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The Unruptured Intracranial Aneurysm Study-II: a critique of the second study
Editorial
The Unruptured Intracranial Aneurysm Study-II: A Critique of the Second Study
n the December 10, 1998 issue of the New England Journal of Medicine, the International Study of Unruptured Intracranial Aneurysms Investigators published the first of two studies on unruptured intracranial aneurysms [8]. The first article was criticized in several issues of Surgical Neurology [1,7,8] and the Journal of Neurosurgery [10]. That first study was a retrospective analysis of 2 unruptured aneurysm populations. It was found that the rupture rate in one group was 0.05% per year and in the second Group 0.5% per year. Not only were the two rates lower than experienced and reported by neurosurgeons around the world, but also they differed internally by a factor of 10. Many reasons for the low rupture rate were given in the criticisms including a selection bias of the group of patients who were left without surgery in this retrospective review. Forty percent of the patients in the study had aneurysms that would have been difficult to treat in the period covered in the retrospective review, 1970 through 1991, mostly cavernous and paraclinoid aneurysms. There were also a surprisingly low number of anterior communicating artery aneurysms, a fact pointing to the possibility that the aneurysms in this location had ruptured and had been treated surgically, or the patients had died and not been included in the study. The authors of the study defended their data as being “by far and away the most robust to date” [7]. The authors denied that there was any difference in the two cohorts of patients they followed retrospectively. Excluding the cavernous sinus aneurysms made no significant alteration in the rupture rates. In the July 12, 2003 issue of The Lancet [9] the ISUIA investigators reported on the prospective arm of the unruptured aneurysm study. I missed the report at the time it was published and for that reason I am commenting on it a year later.
I
© 2004 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010 –1710
Theoretical Bases of Natural History Studies In performing a natural history study for a clinical disease process, there are several principles involved. First, there is assumed to be a universe of patients who have that disease, in this case unruptured intracranial aneurysms. This universe of patients contains those with single or multiple unruptured aneurysms, aneurysms that are unruptured at the time of another aneurysm rupture, aneurysms at all locations, aneurysms of all sizes and in patients of all ages and states of health. There may be other factors such as racial or genetic that I have not mentioned. In a natural history study, the investigators sample this universe of patients. Admittedly, all studies are based on biased samples because they are taken from patients who are admitted to a single institution which, in itself, may be a selection bias. Some studies might have a selected sample based upon the age of the patients compared to the actual representation of the ages in the universe of unruptured aneurysm patients. Suffice it to say that all reported studies represent biased or selected samples of this universe of patients. The key for the reader is to determine which study most closely approximates the actual composition of that universe of patients with unruptured intracranial aneurysms to determine the natural history of the disease.
Basis of Selection for the ISUIA-II Report In the ISUIA-II report [9], the investigators wanted to determine prospectively the rupture rate of the sample of patients they included in their study. Because the study is prospective it does not have the flaws of a study that looks back at the remaining patients who have survived with unruptured aneu0090-3019/04/$–see front matter doi:10.1016/j.surneu.2004.05.001
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Surg Neurol 2004;62:91–94
rysms, a retrospective study. The investigators enlisted patients in centers in North America and Europe. Other parts of the world were not represented. The patients included were those with unruptured aneurysms from each center. There was no indication if all the patients with unruptured aneurysms from each center were included. Furthermore, it was not stated what percentage of all the aneurysms seen at each center were represented by the cohort of patients reported from each center. Thus, at the outset there is a selection bias, the magnitude of which we do not know. These collective cohorts of patients represents the total group analyzed in this ISUIA-II report. Now, the group at each center was further subdivided into those who were not operated, those who underwent surgical clipping of their unruptured aneurysms or a third group that had coiling of their aneurysms. There is no indication in the ISUIA-II report how this selection of patients was made in each center to allocate the patients to no surgery, surgery, or coiling groups. Obviously, this factor further confounds the sampling of the universe of patients with unruptured aneurysms by leaving the “No Surgery” group a very selected sample of all the unruptured aneurysms presenting to or included in each center’s report. The selection process also raises serious questions on the real value and meaning of the group of patients the study followed for the natural history of the rupture rate of unruptured aneurysms (the “No Surgery” group). To me this initial bias alone makes the study of little value or useless. How have the surgical and endovascular selections from the original group of unruptured aneurysms altered the remaining group of patients labeled as “No Surgery?” Is this group in any way similar to the patient in my office today or tomorrow with an unruptured aneurysm? The answer to these questions from the reader’s perspective is, “I do not know.” Thus, the data are virtually useless, in my opinion. To support this obvious bias further, one need only to look at the composition of each of the groups of patients. There were 1,692 patients with unruptured aneurysms who had no treatment, 1,917 patients who underwent surgery (the reasons for the selection were not stated) and 451 patients who had coiling of their aneurysms. The maximum and (mean) diameters of the aneurysms in the no surgery group was 7.4 mm (6.9 mm), the surgery group 9.6 mm (6.7 mm) and in the coiling group 13.1 mm (9.7 mm), respectively. These differences were significant and indicated that the larger aneurysms were subjected to coiling, a factor raising the risk of treatment in that group of patients. In the nonsur-
Editorial
gery group 62% of the patients had aneurysms from 2 to 7 mm in size. In the surgery group 38.6% were 2 to 7 mm in size and 40% were from 7 to 12 mm in size. Twenty-one percent (21%) of the surgery group had aneurysms greater than 12 mm in diameter. In the coiling group, 27% were 2 to 7 mm, 30% were 7 to 12 mm, and 41% were greater than 12 mm in size. So, the groups are dissimilar in regard to aneurysm size. The nonsurgical group has smaller sized aneurysms. How can the nonsurgery group represent the universe of patients with unruptured intracranial aneurysms? As far as location is concerned, the nonsurgical group had 12.4% on the cavernous carotid; the surgical group had 2% in this location, and the coiling group had almost 20% in this category. There were only 10% of the aneurysms in the nonsurgical group on the anterior communicating or cerebral arteries, 14.8% in the surgical group, and 9.1% in the coiling group. This percentage of anterior communicating or anterior cerebral aneurysms is low compared to other larger studies. The percentage should approach 30%. Why are there so few anterior cerebral or communicating artery aneurysms in these groups? What happened to the rest of the anterior cerebral complex aneurysms? This percentage was also low in the first ISUIA retrospective report. What does this low percentage tell us about the selection of this sample of patients from the universe of unruptured aneurysms? As in the ISUIA-I study the unruptured aneurysms were divided into two groups, one with unruptured aneurysms only and a second with an unruptured aneurysm in a patient who previously had a different aneurysm rupture. The patients who did not have surgery were followed by questionnaire, while their physicians followed those with interventional procedures yearly. So, the type of follow-up also differed between the nontreatment and treatment groups.
Results In the unoperated and uncoiled group (no surgery group) there were 1,692 patients of whom 1,077 had no previously ruptured aneurysm and 615 who had a previously ruptured aneurysm at another site. “Patients were removed from follow-up if they had treatment (410 had subsequent surgery and 124 had endovascular treatment), as were those who died (193 patients)” [9]. What does this statement mean? To me, it means that in the group of patients we are supposed to be following for natural history, one-third were removed because they became can-
Editorial
didates for treatment for reasons that are not explained! So, that means that the sample of patients with unruptured aneurysms that we are following for the natural history data has become even more selected and biased. The rupture rates reported in this study of this very selected group of patients with unruptured aneurysms was as follows: For patients with aneurysms less than 7 mm in diameter, the rupture rate was from 0% on the cavernous carotid artery in 5 years to 1.5 to 3.4% in 5 years for Anterior Cerebral, Middle Cerebral, and Internal Carotid (AC/MC/IC) aneurysms. For aneurysms from 7 to 12 mm in diameter, the cavernous carotid was still 0%, but the rupture rate rose to 2.6% for the AC/MC/IC and to 14.5% for the posterior communicating or posterior cerebral arteries (PC-Pcom) in a 5-year period. The rupture rate for all of the aneurysms except the posterior communicating and posterior cerebral is less than the 1 to 2% per year widely used from other studies but higher than reported in ISUIA-I in the retrospective study [4]. As the aneurysm size increased above 12 mm, the rupture rates also increased to a high of ⬎50% in 5 years for the PCPcom aneurysms. The surgical morbidity and mortality was 12.6% for the surgery group in the ISUIA-II report. These statistics included a functional score and cognitive assessment. These data are helpful in establishing an overall risk of treatment morbidity and mortality versus no treatment. In the endovascular group complete obliteration of the aneurysm was accomplished in 50 to 55% with an additional incomplete obliteration of 21 to 24%. The morbidity and mortality of the coiled group was 9.8%. Even though the aneurysms in the endovascular group were larger and presumably more difficult to treat, these results, for whatever the selected population for coiling represents, provide a number. It is unclear what this number means and how it can be used when applied to other populations of patients undergoing coiling.
Discussion So, what have we learned from this presumed multimillion dollar study with over 60 centers and more than 100 neuroscientists who were involved? To me, not much. Why? What data am I going to use from this study that will help me with my next patient who has an unruptured aneurysm? The sample of patients with unruptured intracranial aneurysms from the universe of patients with unruptured intracranial aneurysms is so selected and
Surg Neurol 2004;62:91–94
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super selected again that I do not know what patient group I am quoting for natural history data. What does this group of patients with unruptured intracranial aneurysms represent from this universe of patients? I do not know, and thus, the study is useless to me. There are two fine studies in the literature on unruptured intracranial aneurysms. The studies are by Juvela et al from Finland [4,5]. They followed a consecutive series of patients with unruptured intracranial aneurysms. Most of the patients with aneurysms are seen in their center in Finland. It was the institution’s policy before 1979 to follow all patients with unruptured aneurysms. So, their study group was unselected and seemed to be as closely representative of the universe of patients with unruptured intracranial aneurysms as we can find. The rupture rate they reported was 1.3%/year [5]. In another excellent study published in 2002, Dickey and Kailasnath reported that the rupture rate increases according to the third power of the diameter of the aneurysm and thus makes sense of all of the reported studies depending upon their composition of patients [3]. If studies have populations with small aneurysms the rupture rates are lower.
Conclusion This is my analysis of this ISUIA-II study. I am unimpressed with the study and find the data of no use to me for all the reasons I stated. The morbidity and mortality statistics for surgical treatment that include cognitive and functional outcomes are helpful for comparing with no treatment options. You have to decide what you think. James I. Ausman, M.D., Ph.D. Editor REFERENCES 1. Ausman JI. The New England Journal of Medicine report on unruptured intracranial aneurysms: a critique. Surg Neurol 1999;51:227–9. 2. Ausman JI. Why the ISUIA has lost credibility with neuroscientists. Surg Neurol 2002;58:287–90. 3. Dickey P, Kailasnath P. The diameter-cube hypothesis: a new biophysical model of aneurysm rupture. Surg Neurol 2002;58:166 –81. 4. Juvela S, Porras M, Heiskanen O. Natural History of unruptured intracranial aneurysms: a long term follow-up study. J Neurosurg 1993;79:174 –82. 5. Juvela S, Porras M, Poussa K. Natural History of unruptured intracranial aneurysms: probability and risk factors for aneurysm rupture. J Neurosurg 2000;93: 379 –87.
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Surg Neurol 2004;62:91–94
6. Kobyashi S, Orz Y, George B, et al. Treatment of unruptured cerebral aneurysms. Surg Neurol 1999;51: 355–62. 7. Piepgras DG, Kassell NF, Torner J. A response from the ISUIA. Surg Neurol 1999;52:428 –9. 8. The International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms: risk of rupture and risks of surgical intervention. N Engl J Med 1998;339:1725–33.
Editorial
9. Wiebers DO, International Study of Unruptured Intracranial Aneusysms Investigators. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003;362:103–10. 10. Winn HR, Jane JA Sr, Taylor J, et al. Prevalence of asymptomatic incidental aneurysms: review of 4568 arteriograms. J Neurosurg 2002;96:43–9.
The Unruptured Intracranial Aneurysm Study-II: A Critique of the Second Study
n the December 10, 1998 issue of the New England Journal of Medicine, the International Study of Unruptured Intracranial Aneurysms Investigators published the first of two studies on unruptured intracranial aneurysms [8]. The first article was criticized in several issues of Surgical Neurology [1,7,8] and the Journal of Neurosurgery [10]. That first study was a retrospective analysis of 2 unruptured aneurysm populations. It was found that the rupture rate in one group was 0.05% per year and in the second Group 0.5% per year. Not only were the two rates lower than experienced and reported by neurosurgeons around the world, but also they differed internally by a factor of 10. Many reasons for the low rupture rate were given in the criticisms including a selection bias of the group of patients who were left without surgery in this retrospective review. Forty percent of the patients in the study had aneurysms that would have been difficult to treat in the period covered in the retrospective review, 1970 through 1991, mostly cavernous and paraclinoid aneurysms. There were also a surprisingly low number of anterior communicating artery aneurysms, a fact pointing to the possibility that the aneurysms in this location had ruptured and had been treated surgically, or the patients had died and not been included in the study. The authors of the study defended their data as being “by far and away the most robust to date” [7]. The authors denied that there was any difference in the two cohorts of patients they followed retrospectively. Excluding the cavernous sinus aneurysms made no significant alteration in the rupture rates. In the July 12, 2003 issue of The Lancet [9] the ISUIA investigators reported on the prospective arm of the unruptured aneurysm study. I missed the report at the time it was published and for that reason I am commenting on it a year later.
I
© 2004 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010 –1710
Theoretical Bases of Natural History Studies In performing a natural history study for a clinical disease process, there are several principles involved. First, there is assumed to be a universe of patients who have that disease, in this case unruptured intracranial aneurysms. This universe of patients contains those with single or multiple unruptured aneurysms, aneurysms that are unruptured at the time of another aneurysm rupture, aneurysms at all locations, aneurysms of all sizes and in patients of all ages and states of health. There may be other factors such as racial or genetic that I have not mentioned. In a natural history study, the investigators sample this universe of patients. Admittedly, all studies are based on biased samples because they are taken from patients who are admitted to a single institution which, in itself, may be a selection bias. Some studies might have a selected sample based upon the age of the patients compared to the actual representation of the ages in the universe of unruptured aneurysm patients. Suffice it to say that all reported studies represent biased or selected samples of this universe of patients. The key for the reader is to determine which study most closely approximates the actual composition of that universe of patients with unruptured intracranial aneurysms to determine the natural history of the disease.
Basis of Selection for the ISUIA-II Report In the ISUIA-II report [9], the investigators wanted to determine prospectively the rupture rate of the sample of patients they included in their study. Because the study is prospective it does not have the flaws of a study that looks back at the remaining patients who have survived with unruptured aneu0090-3019/04/$–see front matter doi:10.1016/j.surneu.2004.05.001
92
Surg Neurol 2004;62:91–94
rysms, a retrospective study. The investigators enlisted patients in centers in North America and Europe. Other parts of the world were not represented. The patients included were those with unruptured aneurysms from each center. There was no indication if all the patients with unruptured aneurysms from each center were included. Furthermore, it was not stated what percentage of all the aneurysms seen at each center were represented by the cohort of patients reported from each center. Thus, at the outset there is a selection bias, the magnitude of which we do not know. These collective cohorts of patients represents the total group analyzed in this ISUIA-II report. Now, the group at each center was further subdivided into those who were not operated, those who underwent surgical clipping of their unruptured aneurysms or a third group that had coiling of their aneurysms. There is no indication in the ISUIA-II report how this selection of patients was made in each center to allocate the patients to no surgery, surgery, or coiling groups. Obviously, this factor further confounds the sampling of the universe of patients with unruptured aneurysms by leaving the “No Surgery” group a very selected sample of all the unruptured aneurysms presenting to or included in each center’s report. The selection process also raises serious questions on the real value and meaning of the group of patients the study followed for the natural history of the rupture rate of unruptured aneurysms (the “No Surgery” group). To me this initial bias alone makes the study of little value or useless. How have the surgical and endovascular selections from the original group of unruptured aneurysms altered the remaining group of patients labeled as “No Surgery?” Is this group in any way similar to the patient in my office today or tomorrow with an unruptured aneurysm? The answer to these questions from the reader’s perspective is, “I do not know.” Thus, the data are virtually useless, in my opinion. To support this obvious bias further, one need only to look at the composition of each of the groups of patients. There were 1,692 patients with unruptured aneurysms who had no treatment, 1,917 patients who underwent surgery (the reasons for the selection were not stated) and 451 patients who had coiling of their aneurysms. The maximum and (mean) diameters of the aneurysms in the no surgery group was 7.4 mm (6.9 mm), the surgery group 9.6 mm (6.7 mm) and in the coiling group 13.1 mm (9.7 mm), respectively. These differences were significant and indicated that the larger aneurysms were subjected to coiling, a factor raising the risk of treatment in that group of patients. In the nonsur-
Editorial
gery group 62% of the patients had aneurysms from 2 to 7 mm in size. In the surgery group 38.6% were 2 to 7 mm in size and 40% were from 7 to 12 mm in size. Twenty-one percent (21%) of the surgery group had aneurysms greater than 12 mm in diameter. In the coiling group, 27% were 2 to 7 mm, 30% were 7 to 12 mm, and 41% were greater than 12 mm in size. So, the groups are dissimilar in regard to aneurysm size. The nonsurgical group has smaller sized aneurysms. How can the nonsurgery group represent the universe of patients with unruptured intracranial aneurysms? As far as location is concerned, the nonsurgical group had 12.4% on the cavernous carotid; the surgical group had 2% in this location, and the coiling group had almost 20% in this category. There were only 10% of the aneurysms in the nonsurgical group on the anterior communicating or cerebral arteries, 14.8% in the surgical group, and 9.1% in the coiling group. This percentage of anterior communicating or anterior cerebral aneurysms is low compared to other larger studies. The percentage should approach 30%. Why are there so few anterior cerebral or communicating artery aneurysms in these groups? What happened to the rest of the anterior cerebral complex aneurysms? This percentage was also low in the first ISUIA retrospective report. What does this low percentage tell us about the selection of this sample of patients from the universe of unruptured aneurysms? As in the ISUIA-I study the unruptured aneurysms were divided into two groups, one with unruptured aneurysms only and a second with an unruptured aneurysm in a patient who previously had a different aneurysm rupture. The patients who did not have surgery were followed by questionnaire, while their physicians followed those with interventional procedures yearly. So, the type of follow-up also differed between the nontreatment and treatment groups.
Results In the unoperated and uncoiled group (no surgery group) there were 1,692 patients of whom 1,077 had no previously ruptured aneurysm and 615 who had a previously ruptured aneurysm at another site. “Patients were removed from follow-up if they had treatment (410 had subsequent surgery and 124 had endovascular treatment), as were those who died (193 patients)” [9]. What does this statement mean? To me, it means that in the group of patients we are supposed to be following for natural history, one-third were removed because they became can-
Editorial
didates for treatment for reasons that are not explained! So, that means that the sample of patients with unruptured aneurysms that we are following for the natural history data has become even more selected and biased. The rupture rates reported in this study of this very selected group of patients with unruptured aneurysms was as follows: For patients with aneurysms less than 7 mm in diameter, the rupture rate was from 0% on the cavernous carotid artery in 5 years to 1.5 to 3.4% in 5 years for Anterior Cerebral, Middle Cerebral, and Internal Carotid (AC/MC/IC) aneurysms. For aneurysms from 7 to 12 mm in diameter, the cavernous carotid was still 0%, but the rupture rate rose to 2.6% for the AC/MC/IC and to 14.5% for the posterior communicating or posterior cerebral arteries (PC-Pcom) in a 5-year period. The rupture rate for all of the aneurysms except the posterior communicating and posterior cerebral is less than the 1 to 2% per year widely used from other studies but higher than reported in ISUIA-I in the retrospective study [4]. As the aneurysm size increased above 12 mm, the rupture rates also increased to a high of ⬎50% in 5 years for the PCPcom aneurysms. The surgical morbidity and mortality was 12.6% for the surgery group in the ISUIA-II report. These statistics included a functional score and cognitive assessment. These data are helpful in establishing an overall risk of treatment morbidity and mortality versus no treatment. In the endovascular group complete obliteration of the aneurysm was accomplished in 50 to 55% with an additional incomplete obliteration of 21 to 24%. The morbidity and mortality of the coiled group was 9.8%. Even though the aneurysms in the endovascular group were larger and presumably more difficult to treat, these results, for whatever the selected population for coiling represents, provide a number. It is unclear what this number means and how it can be used when applied to other populations of patients undergoing coiling.
Discussion So, what have we learned from this presumed multimillion dollar study with over 60 centers and more than 100 neuroscientists who were involved? To me, not much. Why? What data am I going to use from this study that will help me with my next patient who has an unruptured aneurysm? The sample of patients with unruptured intracranial aneurysms from the universe of patients with unruptured intracranial aneurysms is so selected and
Surg Neurol 2004;62:91–94
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super selected again that I do not know what patient group I am quoting for natural history data. What does this group of patients with unruptured intracranial aneurysms represent from this universe of patients? I do not know, and thus, the study is useless to me. There are two fine studies in the literature on unruptured intracranial aneurysms. The studies are by Juvela et al from Finland [4,5]. They followed a consecutive series of patients with unruptured intracranial aneurysms. Most of the patients with aneurysms are seen in their center in Finland. It was the institution’s policy before 1979 to follow all patients with unruptured aneurysms. So, their study group was unselected and seemed to be as closely representative of the universe of patients with unruptured intracranial aneurysms as we can find. The rupture rate they reported was 1.3%/year [5]. In another excellent study published in 2002, Dickey and Kailasnath reported that the rupture rate increases according to the third power of the diameter of the aneurysm and thus makes sense of all of the reported studies depending upon their composition of patients [3]. If studies have populations with small aneurysms the rupture rates are lower.
Conclusion This is my analysis of this ISUIA-II study. I am unimpressed with the study and find the data of no use to me for all the reasons I stated. The morbidity and mortality statistics for surgical treatment that include cognitive and functional outcomes are helpful for comparing with no treatment options. You have to decide what you think. James I. Ausman, M.D., Ph.D. Editor REFERENCES 1. Ausman JI. The New England Journal of Medicine report on unruptured intracranial aneurysms: a critique. Surg Neurol 1999;51:227–9. 2. Ausman JI. Why the ISUIA has lost credibility with neuroscientists. Surg Neurol 2002;58:287–90. 3. Dickey P, Kailasnath P. The diameter-cube hypothesis: a new biophysical model of aneurysm rupture. Surg Neurol 2002;58:166 –81. 4. Juvela S, Porras M, Heiskanen O. Natural History of unruptured intracranial aneurysms: a long term follow-up study. J Neurosurg 1993;79:174 –82. 5. Juvela S, Porras M, Poussa K. Natural History of unruptured intracranial aneurysms: probability and risk factors for aneurysm rupture. J Neurosurg 2000;93: 379 –87.
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Surg Neurol 2004;62:91–94
6. Kobyashi S, Orz Y, George B, et al. Treatment of unruptured cerebral aneurysms. Surg Neurol 1999;51: 355–62. 7. Piepgras DG, Kassell NF, Torner J. A response from the ISUIA. Surg Neurol 1999;52:428 –9. 8. The International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms: risk of rupture and risks of surgical intervention. N Engl J Med 1998;339:1725–33.
Editorial
9. Wiebers DO, International Study of Unruptured Intracranial Aneusysms Investigators. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003;362:103–10. 10. Winn HR, Jane JA Sr, Taylor J, et al. Prevalence of asymptomatic incidental aneurysms: review of 4568 arteriograms. J Neurosurg 2002;96:43–9.