.
Beta-blockers are first-line therapy to manage complicated IHs, with propranolol yielding a 98% response rate for all complicated IHs in the literature, said Dr. Puttgen.
Propranolol can decrease the volume and color of IHs and speed involution, in part by its ability to continue working after the proliferative growth phase of an IH. It’s also been shown to reduce the need for surgery in nasal IH, and it’s well tolerated, she added.
Evidence-based therapies for ulcerated hemangiomas include systemic propranolol at 1-3 mg/kg per day. That protocol will result in a healed ulcer within 2-6 weeks in most of the published case series, Dr. Puttgen noted.
Topical timolol also has evidence supporting its use for an ulcerated IH, and it has been found generally safe. In one study of 30 patients with IH, she said, three had mild adverse events consisting of sleep disturbance, diarrhea, and acrocyanosis. Another study reported success when brimonidine 0.2% and timolol 0.5% were used together. It’s possible, said Dr. Puttgen, that there’s a synergistic effect when combining the selective alpha-2 adrenergic agonist effect of brimonidine with timolol, which provides nonselective beta adrenergic blockade. However, she said, there has been an isolated report of brimonidine toxicity.
The ulcerated IHs need wound care, Dr. Puttgen added, with barrier creams and dressings. Pain management should be considered, because an ulcerated IH may have a large, friable, bleeding area. Pulsed-dye laser can also be a useful treatment modality for an ulcerating IH.
Going beyond the treatments for which the evidence is strongest and moving into more “state-of-the-art” treatments, “there may be a niche role for oral corticosteroids” as combination systemic therapy with propranolol, Dr. Puttgen said.
She shared images from a recently published report, in which she’s the senior author, showing the progression of an ulcerated IH. The hemangioma had received wound care and pulsed-dye laser treatment, and the infant was started on systemic propranolol. After 2 weeks, the IH had decreased significantly in volume, but the ulcerated area had actually increased. With the addition of oral corticosteroids, there was a reduction in ulceration after 2 weeks; and after 5 weeks of prednisolone, “the ulceration resolved without rebound,” said Dr. Puttgen. The corticosteroid was then tapered and propranolol was continued for an additional 2 months, then tapered. By 10 months, the IH had almost completely resolved (Br J Dermatol. 2017 Apr;176[4]:1064-7).
If a corticosteroid is added to propranolol, there may be benefit to a slower propranolol dose, Dr. Puttgen said. She suggests an altered dosing schedule, beginning with 1 mg/kg per day in two or three divided doses. Then, over a period of 2-7 days, the total daily dose can be increased to 1.5 mg/kg per day. Bumping the dose up to 2 mg/kg per day or higher should not happen until after 2 weeks at the reduced dosing schedule, she explained.
Dr. Puttgen disclosed that she is on the advisory board and has received honoraria from Pierre Fabre Dermatologie.
[email protected]
On Twitter @karioakes
EXPERT ANALYSIS FROM WCPD 2017
New-onset AF after aortic valve replacement did not affect long-term survival
New-onset atrial fibrillation after aortic valve replacement was not an independent risk factor for decreased long-term survival, according to the results of a single-center, retrospective study reported by Ben M. Swinkels, MD, of St Antonius Hospital, Nieuwegein, and his colleagues in the Netherlands.
Key to this success, however, is restoring normal sinus rhythm before hospital discharge, they said.
In this retrospective, longitudinal cohort study, 569 consecutive patients with no history of AF who underwent AVR with or without concomitant coronary artery bypass grafting during 1990-1993 were followed for a mean of 17.8 years (J Thorac Cardiovasc Surg. 2017;154:492-8).
Thirty-day and long-term survival rates were determined in the 241 patients (42%) with and the 328 patients (58%) without new-onset postoperative atrial fibrillation (POAF), which was defined as electrocardiographically documented AF lasting for at least several hours, and occurring after AVR while the patient was still admitted. Standard therapy to prevent new onset POAF was the use of sotalol in patients who were not on beta-blocker therapy, and continuation of beta-blocker therapy for those who were already on it.
There were no significant differences between the two groups in demographic characteristics. There were also no significant differences between the two groups in operative characteristics, postoperative in-hospital adverse events, and postoperative hospital lengths of stay until discharge home, except for mechanical ventilation time, which was significantly longer in the patients with new-onset POAF (P = .011).
Thirty-day mortality was 1.2% in the patients with POAF, and 2.7% in those without, a nonsignificant difference. There was no statistically significant difference between the two survival curves and the Kaplan-Meier overall cumulative survival rates at 15 years of follow-up in the patients with new-onset POAF vs. those without were not statistically different (41.5% vs. 41.3%, respectively).
In addition, the 18-year probability of long-term first adverse events, including recurrent AF, transient ischemic attack, ischemic or hemorrhagic stroke, peripheral venous thromboembolism, or major or minor bleeding was not significantly different between the two groups.
“New-onset POAF after AVR does not affect long-term survival when treatment is aimed to restore sinus rhythm before the patient is discharged home. Future studies with a prospective, randomized design should be done to confirm this finding in patients undergoing different kinds of cardiac surgery,” the researchers concluded.
The study was funded by the authors’ home institution; the authors reported they had nothing to disclose.
The incidence of atrial fibrillation after valve surgery has been described to be as high as 50%, Manuel J. Antunes, MD, said in an editorial commentary. “The adverse effect on long-term survival may not be related to the short-lived new-onset AF but rather to the underlying pathology associated to the arrhythmia, especially pathology that affects the myocardium, principally in atherosclerotic coronary artery disease,” he wrote. “It is not survival alone, however, that should be cause for concern; AF, even in episodes of limited duration, may result in transient ischemic attacks, ischemic, or hemorrhagic strokes, and peripheral thromboembolism, which is why affected patients should immediately be anticoagulated.”
This study, however, is at odds with previously published studies, with opposite conclusions, according to Dr. Antunes. Swinkels and his colleagues suggest that one of the reasons for the discrepancy was the homogeneous character of their series, which consisted almost entirely of patients who had isolated AVR. Dr. Antunes also adds that another important aspect to consider is that the antiarrhythmic drugs used prophylactically or therapeutically for this patient cohort (treated during 1990-1993) are no longer used or have been replaced by new and more efficacious pharmacologic agents.
Manuel J. Antunes, MD, of the University Hospital and Faculty of Medicine, Coimbra, Portugal, made these remarks in an invited editorial (J Thorac Cardiovasc Surg. 2017;154:490-1). He reported having nothing to disclose.
The incidence of atrial fibrillation after valve surgery has been described to be as high as 50%, Manuel J. Antunes, MD, said in an editorial commentary. “The adverse effect on long-term survival may not be related to the short-lived new-onset AF but rather to the underlying pathology associated to the arrhythmia, especially pathology that affects the myocardium, principally in atherosclerotic coronary artery disease,” he wrote. “It is not survival alone, however, that should be cause for concern; AF, even in episodes of limited duration, may result in transient ischemic attacks, ischemic, or hemorrhagic strokes, and peripheral thromboembolism, which is why affected patients should immediately be anticoagulated.”
This study, however, is at odds with previously published studies, with opposite conclusions, according to Dr. Antunes. Swinkels and his colleagues suggest that one of the reasons for the discrepancy was the homogeneous character of their series, which consisted almost entirely of patients who had isolated AVR. Dr. Antunes also adds that another important aspect to consider is that the antiarrhythmic drugs used prophylactically or therapeutically for this patient cohort (treated during 1990-1993) are no longer used or have been replaced by new and more efficacious pharmacologic agents.
Manuel J. Antunes, MD, of the University Hospital and Faculty of Medicine, Coimbra, Portugal, made these remarks in an invited editorial (J Thorac Cardiovasc Surg. 2017;154:490-1). He reported having nothing to disclose.
The incidence of atrial fibrillation after valve surgery has been described to be as high as 50%, Manuel J. Antunes, MD, said in an editorial commentary. “The adverse effect on long-term survival may not be related to the short-lived new-onset AF but rather to the underlying pathology associated to the arrhythmia, especially pathology that affects the myocardium, principally in atherosclerotic coronary artery disease,” he wrote. “It is not survival alone, however, that should be cause for concern; AF, even in episodes of limited duration, may result in transient ischemic attacks, ischemic, or hemorrhagic strokes, and peripheral thromboembolism, which is why affected patients should immediately be anticoagulated.”
This study, however, is at odds with previously published studies, with opposite conclusions, according to Dr. Antunes. Swinkels and his colleagues suggest that one of the reasons for the discrepancy was the homogeneous character of their series, which consisted almost entirely of patients who had isolated AVR. Dr. Antunes also adds that another important aspect to consider is that the antiarrhythmic drugs used prophylactically or therapeutically for this patient cohort (treated during 1990-1993) are no longer used or have been replaced by new and more efficacious pharmacologic agents.
Manuel J. Antunes, MD, of the University Hospital and Faculty of Medicine, Coimbra, Portugal, made these remarks in an invited editorial (J Thorac Cardiovasc Surg. 2017;154:490-1). He reported having nothing to disclose.
New-onset atrial fibrillation after aortic valve replacement was not an independent risk factor for decreased long-term survival, according to the results of a single-center, retrospective study reported by Ben M. Swinkels, MD, of St Antonius Hospital, Nieuwegein, and his colleagues in the Netherlands.
Key to this success, however, is restoring normal sinus rhythm before hospital discharge, they said.
In this retrospective, longitudinal cohort study, 569 consecutive patients with no history of AF who underwent AVR with or without concomitant coronary artery bypass grafting during 1990-1993 were followed for a mean of 17.8 years (J Thorac Cardiovasc Surg. 2017;154:492-8).
Thirty-day and long-term survival rates were determined in the 241 patients (42%) with and the 328 patients (58%) without new-onset postoperative atrial fibrillation (POAF), which was defined as electrocardiographically documented AF lasting for at least several hours, and occurring after AVR while the patient was still admitted. Standard therapy to prevent new onset POAF was the use of sotalol in patients who were not on beta-blocker therapy, and continuation of beta-blocker therapy for those who were already on it.
There were no significant differences between the two groups in demographic characteristics. There were also no significant differences between the two groups in operative characteristics, postoperative in-hospital adverse events, and postoperative hospital lengths of stay until discharge home, except for mechanical ventilation time, which was significantly longer in the patients with new-onset POAF (P = .011).
Thirty-day mortality was 1.2% in the patients with POAF, and 2.7% in those without, a nonsignificant difference. There was no statistically significant difference between the two survival curves and the Kaplan-Meier overall cumulative survival rates at 15 years of follow-up in the patients with new-onset POAF vs. those without were not statistically different (41.5% vs. 41.3%, respectively).
In addition, the 18-year probability of long-term first adverse events, including recurrent AF, transient ischemic attack, ischemic or hemorrhagic stroke, peripheral venous thromboembolism, or major or minor bleeding was not significantly different between the two groups.
“New-onset POAF after AVR does not affect long-term survival when treatment is aimed to restore sinus rhythm before the patient is discharged home. Future studies with a prospective, randomized design should be done to confirm this finding in patients undergoing different kinds of cardiac surgery,” the researchers concluded.
The study was funded by the authors’ home institution; the authors reported they had nothing to disclose.
New-onset atrial fibrillation after aortic valve replacement was not an independent risk factor for decreased long-term survival, according to the results of a single-center, retrospective study reported by Ben M. Swinkels, MD, of St Antonius Hospital, Nieuwegein, and his colleagues in the Netherlands.
Key to this success, however, is restoring normal sinus rhythm before hospital discharge, they said.
In this retrospective, longitudinal cohort study, 569 consecutive patients with no history of AF who underwent AVR with or without concomitant coronary artery bypass grafting during 1990-1993 were followed for a mean of 17.8 years (J Thorac Cardiovasc Surg. 2017;154:492-8).
Thirty-day and long-term survival rates were determined in the 241 patients (42%) with and the 328 patients (58%) without new-onset postoperative atrial fibrillation (POAF), which was defined as electrocardiographically documented AF lasting for at least several hours, and occurring after AVR while the patient was still admitted. Standard therapy to prevent new onset POAF was the use of sotalol in patients who were not on beta-blocker therapy, and continuation of beta-blocker therapy for those who were already on it.
There were no significant differences between the two groups in demographic characteristics. There were also no significant differences between the two groups in operative characteristics, postoperative in-hospital adverse events, and postoperative hospital lengths of stay until discharge home, except for mechanical ventilation time, which was significantly longer in the patients with new-onset POAF (P = .011).
Thirty-day mortality was 1.2% in the patients with POAF, and 2.7% in those without, a nonsignificant difference. There was no statistically significant difference between the two survival curves and the Kaplan-Meier overall cumulative survival rates at 15 years of follow-up in the patients with new-onset POAF vs. those without were not statistically different (41.5% vs. 41.3%, respectively).
In addition, the 18-year probability of long-term first adverse events, including recurrent AF, transient ischemic attack, ischemic or hemorrhagic stroke, peripheral venous thromboembolism, or major or minor bleeding was not significantly different between the two groups.
“New-onset POAF after AVR does not affect long-term survival when treatment is aimed to restore sinus rhythm before the patient is discharged home. Future studies with a prospective, randomized design should be done to confirm this finding in patients undergoing different kinds of cardiac surgery,” the researchers concluded.
The study was funded by the authors’ home institution; the authors reported they had nothing to disclose.
FROM THE JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
Key clinical point:
Major finding: Cumulative 15-year survival rates were similar in the patients with new-onset postop AF (41.5%) to those without (41.3%).
Data source: A retrospective longitudinal cohort study of 569 consecutive patients without a history of AF who were followed for a mean of 17.8 years after AVR with or without concomitant CABG.
Disclosures: The study was funded by the authors’ home institution and the authors reported they had nothing to disclose.
New test could cause OSA’s treatment success rate to rise
A novel device has shown a high rate of accuracy in predicting which patients with obstructive sleep apnea (OSA) will improve with oral appliance therapy, according to a study.
“At the present time CPAP is our go-to standard medical therapy [for treating OSA]. While it is a wonderful therapy, it has a very serious drawback, which is poor compliance, and that undercuts its long-term effectiveness in reducing the incidence of cardiovascular disease,” said John E. Remmers, MD, the principal investigator, in an interview.
Referring to the Sleep Apnea Cardiovascular Endpoints (SAVE) trial’s finding that continuous positive airway pressure (CPAP) did not reduce long-term cardiovascular incidents, he claimed that “these incidents are not being reduced by CPAP, because people don’t use it” (N Engl J Med. 2016 Sept 8;375[10]:919-31).
In Dr. Remmers’ new two-part study, 202 adults – primarily overweight, middle-aged men, diagnosed with moderate sleep apnea – were divided into two groups. The first included 149 people who were given a two-night, in-home, feedback controlled mandibular positioner (FCMP) test, using equipment manufactured by Zephyr Sleep Technologies. In this test, a custom-fit oral appliance is simulated using a temporary set of trays and impression material. The trays are connected to a small motor controlled by a little computer that sits on the stomach and moves the mandible when the patient has a problem breathing.
All patients received a custom oral appliance designed using data acquired from the test. The patients then wore the custom oral appliances while connected to a validated monitor as an outcomes study.
Finally, the researchers fed all of the data they collected from this first group of patients into a machine learning model. Then the second set of patients participated in the testing. Outcomes data on the appliance’s performance in each individual in the first group were used to create a classification system to predict therapeutic outcomes for the 53 patients in the second group. The patients in the second group then received their custom oral appliances, connected to the same type of monitor used by the first group.
Therapeutic success or failure was defined as having mean oxygen desaturation index values of less than or greater than 10 events/hour, respectively. The investigators determined that the test had an 85% sensitivity level with 93% specificity, a positive predictive value of 97%, and a negative predictive value of 72%. Of those who were predicted to respond to therapy, the mandibular protrusive position was efficacious in 86% of patients.
The high rate of accuracy for predicting who will derive the most benefit from the appliance, along with the demonstrated preference for oral appliances compared to continuous positive airway pressure devices among patients, increases the clinical utility of the appliance, and expands options for clinical management of sleep apnea, according to the study authors (Clin Sleep Med. 2017;13[7]:871-80).
“Our test allows the physician to prescribe the therapy knowing it will get rid of sleep apnea, and it tells the dentist how far the mandible needs to be pulled out by the custom fit device,” Dr. Remmers explained.
Dentists will also benefit from the test, because it allows them to make an appliance that will not need to be adjusted and will have a higher success rate than the current 60% success rate that oral appliances have at treating sleep apnea, he noted.
“This opens up a new an alternative clinical avenue at a critical time, when we have just learned over the past few years that there are serious questions about the effectiveness of CPAP in the long term,” Dr. Remmers added. “[With oral appliance therapy] you have an opportunity for higher compliance, because people prefer the less obtrusive oral appliance therapy over CPAP, and they use it more than CPAP. ... Because our product says you don’t treat everybody, you only undertake oral appliance therapy for those who we know in advance will have a favorable outcome, it removes a major barrier to oral appliance therapy that has been the barrier for many years.”
Dr. Remmers noted that his test was not nearly as good at identifying people who would be failures as it was at identifying people who would be successes and that he is carrying out another trial with a similar device.
Some participants reported sore gums when using the device, but there were no long-lasting adverse events reported.
The mandibular positioner home test has not been approved or cleared for use by the Food and Drug Administration, but is currently being sold in Canada, according to Dr. Remmers.
Zephyr Sleep Technologies and Alberta Innovates Technology Futures sponsored the study. It is registered on clinicaltrials.gov as NCT03011762. All of the investigators, other than Nikola Vranjes, are employed or associated with Zephyr Sleep Technologies.
Whitney McKnight contributed to this report.
A novel device has shown a high rate of accuracy in predicting which patients with obstructive sleep apnea (OSA) will improve with oral appliance therapy, according to a study.
“At the present time CPAP is our go-to standard medical therapy [for treating OSA]. While it is a wonderful therapy, it has a very serious drawback, which is poor compliance, and that undercuts its long-term effectiveness in reducing the incidence of cardiovascular disease,” said John E. Remmers, MD, the principal investigator, in an interview.
Referring to the Sleep Apnea Cardiovascular Endpoints (SAVE) trial’s finding that continuous positive airway pressure (CPAP) did not reduce long-term cardiovascular incidents, he claimed that “these incidents are not being reduced by CPAP, because people don’t use it” (N Engl J Med. 2016 Sept 8;375[10]:919-31).
In Dr. Remmers’ new two-part study, 202 adults – primarily overweight, middle-aged men, diagnosed with moderate sleep apnea – were divided into two groups. The first included 149 people who were given a two-night, in-home, feedback controlled mandibular positioner (FCMP) test, using equipment manufactured by Zephyr Sleep Technologies. In this test, a custom-fit oral appliance is simulated using a temporary set of trays and impression material. The trays are connected to a small motor controlled by a little computer that sits on the stomach and moves the mandible when the patient has a problem breathing.
All patients received a custom oral appliance designed using data acquired from the test. The patients then wore the custom oral appliances while connected to a validated monitor as an outcomes study.
Finally, the researchers fed all of the data they collected from this first group of patients into a machine learning model. Then the second set of patients participated in the testing. Outcomes data on the appliance’s performance in each individual in the first group were used to create a classification system to predict therapeutic outcomes for the 53 patients in the second group. The patients in the second group then received their custom oral appliances, connected to the same type of monitor used by the first group.
Therapeutic success or failure was defined as having mean oxygen desaturation index values of less than or greater than 10 events/hour, respectively. The investigators determined that the test had an 85% sensitivity level with 93% specificity, a positive predictive value of 97%, and a negative predictive value of 72%. Of those who were predicted to respond to therapy, the mandibular protrusive position was efficacious in 86% of patients.
The high rate of accuracy for predicting who will derive the most benefit from the appliance, along with the demonstrated preference for oral appliances compared to continuous positive airway pressure devices among patients, increases the clinical utility of the appliance, and expands options for clinical management of sleep apnea, according to the study authors (Clin Sleep Med. 2017;13[7]:871-80).
“Our test allows the physician to prescribe the therapy knowing it will get rid of sleep apnea, and it tells the dentist how far the mandible needs to be pulled out by the custom fit device,” Dr. Remmers explained.
Dentists will also benefit from the test, because it allows them to make an appliance that will not need to be adjusted and will have a higher success rate than the current 60% success rate that oral appliances have at treating sleep apnea, he noted.
“This opens up a new an alternative clinical avenue at a critical time, when we have just learned over the past few years that there are serious questions about the effectiveness of CPAP in the long term,” Dr. Remmers added. “[With oral appliance therapy] you have an opportunity for higher compliance, because people prefer the less obtrusive oral appliance therapy over CPAP, and they use it more than CPAP. ... Because our product says you don’t treat everybody, you only undertake oral appliance therapy for those who we know in advance will have a favorable outcome, it removes a major barrier to oral appliance therapy that has been the barrier for many years.”
Dr. Remmers noted that his test was not nearly as good at identifying people who would be failures as it was at identifying people who would be successes and that he is carrying out another trial with a similar device.
Some participants reported sore gums when using the device, but there were no long-lasting adverse events reported.
The mandibular positioner home test has not been approved or cleared for use by the Food and Drug Administration, but is currently being sold in Canada, according to Dr. Remmers.
Zephyr Sleep Technologies and Alberta Innovates Technology Futures sponsored the study. It is registered on clinicaltrials.gov as NCT03011762. All of the investigators, other than Nikola Vranjes, are employed or associated with Zephyr Sleep Technologies.
Whitney McKnight contributed to this report.
A novel device has shown a high rate of accuracy in predicting which patients with obstructive sleep apnea (OSA) will improve with oral appliance therapy, according to a study.
“At the present time CPAP is our go-to standard medical therapy [for treating OSA]. While it is a wonderful therapy, it has a very serious drawback, which is poor compliance, and that undercuts its long-term effectiveness in reducing the incidence of cardiovascular disease,” said John E. Remmers, MD, the principal investigator, in an interview.
Referring to the Sleep Apnea Cardiovascular Endpoints (SAVE) trial’s finding that continuous positive airway pressure (CPAP) did not reduce long-term cardiovascular incidents, he claimed that “these incidents are not being reduced by CPAP, because people don’t use it” (N Engl J Med. 2016 Sept 8;375[10]:919-31).
In Dr. Remmers’ new two-part study, 202 adults – primarily overweight, middle-aged men, diagnosed with moderate sleep apnea – were divided into two groups. The first included 149 people who were given a two-night, in-home, feedback controlled mandibular positioner (FCMP) test, using equipment manufactured by Zephyr Sleep Technologies. In this test, a custom-fit oral appliance is simulated using a temporary set of trays and impression material. The trays are connected to a small motor controlled by a little computer that sits on the stomach and moves the mandible when the patient has a problem breathing.
All patients received a custom oral appliance designed using data acquired from the test. The patients then wore the custom oral appliances while connected to a validated monitor as an outcomes study.
Finally, the researchers fed all of the data they collected from this first group of patients into a machine learning model. Then the second set of patients participated in the testing. Outcomes data on the appliance’s performance in each individual in the first group were used to create a classification system to predict therapeutic outcomes for the 53 patients in the second group. The patients in the second group then received their custom oral appliances, connected to the same type of monitor used by the first group.
Therapeutic success or failure was defined as having mean oxygen desaturation index values of less than or greater than 10 events/hour, respectively. The investigators determined that the test had an 85% sensitivity level with 93% specificity, a positive predictive value of 97%, and a negative predictive value of 72%. Of those who were predicted to respond to therapy, the mandibular protrusive position was efficacious in 86% of patients.
The high rate of accuracy for predicting who will derive the most benefit from the appliance, along with the demonstrated preference for oral appliances compared to continuous positive airway pressure devices among patients, increases the clinical utility of the appliance, and expands options for clinical management of sleep apnea, according to the study authors (Clin Sleep Med. 2017;13[7]:871-80).
“Our test allows the physician to prescribe the therapy knowing it will get rid of sleep apnea, and it tells the dentist how far the mandible needs to be pulled out by the custom fit device,” Dr. Remmers explained.
Dentists will also benefit from the test, because it allows them to make an appliance that will not need to be adjusted and will have a higher success rate than the current 60% success rate that oral appliances have at treating sleep apnea, he noted.
“This opens up a new an alternative clinical avenue at a critical time, when we have just learned over the past few years that there are serious questions about the effectiveness of CPAP in the long term,” Dr. Remmers added. “[With oral appliance therapy] you have an opportunity for higher compliance, because people prefer the less obtrusive oral appliance therapy over CPAP, and they use it more than CPAP. ... Because our product says you don’t treat everybody, you only undertake oral appliance therapy for those who we know in advance will have a favorable outcome, it removes a major barrier to oral appliance therapy that has been the barrier for many years.”
Dr. Remmers noted that his test was not nearly as good at identifying people who would be failures as it was at identifying people who would be successes and that he is carrying out another trial with a similar device.
Some participants reported sore gums when using the device, but there were no long-lasting adverse events reported.
The mandibular positioner home test has not been approved or cleared for use by the Food and Drug Administration, but is currently being sold in Canada, according to Dr. Remmers.
Zephyr Sleep Technologies and Alberta Innovates Technology Futures sponsored the study. It is registered on clinicaltrials.gov as NCT03011762. All of the investigators, other than Nikola Vranjes, are employed or associated with Zephyr Sleep Technologies.
Whitney McKnight contributed to this report.
Say ‘Aloha’ to the best health care
It probably should come as no surprise that Hawaii, which has been named the healthiest state for 5 consecutive years, is now being honored for having the best health care by personal finance website WalletHub.
The state’s high scores in two of the three broad dimensions of health care – first in outcomes and third in cost – used in the WalletHub analysis allowed it to overcome its ranking of 42nd in the third dimension, access, and finish ahead of Iowa and Minnesota, which tied for second. New Hampshire earned a fourth-place finish and the District of Columbia was fifth, courtesy of its first-place finish in the cost dimension, WalletHub reported. Maine, which finished 14th overall, was No. 1 in access.
The state in 51st place is Louisiana, which placed in the top 5 in both cancer and heart disease rates. Mississippi was credited with the 50th-best health care system, just behind Alaska (49), Arkansas (48), North Carolina (47), and Georgia (46). The lowest ranking in each dimension went to Alaska (cost), Texas (access), and Mississippi (outcomes), according to WalletHub’s analysts.
A closer look at some of the individual metrics shows that the District of Columbia has the most physicians per capita and Idaho has the fewest, Medicare acceptance is highest among physicians in North Dakota and lowest in Hawaii, and infant mortality is lowest in New Hampshire and highest in Mississippi, according to the WalletHub analysis, which was based on data from 19 sources, including the Centers for Medicare & Medicaid Services, the Association of American Medical Colleges, and the Social Science Research Council.
It probably should come as no surprise that Hawaii, which has been named the healthiest state for 5 consecutive years, is now being honored for having the best health care by personal finance website WalletHub.
The state’s high scores in two of the three broad dimensions of health care – first in outcomes and third in cost – used in the WalletHub analysis allowed it to overcome its ranking of 42nd in the third dimension, access, and finish ahead of Iowa and Minnesota, which tied for second. New Hampshire earned a fourth-place finish and the District of Columbia was fifth, courtesy of its first-place finish in the cost dimension, WalletHub reported. Maine, which finished 14th overall, was No. 1 in access.
The state in 51st place is Louisiana, which placed in the top 5 in both cancer and heart disease rates. Mississippi was credited with the 50th-best health care system, just behind Alaska (49), Arkansas (48), North Carolina (47), and Georgia (46). The lowest ranking in each dimension went to Alaska (cost), Texas (access), and Mississippi (outcomes), according to WalletHub’s analysts.
A closer look at some of the individual metrics shows that the District of Columbia has the most physicians per capita and Idaho has the fewest, Medicare acceptance is highest among physicians in North Dakota and lowest in Hawaii, and infant mortality is lowest in New Hampshire and highest in Mississippi, according to the WalletHub analysis, which was based on data from 19 sources, including the Centers for Medicare & Medicaid Services, the Association of American Medical Colleges, and the Social Science Research Council.
It probably should come as no surprise that Hawaii, which has been named the healthiest state for 5 consecutive years, is now being honored for having the best health care by personal finance website WalletHub.
The state’s high scores in two of the three broad dimensions of health care – first in outcomes and third in cost – used in the WalletHub analysis allowed it to overcome its ranking of 42nd in the third dimension, access, and finish ahead of Iowa and Minnesota, which tied for second. New Hampshire earned a fourth-place finish and the District of Columbia was fifth, courtesy of its first-place finish in the cost dimension, WalletHub reported. Maine, which finished 14th overall, was No. 1 in access.
The state in 51st place is Louisiana, which placed in the top 5 in both cancer and heart disease rates. Mississippi was credited with the 50th-best health care system, just behind Alaska (49), Arkansas (48), North Carolina (47), and Georgia (46). The lowest ranking in each dimension went to Alaska (cost), Texas (access), and Mississippi (outcomes), according to WalletHub’s analysts.
A closer look at some of the individual metrics shows that the District of Columbia has the most physicians per capita and Idaho has the fewest, Medicare acceptance is highest among physicians in North Dakota and lowest in Hawaii, and infant mortality is lowest in New Hampshire and highest in Mississippi, according to the WalletHub analysis, which was based on data from 19 sources, including the Centers for Medicare & Medicaid Services, the Association of American Medical Colleges, and the Social Science Research Council.
IV ketamine proves superior to active placebo in low, high doses
MIAMI – Intravenous ketamine in a range of doses is superior to active placebo, according to analyses from a study of the drug for treatment-resistant depression.
Most of the effect was attributable to differences recorded at Day 1 of the 3-day study, according to George I. Papakostas, MD, scientific director of the Massachusetts General Hospital Clinical Trials Network and Institute and coinvestigator of the study, who presented these findings at a meeting of the American Society of Clinical Psychopharmacology, formerly the New Clinical Drug Evaluation meeting.
The 99 adults with treatment-resistant depression – primarily white women in their mid-40s – were randomly assigned either to an active placebo group given 0.045 mg/kg of midazolam or to one of four treatment arms given a single infusion of intravenous ketamine at either 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, or 1.0 mg/kg.
Baseline scores on the 6-item Hamilton Depression Rating Scale (HAMD-6) ranged between 12.6 and 13.1 across the study.
To determine the efficacy of intravenous ketamine at different doses over the course of 72 hours, Dr. Papakostas, who also directs treatment-resistant depression studies at Massachusetts General, and his colleagues used multiple statistical models. The first analysis was a comparison of the effects of the active placebo and all ketamine groups combined at Day 1 and at Day 3.
At Day 1, the change in baseline HAMD-6 scores for all the ketamine arms combined, compared with the active placebo group, was statistically significant (P = .0278). At Day 3, the change in baseline HAMD-6 scores for the combined ketamine groups, compared with the active placebo arm, also was statistically significant (P = .0391).
A secondary analysis of the patient-reported Symptoms of Depression Questionnaire also showed a statistically significant improvement (P = .09) from baseline in the combined ketamine groups, compared with the active placebo group.
At Day 1, the combined ketamine groups’ changes from baseline HAMD-6 were –3.25 with an effect size of 0.86, a statistically significant finding. However, by the Day 3, the combined ketamine groups’ effects size fell away. “There is no longer a statistically significant difference, so it’s a rapid effect – like we’ve seen in the other studies for the combined doses – but it is not an effect that is sustained,” said Dr. Papakostas, also an associate professor of psychiatry at Harvard Medical School, Boston.
For the individual doses, compared with active placebo, the ketamine 0.1 mg/kg arm had an overall –0.35 change in baseline HAMD-6 scores, which Dr. Papakostas said had “a large effect size of 0.82.”
Dr. Papakostas also said the ketamine 0.2 mg/kg arm “did not really seem to move things around at all.” Meanwhile, the 0.5 mg/kg and 1.0 mg/kg arms each had “big differences” in baseline HAMD-6 scores, compared with active placebo, of –4.79 and –3.76, respectively. They also exhibited statistically significant effect sizes of 1.21 and 0.95 at Day 1, respectively. However, at Day 3, there were neither numerical nor statistical differences, indicating the effect is not sustained.
Changes in the Symptoms of Depression Questionnaire for the combined drug arms at Day 1 were statistically significant with an unadjusted P value of .07 and an adjusted P value of .13.
Results for the Clinician Administered Dissociative States Scale showed that neither the ketamine 0.1 mg/kg arm nor the ketamine 0.2 mg/kg arm separated from active placebo, while the ketamine 0.5 mg/kg arm and the ketamine 1.0 mg/kg arm were each different from active placebo to numerically and statistically significant degrees. Each of the 0.5 mg/kg and the 1.0 mg/kg ketamine arms were associated with rises in blood pressure, according to Dr. Papakostas.
“So, it seems as though the doses that caused a dissociation seemed to cause a clinical effect that is equivalent, whereas in the lower doses, there didn’t seem to be any dissociative effects or blood pressure effects,” Dr. Papakostas said. “If you combine the findings, in my opinion, there is a signal in the 0.1 mg/kg treatment arm, even though it just misses it on the P value.”
Dr. Papakostas said that, although more data are needed to determine optimal dosing and a clearer risk-benefit ratio, the results suggested that intravenous ketamine could offer transient, beneficial effects for patients with treatment-resistant depression.
Dr. Papakostas is the scientific director of the MGH Clinical Trials Network and Institute. This study’s coinvestigator, Maurizio Fava, MD, has numerous relevant financial ties to industry. This trial was part of the National Institute of Mental Health’s Rapidly-Acting Treatments for Treatment-Resistant Depression research program.
[email protected]
On Twitter @whitneymcknight
MIAMI – Intravenous ketamine in a range of doses is superior to active placebo, according to analyses from a study of the drug for treatment-resistant depression.
Most of the effect was attributable to differences recorded at Day 1 of the 3-day study, according to George I. Papakostas, MD, scientific director of the Massachusetts General Hospital Clinical Trials Network and Institute and coinvestigator of the study, who presented these findings at a meeting of the American Society of Clinical Psychopharmacology, formerly the New Clinical Drug Evaluation meeting.
The 99 adults with treatment-resistant depression – primarily white women in their mid-40s – were randomly assigned either to an active placebo group given 0.045 mg/kg of midazolam or to one of four treatment arms given a single infusion of intravenous ketamine at either 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, or 1.0 mg/kg.
Baseline scores on the 6-item Hamilton Depression Rating Scale (HAMD-6) ranged between 12.6 and 13.1 across the study.
To determine the efficacy of intravenous ketamine at different doses over the course of 72 hours, Dr. Papakostas, who also directs treatment-resistant depression studies at Massachusetts General, and his colleagues used multiple statistical models. The first analysis was a comparison of the effects of the active placebo and all ketamine groups combined at Day 1 and at Day 3.
At Day 1, the change in baseline HAMD-6 scores for all the ketamine arms combined, compared with the active placebo group, was statistically significant (P = .0278). At Day 3, the change in baseline HAMD-6 scores for the combined ketamine groups, compared with the active placebo arm, also was statistically significant (P = .0391).
A secondary analysis of the patient-reported Symptoms of Depression Questionnaire also showed a statistically significant improvement (P = .09) from baseline in the combined ketamine groups, compared with the active placebo group.
At Day 1, the combined ketamine groups’ changes from baseline HAMD-6 were –3.25 with an effect size of 0.86, a statistically significant finding. However, by the Day 3, the combined ketamine groups’ effects size fell away. “There is no longer a statistically significant difference, so it’s a rapid effect – like we’ve seen in the other studies for the combined doses – but it is not an effect that is sustained,” said Dr. Papakostas, also an associate professor of psychiatry at Harvard Medical School, Boston.
For the individual doses, compared with active placebo, the ketamine 0.1 mg/kg arm had an overall –0.35 change in baseline HAMD-6 scores, which Dr. Papakostas said had “a large effect size of 0.82.”
Dr. Papakostas also said the ketamine 0.2 mg/kg arm “did not really seem to move things around at all.” Meanwhile, the 0.5 mg/kg and 1.0 mg/kg arms each had “big differences” in baseline HAMD-6 scores, compared with active placebo, of –4.79 and –3.76, respectively. They also exhibited statistically significant effect sizes of 1.21 and 0.95 at Day 1, respectively. However, at Day 3, there were neither numerical nor statistical differences, indicating the effect is not sustained.
Changes in the Symptoms of Depression Questionnaire for the combined drug arms at Day 1 were statistically significant with an unadjusted P value of .07 and an adjusted P value of .13.
Results for the Clinician Administered Dissociative States Scale showed that neither the ketamine 0.1 mg/kg arm nor the ketamine 0.2 mg/kg arm separated from active placebo, while the ketamine 0.5 mg/kg arm and the ketamine 1.0 mg/kg arm were each different from active placebo to numerically and statistically significant degrees. Each of the 0.5 mg/kg and the 1.0 mg/kg ketamine arms were associated with rises in blood pressure, according to Dr. Papakostas.
“So, it seems as though the doses that caused a dissociation seemed to cause a clinical effect that is equivalent, whereas in the lower doses, there didn’t seem to be any dissociative effects or blood pressure effects,” Dr. Papakostas said. “If you combine the findings, in my opinion, there is a signal in the 0.1 mg/kg treatment arm, even though it just misses it on the P value.”
Dr. Papakostas said that, although more data are needed to determine optimal dosing and a clearer risk-benefit ratio, the results suggested that intravenous ketamine could offer transient, beneficial effects for patients with treatment-resistant depression.
Dr. Papakostas is the scientific director of the MGH Clinical Trials Network and Institute. This study’s coinvestigator, Maurizio Fava, MD, has numerous relevant financial ties to industry. This trial was part of the National Institute of Mental Health’s Rapidly-Acting Treatments for Treatment-Resistant Depression research program.
[email protected]
On Twitter @whitneymcknight
MIAMI – Intravenous ketamine in a range of doses is superior to active placebo, according to analyses from a study of the drug for treatment-resistant depression.
Most of the effect was attributable to differences recorded at Day 1 of the 3-day study, according to George I. Papakostas, MD, scientific director of the Massachusetts General Hospital Clinical Trials Network and Institute and coinvestigator of the study, who presented these findings at a meeting of the American Society of Clinical Psychopharmacology, formerly the New Clinical Drug Evaluation meeting.
The 99 adults with treatment-resistant depression – primarily white women in their mid-40s – were randomly assigned either to an active placebo group given 0.045 mg/kg of midazolam or to one of four treatment arms given a single infusion of intravenous ketamine at either 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, or 1.0 mg/kg.
Baseline scores on the 6-item Hamilton Depression Rating Scale (HAMD-6) ranged between 12.6 and 13.1 across the study.
To determine the efficacy of intravenous ketamine at different doses over the course of 72 hours, Dr. Papakostas, who also directs treatment-resistant depression studies at Massachusetts General, and his colleagues used multiple statistical models. The first analysis was a comparison of the effects of the active placebo and all ketamine groups combined at Day 1 and at Day 3.
At Day 1, the change in baseline HAMD-6 scores for all the ketamine arms combined, compared with the active placebo group, was statistically significant (P = .0278). At Day 3, the change in baseline HAMD-6 scores for the combined ketamine groups, compared with the active placebo arm, also was statistically significant (P = .0391).
A secondary analysis of the patient-reported Symptoms of Depression Questionnaire also showed a statistically significant improvement (P = .09) from baseline in the combined ketamine groups, compared with the active placebo group.
At Day 1, the combined ketamine groups’ changes from baseline HAMD-6 were –3.25 with an effect size of 0.86, a statistically significant finding. However, by the Day 3, the combined ketamine groups’ effects size fell away. “There is no longer a statistically significant difference, so it’s a rapid effect – like we’ve seen in the other studies for the combined doses – but it is not an effect that is sustained,” said Dr. Papakostas, also an associate professor of psychiatry at Harvard Medical School, Boston.
For the individual doses, compared with active placebo, the ketamine 0.1 mg/kg arm had an overall –0.35 change in baseline HAMD-6 scores, which Dr. Papakostas said had “a large effect size of 0.82.”
Dr. Papakostas also said the ketamine 0.2 mg/kg arm “did not really seem to move things around at all.” Meanwhile, the 0.5 mg/kg and 1.0 mg/kg arms each had “big differences” in baseline HAMD-6 scores, compared with active placebo, of –4.79 and –3.76, respectively. They also exhibited statistically significant effect sizes of 1.21 and 0.95 at Day 1, respectively. However, at Day 3, there were neither numerical nor statistical differences, indicating the effect is not sustained.
Changes in the Symptoms of Depression Questionnaire for the combined drug arms at Day 1 were statistically significant with an unadjusted P value of .07 and an adjusted P value of .13.
Results for the Clinician Administered Dissociative States Scale showed that neither the ketamine 0.1 mg/kg arm nor the ketamine 0.2 mg/kg arm separated from active placebo, while the ketamine 0.5 mg/kg arm and the ketamine 1.0 mg/kg arm were each different from active placebo to numerically and statistically significant degrees. Each of the 0.5 mg/kg and the 1.0 mg/kg ketamine arms were associated with rises in blood pressure, according to Dr. Papakostas.
“So, it seems as though the doses that caused a dissociation seemed to cause a clinical effect that is equivalent, whereas in the lower doses, there didn’t seem to be any dissociative effects or blood pressure effects,” Dr. Papakostas said. “If you combine the findings, in my opinion, there is a signal in the 0.1 mg/kg treatment arm, even though it just misses it on the P value.”
Dr. Papakostas said that, although more data are needed to determine optimal dosing and a clearer risk-benefit ratio, the results suggested that intravenous ketamine could offer transient, beneficial effects for patients with treatment-resistant depression.
Dr. Papakostas is the scientific director of the MGH Clinical Trials Network and Institute. This study’s coinvestigator, Maurizio Fava, MD, has numerous relevant financial ties to industry. This trial was part of the National Institute of Mental Health’s Rapidly-Acting Treatments for Treatment-Resistant Depression research program.
[email protected]
On Twitter @whitneymcknight
FROM THE ASCP ANNUAL MEETING
Key clinical point:
Major finding: Ketamine’s effect size and improvement from baseline depression scores showed significant separation from placebo in most analyses conducted in this study.
Data source: Multicenter, randomly controlled, double-blind study of 99 adults with treatment-resistant depression given active placebo or various doses of intravenous ketamine.
Disclosures: Dr. Papakostas is the scientific director of the Massachusetts General Hospital Clinical Trials Network and Institute. This study’s coinvestigator, Dr. Maurizio Fava, has numerous relevant financial ties to industry. This trial was part of the National Institute of Mental Health’s Rapidly-Acting Treatments for Treatment-Resistant Depression research program.
VIDEO: How to prevent, manage perinatal HIV infection
PARK CITY, UTAH – Despite notable progress in recent years, . Early recognition and treatment of HIV infection in pregnancy, prophylaxis for at-risk women, and retention of infected women in postpartum HIV care remain important goals, but they aren’t always met.
In a wide-ranging interview at the annual scientific meeting of the Infectious Diseases Society for Obstetrics and Gynecology, Gweneth Lazenby, MD, associate professor of obstetrics and gynecology at the Medical University of South Carolina, Charleston, explained what to do to improve the situation. Among the many pearls she shared: One HIV test isn’t enough for at-risk women.
PARK CITY, UTAH – Despite notable progress in recent years, . Early recognition and treatment of HIV infection in pregnancy, prophylaxis for at-risk women, and retention of infected women in postpartum HIV care remain important goals, but they aren’t always met.
In a wide-ranging interview at the annual scientific meeting of the Infectious Diseases Society for Obstetrics and Gynecology, Gweneth Lazenby, MD, associate professor of obstetrics and gynecology at the Medical University of South Carolina, Charleston, explained what to do to improve the situation. Among the many pearls she shared: One HIV test isn’t enough for at-risk women.
PARK CITY, UTAH – Despite notable progress in recent years, . Early recognition and treatment of HIV infection in pregnancy, prophylaxis for at-risk women, and retention of infected women in postpartum HIV care remain important goals, but they aren’t always met.
In a wide-ranging interview at the annual scientific meeting of the Infectious Diseases Society for Obstetrics and Gynecology, Gweneth Lazenby, MD, associate professor of obstetrics and gynecology at the Medical University of South Carolina, Charleston, explained what to do to improve the situation. Among the many pearls she shared: One HIV test isn’t enough for at-risk women.
AT IDSOG
APAP improves aerophagia symptoms
Switching continuous positive airway pressure–treated patients to autotitrating positive airway pressure (APAP) systems resulted in reduced severity of patient-reported aerophagia symptoms, according to results from a double-blind, randomized study.
Aerophagia, the swallowing of air leading to gastrointestinal distress, is a frequently reported adverse effect among people treated for obstructive sleep apnea with continuous positive airway pressure (CPAP).
The APAP-treated group saw significantly reduced median therapeutic pressure levels compared with the CPAP-treated patients (9.8 vs. 14.0 cm H2O, P less than .001) and slight but statistically significant reductions in self-reported symptoms of bloating, flatulence, and belching. No significant difference was seen in compliance with therapy between the two treatment groups in this study, published in the August 2017 issue of Journal of Clinical Sleep Medicine (J Clin Sleep Med. 2017;13[7]:881-8).
For their research, Teresa Shirlaw and her colleagues in the sleep clinic at Princess Alexandra Hospital in Woolloongabba, Queensland, Australia, analyzed results from 56 adult patients with sleep apnea who had been recently treated with CPAP and reported bloating, flatulence, or belching following therapy.
Patients were randomized 1:1 to in-clinic nighttime CPAP or APAP for 2 weeks and blinded to treatment assignment, while investigators recorded therapy usage hours, pressure, leak, and residual apnea-hypopnea index across the study period. Most of the subjects (n = 39) used full face masks, while others used nasal-only systems.
The researchers considered differences in PAP therapy usage of at least 30 minutes per night to be statistically significant. The APAP group used the assigned therapy a mean 7 hours per night, vs. 6.8 for the CPAP group. Daytime sleepiness outcomes were also similar for the two treatment groups.
Ms. Shirlaw and her colleagues described the compliance findings as a surprise, noting that an earlier meta-analysis had shown slight improvements in compliance associated with APAP (Syst Rev. 2012;1[1]:20). In clinical practice, patients complaining of aerophagia associated with CPAP are frequently switched to APAP based on the belief that doing so “will lead to improved therapy acceptance and … improved compliance,” they wrote.
The investigators described the self-reporting of aerophagia symptoms as one of the study’s limitations. They surmised that the lack of difference seen for compliance measures might be explained in part by the 30-minute usage increments in the study design (compared with 10-minute increments used in some other studies), and the fact that the cohort had relatively high compliance with CPAP at baseline (5.5 hours/night), suggesting a motivated patient population at entry.
The study received some funding from the government of Queensland, and the authors disclosed no conflicts of interest related to their findings.
Switching continuous positive airway pressure–treated patients to autotitrating positive airway pressure (APAP) systems resulted in reduced severity of patient-reported aerophagia symptoms, according to results from a double-blind, randomized study.
Aerophagia, the swallowing of air leading to gastrointestinal distress, is a frequently reported adverse effect among people treated for obstructive sleep apnea with continuous positive airway pressure (CPAP).
The APAP-treated group saw significantly reduced median therapeutic pressure levels compared with the CPAP-treated patients (9.8 vs. 14.0 cm H2O, P less than .001) and slight but statistically significant reductions in self-reported symptoms of bloating, flatulence, and belching. No significant difference was seen in compliance with therapy between the two treatment groups in this study, published in the August 2017 issue of Journal of Clinical Sleep Medicine (J Clin Sleep Med. 2017;13[7]:881-8).
For their research, Teresa Shirlaw and her colleagues in the sleep clinic at Princess Alexandra Hospital in Woolloongabba, Queensland, Australia, analyzed results from 56 adult patients with sleep apnea who had been recently treated with CPAP and reported bloating, flatulence, or belching following therapy.
Patients were randomized 1:1 to in-clinic nighttime CPAP or APAP for 2 weeks and blinded to treatment assignment, while investigators recorded therapy usage hours, pressure, leak, and residual apnea-hypopnea index across the study period. Most of the subjects (n = 39) used full face masks, while others used nasal-only systems.
The researchers considered differences in PAP therapy usage of at least 30 minutes per night to be statistically significant. The APAP group used the assigned therapy a mean 7 hours per night, vs. 6.8 for the CPAP group. Daytime sleepiness outcomes were also similar for the two treatment groups.
Ms. Shirlaw and her colleagues described the compliance findings as a surprise, noting that an earlier meta-analysis had shown slight improvements in compliance associated with APAP (Syst Rev. 2012;1[1]:20). In clinical practice, patients complaining of aerophagia associated with CPAP are frequently switched to APAP based on the belief that doing so “will lead to improved therapy acceptance and … improved compliance,” they wrote.
The investigators described the self-reporting of aerophagia symptoms as one of the study’s limitations. They surmised that the lack of difference seen for compliance measures might be explained in part by the 30-minute usage increments in the study design (compared with 10-minute increments used in some other studies), and the fact that the cohort had relatively high compliance with CPAP at baseline (5.5 hours/night), suggesting a motivated patient population at entry.
The study received some funding from the government of Queensland, and the authors disclosed no conflicts of interest related to their findings.
Switching continuous positive airway pressure–treated patients to autotitrating positive airway pressure (APAP) systems resulted in reduced severity of patient-reported aerophagia symptoms, according to results from a double-blind, randomized study.
Aerophagia, the swallowing of air leading to gastrointestinal distress, is a frequently reported adverse effect among people treated for obstructive sleep apnea with continuous positive airway pressure (CPAP).
The APAP-treated group saw significantly reduced median therapeutic pressure levels compared with the CPAP-treated patients (9.8 vs. 14.0 cm H2O, P less than .001) and slight but statistically significant reductions in self-reported symptoms of bloating, flatulence, and belching. No significant difference was seen in compliance with therapy between the two treatment groups in this study, published in the August 2017 issue of Journal of Clinical Sleep Medicine (J Clin Sleep Med. 2017;13[7]:881-8).
For their research, Teresa Shirlaw and her colleagues in the sleep clinic at Princess Alexandra Hospital in Woolloongabba, Queensland, Australia, analyzed results from 56 adult patients with sleep apnea who had been recently treated with CPAP and reported bloating, flatulence, or belching following therapy.
Patients were randomized 1:1 to in-clinic nighttime CPAP or APAP for 2 weeks and blinded to treatment assignment, while investigators recorded therapy usage hours, pressure, leak, and residual apnea-hypopnea index across the study period. Most of the subjects (n = 39) used full face masks, while others used nasal-only systems.
The researchers considered differences in PAP therapy usage of at least 30 minutes per night to be statistically significant. The APAP group used the assigned therapy a mean 7 hours per night, vs. 6.8 for the CPAP group. Daytime sleepiness outcomes were also similar for the two treatment groups.
Ms. Shirlaw and her colleagues described the compliance findings as a surprise, noting that an earlier meta-analysis had shown slight improvements in compliance associated with APAP (Syst Rev. 2012;1[1]:20). In clinical practice, patients complaining of aerophagia associated with CPAP are frequently switched to APAP based on the belief that doing so “will lead to improved therapy acceptance and … improved compliance,” they wrote.
The investigators described the self-reporting of aerophagia symptoms as one of the study’s limitations. They surmised that the lack of difference seen for compliance measures might be explained in part by the 30-minute usage increments in the study design (compared with 10-minute increments used in some other studies), and the fact that the cohort had relatively high compliance with CPAP at baseline (5.5 hours/night), suggesting a motivated patient population at entry.
The study received some funding from the government of Queensland, and the authors disclosed no conflicts of interest related to their findings.
FROM THE JOURNAL OF CLINICAL SLEEP MEDICINE
Key clinical point: Sleep apnea patients complaining of aerophagia associated with continuous positive airway pressure may find relief using autotitrating positive airway pressure.
Major finding: The APAP-treated group saw significantly reduced median therapeutic pressure levels compared with the CPAP-treated patients (9.8 vs. 14.0 cm H2O, P less than .001) and slight but statistically significant reductions in self-reported symptoms of bloating, flatulence, and belching.
Data source: A randomized, double-blinded trial of 56 adult sleep apnea patients, with previous CPAP and aerophagia, treated at a hospital sleep clinic in Australia.
Disclosures: The government of Queensland helped fund the study. The authors disclosed no conflicts of interest.
Treating women with opioid use disorders poses unique challenges
The opioid epidemic in the United States is reaching a boiling point, with President Trump calling it a “national emergency” and instructing his administration to use all appropriate authority to respond. Experts say that women are disproportionately affected and require unique treatment approaches.
The rate of prescription opioid–related overdoses increased by 471% among women in 2015, compared with an increase of 218% among men. Heroin deaths among women have risen at more than twice the rate among men, according to a report from the Office of Women’s Health (OWH), part of the U.S. Department of Health & Human Services.
The OWH report, released in July, paints a different picture of addiction for women than for men. Women are more likely to experience chronic pain and turn to prescription opioids for longer periods of time and in higher doses. But women also become dependent at smaller doses and in a shorter period of time. Add to this the fact that psychological and emotional distress are risk factors for opioid abuse among women, but not among men, according to the report.
ACOG guidance
In August, the American College of Obstetricians and Gynecologists (ACOG) updated its recommendations for treatments and best practices related to opioid use among pregnant women (Obstet Gynecol. 2017;130:e81-94).
The committee opinion, developed with the American Society of Addiction Medicine, focuses on tearing down stereotypes about women with substance use disorders that could cause patients to slip through the cracks. ACOG recommended universal screening as a part of regular obstetric care, starting with the first prenatal visit.
While screening can involve laboratory testing, the recommendations focus more on creating a comfortable environment for pregnant women to share substance use history and to have a frank conversation about what treatment options are available.
“The document highlights the use of a verbal screening tool which enables the obstetric provider to have a direct conversation with the patient about their answers,” Maria Mascola, MD, an ob.gyn. at the Marshfield (Wis.) Clinic and lead author of the ACOG committee opinion, said in an interview. “It talks about substance use and then provides an opportunity to understand what substances and how much, why these substances might be bad, why this behavior should be changed, and how obstetricians can try to help the person make those changes.”
ACOG continues to recommend medication-assisted treatment (MAT) – typically with methadone or buprenorphine – as the most effective pathway for pregnant women to deal with substance use disorders. However, in cases in which the patient does not accept treatment with an opioid agonist or the treatment is unavailable, medically supervised withdrawal can be considered. ACOG cautions that relapse rates are high (from 59% to more than 90%) and that withdrawal often involves inpatient care and intensive outpatient follow-up. But recent evidence suggests medically supervised withdrawal is not associated with fetal death or preterm delivery.
“There have been some studies looking at smaller groups that have shown pregnant women going through medically supervised withdrawals and there have been some data from those studies that indicate women may be able to successfully go through this withdrawal without harm to the baby,” Dr. Mascola said. “The information we have on medically supervised withdrawal is a small amount of data, and we definitely need more before this is a primary approach.”
Access to care
Regardless of the treatment approach, the larger issue may be accessibility of care. Just 20% of adults with an opioid use disorder get the treatment and care they need each year, according to the OWH, with access and cost cited as the primary barriers to care. This problem is likely worse in rural areas.
“Rural health care is tougher. There is less access; that is an absolute truth, and it’s a burden then for those women to travel long distances to get the care they need,” Dr. Mascola said. “I think ob.gyns. should advocate for more attention in those areas where patients are underserved.”
One potential solution is for ob.gyns. to become certified in providing buprenorphine, which would allow physicians in rural areas to dispense these approved pharmacotherapies to patients who would otherwise be unable to have the proper treatment and follow-up necessary to prevent relapse, Dr. Mascola said.
There is already some federal funding available for this approach. In 2016, the Health Resources and Services Administration awarded $94 million to health centers across the country to expand substance use services, specifically increasing screening for substance use disorders, improving access to medication-assisted treatment, and training clinicians. Similarly, the Substance Abuse and Mental Health Services Administration recently announced it will allocate an additional $485 million to states through the State Targeted Response to the Opioid Crisis Grants to fund medication-assisted treatment and other services.
Unique challenges
Treating women with opioid use disorder isn’t just about identifying the best treatment approach. Social factors appear to play a larger role among women.
“Another difference with women over men is the prevalence of sexual trauma, as well as being in unhealthy relationships where the women are more likely to be enticed into leaving treatment,” she added.
Trauma among women with substance abuse disorders is prevalent, with 55%-99% of women reporting experiencing some form of trauma, compared with 36%-51% of the general population, according to the OWH report.
Beyond exploratory research, there needs to be a major shift in the public perception of opioid substance use, which currently does not approach the disorder as a chronic disease, according to Dr. Jones.
“The treatment process cannot just involve a detoxification program and then send patients off because that will commonly just end in relapse.” Dr. Jones said. “We need to approach substance use disorders with a recovery-oriented system of care in order to create a true safety net they can rely on.”
[email protected]
On Twitter @eaztweets
The opioid epidemic in the United States is reaching a boiling point, with President Trump calling it a “national emergency” and instructing his administration to use all appropriate authority to respond. Experts say that women are disproportionately affected and require unique treatment approaches.
The rate of prescription opioid–related overdoses increased by 471% among women in 2015, compared with an increase of 218% among men. Heroin deaths among women have risen at more than twice the rate among men, according to a report from the Office of Women’s Health (OWH), part of the U.S. Department of Health & Human Services.
The OWH report, released in July, paints a different picture of addiction for women than for men. Women are more likely to experience chronic pain and turn to prescription opioids for longer periods of time and in higher doses. But women also become dependent at smaller doses and in a shorter period of time. Add to this the fact that psychological and emotional distress are risk factors for opioid abuse among women, but not among men, according to the report.
ACOG guidance
In August, the American College of Obstetricians and Gynecologists (ACOG) updated its recommendations for treatments and best practices related to opioid use among pregnant women (Obstet Gynecol. 2017;130:e81-94).
The committee opinion, developed with the American Society of Addiction Medicine, focuses on tearing down stereotypes about women with substance use disorders that could cause patients to slip through the cracks. ACOG recommended universal screening as a part of regular obstetric care, starting with the first prenatal visit.
While screening can involve laboratory testing, the recommendations focus more on creating a comfortable environment for pregnant women to share substance use history and to have a frank conversation about what treatment options are available.
“The document highlights the use of a verbal screening tool which enables the obstetric provider to have a direct conversation with the patient about their answers,” Maria Mascola, MD, an ob.gyn. at the Marshfield (Wis.) Clinic and lead author of the ACOG committee opinion, said in an interview. “It talks about substance use and then provides an opportunity to understand what substances and how much, why these substances might be bad, why this behavior should be changed, and how obstetricians can try to help the person make those changes.”
ACOG continues to recommend medication-assisted treatment (MAT) – typically with methadone or buprenorphine – as the most effective pathway for pregnant women to deal with substance use disorders. However, in cases in which the patient does not accept treatment with an opioid agonist or the treatment is unavailable, medically supervised withdrawal can be considered. ACOG cautions that relapse rates are high (from 59% to more than 90%) and that withdrawal often involves inpatient care and intensive outpatient follow-up. But recent evidence suggests medically supervised withdrawal is not associated with fetal death or preterm delivery.
“There have been some studies looking at smaller groups that have shown pregnant women going through medically supervised withdrawals and there have been some data from those studies that indicate women may be able to successfully go through this withdrawal without harm to the baby,” Dr. Mascola said. “The information we have on medically supervised withdrawal is a small amount of data, and we definitely need more before this is a primary approach.”
Access to care
Regardless of the treatment approach, the larger issue may be accessibility of care. Just 20% of adults with an opioid use disorder get the treatment and care they need each year, according to the OWH, with access and cost cited as the primary barriers to care. This problem is likely worse in rural areas.
“Rural health care is tougher. There is less access; that is an absolute truth, and it’s a burden then for those women to travel long distances to get the care they need,” Dr. Mascola said. “I think ob.gyns. should advocate for more attention in those areas where patients are underserved.”
One potential solution is for ob.gyns. to become certified in providing buprenorphine, which would allow physicians in rural areas to dispense these approved pharmacotherapies to patients who would otherwise be unable to have the proper treatment and follow-up necessary to prevent relapse, Dr. Mascola said.
There is already some federal funding available for this approach. In 2016, the Health Resources and Services Administration awarded $94 million to health centers across the country to expand substance use services, specifically increasing screening for substance use disorders, improving access to medication-assisted treatment, and training clinicians. Similarly, the Substance Abuse and Mental Health Services Administration recently announced it will allocate an additional $485 million to states through the State Targeted Response to the Opioid Crisis Grants to fund medication-assisted treatment and other services.
Unique challenges
Treating women with opioid use disorder isn’t just about identifying the best treatment approach. Social factors appear to play a larger role among women.
“Another difference with women over men is the prevalence of sexual trauma, as well as being in unhealthy relationships where the women are more likely to be enticed into leaving treatment,” she added.
Trauma among women with substance abuse disorders is prevalent, with 55%-99% of women reporting experiencing some form of trauma, compared with 36%-51% of the general population, according to the OWH report.
Beyond exploratory research, there needs to be a major shift in the public perception of opioid substance use, which currently does not approach the disorder as a chronic disease, according to Dr. Jones.
“The treatment process cannot just involve a detoxification program and then send patients off because that will commonly just end in relapse.” Dr. Jones said. “We need to approach substance use disorders with a recovery-oriented system of care in order to create a true safety net they can rely on.”
[email protected]
On Twitter @eaztweets
The opioid epidemic in the United States is reaching a boiling point, with President Trump calling it a “national emergency” and instructing his administration to use all appropriate authority to respond. Experts say that women are disproportionately affected and require unique treatment approaches.
The rate of prescription opioid–related overdoses increased by 471% among women in 2015, compared with an increase of 218% among men. Heroin deaths among women have risen at more than twice the rate among men, according to a report from the Office of Women’s Health (OWH), part of the U.S. Department of Health & Human Services.
The OWH report, released in July, paints a different picture of addiction for women than for men. Women are more likely to experience chronic pain and turn to prescription opioids for longer periods of time and in higher doses. But women also become dependent at smaller doses and in a shorter period of time. Add to this the fact that psychological and emotional distress are risk factors for opioid abuse among women, but not among men, according to the report.
ACOG guidance
In August, the American College of Obstetricians and Gynecologists (ACOG) updated its recommendations for treatments and best practices related to opioid use among pregnant women (Obstet Gynecol. 2017;130:e81-94).
The committee opinion, developed with the American Society of Addiction Medicine, focuses on tearing down stereotypes about women with substance use disorders that could cause patients to slip through the cracks. ACOG recommended universal screening as a part of regular obstetric care, starting with the first prenatal visit.
While screening can involve laboratory testing, the recommendations focus more on creating a comfortable environment for pregnant women to share substance use history and to have a frank conversation about what treatment options are available.
“The document highlights the use of a verbal screening tool which enables the obstetric provider to have a direct conversation with the patient about their answers,” Maria Mascola, MD, an ob.gyn. at the Marshfield (Wis.) Clinic and lead author of the ACOG committee opinion, said in an interview. “It talks about substance use and then provides an opportunity to understand what substances and how much, why these substances might be bad, why this behavior should be changed, and how obstetricians can try to help the person make those changes.”
ACOG continues to recommend medication-assisted treatment (MAT) – typically with methadone or buprenorphine – as the most effective pathway for pregnant women to deal with substance use disorders. However, in cases in which the patient does not accept treatment with an opioid agonist or the treatment is unavailable, medically supervised withdrawal can be considered. ACOG cautions that relapse rates are high (from 59% to more than 90%) and that withdrawal often involves inpatient care and intensive outpatient follow-up. But recent evidence suggests medically supervised withdrawal is not associated with fetal death or preterm delivery.
“There have been some studies looking at smaller groups that have shown pregnant women going through medically supervised withdrawals and there have been some data from those studies that indicate women may be able to successfully go through this withdrawal without harm to the baby,” Dr. Mascola said. “The information we have on medically supervised withdrawal is a small amount of data, and we definitely need more before this is a primary approach.”
Access to care
Regardless of the treatment approach, the larger issue may be accessibility of care. Just 20% of adults with an opioid use disorder get the treatment and care they need each year, according to the OWH, with access and cost cited as the primary barriers to care. This problem is likely worse in rural areas.
“Rural health care is tougher. There is less access; that is an absolute truth, and it’s a burden then for those women to travel long distances to get the care they need,” Dr. Mascola said. “I think ob.gyns. should advocate for more attention in those areas where patients are underserved.”
One potential solution is for ob.gyns. to become certified in providing buprenorphine, which would allow physicians in rural areas to dispense these approved pharmacotherapies to patients who would otherwise be unable to have the proper treatment and follow-up necessary to prevent relapse, Dr. Mascola said.
There is already some federal funding available for this approach. In 2016, the Health Resources and Services Administration awarded $94 million to health centers across the country to expand substance use services, specifically increasing screening for substance use disorders, improving access to medication-assisted treatment, and training clinicians. Similarly, the Substance Abuse and Mental Health Services Administration recently announced it will allocate an additional $485 million to states through the State Targeted Response to the Opioid Crisis Grants to fund medication-assisted treatment and other services.
Unique challenges
Treating women with opioid use disorder isn’t just about identifying the best treatment approach. Social factors appear to play a larger role among women.
“Another difference with women over men is the prevalence of sexual trauma, as well as being in unhealthy relationships where the women are more likely to be enticed into leaving treatment,” she added.
Trauma among women with substance abuse disorders is prevalent, with 55%-99% of women reporting experiencing some form of trauma, compared with 36%-51% of the general population, according to the OWH report.
Beyond exploratory research, there needs to be a major shift in the public perception of opioid substance use, which currently does not approach the disorder as a chronic disease, according to Dr. Jones.
“The treatment process cannot just involve a detoxification program and then send patients off because that will commonly just end in relapse.” Dr. Jones said. “We need to approach substance use disorders with a recovery-oriented system of care in order to create a true safety net they can rely on.”
[email protected]
On Twitter @eaztweets
How to manage submassive pulmonary embolism
The case
A 49-year-old morbidly obese woman presented to the emergency department with shortness of breath and abdominal distention. On presentation, her blood pressure was 100/60 mm Hg with a heart rate of 110, respiratory rate of 24, and a pulse oximetric saturation (SpO2) of 86% on room air. Troponin T was elevated at 0.3 ng/mL. Computed tomography (CT) of the chest with intravenous contrast showed saddle pulmonary embolism (PE) with dilated right ventricle (RV). CT abdomen/pelvis revealed a very large uterine mass with diffuse lymphadenopathy.
Heparin infusion was started promptly. Echocardiogram demonstrated RV strain. Findings on duplex ultrasound of the lower extremities were consistent with acute deep vein thromboses (DVT) involving the left common femoral vein and the right popliteal vein. Biopsy of a supraclavicular lymph node showed high grade undifferentiated carcinoma most likely of uterine origin.
Clinical questions
What, if any, therapeutic options should be considered beyond standard systemic anticoagulation? Is there a role for:
1. Systemic thrombolysis?
2. Catheter-directed thrombolysis (CDT)?
3. Inferior vena cava (IVC) filter placement?
What is the appropriate management of “submassive” PE?
In the case of massive PE, where the thrombus is located in the central pulmonary vasculature and associated with hypotension due to impaired cardiac output, systemic thrombolysis, embolectomy, and CDT are indicated as potentially life-saving measures. However, the evidence is less clear when the PE is large and has led to RV strain, but without overt hemodynamic instability. This is commonly known as an intermediate risk or “submassive” PE. Submassive PE based on American Heart Association (AHA) guidelines is:1
An acute PE without systemic hypotension (systolic blood pressure less than 90 mm Hg) but with either RV dysfunction or myocardial necrosis. RV dysfunction is defined by the presence of at least one of these following:
• RV dilation (apical 4-chamber RV diameter divided by LV diameter greater than 0.9) or RV systolic dysfunction on echocardiography;
• RV dilation on CT, elevation of BNP (greater than 90 pg/mL), elevation of N-terminal pro-BNP (greater than 500 pg/mL);
• Electrocardiographic changes (new complete or incomplete right bundle branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion).
Myocardial necrosis is defined as elevated troponin I (greater than 0.4 ng/mL) or elevated troponin T (greater than 0.1 ng/mL).
Why is submassive PE of clinical significance?
In 1999, analysis of the International Cooperative Pulmonary Embolism Registry (ICOPER) revealed that RV dysfunction in PE patients was associated with a near doubling of the 3-month mortality risk (hazard ratio 2.0, 1.3-2.9).2 Given this increased risk, one could draw the logical conclusion that we need to treat submassive PE more aggressively than PE without RV strain. But will this necessarily result in a better outcome for the patient given the 3% risk of intracranial hemorrhage associated with thrombolytic therapy?
In the clinical scenario above, the patient did meet the definition of submassive PE. While the patient did not experience systemic hypotension, she did have RV dilation on CT, RV systolic dysfunction on echo as well as an elevated Troponin T level. In addition to starting anticoagulant therapy, what more should be done to increase her probability of a good outcome?
The AHA recommends that systemic thrombolysis and CDT be considered for patients with acute submassive PE if they have clinical evidence of adverse prognosis, including worsening respiratory failure, severe RV dysfunction, or major myocardial necrosis and low risk of bleeding complications (Class IIB; Level of Evidence C).1
The 2016 American College of Chest Physicians (CHEST) guidelines update3 recommends systemically administered thrombolytic therapy over no therapy in selected patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk (Grade 2C recommendation).
Systemic thrombolysis
Systemic thrombolysis is administered as an intravenous thrombolytic infusion delivered over a period of time. The Food and Drug Administration–approved thrombolytic drugs currently include tissue plasminogen activator (tPA)/alteplase, streptokinase and urokinase.
Efficacy of low dose thrombolysis was studied in MOPETT 2013,5 a single-center, prospective, randomized, open label study, in which 126 participants found to have submassive PE based on symptoms and CT angiographic or ventilation/perfusion scan data received either 50 mg tPA plus heparin or heparin anticoagulation alone. The composite endpoint of pulmonary hypertension and recurrent PE at 28 months was 16% in the tPA group compared to 63% in the control group (P less than .001). Systemic thrombolysis was associated with lower risk of pulmonary hypertension and recurrent PE, although no mortality benefit was seen in this small study.
In the randomized, double-blind PEITHO trial (n = 1,006) of 20146 comparing tenecteplase plus heparin versus heparin in the submassive PE patients, the primary outcomes of death and hemodynamic decompensation occurred in 2.6% of the tenecteplase group, compared to 5.6% in the placebo group (P = .02). Thrombolytic therapy was associated with 2% rate of hemorrhagic stroke, whereas hemorrhagic stroke in the placebo group was 0.2% (P = .03). In this case, systemic thrombolysis was associated with a 3% lower risk of death and hemodynamic instability, but also a 1.8% increased risk of hemorrhagic stroke.
Catheter-directed thrombolysis (CDT)
CDT was originally developed to treat arterial, dialysis graft and deep vein thromboses, but is now approved by the FDA for the treatment of acute submassive or massive PE.
A wire is passed through the embolus and a multihole infusion catheter is placed, through which a thrombolytic drug is infused over 12-24 hours. The direct delivery of the drug into the thrombus is thought to be as effective as systemic therapy but with a lower risk of bleeding. If more rapid thrombus removal is indicated due to large clot burden and hemodynamic instability, mechanical therapies, such as fragmentation and aspiration, can be used as an adjunct to CDT. However, these mechanical techniques carry the risk of pulmonary artery injury, and therefore should only be used as a last resort. An ultrasound-emitting wire can be added to the multihole infusion catheter to expedite thrombolysis by ultrasonically disrupting the thrombus, a technique known as ultrasound-enhanced thrombolysis (EKOS).7,10
The ULTIMA 2014 trial,8 a small, randomized, open-label study of Ultrasound-Assisted Catheter Directed Thrombolysis (USAT, the term can be used interchangeably with EKOS) versus heparin anticoagulation alone in 59 patients, was designed to study if the former strategy was better at improving the primary outcome measure of RV/LV ratio in submassive PE patients. The mean reduction in RV/LV ratio was 0.30 +/– 0.20 in the USAT group compared to 0.03 +/– 0.16 in the heparin group (P less than .001). However, no significant difference in mortality or bleeding was observed in the groups at 90-day follow up.
The PERFECT 2015 Trial,9 a multicenter registry-based study, prospectively enrolled 101 patients who received CDT as first-line therapy for massive and submassive PE. Among patients with submassive PE, 97.3% were found to have “clinical success” with this treatment, defined as stabilization of hemodynamics, improvement in pulmonary hypertension and right heart strain, and survival to hospital discharge. There was no major bleeding or intracranial hemorrhage. Subgroup analyses in this study comparing USAT against standard CDT did not reveal significant difference in average pulmonary pressure changes, average thrombolytic doses, or average infusion times.
A prospective single-arm multicenter trial, SEATTLE II 2015,10 evaluated the efficacy of EKOS in a sample of 159 patients. Patients with both massive and submassive PE received approximately 24 mg tPA infused via a catheter over 12-24 hours. The primary efficacy outcome was the chest CT-measured RV/LV ratio decrease from the baseline compared to 48 hours post procedure. The pre- and postprocedure ratio was 1.55 versus 1.13 respectively (P less than .001), indicating that EKOS decreased RV dilation. No intracranial hemorrhage was observed and the investigators did not comment on long-term outcomes such as mortality or quality of life. The study was limited by the lack of a comparison group, such as anticoagulation with heparin as monotherapy, or systemic thrombolysis or standard CDT.
Treatment of submassive PE varies between different institutions. There simply are not adequate data comparing low dose systemic thrombolysis, CDT, EKOS, and standard heparin anticoagulation to make firm recommendations. Some investigators feel low-dose systemic thrombolysis is probably as good as the expensive catheter-based thrombolytic therapies.11,12 Low-dose thrombolytic therapy can be followed by use of oral direct factor Xa inhibitors for maintenance of antithrombotic activity.13
Bottom line
In our institution, the interventional radiology team screens patients who meet criteria for submassive PE on a case-by-case basis. We use pulmonary angiographic data (nature and extent of the thrombus), clinical stability, and analysis of other comorbid conditions to decide the best treatment modality for an individual patient. Our team prefers EKOS for submassive PE patients as well as for massive PE patients and as a rescue procedure for patients who have failed systemic thrombolysis.
Until more data are available to support firm guidelines, we feel establishing multidisciplinary teams composed of interventional radiologists, intensivists, cardiologists, and vascular surgeons is prudent to make individualized decisions and to achieve the best outcomes for our patients.14
IVC filter
Since the patient in this case already has a submassive PE, can she tolerate additional clot burden should her remaining DVT embolize again? Is there a role for IVC filter?
The implantation of IVC filters has increased significantly in the past 30 years, without quality evidence justifying their use.15
The 2016 Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report states clearly: In patients with acute DVT of the leg or PE who are treated with anticoagulants, the use of an IVC filter is not recommended (Grade 1B).3 This recommendation is based on findings of the Prevention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) randomized trial,16 and the recently published PREPIC 2 randomized trial,17 both showing that in anticoagulated patients with PE and DVT, concurrent placement of an IVC filter for 3 months did not reduce recurrent PE, including fatal PE.
CHEST guidelines state that an IVC filter should not be routinely placed as an adjunct in patients with PE and DVT. However, what about in the subgroup of patients with submassive or massive PE in whom another PE would be catastrophic? Clinical data are lacking in this area.
Deshpande et al. reported on a series of six patients with massive PE and cardiopulmonary instability; patients all received an IVC filter with anticoagulation. The short-term outcome was excellent, but long-term follow-up was not done.18 Kucher and colleagues reported that from the ICOPER in 2006, out of the 108 massive PE patients with systolic arterial pressure under 90 mm Hg, 11 patients received adjunctive IVC filter placement. None of these 11 patients developed recurrent PE in 90 days and 10 of them survived at least 90 days; IVC filter placement was associated with a reduction in 90-day mortality. In this study, the placement of an IVC filter was entirely decided by the physicians at different sites.19 In a 2012 study examining case fatality rates in 3,770 patients with acute PE who received pulmonary embolectomy, the data showed that in both unstable and stable patients, case fatality rates were lower in those who received an IVC filter.20
Although the above data are favorable for adjunctive IVC filter placement in massive PE patients, at least in short-term outcomes, the small size and lack of randomization preclude establishment of evidence-based guidelines. The 2016 CHEST guidelines point out that as it is uncertain if there is benefit to place an IVC filter adjunctively in anticoagulated patients with severe PE, in this specific subgroup of patients, the recommendation against insertion of an IVC filter in patients with acute PE who are anticoagulated may not apply.3
Bottom line
There is no evidence-based guideline as to whether IVC filters should be placed adjunctively in patients with submassive or massive PE; however, based on expert consensus, it may be appropriate to place an IVC filter as an adjunct to anticoagulation in patients with severe PE. The decision should be individualized based on each patient’s characteristics, preferences, and institutional expertise.
In our case, in hope of preventing further embolic burden, the patient received an IVC filter the day after presentation. Despite the initiation of anticoagulation with heparin, she remained tachycardic and tachypneic, prompting referral for CDT. The interventional radiology team did not feel that she was a good candidate, given her persistent vaginal bleeding and widely metastatic uterine carcinoma. She was switched to therapeutic enoxaparin after no further invasive intervention was deemed appropriate. Her respiratory status did not improve and bilevel positive airway pressure was initiated. Taking into consideration the terminal nature of her cancer, she ultimately elected to pursue comfort care and died shortly afterward.
Acknowledgements
The authors would like to thank Benjamin A. Hohmuth, MD, A. Joseph Layon, MD, and Luis L. Nadal, MD, for their review of the article and invaluable feedback.
Dr. Wenqian Wang, Dr. Vedamurthy, and Dr. Wang are based in the department of hospital medicine at The Medicine Institute, Geisinger Health System, Danville, Penn. Contact Dr. Wenqian Wang at [email protected].
Key Points
• Use pulmonary angiographic data, clinical stability, and analysis of other comorbid conditions to decide the best treatment modality.
• Our team prefers ultrasound-enhanced thrombolysis (EKOS) for submassive PE patients, massive PE patients, and as a rescue procedure for patients who fail systemic thrombolysis.
• Establishing multidisciplinary teams composed of interventional radiologists, intensivists, cardiologists, and vascular surgeons is prudent to make individualized decisions.
• It may be appropriate to place an IVC filter as an adjunct to anticoagulation in patients with severe PE.
References
1. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123:1788-1830.
2. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353:1386-9.
3. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315-52.
4. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347:1143-50.
5. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M, “MOPETT” Investigators. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111:273-7.
6. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370:1402-11.
7. Kuo WT. Endovascular therapy for acute pulmonary embolism. J Vasc Interv Radiol 2012;23:167-79. e164
8. Kucher N, Boekstegers P, Muller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129:479-86.
9. Kuo WT, Banerjee A, Kim PS, et al. Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): Initial Results From a Prospective Multicenter Registry. Chest. 2015;148:667-73.
10. Piazza G, Hohlfelder B, Jaff MR, et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv. 2015;8:1382-92.
11. Sharifi M. Systemic Full Dose, Half Dose, and Catheter Directed Thrombolysis for Pulmonary Embolism. When to Use and How to Choose? Curr Treat Options Cardiovasc Med. 2016;18:31.
12. Wang C, Zhai Z, Yang Y, et al. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010;137:254-62.
13. Sharifi M, Vajo Z, Freeman W, Bay C, Sharifi M, Schwartz F. Transforming and simplifying the treatment of pulmonary embolism: “safe dose” thrombolysis plus new oral anticoagulants. Lung. 2015;193:369-74.
14. Kabrhel C, Rosovsky R, Channick R, et al. A Multidisciplinary Pulmonary Embolism Response Team: Initial 30-Month Experience With a Novel Approach to Delivery of Care to Patients With Submassive and Massive Pulmonary Embolism. Chest. 2016;150:384-93.
15. Lessne ML, Sing RF. Counterpoint: Do the Benefits Outweigh the Risks for Most Patients Under Consideration for inferior vena cava filters? No. Chest. 2016; 150(6):1182-4.
16. The PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation. 2005;112(3):416-22.
17. Mismetti P, Laporte S, Pellerin O, et al. Effect of a retrievable inferior vena cava filter plus anticoagulation vs. anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015. 313(16):1627-35.
18. Deshpande KS, Hatem C, Karwa M, et al. The use of inferior vena cava filter as a treatment modality for massive pulmonary embolism. A case series and review of pathophysiology. Respir Med. 2002.96(12):984-9.
19. Kucher N, Rossi E, De Rosa M, et al. Massive Pulmonary embolism. Circulation. 2006;113(4):577-82.
20. Stein P, Matta F. Case Fatality Rate with Pulmonary Embolectomy for Acute Pulmonary Embolism. Am J Med. 2012;125:471-7.
The case
A 49-year-old morbidly obese woman presented to the emergency department with shortness of breath and abdominal distention. On presentation, her blood pressure was 100/60 mm Hg with a heart rate of 110, respiratory rate of 24, and a pulse oximetric saturation (SpO2) of 86% on room air. Troponin T was elevated at 0.3 ng/mL. Computed tomography (CT) of the chest with intravenous contrast showed saddle pulmonary embolism (PE) with dilated right ventricle (RV). CT abdomen/pelvis revealed a very large uterine mass with diffuse lymphadenopathy.
Heparin infusion was started promptly. Echocardiogram demonstrated RV strain. Findings on duplex ultrasound of the lower extremities were consistent with acute deep vein thromboses (DVT) involving the left common femoral vein and the right popliteal vein. Biopsy of a supraclavicular lymph node showed high grade undifferentiated carcinoma most likely of uterine origin.
Clinical questions
What, if any, therapeutic options should be considered beyond standard systemic anticoagulation? Is there a role for:
1. Systemic thrombolysis?
2. Catheter-directed thrombolysis (CDT)?
3. Inferior vena cava (IVC) filter placement?
What is the appropriate management of “submassive” PE?
In the case of massive PE, where the thrombus is located in the central pulmonary vasculature and associated with hypotension due to impaired cardiac output, systemic thrombolysis, embolectomy, and CDT are indicated as potentially life-saving measures. However, the evidence is less clear when the PE is large and has led to RV strain, but without overt hemodynamic instability. This is commonly known as an intermediate risk or “submassive” PE. Submassive PE based on American Heart Association (AHA) guidelines is:1
An acute PE without systemic hypotension (systolic blood pressure less than 90 mm Hg) but with either RV dysfunction or myocardial necrosis. RV dysfunction is defined by the presence of at least one of these following:
• RV dilation (apical 4-chamber RV diameter divided by LV diameter greater than 0.9) or RV systolic dysfunction on echocardiography;
• RV dilation on CT, elevation of BNP (greater than 90 pg/mL), elevation of N-terminal pro-BNP (greater than 500 pg/mL);
• Electrocardiographic changes (new complete or incomplete right bundle branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion).
Myocardial necrosis is defined as elevated troponin I (greater than 0.4 ng/mL) or elevated troponin T (greater than 0.1 ng/mL).
Why is submassive PE of clinical significance?
In 1999, analysis of the International Cooperative Pulmonary Embolism Registry (ICOPER) revealed that RV dysfunction in PE patients was associated with a near doubling of the 3-month mortality risk (hazard ratio 2.0, 1.3-2.9).2 Given this increased risk, one could draw the logical conclusion that we need to treat submassive PE more aggressively than PE without RV strain. But will this necessarily result in a better outcome for the patient given the 3% risk of intracranial hemorrhage associated with thrombolytic therapy?
In the clinical scenario above, the patient did meet the definition of submassive PE. While the patient did not experience systemic hypotension, she did have RV dilation on CT, RV systolic dysfunction on echo as well as an elevated Troponin T level. In addition to starting anticoagulant therapy, what more should be done to increase her probability of a good outcome?
The AHA recommends that systemic thrombolysis and CDT be considered for patients with acute submassive PE if they have clinical evidence of adverse prognosis, including worsening respiratory failure, severe RV dysfunction, or major myocardial necrosis and low risk of bleeding complications (Class IIB; Level of Evidence C).1
The 2016 American College of Chest Physicians (CHEST) guidelines update3 recommends systemically administered thrombolytic therapy over no therapy in selected patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk (Grade 2C recommendation).
Systemic thrombolysis
Systemic thrombolysis is administered as an intravenous thrombolytic infusion delivered over a period of time. The Food and Drug Administration–approved thrombolytic drugs currently include tissue plasminogen activator (tPA)/alteplase, streptokinase and urokinase.
Efficacy of low dose thrombolysis was studied in MOPETT 2013,5 a single-center, prospective, randomized, open label study, in which 126 participants found to have submassive PE based on symptoms and CT angiographic or ventilation/perfusion scan data received either 50 mg tPA plus heparin or heparin anticoagulation alone. The composite endpoint of pulmonary hypertension and recurrent PE at 28 months was 16% in the tPA group compared to 63% in the control group (P less than .001). Systemic thrombolysis was associated with lower risk of pulmonary hypertension and recurrent PE, although no mortality benefit was seen in this small study.
In the randomized, double-blind PEITHO trial (n = 1,006) of 20146 comparing tenecteplase plus heparin versus heparin in the submassive PE patients, the primary outcomes of death and hemodynamic decompensation occurred in 2.6% of the tenecteplase group, compared to 5.6% in the placebo group (P = .02). Thrombolytic therapy was associated with 2% rate of hemorrhagic stroke, whereas hemorrhagic stroke in the placebo group was 0.2% (P = .03). In this case, systemic thrombolysis was associated with a 3% lower risk of death and hemodynamic instability, but also a 1.8% increased risk of hemorrhagic stroke.
Catheter-directed thrombolysis (CDT)
CDT was originally developed to treat arterial, dialysis graft and deep vein thromboses, but is now approved by the FDA for the treatment of acute submassive or massive PE.
A wire is passed through the embolus and a multihole infusion catheter is placed, through which a thrombolytic drug is infused over 12-24 hours. The direct delivery of the drug into the thrombus is thought to be as effective as systemic therapy but with a lower risk of bleeding. If more rapid thrombus removal is indicated due to large clot burden and hemodynamic instability, mechanical therapies, such as fragmentation and aspiration, can be used as an adjunct to CDT. However, these mechanical techniques carry the risk of pulmonary artery injury, and therefore should only be used as a last resort. An ultrasound-emitting wire can be added to the multihole infusion catheter to expedite thrombolysis by ultrasonically disrupting the thrombus, a technique known as ultrasound-enhanced thrombolysis (EKOS).7,10
The ULTIMA 2014 trial,8 a small, randomized, open-label study of Ultrasound-Assisted Catheter Directed Thrombolysis (USAT, the term can be used interchangeably with EKOS) versus heparin anticoagulation alone in 59 patients, was designed to study if the former strategy was better at improving the primary outcome measure of RV/LV ratio in submassive PE patients. The mean reduction in RV/LV ratio was 0.30 +/– 0.20 in the USAT group compared to 0.03 +/– 0.16 in the heparin group (P less than .001). However, no significant difference in mortality or bleeding was observed in the groups at 90-day follow up.
The PERFECT 2015 Trial,9 a multicenter registry-based study, prospectively enrolled 101 patients who received CDT as first-line therapy for massive and submassive PE. Among patients with submassive PE, 97.3% were found to have “clinical success” with this treatment, defined as stabilization of hemodynamics, improvement in pulmonary hypertension and right heart strain, and survival to hospital discharge. There was no major bleeding or intracranial hemorrhage. Subgroup analyses in this study comparing USAT against standard CDT did not reveal significant difference in average pulmonary pressure changes, average thrombolytic doses, or average infusion times.
A prospective single-arm multicenter trial, SEATTLE II 2015,10 evaluated the efficacy of EKOS in a sample of 159 patients. Patients with both massive and submassive PE received approximately 24 mg tPA infused via a catheter over 12-24 hours. The primary efficacy outcome was the chest CT-measured RV/LV ratio decrease from the baseline compared to 48 hours post procedure. The pre- and postprocedure ratio was 1.55 versus 1.13 respectively (P less than .001), indicating that EKOS decreased RV dilation. No intracranial hemorrhage was observed and the investigators did not comment on long-term outcomes such as mortality or quality of life. The study was limited by the lack of a comparison group, such as anticoagulation with heparin as monotherapy, or systemic thrombolysis or standard CDT.
Treatment of submassive PE varies between different institutions. There simply are not adequate data comparing low dose systemic thrombolysis, CDT, EKOS, and standard heparin anticoagulation to make firm recommendations. Some investigators feel low-dose systemic thrombolysis is probably as good as the expensive catheter-based thrombolytic therapies.11,12 Low-dose thrombolytic therapy can be followed by use of oral direct factor Xa inhibitors for maintenance of antithrombotic activity.13
Bottom line
In our institution, the interventional radiology team screens patients who meet criteria for submassive PE on a case-by-case basis. We use pulmonary angiographic data (nature and extent of the thrombus), clinical stability, and analysis of other comorbid conditions to decide the best treatment modality for an individual patient. Our team prefers EKOS for submassive PE patients as well as for massive PE patients and as a rescue procedure for patients who have failed systemic thrombolysis.
Until more data are available to support firm guidelines, we feel establishing multidisciplinary teams composed of interventional radiologists, intensivists, cardiologists, and vascular surgeons is prudent to make individualized decisions and to achieve the best outcomes for our patients.14
IVC filter
Since the patient in this case already has a submassive PE, can she tolerate additional clot burden should her remaining DVT embolize again? Is there a role for IVC filter?
The implantation of IVC filters has increased significantly in the past 30 years, without quality evidence justifying their use.15
The 2016 Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report states clearly: In patients with acute DVT of the leg or PE who are treated with anticoagulants, the use of an IVC filter is not recommended (Grade 1B).3 This recommendation is based on findings of the Prevention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) randomized trial,16 and the recently published PREPIC 2 randomized trial,17 both showing that in anticoagulated patients with PE and DVT, concurrent placement of an IVC filter for 3 months did not reduce recurrent PE, including fatal PE.
CHEST guidelines state that an IVC filter should not be routinely placed as an adjunct in patients with PE and DVT. However, what about in the subgroup of patients with submassive or massive PE in whom another PE would be catastrophic? Clinical data are lacking in this area.
Deshpande et al. reported on a series of six patients with massive PE and cardiopulmonary instability; patients all received an IVC filter with anticoagulation. The short-term outcome was excellent, but long-term follow-up was not done.18 Kucher and colleagues reported that from the ICOPER in 2006, out of the 108 massive PE patients with systolic arterial pressure under 90 mm Hg, 11 patients received adjunctive IVC filter placement. None of these 11 patients developed recurrent PE in 90 days and 10 of them survived at least 90 days; IVC filter placement was associated with a reduction in 90-day mortality. In this study, the placement of an IVC filter was entirely decided by the physicians at different sites.19 In a 2012 study examining case fatality rates in 3,770 patients with acute PE who received pulmonary embolectomy, the data showed that in both unstable and stable patients, case fatality rates were lower in those who received an IVC filter.20
Although the above data are favorable for adjunctive IVC filter placement in massive PE patients, at least in short-term outcomes, the small size and lack of randomization preclude establishment of evidence-based guidelines. The 2016 CHEST guidelines point out that as it is uncertain if there is benefit to place an IVC filter adjunctively in anticoagulated patients with severe PE, in this specific subgroup of patients, the recommendation against insertion of an IVC filter in patients with acute PE who are anticoagulated may not apply.3
Bottom line
There is no evidence-based guideline as to whether IVC filters should be placed adjunctively in patients with submassive or massive PE; however, based on expert consensus, it may be appropriate to place an IVC filter as an adjunct to anticoagulation in patients with severe PE. The decision should be individualized based on each patient’s characteristics, preferences, and institutional expertise.
In our case, in hope of preventing further embolic burden, the patient received an IVC filter the day after presentation. Despite the initiation of anticoagulation with heparin, she remained tachycardic and tachypneic, prompting referral for CDT. The interventional radiology team did not feel that she was a good candidate, given her persistent vaginal bleeding and widely metastatic uterine carcinoma. She was switched to therapeutic enoxaparin after no further invasive intervention was deemed appropriate. Her respiratory status did not improve and bilevel positive airway pressure was initiated. Taking into consideration the terminal nature of her cancer, she ultimately elected to pursue comfort care and died shortly afterward.
Acknowledgements
The authors would like to thank Benjamin A. Hohmuth, MD, A. Joseph Layon, MD, and Luis L. Nadal, MD, for their review of the article and invaluable feedback.
Dr. Wenqian Wang, Dr. Vedamurthy, and Dr. Wang are based in the department of hospital medicine at The Medicine Institute, Geisinger Health System, Danville, Penn. Contact Dr. Wenqian Wang at [email protected].
Key Points
• Use pulmonary angiographic data, clinical stability, and analysis of other comorbid conditions to decide the best treatment modality.
• Our team prefers ultrasound-enhanced thrombolysis (EKOS) for submassive PE patients, massive PE patients, and as a rescue procedure for patients who fail systemic thrombolysis.
• Establishing multidisciplinary teams composed of interventional radiologists, intensivists, cardiologists, and vascular surgeons is prudent to make individualized decisions.
• It may be appropriate to place an IVC filter as an adjunct to anticoagulation in patients with severe PE.
References
1. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123:1788-1830.
2. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353:1386-9.
3. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315-52.
4. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347:1143-50.
5. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M, “MOPETT” Investigators. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111:273-7.
6. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370:1402-11.
7. Kuo WT. Endovascular therapy for acute pulmonary embolism. J Vasc Interv Radiol 2012;23:167-79. e164
8. Kucher N, Boekstegers P, Muller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129:479-86.
9. Kuo WT, Banerjee A, Kim PS, et al. Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): Initial Results From a Prospective Multicenter Registry. Chest. 2015;148:667-73.
10. Piazza G, Hohlfelder B, Jaff MR, et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv. 2015;8:1382-92.
11. Sharifi M. Systemic Full Dose, Half Dose, and Catheter Directed Thrombolysis for Pulmonary Embolism. When to Use and How to Choose? Curr Treat Options Cardiovasc Med. 2016;18:31.
12. Wang C, Zhai Z, Yang Y, et al. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010;137:254-62.
13. Sharifi M, Vajo Z, Freeman W, Bay C, Sharifi M, Schwartz F. Transforming and simplifying the treatment of pulmonary embolism: “safe dose” thrombolysis plus new oral anticoagulants. Lung. 2015;193:369-74.
14. Kabrhel C, Rosovsky R, Channick R, et al. A Multidisciplinary Pulmonary Embolism Response Team: Initial 30-Month Experience With a Novel Approach to Delivery of Care to Patients With Submassive and Massive Pulmonary Embolism. Chest. 2016;150:384-93.
15. Lessne ML, Sing RF. Counterpoint: Do the Benefits Outweigh the Risks for Most Patients Under Consideration for inferior vena cava filters? No. Chest. 2016; 150(6):1182-4.
16. The PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation. 2005;112(3):416-22.
17. Mismetti P, Laporte S, Pellerin O, et al. Effect of a retrievable inferior vena cava filter plus anticoagulation vs. anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015. 313(16):1627-35.
18. Deshpande KS, Hatem C, Karwa M, et al. The use of inferior vena cava filter as a treatment modality for massive pulmonary embolism. A case series and review of pathophysiology. Respir Med. 2002.96(12):984-9.
19. Kucher N, Rossi E, De Rosa M, et al. Massive Pulmonary embolism. Circulation. 2006;113(4):577-82.
20. Stein P, Matta F. Case Fatality Rate with Pulmonary Embolectomy for Acute Pulmonary Embolism. Am J Med. 2012;125:471-7.
The case
A 49-year-old morbidly obese woman presented to the emergency department with shortness of breath and abdominal distention. On presentation, her blood pressure was 100/60 mm Hg with a heart rate of 110, respiratory rate of 24, and a pulse oximetric saturation (SpO2) of 86% on room air. Troponin T was elevated at 0.3 ng/mL. Computed tomography (CT) of the chest with intravenous contrast showed saddle pulmonary embolism (PE) with dilated right ventricle (RV). CT abdomen/pelvis revealed a very large uterine mass with diffuse lymphadenopathy.
Heparin infusion was started promptly. Echocardiogram demonstrated RV strain. Findings on duplex ultrasound of the lower extremities were consistent with acute deep vein thromboses (DVT) involving the left common femoral vein and the right popliteal vein. Biopsy of a supraclavicular lymph node showed high grade undifferentiated carcinoma most likely of uterine origin.
Clinical questions
What, if any, therapeutic options should be considered beyond standard systemic anticoagulation? Is there a role for:
1. Systemic thrombolysis?
2. Catheter-directed thrombolysis (CDT)?
3. Inferior vena cava (IVC) filter placement?
What is the appropriate management of “submassive” PE?
In the case of massive PE, where the thrombus is located in the central pulmonary vasculature and associated with hypotension due to impaired cardiac output, systemic thrombolysis, embolectomy, and CDT are indicated as potentially life-saving measures. However, the evidence is less clear when the PE is large and has led to RV strain, but without overt hemodynamic instability. This is commonly known as an intermediate risk or “submassive” PE. Submassive PE based on American Heart Association (AHA) guidelines is:1
An acute PE without systemic hypotension (systolic blood pressure less than 90 mm Hg) but with either RV dysfunction or myocardial necrosis. RV dysfunction is defined by the presence of at least one of these following:
• RV dilation (apical 4-chamber RV diameter divided by LV diameter greater than 0.9) or RV systolic dysfunction on echocardiography;
• RV dilation on CT, elevation of BNP (greater than 90 pg/mL), elevation of N-terminal pro-BNP (greater than 500 pg/mL);
• Electrocardiographic changes (new complete or incomplete right bundle branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion).
Myocardial necrosis is defined as elevated troponin I (greater than 0.4 ng/mL) or elevated troponin T (greater than 0.1 ng/mL).
Why is submassive PE of clinical significance?
In 1999, analysis of the International Cooperative Pulmonary Embolism Registry (ICOPER) revealed that RV dysfunction in PE patients was associated with a near doubling of the 3-month mortality risk (hazard ratio 2.0, 1.3-2.9).2 Given this increased risk, one could draw the logical conclusion that we need to treat submassive PE more aggressively than PE without RV strain. But will this necessarily result in a better outcome for the patient given the 3% risk of intracranial hemorrhage associated with thrombolytic therapy?
In the clinical scenario above, the patient did meet the definition of submassive PE. While the patient did not experience systemic hypotension, she did have RV dilation on CT, RV systolic dysfunction on echo as well as an elevated Troponin T level. In addition to starting anticoagulant therapy, what more should be done to increase her probability of a good outcome?
The AHA recommends that systemic thrombolysis and CDT be considered for patients with acute submassive PE if they have clinical evidence of adverse prognosis, including worsening respiratory failure, severe RV dysfunction, or major myocardial necrosis and low risk of bleeding complications (Class IIB; Level of Evidence C).1
The 2016 American College of Chest Physicians (CHEST) guidelines update3 recommends systemically administered thrombolytic therapy over no therapy in selected patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk (Grade 2C recommendation).
Systemic thrombolysis
Systemic thrombolysis is administered as an intravenous thrombolytic infusion delivered over a period of time. The Food and Drug Administration–approved thrombolytic drugs currently include tissue plasminogen activator (tPA)/alteplase, streptokinase and urokinase.
Efficacy of low dose thrombolysis was studied in MOPETT 2013,5 a single-center, prospective, randomized, open label study, in which 126 participants found to have submassive PE based on symptoms and CT angiographic or ventilation/perfusion scan data received either 50 mg tPA plus heparin or heparin anticoagulation alone. The composite endpoint of pulmonary hypertension and recurrent PE at 28 months was 16% in the tPA group compared to 63% in the control group (P less than .001). Systemic thrombolysis was associated with lower risk of pulmonary hypertension and recurrent PE, although no mortality benefit was seen in this small study.
In the randomized, double-blind PEITHO trial (n = 1,006) of 20146 comparing tenecteplase plus heparin versus heparin in the submassive PE patients, the primary outcomes of death and hemodynamic decompensation occurred in 2.6% of the tenecteplase group, compared to 5.6% in the placebo group (P = .02). Thrombolytic therapy was associated with 2% rate of hemorrhagic stroke, whereas hemorrhagic stroke in the placebo group was 0.2% (P = .03). In this case, systemic thrombolysis was associated with a 3% lower risk of death and hemodynamic instability, but also a 1.8% increased risk of hemorrhagic stroke.
Catheter-directed thrombolysis (CDT)
CDT was originally developed to treat arterial, dialysis graft and deep vein thromboses, but is now approved by the FDA for the treatment of acute submassive or massive PE.
A wire is passed through the embolus and a multihole infusion catheter is placed, through which a thrombolytic drug is infused over 12-24 hours. The direct delivery of the drug into the thrombus is thought to be as effective as systemic therapy but with a lower risk of bleeding. If more rapid thrombus removal is indicated due to large clot burden and hemodynamic instability, mechanical therapies, such as fragmentation and aspiration, can be used as an adjunct to CDT. However, these mechanical techniques carry the risk of pulmonary artery injury, and therefore should only be used as a last resort. An ultrasound-emitting wire can be added to the multihole infusion catheter to expedite thrombolysis by ultrasonically disrupting the thrombus, a technique known as ultrasound-enhanced thrombolysis (EKOS).7,10
The ULTIMA 2014 trial,8 a small, randomized, open-label study of Ultrasound-Assisted Catheter Directed Thrombolysis (USAT, the term can be used interchangeably with EKOS) versus heparin anticoagulation alone in 59 patients, was designed to study if the former strategy was better at improving the primary outcome measure of RV/LV ratio in submassive PE patients. The mean reduction in RV/LV ratio was 0.30 +/– 0.20 in the USAT group compared to 0.03 +/– 0.16 in the heparin group (P less than .001). However, no significant difference in mortality or bleeding was observed in the groups at 90-day follow up.
The PERFECT 2015 Trial,9 a multicenter registry-based study, prospectively enrolled 101 patients who received CDT as first-line therapy for massive and submassive PE. Among patients with submassive PE, 97.3% were found to have “clinical success” with this treatment, defined as stabilization of hemodynamics, improvement in pulmonary hypertension and right heart strain, and survival to hospital discharge. There was no major bleeding or intracranial hemorrhage. Subgroup analyses in this study comparing USAT against standard CDT did not reveal significant difference in average pulmonary pressure changes, average thrombolytic doses, or average infusion times.
A prospective single-arm multicenter trial, SEATTLE II 2015,10 evaluated the efficacy of EKOS in a sample of 159 patients. Patients with both massive and submassive PE received approximately 24 mg tPA infused via a catheter over 12-24 hours. The primary efficacy outcome was the chest CT-measured RV/LV ratio decrease from the baseline compared to 48 hours post procedure. The pre- and postprocedure ratio was 1.55 versus 1.13 respectively (P less than .001), indicating that EKOS decreased RV dilation. No intracranial hemorrhage was observed and the investigators did not comment on long-term outcomes such as mortality or quality of life. The study was limited by the lack of a comparison group, such as anticoagulation with heparin as monotherapy, or systemic thrombolysis or standard CDT.
Treatment of submassive PE varies between different institutions. There simply are not adequate data comparing low dose systemic thrombolysis, CDT, EKOS, and standard heparin anticoagulation to make firm recommendations. Some investigators feel low-dose systemic thrombolysis is probably as good as the expensive catheter-based thrombolytic therapies.11,12 Low-dose thrombolytic therapy can be followed by use of oral direct factor Xa inhibitors for maintenance of antithrombotic activity.13
Bottom line
In our institution, the interventional radiology team screens patients who meet criteria for submassive PE on a case-by-case basis. We use pulmonary angiographic data (nature and extent of the thrombus), clinical stability, and analysis of other comorbid conditions to decide the best treatment modality for an individual patient. Our team prefers EKOS for submassive PE patients as well as for massive PE patients and as a rescue procedure for patients who have failed systemic thrombolysis.
Until more data are available to support firm guidelines, we feel establishing multidisciplinary teams composed of interventional radiologists, intensivists, cardiologists, and vascular surgeons is prudent to make individualized decisions and to achieve the best outcomes for our patients.14
IVC filter
Since the patient in this case already has a submassive PE, can she tolerate additional clot burden should her remaining DVT embolize again? Is there a role for IVC filter?
The implantation of IVC filters has increased significantly in the past 30 years, without quality evidence justifying their use.15
The 2016 Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report states clearly: In patients with acute DVT of the leg or PE who are treated with anticoagulants, the use of an IVC filter is not recommended (Grade 1B).3 This recommendation is based on findings of the Prevention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) randomized trial,16 and the recently published PREPIC 2 randomized trial,17 both showing that in anticoagulated patients with PE and DVT, concurrent placement of an IVC filter for 3 months did not reduce recurrent PE, including fatal PE.
CHEST guidelines state that an IVC filter should not be routinely placed as an adjunct in patients with PE and DVT. However, what about in the subgroup of patients with submassive or massive PE in whom another PE would be catastrophic? Clinical data are lacking in this area.
Deshpande et al. reported on a series of six patients with massive PE and cardiopulmonary instability; patients all received an IVC filter with anticoagulation. The short-term outcome was excellent, but long-term follow-up was not done.18 Kucher and colleagues reported that from the ICOPER in 2006, out of the 108 massive PE patients with systolic arterial pressure under 90 mm Hg, 11 patients received adjunctive IVC filter placement. None of these 11 patients developed recurrent PE in 90 days and 10 of them survived at least 90 days; IVC filter placement was associated with a reduction in 90-day mortality. In this study, the placement of an IVC filter was entirely decided by the physicians at different sites.19 In a 2012 study examining case fatality rates in 3,770 patients with acute PE who received pulmonary embolectomy, the data showed that in both unstable and stable patients, case fatality rates were lower in those who received an IVC filter.20
Although the above data are favorable for adjunctive IVC filter placement in massive PE patients, at least in short-term outcomes, the small size and lack of randomization preclude establishment of evidence-based guidelines. The 2016 CHEST guidelines point out that as it is uncertain if there is benefit to place an IVC filter adjunctively in anticoagulated patients with severe PE, in this specific subgroup of patients, the recommendation against insertion of an IVC filter in patients with acute PE who are anticoagulated may not apply.3
Bottom line
There is no evidence-based guideline as to whether IVC filters should be placed adjunctively in patients with submassive or massive PE; however, based on expert consensus, it may be appropriate to place an IVC filter as an adjunct to anticoagulation in patients with severe PE. The decision should be individualized based on each patient’s characteristics, preferences, and institutional expertise.
In our case, in hope of preventing further embolic burden, the patient received an IVC filter the day after presentation. Despite the initiation of anticoagulation with heparin, she remained tachycardic and tachypneic, prompting referral for CDT. The interventional radiology team did not feel that she was a good candidate, given her persistent vaginal bleeding and widely metastatic uterine carcinoma. She was switched to therapeutic enoxaparin after no further invasive intervention was deemed appropriate. Her respiratory status did not improve and bilevel positive airway pressure was initiated. Taking into consideration the terminal nature of her cancer, she ultimately elected to pursue comfort care and died shortly afterward.
Acknowledgements
The authors would like to thank Benjamin A. Hohmuth, MD, A. Joseph Layon, MD, and Luis L. Nadal, MD, for their review of the article and invaluable feedback.
Dr. Wenqian Wang, Dr. Vedamurthy, and Dr. Wang are based in the department of hospital medicine at The Medicine Institute, Geisinger Health System, Danville, Penn. Contact Dr. Wenqian Wang at [email protected].
Key Points
• Use pulmonary angiographic data, clinical stability, and analysis of other comorbid conditions to decide the best treatment modality.
• Our team prefers ultrasound-enhanced thrombolysis (EKOS) for submassive PE patients, massive PE patients, and as a rescue procedure for patients who fail systemic thrombolysis.
• Establishing multidisciplinary teams composed of interventional radiologists, intensivists, cardiologists, and vascular surgeons is prudent to make individualized decisions.
• It may be appropriate to place an IVC filter as an adjunct to anticoagulation in patients with severe PE.
References
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