Correspondence
www.thelancet.com Vol 383 May 10, 2014
randomised to intervention who are in the middle of their treatment programme, is this to be continued or aborted? Presumably the 20 patients yet to start treatment will not now start. The only solution to this dilemma is continued follow-up, which should cost very little, not only for the planned 5 years, but for decades. After all, the average age of the ARUBA patients is only 45 years, so they have roughly another 30–40 years to live with an unoperated arteriovenous malformation. Being told that “medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke”1 over the next 33 months is hardly reassuring. To compound the difficulty and possibly render any solution impossible, the sample size was not allowed to reach even the modified target of 400, and there will almost certainly now be many partial and full cross-overs from intervention to conservative management. Therefore, sadly, in view of the effort and cost put into the trial, its power to answer any of the important questions to do with arteriovenous malformations intervention is very restricted. I declare that I have no competing interests.
Charles Warlow [email protected] Western General Hospital, Department of Clinical Neuroscience, Edinburgh EH4 2XU, UK 1
Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 2014; 383: 614–21.
It is difficult to conduct a randomised controlled trial to compare policies of conservative management versus interventional treatment for brain ‘‘timebombs’’ that could bleed.1 Incomplete understanding of natural history often leads to extrapolations of short-term event rates to patients’ lifetimes and so an
unfavourable indirect comparison with clinicians’ estimates of the risks of intervention. These issues result in the recruitment of a small number of eligible patients in clinical practice.1,2 Furthermore, some patients and clinicians (probably more so those who treat the conditions in fee-forservice health-care systems) might prefer preventative interventions. Consequently, despite the fact that ARUBA delivered a result deemed definitive by its Data Monitoring Committee,2 the external validity— or generalisability 3—of ARUBA’s participants and interventions has been criticised both before4 and after5 ARUBA’s results were known. However, reassurance about generalisability is afforded by the strong similarities between the participants, intervention, comparator, and outcome in ARUBA and a population-based study that took the opportunity to examine this therapeutic dilemma in a non-randomised design. 6 Treated participants were similar in age and sex, and in the frequencies of incidental presentation, location of arteriovenous malformation, superficial venous drainage pattern, and Spetzler-Martin grades. 2,6 Interventions in ARUBA were done in routine clinical practice rather than under special circumstances, 3 and the frequency of multimodality intervention was similar in ARUBA and the observational study. 2,6 In the conservative management group, the event rate was similar in ARUBA and the observational study. 2,6 Finally, the association between conservative management and stroke or death related to brain arteriovenous malformation or its intervention during 12 years in the observational study (adjusted hazard ratio 0·37, 95% CI 0·19–0·72) was similar to the effect of conservative management on stroke or death of any cause during 6 years in the ARUBA randomised analysis (0·27, 0·14–0·54).2,6
Lunagrafix/Science Photo Library
their Data and Safety Monitoring Board who recommended halting randomisation at a mean of less than 3 years, before—possibly long before—enough follow-up had accrued to answer the crucial question: are the inevitable and already well known early risks of intervention, as well as any later ones that might emerge, worth taking in the long run for a condition that might or might not cause stroke or death several decades after presentation? This is a general problem with trials of surgery and other interventions with high upfront risk, for example of carotid endarterectomy to prevent stroke. If the randomised controlled trials of carotid endarterectomy had been stopped early after only a year of follow-up, when it must have been very clear that at that point surgery was not advantageous because most strokes were perioperative rather than in the no-surgery group, then the longer-term benefits of surgery might never have emerged. The decision to stop early in ARUBA is even more problematic because not only is any useful effect of intervention unlikely to be seen within months, as it is after carotid surgery, but also some patients in the intervention group had still not completed their interventional neuroradiology treatment, which might be scheduled for several occasions during several months, or perhaps their full radiotherapy programme. Unlike carotid surgery, for which the risks of intervention are all within a few days of surgery, for arteriovenous malformations the risk of intervention is, like the intervention itself, spread over some months as might be inferred from figure 2,1 in which stroke risk flattens off at about 30 months for the intervention group, whereas it is still increasing in the medical management only group. And what is to happen to the 53 of 114 patients
1633
Correspondence
I was a member of the Executive Committee and the UK Chief Investigator for ARUBA, but received no funding for these roles. I declare that I have no other competing interests.
Rustam Al-Shahi Salman [email protected] Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK 1
2
3
4
5
6
Raymond J, Darsaut TE, Molyneux AJ, et al, for the TEAM collaborative Group. A trial on unruptured intracranial aneurysms (the TEAM trial): results, lessons from a failure and the necessity for clinical care trials. Trials 2011; 12: 64. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 2014; 383: 614–21. Rothwell PM. External validity of randomised controlled trials: “To whom do the results of this trial apply?” Lancet 2005; 365: 82–93. Mohr JP, Moskowitz AJ, Parides M, Stapf C, Young WL. Hull down on the horizon: a randomized trial of unruptured brain arteriovenous malformations (ARUBA) trial. Stroke 2012; 43: 1744–45. Knopman J, Stieg PE. Management of unruptured brain arteriovenous malformations. Lancet 2014; 383: 581–83. Al-Shahi Salman R, White PM, Counsell CE, et al, for the Scottish Audit of Intracranial Vascular Malformations collaborators. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA 2014; 311: 1661–69.
The management of cerebral arteriovenous malformations requires balancing the risk of treatment against the natural history of the lesion left untreated. A properly designed randomised trial would, therefore, be very instructive. Unfortunately, the ARUBA study1 is poorly designed, in large part, because it treats all unruptured arteriovenous malformations the same when in fact they represent a heterogeneous disease. Size, location, age, anatomy of venous drainage, associated aneurysms, eloquence of involved cortex, and other factors have a large and well-documented role in determining substantial differences in the risk of both rupture and treatment. To make matters worse, the investigators lump microsurgery, embolisation, stereotactic radiosurgery, and combinations of these 1634
treatments into a category called interventional therapy, as if these treatments were equivalent in terms of their risks, benefits, and indications. Nothing could be further from the truth. Finally, the stroke endpoint is not a validated outcome measure. A more meaningful endpoint would be modified Rankin score at 10 years, at least for those treated with surgery with or without embolisation. For radiosurgery, a much longer time would be needed to gauge effectiveness, and for embolisation alone, we would need further data about the final angiographic result. The exercise, however, becomes futile when taking into account arteriovenous malformation-specific and patientspecific factors, because the study is fatally underpowered. In summary, the data reported in this Article,1 while sure to be widely quoted, will do little, regardless of additional follow-up, to meaningfully direct the care of patients with unruptured arteriovenous malformations. We declare that we have no competing interests.
*Robert A Solomon, E Sander Connolly Jr [email protected] Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, Columbia University Medical Center, New York, NY 10032, USA 1
Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 2014; 383: 614–21.
embolisation to increase this rate increases morbidity. Radiosurgery obliteration rates are less than 70%.4 The delayed course of radiationinduced obliteration could surpass the duration of ARUBA. Therefore, an unknown but large percentage of arteriovenous malformations in the interventional group were not cured, and morbidity could be due to both treatment and natural history. The authors should report cure rates. The trial’s primary endpoint is the composite of death or stroke, defined as “any new focal neurological deficit, seizure, or new-onset headache” associated with imaging findings.1 These definitions overestimate treatment morbidity. A postintervention headache or seizure with oedema or hint of blood after embolisation could be counted as a stroke without causing permanent morbidity. An unknown but possibly large percentage of patients who reached the primary endpoint might have had minimum neurological effects, thereby misrepresenting risks. The authors should report modified Rankin scores. Microsurgical resection in selected patients with low Spetzler-Martin grades remains an effective, safe, immediate, and curative therapy for arteriovenous malformations. Efforts to show surgery’s gold standard5 status are continuing. As we determine the trial’s effect on clinical practice, we should not overgeneralise the results to microsurgery. We declare that we have no competing interests.
In response to ARUBA, 1 many clinicians concluded that observation of unruptured brain arteriovenous malformations is superior to microsurgical resection. However, ARUBA turned out to be a strikingly non-surgical trial (18 surgical patients, 19%), showing a trend away from microsurgery. 76 (81%) patients were treated with non-surgical modalities; a glaring omission was the associated cure rate. Cures with embolisation are less than 25%,2,3 and aggressive
*Michael T Lawton, Adib A Abla [email protected] University of California, San Francisco, San Francisco, CA 94143, USA 1
2
Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 2014; 383: 614–21. Raymond J, Iancu D, Weill A, et al. Embolization as one modality in a combined strategy for the management of cerebral arteriovenous malformations. Interv Neuroradiol 2005; 11: 57–62.
www.thelancet.com Vol 383 May 10, 2014
www.thelancet.com Vol 383 May 10, 2014
randomised to intervention who are in the middle of their treatment programme, is this to be continued or aborted? Presumably the 20 patients yet to start treatment will not now start. The only solution to this dilemma is continued follow-up, which should cost very little, not only for the planned 5 years, but for decades. After all, the average age of the ARUBA patients is only 45 years, so they have roughly another 30–40 years to live with an unoperated arteriovenous malformation. Being told that “medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke”1 over the next 33 months is hardly reassuring. To compound the difficulty and possibly render any solution impossible, the sample size was not allowed to reach even the modified target of 400, and there will almost certainly now be many partial and full cross-overs from intervention to conservative management. Therefore, sadly, in view of the effort and cost put into the trial, its power to answer any of the important questions to do with arteriovenous malformations intervention is very restricted. I declare that I have no competing interests.
Charles Warlow [email protected] Western General Hospital, Department of Clinical Neuroscience, Edinburgh EH4 2XU, UK 1
Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 2014; 383: 614–21.
It is difficult to conduct a randomised controlled trial to compare policies of conservative management versus interventional treatment for brain ‘‘timebombs’’ that could bleed.1 Incomplete understanding of natural history often leads to extrapolations of short-term event rates to patients’ lifetimes and so an
unfavourable indirect comparison with clinicians’ estimates of the risks of intervention. These issues result in the recruitment of a small number of eligible patients in clinical practice.1,2 Furthermore, some patients and clinicians (probably more so those who treat the conditions in fee-forservice health-care systems) might prefer preventative interventions. Consequently, despite the fact that ARUBA delivered a result deemed definitive by its Data Monitoring Committee,2 the external validity— or generalisability 3—of ARUBA’s participants and interventions has been criticised both before4 and after5 ARUBA’s results were known. However, reassurance about generalisability is afforded by the strong similarities between the participants, intervention, comparator, and outcome in ARUBA and a population-based study that took the opportunity to examine this therapeutic dilemma in a non-randomised design. 6 Treated participants were similar in age and sex, and in the frequencies of incidental presentation, location of arteriovenous malformation, superficial venous drainage pattern, and Spetzler-Martin grades. 2,6 Interventions in ARUBA were done in routine clinical practice rather than under special circumstances, 3 and the frequency of multimodality intervention was similar in ARUBA and the observational study. 2,6 In the conservative management group, the event rate was similar in ARUBA and the observational study. 2,6 Finally, the association between conservative management and stroke or death related to brain arteriovenous malformation or its intervention during 12 years in the observational study (adjusted hazard ratio 0·37, 95% CI 0·19–0·72) was similar to the effect of conservative management on stroke or death of any cause during 6 years in the ARUBA randomised analysis (0·27, 0·14–0·54).2,6
Lunagrafix/Science Photo Library
their Data and Safety Monitoring Board who recommended halting randomisation at a mean of less than 3 years, before—possibly long before—enough follow-up had accrued to answer the crucial question: are the inevitable and already well known early risks of intervention, as well as any later ones that might emerge, worth taking in the long run for a condition that might or might not cause stroke or death several decades after presentation? This is a general problem with trials of surgery and other interventions with high upfront risk, for example of carotid endarterectomy to prevent stroke. If the randomised controlled trials of carotid endarterectomy had been stopped early after only a year of follow-up, when it must have been very clear that at that point surgery was not advantageous because most strokes were perioperative rather than in the no-surgery group, then the longer-term benefits of surgery might never have emerged. The decision to stop early in ARUBA is even more problematic because not only is any useful effect of intervention unlikely to be seen within months, as it is after carotid surgery, but also some patients in the intervention group had still not completed their interventional neuroradiology treatment, which might be scheduled for several occasions during several months, or perhaps their full radiotherapy programme. Unlike carotid surgery, for which the risks of intervention are all within a few days of surgery, for arteriovenous malformations the risk of intervention is, like the intervention itself, spread over some months as might be inferred from figure 2,1 in which stroke risk flattens off at about 30 months for the intervention group, whereas it is still increasing in the medical management only group. And what is to happen to the 53 of 114 patients
1633
Correspondence
I was a member of the Executive Committee and the UK Chief Investigator for ARUBA, but received no funding for these roles. I declare that I have no other competing interests.
Rustam Al-Shahi Salman [email protected] Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK 1
2
3
4
5
6
Raymond J, Darsaut TE, Molyneux AJ, et al, for the TEAM collaborative Group. A trial on unruptured intracranial aneurysms (the TEAM trial): results, lessons from a failure and the necessity for clinical care trials. Trials 2011; 12: 64. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 2014; 383: 614–21. Rothwell PM. External validity of randomised controlled trials: “To whom do the results of this trial apply?” Lancet 2005; 365: 82–93. Mohr JP, Moskowitz AJ, Parides M, Stapf C, Young WL. Hull down on the horizon: a randomized trial of unruptured brain arteriovenous malformations (ARUBA) trial. Stroke 2012; 43: 1744–45. Knopman J, Stieg PE. Management of unruptured brain arteriovenous malformations. Lancet 2014; 383: 581–83. Al-Shahi Salman R, White PM, Counsell CE, et al, for the Scottish Audit of Intracranial Vascular Malformations collaborators. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA 2014; 311: 1661–69.
The management of cerebral arteriovenous malformations requires balancing the risk of treatment against the natural history of the lesion left untreated. A properly designed randomised trial would, therefore, be very instructive. Unfortunately, the ARUBA study1 is poorly designed, in large part, because it treats all unruptured arteriovenous malformations the same when in fact they represent a heterogeneous disease. Size, location, age, anatomy of venous drainage, associated aneurysms, eloquence of involved cortex, and other factors have a large and well-documented role in determining substantial differences in the risk of both rupture and treatment. To make matters worse, the investigators lump microsurgery, embolisation, stereotactic radiosurgery, and combinations of these 1634
treatments into a category called interventional therapy, as if these treatments were equivalent in terms of their risks, benefits, and indications. Nothing could be further from the truth. Finally, the stroke endpoint is not a validated outcome measure. A more meaningful endpoint would be modified Rankin score at 10 years, at least for those treated with surgery with or without embolisation. For radiosurgery, a much longer time would be needed to gauge effectiveness, and for embolisation alone, we would need further data about the final angiographic result. The exercise, however, becomes futile when taking into account arteriovenous malformation-specific and patientspecific factors, because the study is fatally underpowered. In summary, the data reported in this Article,1 while sure to be widely quoted, will do little, regardless of additional follow-up, to meaningfully direct the care of patients with unruptured arteriovenous malformations. We declare that we have no competing interests.
*Robert A Solomon, E Sander Connolly Jr [email protected] Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, Columbia University Medical Center, New York, NY 10032, USA 1
Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 2014; 383: 614–21.
embolisation to increase this rate increases morbidity. Radiosurgery obliteration rates are less than 70%.4 The delayed course of radiationinduced obliteration could surpass the duration of ARUBA. Therefore, an unknown but large percentage of arteriovenous malformations in the interventional group were not cured, and morbidity could be due to both treatment and natural history. The authors should report cure rates. The trial’s primary endpoint is the composite of death or stroke, defined as “any new focal neurological deficit, seizure, or new-onset headache” associated with imaging findings.1 These definitions overestimate treatment morbidity. A postintervention headache or seizure with oedema or hint of blood after embolisation could be counted as a stroke without causing permanent morbidity. An unknown but possibly large percentage of patients who reached the primary endpoint might have had minimum neurological effects, thereby misrepresenting risks. The authors should report modified Rankin scores. Microsurgical resection in selected patients with low Spetzler-Martin grades remains an effective, safe, immediate, and curative therapy for arteriovenous malformations. Efforts to show surgery’s gold standard5 status are continuing. As we determine the trial’s effect on clinical practice, we should not overgeneralise the results to microsurgery. We declare that we have no competing interests.
In response to ARUBA, 1 many clinicians concluded that observation of unruptured brain arteriovenous malformations is superior to microsurgical resection. However, ARUBA turned out to be a strikingly non-surgical trial (18 surgical patients, 19%), showing a trend away from microsurgery. 76 (81%) patients were treated with non-surgical modalities; a glaring omission was the associated cure rate. Cures with embolisation are less than 25%,2,3 and aggressive
*Michael T Lawton, Adib A Abla [email protected] University of California, San Francisco, San Francisco, CA 94143, USA 1
2
Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 2014; 383: 614–21. Raymond J, Iancu D, Weill A, et al. Embolization as one modality in a combined strategy for the management of cerebral arteriovenous malformations. Interv Neuroradiol 2005; 11: 57–62.
www.thelancet.com Vol 383 May 10, 2014
