The University of Chicago Journal Club, October 2010

Editor, B Roitberg, MD

Articles discussed:

1. “ISAT 2002”: Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, Holman R; International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. 2002 Oct 26;360(9342):1267-74.
2. “ISAT 2005”: Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA, Sandercock P; International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 2005 Sep 3-9;366(9488):809-17.
3. “ISAT 2009”: Molyneux AJ, Kerr RS, Birks J, Ramzi N, Yarnold J, Sneade M, Rischmiller J; ISAT Collaborators. Risk of recurrent subarachnoid haemorrhage, death, or dependence and standardised mortality ratios after clipping or coiling of an intracranial aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): long-term follow-up. Lancet Neurol. 2009 May;8(5):427-33.
4. Lanterna LA, Tredici G, Dimitrov BD, Biroli F.Treatment of unruptured cerebral aneurysms by embolization with Guglielmi detachable coils: case-fatality, morbidity, and effectiveness in preventing bleeding – a systemic review of the literature. Neurosurgery. 2004 Oct;55(4):767-75; discussion 775-8.
5. P. Mitchell, R. Kerr, Mendelow, Molyneux. Could late rebleeding overturn the superiority of cranial aneurysm coil embolization over clip ligation seen in the ISAT? J Neurosurg. 2008 Mar;108(3):437-42.
6. Bakker NA, Metzemaekers JD, Groen RJ, Mooij JJ, Van Dijk JM. International Subarachnoid Aneurysm Trial 2009: Endovascular Coiling of Ruptured Intracranial Aneurysms Has No Significant Advantage Over Neurosurgical Clipping. Neurosurgery. 2010 May;66(5):961-2.

Participants:

Faculty: Issam Awad, Ben Roitberg, Patrick Gabikian, Gregory Christoforidis

Residents: Anita Bhansali, Sherise Ferguson, Ricky Wong, Joseph Hsieh, Javed Khader-Eliyas

1) ISAT 2002

Anita Bhansali:

The goal of this study was to compare the rates of dependency and death (defined by modified Rankin Score of 3-6in aneurysmal subarachnoid hemorrhage (SAH) when treated with detachable platinum coils versus craniotomy and microsurgical clipping at 1 year.)

(Modified Rankin Score(mRS): 0 - No symptoms;1 - No significant disability. Able to carry out all usual activities, despite some symptoms; 2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities; 3 - Moderate disability. Requires some help, but able to walk unassisted; 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted; 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent; 6 - Dead.)

This was a randomized trial that began in 1997, and drew patients from 42 centers in Europe and the UK. Patient eligibility criteria included: 1) SAH on CT or lumbar puncture within the 28 days preceding randomization; 2) an aneurysm identifiable on CT or conventional angiography that could be the cause; 3) the patient had a clinical indication for treatment; 4) either treatment modality could be used, based on the judgment of both a neurosurgeon and an endovascular operator; 5) ambiguity existed about which of the 2 treatments to use (ie, one modality was not clearly indicated over another); 6) consent from the patient or their proxy. The endovascular procedures had to be done by a provider with >30 procedures, while the neurosurgical provider had to have ‘experience’ with aneurysm surgery. All endovascular procedures required conventional angiography to confirm the degree of occlusion, while neurosurgical procedures did not. Of the 9559 cases of SAH assessed for eligibility, 2143 were allocated (1073 to coiling, 1070 to clipping). At the end of 1 year, 801 coiled cases and 793 clipped cases were available for follow-up. The study used an intent-to-treat analysis; 38 cases originally allocated to clipping switched to coiling, while 9 coiling allocations switched to clipping. 97% of the aneurysms were in the anterior circulation. 121 coiled patients had a repeat procedure within the first year, compared with 33 clipped patients.

At 2 months, 25.4% of coiled patients had an mRS 3-6, versus 36.4% of clipped patients. At 1 year, those numbers decreased to 23.7% and 30.6%, respectively. The relative risk reduction of coiling versus clipping at 1 year was 22.6%, while the absolute risk reduction was 6.9%. Recruitment ended early following these results. There was no difference in case-fatality rate.

Before 30 days had elapsed from the procedure, 20 coiled cases had rebleeds: 5 had had no coil placed, 7 had incomplete occlusion, and 3 were considered completely occluded. 5 patients had received thrombolytics for complications related to the coiling, and all 5 died. Of the clipped patients, 3 incomplete occlusions and 3 fully clipped cases rebled. After 30 days and prior to 1 year, 6 coiled cases (1 failed coil, 2 incomplete occlusions, and 3 fully occluded patients) rebled, and 4 clipped cases (2 incomplete occlusions, 2 complete occlusions) rebled. After 1 year, the risk of rebleed was 2/1276 in coiled versus 0/1081 in clipped patients.

As a group, the eligible patients tended to have good clinical SAH grade with small-diameter aneurysms in the anterior circulation. Less data was available for posterior circulation and MCA aneurysms, as well as poor grade SAH. The investigators noted that, since surgery on posterior circulation aneurysms is high-risk and most centers consider coiling the treatment of choice, including more such patients would have been unethical. Elderly patients with poor grade SAH tended to get early endovascular treatment at these centers. The authors addressed the high case-fatality rate with thrombolytic use as an effect that would be seen less with newer antiplatelet medications, such as abciximab, which are used more commonly used now with endovascular procedures and are safer in terms of rebleed risk. Similarly, new coil systems, materials and balloon remodeling may have an effect on outcomes not reflected in this study. The increasing experience of the endovascular operators also led to improved outcomes noted over the course of the study. The investigators recommend prompt neurosurgical intervention after failure to coil.

Discussion:

Bhansali:

This study showed that, at 1 year, outcomes with coiling small, anterior circulation aneurysms in good SAH grade patients were better with coiling versus clipping, in the selected group of patients, at the participating institutions. It’s important to note the specific characteristics of the patient population and aneurysms being treated when using studies to alter medical practice. In the study, posterior circulation aneurysms were undrerepresented. The authors themselves don’t explain what ‘experience’ with neurosurgical managment of aneurysms entails, further limiting the utility of this study in changing practices outside of Europe and the UK. This low generalizability is also illustrated in the mere 20% of all SAH cases that could be randomized. I believe the authors did a reasonable job of emphasizing that these results described short-term outcomes in a specific group of patients, and that more data and analysis to guide medical decision-making was forthcoming.

Awad:

One of the key points to note is patient selection - in order to be eligible aneurysms had to be treatable by both treatment modalities (clipping and endovascular). It is also important to recognize that only a small fraction of available aneurysms were randomized (i.e. 80%- 7416 excluded because one treatment better than the other). This may speak to the generalizability of the results. Since the studies were all done in European, the experience, patient population etc. may not be the same as in the US. Hence, once again the generalizability of the study can be scrutinized.

Another point – this trial was designed to look at 1 year outcome. Would this design be reasonable for unruptured aneurysms? Probably not – young patients will live much longer than one year.

On the positive side, the study had a large number of cases to make sure the groups were equalized; crossover was also limited in this study, which is admirable. However, WFNS grades 3-5 were not adequately represented, so this was effectively a study of good grade patients. Posterior circulation was also underrepresented - only 3% of cases were posterior circulation whereas in reality posterior circulation makes up approximately 15%, so we can’t base treatment of certain aneurysms on ISAT data. Would you change your practice based on this study?

Gabikian:

None of the studies were done in the US. In the British system, where I worked for some time, most aneurysm clipping cases were considered senior registrar cases. On the other hand, endovascular cases are always staffed by a more experienced senior consultant.

Cristoforidis:

I think we cannot ignore the results of this study. Data not perfect but can be used as a guide in managing patients.

Roitberg:

The study is valuable; it included a large number of patients, and looked at a very important parameter – functional recovery. Such studies are difficult and expensive, require years of dedicated work, and command well deserved respect. However, ISAT was not designed in a way that makes it a tool for guiding the treatment choice for our next patient. Sometimes results of a large randomized study can mislead precisely because they are given weight beyond their design limitations. The study consisted of patients in a good grade; we can reasonably assume that coiling is less traumatic than open craniotomy, therefore the functional outcome at one year in patients who were in a good neurological grade to begin with is likely to be better with coiling. The patients who had clipping waited longer for the procedure. Would the results be the same if they were operated sooner? Do ISAT results mean that the best choice for our next patient is coiling? The 2002 ISAT report does not provide enough information. In real life the goal of treatment is to safely and effectively occlude the aneurysm is a way that prevents it from rebleeding. The long term ratio of risk and benefit is crucial to making a rational choice. Let’s suppose that clipping permanently obliterates the aneurysm, whereas coiling leaves the patient with just 0.5% annual risk of re-rupture. Would coiling remain the preferred option, and for which patient?

The other critical design limitation was the exclusion of almost 80% of the patients from the study. The design is justified on ethical grounds – there has to be equipoise regarding treatment selection before patients are randomized, but can we make conclusions from the selected 20% that apply to the 80% that were excluded? Logically, we can not.

2) ISAT 2005 and ISAT 2009 follow up studies

Javed Khader-Eliyas:

In the original ISAT study from 2002 follow up results at 1 year were available for three quarters of the study population only. In ISAT 2005, in addition to one year follow up results for the entire study group, authors also present secondary outcome measures: re-bleeding following treatment, angiographic re-canalization, risk of seizures and medium term follow up. This article also presents the primary outcome data for the various sub-groups in the study, namely the World Federation of Neurosurgical Societies (WFNS) grade for sub-arachnoid hemorrhage (SAH), age group, Fischer grade based on computed tomography (CT) appearance and site & location of the aneurysm.

Patients in good clinical grade were 88% of the study population; 95% of the aneurysms were in the anterior circulation and 90% were smaller than 10mm. Unusually, posterior communicating artery (PCOM) aneurysm was categorized as posterior circulation. A total of 2143 patients were recruited by the study out of which 1070 underwent neurosurgical clipping and 1073 were coiled with endovascular technique. Only 0.4% of patients were lost to follow up. At 2 months approximately 26% of the endovascular group and almost 37% patients belonging to neurosurgical group was either dead or dependant. The relative risk reduction was calculated to be 0.71 with a p value of < 0.0001. By one year, the dead/dependant rate for endovascular was 23.5% and that for neurosurgery was 30.9%. This meant a relative risk (RR) reduction of almost 24% when for coiling over clipping. The absolute risk reduction was calculated to be 7.4% and hence by treating 1000 people with endovascular coiling, the authors argued that 74 can be saved from either death or dependency state.

The study followed up patients treated by endovascular coiling with regular angiograms while neurosurgical patients received angiograms only when incomplete aneurismal occlusion was suspected by the surgeon. Of the surviving patients who received coiling, 89% had follow up angiograms performed. Only 2/3rd of these angiograms showed complete occlusion while 26% had a neck remnant and another 8% were incompletely coiled. In the neurosurgical group 47% of patients had angiograms done post treatment out of suspicion of incomplete occlusion. 82% of these patients had complete occlusion and only 12% had a neck remnant. The authors fail to address why 47 patients in the endovascular group had magnetic resonance angiogram (MRA) instead of conventional angiograms and also do not discuss their results. The paper presents the re-bleeding rates to be very similar between both groups but it is important to note that there were 17 re-bleeds before treatment in the endovascular group and 28 in the neurosurgical group. Looking only at re-bleeding rates after treatment, the endovascular group has a higher risk of re-bleeds than the neurosurgical group, by 28 to 11 in the first year. After the first year the coiled patients have a small but significant risk of re-bleeding which is higher than in surgically clipped patients. Endovascular treatment significantly reduces the risk of seizure which has been confirmed in this study. The whole study population has an increased risk for new aneurysm formation and rupture.

The last edition of ISAT results came out in 2009. The investigators wanted to provide long-term follow up especially to refute any loss of benefit from coiling in the long term. The mean follow up period was 9 years with a range from 6 years to 14 years. The methodology used consisted of annual questionnaire enquiring about dependency, a quality of life survey and data from the Office of National Statistics about further admissions and future bleeds of study participants. Survival analysis was performed for time to re-bleed and time to death from the time of initial SAH. SMR (Standardized Mortality Ratio) was also calculated using national standardized death rate from England and Wales. As before, only a small percentage of the study group was lost to follow up (2.7%). Confirmed re-bleed occurred in 24 patients and a majority of them from previously treated aneurysm or the same site (13/24). There was a higher incidence of re-bleed from the same site following coiling than clipping when analyzed by actual treatment received (p=0.02). 2/3rd of the patients who had re-bleed were either dead or disabled unrelated to their initial treatment modality. Late re-treatment was done in 9% of patients who had coiling initially. Re-bleeds in patients that had coiling occurred between 2 to 5 years while those in clipped patients happened between 4 to 7 years. This seems to point to any earlier presentation with aneurysms treated by endovascular methods and could be due to coil migration causing higher rates of re-canalization. The case fatality rate was 8.0% and 9.9% with endovascular coiling and neurosurgical clipping respectively but with overlapping confidence intervals and statistically insignificant odd’s ratio. There was no difference between the groups in terms of RR (Relative Risk Reduction) for non-independence and at 5 years, the number of participants with an mRS score of 2 or less were 83% in the endovascular arm and 82% in the neurosurgical arm. Longer follow up confirmed the greater mortality rate of these patients in comparison with the general population, with cancers and cardiovascular diseases being the commonest causes.

Discussion:

Khader-Elias:

To me it seems that the initial benefit that the endovascular group enjoyed was diluted in the long run due to factors such as re-canalization and re-bleeds. Also readers need to keep in mind that this study was an analysis of intent to treat and even though crossover between both the groups was small, the result is still different when actual treatment outcomes are analyzed. The study was conducted in Europe, mostly England, where patient follow up is less of an issue compared to the US. Despite limitations, ISAT does provide useful information about SAH arising from ruptured small anterior circulation aneurysm and its treatment.

Roitberg:

The generalizability of the ISAT does not improve with follow up; we are still dealing with a limited subset of the universe of patients with subarachnoid hemorrhage. However, by performing a long term follow up, ISAT has done an immense service. It helps define the trade-off involved in selecting coiling or clipping when both appear reasonable. Unlike the intial study in 2002, we now have a better perspective. However, the field is dynamic – current technology has improved, and more aneurysms are now amenable to endovascular management than 10 years ago. Ongoing prospective outcome database is a good way to find out what the best choice for our patients, but nothing can replace sound, individualized clinical judgment. The ISAT data support the notion that when the aneurysm appears “coilable” with low risk, and experienced endovascular surgeons are available, it is reasonable to offer coiling first.

Cristoforidis:

What is the risk of angiography? It was not addressed in this paper – clinical consideration must include the total risk of each treatment approach over time.

Awad:

Majority of subgroup analyses showed that coiling is superior to clipping The follow up studies confirm that endovascular treatment is better for good grade patients.

In the 2009 study mean follow up was 9 years. Every patient was followed for at least 6 years. This study is now good enough to start making decisions on patients in the long term.

3) Counterpoints to ISAT

Ricky Wong:

Mitchell et al:

Could late rebleeding overturn the superiority of cranial aneurysm coil embolization over clip ligation seen in the ISAT?

This article addresses the issue of long term durability of coil embolization and, in particular, when it is compared to surgical clipping. Initial assessments of ISAT data led to conclusions that within that selected patient population, coiling proves to be more advantageous than surgical clipping. This conclusion has been called in to question due to the purported higher risk of rebleeding with coil embolization. ISAT data provides information on rebleeding among three groups: rebleeding at less than 30 days, between 30 days and 1 year, and greater than 1 year (late rebleeds). Comparing long term rebleeding rates proved difficult as there were not many in either coil embolization or surgical clipping which led to a large confidence interval. The rate of “long term” rebleeds for coil embolization patients was 0.24% and for surgical clipping, it was 0.032%. To allow risk calculation, the authors assumed that after an initially higher rebleeding rate/risk during the first year, it stabilizes. They combined the risk of unfavorable outcome after a re-bleed and combined it with the risk of re-bleeding for each group. Within these assumptions and give the breadth of the confidence interval, long term results could favor surgical clipping. Overall, the decision on whether to clip or coil is one that is complex that must take into account a myriad of factors that include, but are not limited to, expertise, aneurysm characteristics/location, patient characteristics and the re-bleeding rate of coil embolized patients.

International Subarachnoid Aneurysm Trial 2009: Endovascular Coiling of Ruptured Intracranial Aneurysms Has No Significant Advantage Over Neurosurgical Clipping.

The authors of this article criticize the design and analysis of the ISAT. The intent-to-treat analysis is confounded by pretreatment events. Between the two groups, there were patients who were randomized to a group (either clipping or coiling), but suffered unfavorable events prior to the actual treatment. The authors of this paper attribute this to the significant wait for treatment time, which was longer for clipping . The data therefore seems to favor coiling. When a modified-intent-to-treat analysis is used, which excludes all the patients who suffered an unfavorable event prior to the actual treatment, the apparent advantage is no longer present.

Discussion:

Cristoforidis:

The finding that older patients may do better with clipping is not intuitive at first – we might expect greater risk of craniotomy. However, the vessels of older patients are stiffer and more tortuous, making endovascular treatment more difficult.

Awad:

The data showed that in patients with several decades to live the risk of re-bleeding may wipe out the benefit of coiling. We must take into account the team and surgery volume (high versus low). For example, if a center has a great surgery team versus a mediocre endovascular team - this may affect outcome. Based on ISAT data, this is the best you can tell patients: Coiling is better tolerated and easier on the patient but in young patients durability is an issue. Some patients may refuse surgery no matter what but we have to give options based on the available data.

Gabikian:

We have to consider 3 factors when planning treatment:

1. Experience of the team.
2. Patient factors, including risk of anesthesia
3. Aneurysm factors – anatomy, access.

Ultimately the patient will have to decide.

Roitberg:

The issue of wait time for definitive treatment of the aneurysm is very important. The ISAT and the Bakker et al. analyses demonstrate that many complications can be avoided by very early treatment of the aneurysm. Looks like much of the apparent advantage of coiling was simply the advantage of earlier treatment of the ruptured aneurysm.

4) Lanterna et al, Review of coiling literature

Joseph Hsieh:

Guglielmi detachable coils (GDCs) are commonly used to treat unruptured cerebral aneurysms (UCAs). Lanterna et al attempted to evaluate the case-fatality and permanent morbidity rates of GDC embolization of UCAs and postembolization bleeding rate through systematic literature review. They performed a MEDLINE search from January 1990 to December 2002 for GDC embolization of UCAs. Inclusion criteria were: attempted GDC embolization of at least five consecutive UCA patients and reported percentage of at least case-fatality rate (defined as any death caused by a complication occurring during embolization) and permanent morbidity rate (new, permanent neurologic deficit caused by a complication occurring during embolization as defined by the author). Publication search was limited to English, French, or Italian.

Additional sub-analyses most prominently included bleeding rate and evaluation of publication quality. Bleeding rate following embolization was calculated as number of postembolization hemorrhages divided by the number of patient-years of follow-up. Bleeding rate was assessed in small (<10 mm) and large (≥ 10 mm) aneurysms with complete or partial occlusion. Publications were defined as “high quality” if they had more than 20 consecutive patients, prospective design, clear definitions of outcome measures, no selection of specific groups of patients or aneurysms, predefined moment of follow-up, and blinding in outcome evaluation.

Of 213 studies reviewed, only 30 papers met inclusion criteria (5 prospective, 14 retrospective, and 11 with undefined data collection). In 25 of 30 studies, the physician performing the embolization was also the author and observer of the outcome. Within these 30 publications, 1379 patients were used to calculate case-fatality rate (29 publications), 794 for permanent morbidity rate (24 publications) , and 703 for bleeding rate (20 publications). In total, case fatality was 0.6% (95% CI, 0.2 – 1%). Permanent morbidity rate was 7% (95% CI, 5.3-8.7%) with a mean average follow-up time of 2.015 years. Bleeding rate was 0.9% per year (95% CI, 0.41 – 1.4%) and incompletely coiled UCAs of 10 mm or more accounted for all bleeding events. No publications met all criteria for “high quality.” Morbidity in which the midyear of study was 1995 and later decreased from 8.6% to 4.5% (p< 0.05).

Discussion:

Hsieh:

The systematic review by Lanterna et al highlights the paucity of robust literature surrounding GDC coiling for UCAs. While the authors conclude that GDC embolizations of UCAs are relatively safe with outcomes improving over time, they are doing so based on literature in which no publications meet their criteria of “high quality” and over a third have “undefined data collection.” Follow-up to evaluate morbidity and bleeding rates is poorly defined and limited to a mean of approximately 2 years. There is also an observer bias as the author serves as both the provider of care and observer of outcome in 25 of 30 studies. Several assumptions are also questionable, including calculations of bleeding rate which assume stable bleeding rates after coiling. More than anything else, Lanterna et al’s paper clearly expresses the poor quality of existing literature on GDC coiling of UCAs.

Awad:

Let’s discuss the methodology of systemic review. Just looking up papers in PubMed is not a systematic review; it is a “topic review”. In systematic review the literature search is defined prospectively: i.e., what articles to include, exclude etc., what search engine, what date range included. Have to state how many papers found, excluded, what key words used etc. This way you never risk a reviewer having written a paper you didn’t pick! And, seriously, you do a better job understanding the literature.

Meta-analysis of trash begets trash. Most of the papers included in the review are small case reports. Unfortunately, the situation of the coiling literature is not much better currently, years after the publication of the Lanterna review. Endovascular cure of aneurysm is an elusive entity…we still can’t be sure of long team cure rate. The use of coiling for unruptured aneurysm does not have a clearly defined efficacy, and we cannot apply ISAT data which were collected for patients with ruptured aneurysms.

Roitberg:

What we really need to know to make intelligent clinical decisions, is the difference between the bleeding rates after coiling and the natural history of the unruptured aneurysm. There is still no adequate data to guide our recommendations.