Is Intervention Recommended for Patients With Unruptured AVMs?

SAN DIEGO—Should a patient with an unruptured arteriovenous malformation (AVM) be referred for intervention? How clinicians answer that question may depend largely on their interpretations of the results of the recent ARUBA study, as reported at the 2014 International Stroke Conference.

An international, multicenter, randomized controlled trial, ARUBA (A Randomized Trial of Unruptured Brain AVMs) compared the risk of death and symptomatic stroke in participants with unruptured brain AVMs assigned to medical management alone or medical management and interventional therapy (ie, neurosurgery, embolization, or stereotactic radiotherapy alone or in combination). An independent data and safety monitoring board halted the trial, which was funded by NINDS, because of the superiority of the medical management group.

Based on outcome data available for 223 patients—114 randomized to interventional therapy and 109 to medical management—the ARUBA investigators concluded that medical management alone is superior to medical management and interventional therapy for preventing death or stroke in patients with unruptured AVMs followed up for 33 months. But the absence of a widely recognized standard of treatment for unruptured AVMs makes it difficult to interpret the study’s findings.

Conflicting Interpretations of the ARUBA Study
The ARUBA results are not applicable to all patients with unruptured AVMs, said Sepideh Amin-Hanjani, MD, Professor and Codirector of Neurovascular Surgery at the University of Illinois at Chicago. ARUBA’s study design had the conceptual flaw of grouping all unruptured AVMs together, she said. The study’s implementation also had flaws, including a failure to account for enrollment bias, a lack of meaningful credentialing criteria for study sites, and a length of follow-up that precluded the assessment of disease-relevant outcomes, she added.

“Ultimately, ARUBA doesn’t really address [the question of whether] a patient should be treated because the generalizability and follow-up of the selected cohort [were] limited,” said Dr. Amin-Hanjani. “It doesn’t address which patients should be treated because heterogeneous diseases were lumped together. It doesn’t address which modality [should be used] because the treatments were not standardized or compared…. ARUBA as a justification for implicit denial of treatment to all unruptured AVMs would be, at best, irresponsible on the part of the medical community, and at worst, negligent.”

Sepideh Amin- Hanjani, MD	J. P. Mohr, MD

Yet negative outcomes were more common among patients who received intervention and medical management than among patients who received medical management alone. As of month 84, when patients had been followed up for a mean period of four years, two AVM-related deaths had occurred in the interventional arm, compared with none in the medical management arm, said J. P. Mohr, MD, Daniel Sciarra Professor of Neurology at Columbia University Medical Center in New York City and one of the lead investigators of the ARUBA study. The difference between the two groups for such end points as death or stroke, all-cause or AVM-related stroke, and first stroke (ie, all, hemorrhagic, or ischemic) was large.

“We have been faced with the prospect of having to consider the ARUBA results definitive,” said Dr. Mohr. Statisticians have demonstrated that it would take between 12 and 30 years for the two groups’ outcome rates to converge. “Some cynics would say, ‘Why don’t we do the intervention now, and the patient would be spared the anxiety of having a stroke at some future time?’ Our view would be that maybe the patient should be spared the concern that the intervention might generate the stroke ahead of schedule.”

Different Treatments May Have Different Complication Rates
During a pro/con symposium at the conference, a neurologist and a neurosurgeon debated whether a 25-year-old woman with an unruptured, Spetzler–­Martin grade 3 AVM should be referred for interventional treatment or managed with medical therapy alone. When clinicians encounter a patient with an unruptured AVM, rupture should be their primary concern, according to Dr. Amin-Hanjani, who cited data from meta-analyses, as well as from the prospective medical arm of ARUBA, which indicated a rupture risk of approximately 2% per year.

Rather than group all treatment modalities together when considering complication rates, as has been done in recent meta-analyses, it is more helpful to identify rates for specific treatments and types of patients, said Dr. Amin-Hanjani. For example, Spetzler–Martin grades are a useful risk-stratification tool for predicting complications of surgery by looking at the AVM size, eloquence, and venous drainage. “This [tool] was never a grading system for hemorrhage risk but … for complication risk from surgery,” said Dr. Amin-Hanjani. “We know from many publications that grade 1 and 2 AVMs tend to do favorably with surgery, grade 4 and 5 AVMs don’t do well with surgery, and what we’re left with is grade 3 AVMs in the gray zone.”

Researchers have developed similar prognostication scores for predicting outcomes of radiosurgery and embolization. “These treatments have widely differing efficacies—surgery having the most up-front immediate obliteration rate, which is almost 100%, and endovascular therapy, as a stand-alone, being rarely curative,” she said.

Regarding the 25-year-old wo-man in question, Dr. Amin-Hanjani proposed that clinicians evaluating the patient be “splitters” rather than “lumpers” when considering treatment options and complication rates. “With that 2% per year rupture risk, she’s going to have an approximately 70% to 75% lifetime risk of rupture and a significant risk of a morbidity … defined as a modified Rankin Scale (mRS) score of worse than 2,” she said. “She’s a female, she’s in her childbearing years—and there are some data [suggesting] an eightfold increased risk of hemorrhage in pregnancy.

“All we’ve been told about this case is that she has a grade 3 AVM [that is] 4 cm [large], so it could be [an] AVM that’s in noneloquent territory with deep venous drainage that would do well with surgery, or it could be in eloquent territory and may require treatment with a combination of other modalities like embolization and radiosurgery. But we have some data that support that, either way, you could construct a management strategy that’s going to give her a better-than-90% favorable outcome.”

Dr. Amin-Hanjani recommended referring the 25-year-old woman for interventional treatment. She disagreed with the interpretation of ARUBA that medical therapy is superior for all unruptured AVMs. The investigators had difficulty recruiting participants in the United States, and the study may have been influenced by a pre-enrollment selection bias, Dr. Amin-Hanjani noted. Furthermore, patients who might benefit from treatment (eg, those perceived to have a higher rupture risk based on the features of their AVMs) may have been excluded.

The ARUBA results cannot be applied to all patients with unruptured AVM, including the theoretical 25-year-old, said Dr. Amin-Hanjani. “She’s expected to live 60 years. How can we rely on a study with a mean follow-up of less than three years? We can’t really extrapolate the risk of treating her grade 3 AVM from ARUBA, since the aggregate data are not generalizable, and we can’t determine which treatment to offer her because the study wasn’t designed to compare treatment modalities.”

Patients May Live for Years Without a Hemorrhage
Some patients, however, fare well without interventional therapy. Dr. Mohr described individuals with unruptured AVMs who survived for 20 years or longer without a hemorrhage. One woman presented to his institution in 1973 with her first-ever AVM-related hemorrhage, which doctors decided was too dangerous to operate on. “[They] sent her home hoping that God would be good to her,” Dr. Mohr recalled. “And God was—she had three children, is a grandmother now, and returned with her second hemorrhage in 2008…. She was not considered suitable for treatment then and, with disappointment, went back to Connecticut, asking us [whether we] hadn’t improved the treatment plan in over 30 years.”

Concerns about selection bias in the ARUBA study may be irrelevant, according to Dr. Mohr. Patients with smaller, more easily treated AVMs are indeed overrepresented in the study population, he said. “When we look at the actual outcomes, we can see that the Spetzler–Martin scale predicted quite well the increased degree of complication in the treatment as a function of the larger brain.” But no clear link is evident between Spetzler–Martin grade and outcome in patients in the medical arm who experienced an event, he added.

The mRS scores for patients in the medical arm correlated with small or minor events among those who had such events, but few patients who underwent interventional treatment had subsequent improvement in their mRS scores.

Dr. Mohr and his coinvestigators requested funding for a long-term follow-up of both arms to test whether participants in the medical arm would eventually catch up to the interventional arm and whether mRS scores for the interventional patients who had lesions or other disturbances would return to normal. “To our surprise, the NINDS Study Section … agreed with the ARUBA statisticians and those statisticians who reviewed these data that the long-term follow-up is unlikely to change the statistical outcome,” he said. “So there will be no NINDS-funded follow-up, but we’re still hoping to continue follow-up among the participants for the next few years so we can increase the per-year follow-up rate.”

—Fred Balzac

SAN DIEGO—Should a patient with an unruptured arteriovenous malformation (AVM) be referred for intervention? How clinicians answer that question may depend largely on their interpretations of the results of the recent ARUBA study, as reported at the 2014 International Stroke Conference.

An international, multicenter, randomized controlled trial, ARUBA (A Randomized Trial of Unruptured Brain AVMs) compared the risk of death and symptomatic stroke in participants with unruptured brain AVMs assigned to medical management alone or medical management and interventional therapy (ie, neurosurgery, embolization, or stereotactic radiotherapy alone or in combination). An independent data and safety monitoring board halted the trial, which was funded by NINDS, because of the superiority of the medical management group.

Based on outcome data available for 223 patients—114 randomized to interventional therapy and 109 to medical management—the ARUBA investigators concluded that medical management alone is superior to medical management and interventional therapy for preventing death or stroke in patients with unruptured AVMs followed up for 33 months. But the absence of a widely recognized standard of treatment for unruptured AVMs makes it difficult to interpret the study’s findings.

Conflicting Interpretations of the ARUBA Study
The ARUBA results are not applicable to all patients with unruptured AVMs, said Sepideh Amin-Hanjani, MD, Professor and Codirector of Neurovascular Surgery at the University of Illinois at Chicago. ARUBA’s study design had the conceptual flaw of grouping all unruptured AVMs together, she said. The study’s implementation also had flaws, including a failure to account for enrollment bias, a lack of meaningful credentialing criteria for study sites, and a length of follow-up that precluded the assessment of disease-relevant outcomes, she added.

“Ultimately, ARUBA doesn’t really address [the question of whether] a patient should be treated because the generalizability and follow-up of the selected cohort [were] limited,” said Dr. Amin-Hanjani. “It doesn’t address which patients should be treated because heterogeneous diseases were lumped together. It doesn’t address which modality [should be used] because the treatments were not standardized or compared…. ARUBA as a justification for implicit denial of treatment to all unruptured AVMs would be, at best, irresponsible on the part of the medical community, and at worst, negligent.”

Sepideh Amin- Hanjani, MD	J. P. Mohr, MD

Yet negative outcomes were more common among patients who received intervention and medical management than among patients who received medical management alone. As of month 84, when patients had been followed up for a mean period of four years, two AVM-related deaths had occurred in the interventional arm, compared with none in the medical management arm, said J. P. Mohr, MD, Daniel Sciarra Professor of Neurology at Columbia University Medical Center in New York City and one of the lead investigators of the ARUBA study. The difference between the two groups for such end points as death or stroke, all-cause or AVM-related stroke, and first stroke (ie, all, hemorrhagic, or ischemic) was large.

“We have been faced with the prospect of having to consider the ARUBA results definitive,” said Dr. Mohr. Statisticians have demonstrated that it would take between 12 and 30 years for the two groups’ outcome rates to converge. “Some cynics would say, ‘Why don’t we do the intervention now, and the patient would be spared the anxiety of having a stroke at some future time?’ Our view would be that maybe the patient should be spared the concern that the intervention might generate the stroke ahead of schedule.”

Different Treatments May Have Different Complication Rates
During a pro/con symposium at the conference, a neurologist and a neurosurgeon debated whether a 25-year-old woman with an unruptured, Spetzler–­Martin grade 3 AVM should be referred for interventional treatment or managed with medical therapy alone. When clinicians encounter a patient with an unruptured AVM, rupture should be their primary concern, according to Dr. Amin-Hanjani, who cited data from meta-analyses, as well as from the prospective medical arm of ARUBA, which indicated a rupture risk of approximately 2% per year.

Rather than group all treatment modalities together when considering complication rates, as has been done in recent meta-analyses, it is more helpful to identify rates for specific treatments and types of patients, said Dr. Amin-Hanjani. For example, Spetzler–Martin grades are a useful risk-stratification tool for predicting complications of surgery by looking at the AVM size, eloquence, and venous drainage. “This [tool] was never a grading system for hemorrhage risk but … for complication risk from surgery,” said Dr. Amin-Hanjani. “We know from many publications that grade 1 and 2 AVMs tend to do favorably with surgery, grade 4 and 5 AVMs don’t do well with surgery, and what we’re left with is grade 3 AVMs in the gray zone.”

Researchers have developed similar prognostication scores for predicting outcomes of radiosurgery and embolization. “These treatments have widely differing efficacies—surgery having the most up-front immediate obliteration rate, which is almost 100%, and endovascular therapy, as a stand-alone, being rarely curative,” she said.

Regarding the 25-year-old wo-man in question, Dr. Amin-Hanjani proposed that clinicians evaluating the patient be “splitters” rather than “lumpers” when considering treatment options and complication rates. “With that 2% per year rupture risk, she’s going to have an approximately 70% to 75% lifetime risk of rupture and a significant risk of a morbidity … defined as a modified Rankin Scale (mRS) score of worse than 2,” she said. “She’s a female, she’s in her childbearing years—and there are some data [suggesting] an eightfold increased risk of hemorrhage in pregnancy.

“All we’ve been told about this case is that she has a grade 3 AVM [that is] 4 cm [large], so it could be [an] AVM that’s in noneloquent territory with deep venous drainage that would do well with surgery, or it could be in eloquent territory and may require treatment with a combination of other modalities like embolization and radiosurgery. But we have some data that support that, either way, you could construct a management strategy that’s going to give her a better-than-90% favorable outcome.”

Dr. Amin-Hanjani recommended referring the 25-year-old woman for interventional treatment. She disagreed with the interpretation of ARUBA that medical therapy is superior for all unruptured AVMs. The investigators had difficulty recruiting participants in the United States, and the study may have been influenced by a pre-enrollment selection bias, Dr. Amin-Hanjani noted. Furthermore, patients who might benefit from treatment (eg, those perceived to have a higher rupture risk based on the features of their AVMs) may have been excluded.

The ARUBA results cannot be applied to all patients with unruptured AVM, including the theoretical 25-year-old, said Dr. Amin-Hanjani. “She’s expected to live 60 years. How can we rely on a study with a mean follow-up of less than three years? We can’t really extrapolate the risk of treating her grade 3 AVM from ARUBA, since the aggregate data are not generalizable, and we can’t determine which treatment to offer her because the study wasn’t designed to compare treatment modalities.”

Patients May Live for Years Without a Hemorrhage
Some patients, however, fare well without interventional therapy. Dr. Mohr described individuals with unruptured AVMs who survived for 20 years or longer without a hemorrhage. One woman presented to his institution in 1973 with her first-ever AVM-related hemorrhage, which doctors decided was too dangerous to operate on. “[They] sent her home hoping that God would be good to her,” Dr. Mohr recalled. “And God was—she had three children, is a grandmother now, and returned with her second hemorrhage in 2008…. She was not considered suitable for treatment then and, with disappointment, went back to Connecticut, asking us [whether we] hadn’t improved the treatment plan in over 30 years.”

Concerns about selection bias in the ARUBA study may be irrelevant, according to Dr. Mohr. Patients with smaller, more easily treated AVMs are indeed overrepresented in the study population, he said. “When we look at the actual outcomes, we can see that the Spetzler–Martin scale predicted quite well the increased degree of complication in the treatment as a function of the larger brain.” But no clear link is evident between Spetzler–Martin grade and outcome in patients in the medical arm who experienced an event, he added.

The mRS scores for patients in the medical arm correlated with small or minor events among those who had such events, but few patients who underwent interventional treatment had subsequent improvement in their mRS scores.

Dr. Mohr and his coinvestigators requested funding for a long-term follow-up of both arms to test whether participants in the medical arm would eventually catch up to the interventional arm and whether mRS scores for the interventional patients who had lesions or other disturbances would return to normal. “To our surprise, the NINDS Study Section … agreed with the ARUBA statisticians and those statisticians who reviewed these data that the long-term follow-up is unlikely to change the statistical outcome,” he said. “So there will be no NINDS-funded follow-up, but we’re still hoping to continue follow-up among the participants for the next few years so we can increase the per-year follow-up rate.”

—Fred Balzac

SAN DIEGO—Should a patient with an unruptured arteriovenous malformation (AVM) be referred for intervention? How clinicians answer that question may depend largely on their interpretations of the results of the recent ARUBA study, as reported at the 2014 International Stroke Conference.

An international, multicenter, randomized controlled trial, ARUBA (A Randomized Trial of Unruptured Brain AVMs) compared the risk of death and symptomatic stroke in participants with unruptured brain AVMs assigned to medical management alone or medical management and interventional therapy (ie, neurosurgery, embolization, or stereotactic radiotherapy alone or in combination). An independent data and safety monitoring board halted the trial, which was funded by NINDS, because of the superiority of the medical management group.

Based on outcome data available for 223 patients—114 randomized to interventional therapy and 109 to medical management—the ARUBA investigators concluded that medical management alone is superior to medical management and interventional therapy for preventing death or stroke in patients with unruptured AVMs followed up for 33 months. But the absence of a widely recognized standard of treatment for unruptured AVMs makes it difficult to interpret the study’s findings.

Conflicting Interpretations of the ARUBA Study
The ARUBA results are not applicable to all patients with unruptured AVMs, said Sepideh Amin-Hanjani, MD, Professor and Codirector of Neurovascular Surgery at the University of Illinois at Chicago. ARUBA’s study design had the conceptual flaw of grouping all unruptured AVMs together, she said. The study’s implementation also had flaws, including a failure to account for enrollment bias, a lack of meaningful credentialing criteria for study sites, and a length of follow-up that precluded the assessment of disease-relevant outcomes, she added.

“Ultimately, ARUBA doesn’t really address [the question of whether] a patient should be treated because the generalizability and follow-up of the selected cohort [were] limited,” said Dr. Amin-Hanjani. “It doesn’t address which patients should be treated because heterogeneous diseases were lumped together. It doesn’t address which modality [should be used] because the treatments were not standardized or compared…. ARUBA as a justification for implicit denial of treatment to all unruptured AVMs would be, at best, irresponsible on the part of the medical community, and at worst, negligent.”

Sepideh Amin- Hanjani, MD	J. P. Mohr, MD

Yet negative outcomes were more common among patients who received intervention and medical management than among patients who received medical management alone. As of month 84, when patients had been followed up for a mean period of four years, two AVM-related deaths had occurred in the interventional arm, compared with none in the medical management arm, said J. P. Mohr, MD, Daniel Sciarra Professor of Neurology at Columbia University Medical Center in New York City and one of the lead investigators of the ARUBA study. The difference between the two groups for such end points as death or stroke, all-cause or AVM-related stroke, and first stroke (ie, all, hemorrhagic, or ischemic) was large.

“We have been faced with the prospect of having to consider the ARUBA results definitive,” said Dr. Mohr. Statisticians have demonstrated that it would take between 12 and 30 years for the two groups’ outcome rates to converge. “Some cynics would say, ‘Why don’t we do the intervention now, and the patient would be spared the anxiety of having a stroke at some future time?’ Our view would be that maybe the patient should be spared the concern that the intervention might generate the stroke ahead of schedule.”

Different Treatments May Have Different Complication Rates
During a pro/con symposium at the conference, a neurologist and a neurosurgeon debated whether a 25-year-old woman with an unruptured, Spetzler–­Martin grade 3 AVM should be referred for interventional treatment or managed with medical therapy alone. When clinicians encounter a patient with an unruptured AVM, rupture should be their primary concern, according to Dr. Amin-Hanjani, who cited data from meta-analyses, as well as from the prospective medical arm of ARUBA, which indicated a rupture risk of approximately 2% per year.

Rather than group all treatment modalities together when considering complication rates, as has been done in recent meta-analyses, it is more helpful to identify rates for specific treatments and types of patients, said Dr. Amin-Hanjani. For example, Spetzler–Martin grades are a useful risk-stratification tool for predicting complications of surgery by looking at the AVM size, eloquence, and venous drainage. “This [tool] was never a grading system for hemorrhage risk but … for complication risk from surgery,” said Dr. Amin-Hanjani. “We know from many publications that grade 1 and 2 AVMs tend to do favorably with surgery, grade 4 and 5 AVMs don’t do well with surgery, and what we’re left with is grade 3 AVMs in the gray zone.”

Researchers have developed similar prognostication scores for predicting outcomes of radiosurgery and embolization. “These treatments have widely differing efficacies—surgery having the most up-front immediate obliteration rate, which is almost 100%, and endovascular therapy, as a stand-alone, being rarely curative,” she said.

Regarding the 25-year-old wo-man in question, Dr. Amin-Hanjani proposed that clinicians evaluating the patient be “splitters” rather than “lumpers” when considering treatment options and complication rates. “With that 2% per year rupture risk, she’s going to have an approximately 70% to 75% lifetime risk of rupture and a significant risk of a morbidity … defined as a modified Rankin Scale (mRS) score of worse than 2,” she said. “She’s a female, she’s in her childbearing years—and there are some data [suggesting] an eightfold increased risk of hemorrhage in pregnancy.

“All we’ve been told about this case is that she has a grade 3 AVM [that is] 4 cm [large], so it could be [an] AVM that’s in noneloquent territory with deep venous drainage that would do well with surgery, or it could be in eloquent territory and may require treatment with a combination of other modalities like embolization and radiosurgery. But we have some data that support that, either way, you could construct a management strategy that’s going to give her a better-than-90% favorable outcome.”

Dr. Amin-Hanjani recommended referring the 25-year-old woman for interventional treatment. She disagreed with the interpretation of ARUBA that medical therapy is superior for all unruptured AVMs. The investigators had difficulty recruiting participants in the United States, and the study may have been influenced by a pre-enrollment selection bias, Dr. Amin-Hanjani noted. Furthermore, patients who might benefit from treatment (eg, those perceived to have a higher rupture risk based on the features of their AVMs) may have been excluded.

The ARUBA results cannot be applied to all patients with unruptured AVM, including the theoretical 25-year-old, said Dr. Amin-Hanjani. “She’s expected to live 60 years. How can we rely on a study with a mean follow-up of less than three years? We can’t really extrapolate the risk of treating her grade 3 AVM from ARUBA, since the aggregate data are not generalizable, and we can’t determine which treatment to offer her because the study wasn’t designed to compare treatment modalities.”

Patients May Live for Years Without a Hemorrhage
Some patients, however, fare well without interventional therapy. Dr. Mohr described individuals with unruptured AVMs who survived for 20 years or longer without a hemorrhage. One woman presented to his institution in 1973 with her first-ever AVM-related hemorrhage, which doctors decided was too dangerous to operate on. “[They] sent her home hoping that God would be good to her,” Dr. Mohr recalled. “And God was—she had three children, is a grandmother now, and returned with her second hemorrhage in 2008…. She was not considered suitable for treatment then and, with disappointment, went back to Connecticut, asking us [whether we] hadn’t improved the treatment plan in over 30 years.”

Concerns about selection bias in the ARUBA study may be irrelevant, according to Dr. Mohr. Patients with smaller, more easily treated AVMs are indeed overrepresented in the study population, he said. “When we look at the actual outcomes, we can see that the Spetzler–Martin scale predicted quite well the increased degree of complication in the treatment as a function of the larger brain.” But no clear link is evident between Spetzler–Martin grade and outcome in patients in the medical arm who experienced an event, he added.

The mRS scores for patients in the medical arm correlated with small or minor events among those who had such events, but few patients who underwent interventional treatment had subsequent improvement in their mRS scores.

Dr. Mohr and his coinvestigators requested funding for a long-term follow-up of both arms to test whether participants in the medical arm would eventually catch up to the interventional arm and whether mRS scores for the interventional patients who had lesions or other disturbances would return to normal. “To our surprise, the NINDS Study Section … agreed with the ARUBA statisticians and those statisticians who reviewed these data that the long-term follow-up is unlikely to change the statistical outcome,” he said. “So there will be no NINDS-funded follow-up, but we’re still hoping to continue follow-up among the participants for the next few years so we can increase the per-year follow-up rate.”

—Fred Balzac