The International Subarachnoidal Aneurysm Trial (ISAT)

Título

The International Subarachnoidal Aneurysm Trial (ISAT)

Autor

James V. Byrne

Fecha

Diciembre 2004

Texto


COMENTARIOS DEL 38° CONGRESO DE LA AANC

THE INTERNATIONAL SUBARACHNOIDAL ANEURYSM TRIAL (ISAT)
Resumen de Conferencia

The International Subarachnoid Aneurysm Trail (ISAT)1 was a multicentre randomized control trial of endovascular embolization of intracranial aneurysms using coils versus the established optimum neurosurgical operation of craniotomy and clipping. It was stopped in May 2002 by its data monitoring committee when they identified that patients randomized to endovascular treatment (EVT) were enjoying a significant benefit. Coils had been used to embolise intra-cranial aneurysms since 19872 because it was obvious to some practitioners that the then current endosaccular (i.e. intra-aneurysmal) balloon embolisation was causing delayed aneurysm rupture. Within 5 years, technical improvements provided interventional neuroradiology with a controlled detachment coil system (the Guglielmi Detachable Coil - GDC) and it was obvious by 1994 that EVT was a viable alternative to neurosurgery for patients with operable aneurysms, particular recently ruptured aneurysms3. A randomized trial was then needed to provide the evidence to support a general shift towards this minimally invasive form of surgery.
ISAT was designed pragmatically to compare the two methods ofpreventing rebleeding amongst patients after aneurysm rupture, i.e, subarachnoid hemorrhage (SAH). The trial randomized 2143 patients (1070 neurosurgery and 1073 EVT) in 43 hospitals and compared clinical outcomes 2 months and 1 year after randomization. Outcomes were defined on a modified Rankin scale using data provided by the patient (or their carer) on a standardised questionnaire, The frequency of patients being dependent or dead at 1 year was 30.7% for those assigned to neurosurgery and 23.7% for their EVT counterparts. This represented relative and absolute risks reductions for this outcome of 22.6% (95% CI 8.934.2) and 6,9% (2.5-11.3) respectively and a resounding win for the coils.
The trial was controversial before it started recruitment. Opposition came largely from Interventional Neuroradiologists. The arguments against a trial can be simplified into those that considered such a trial unnecessary since EVT was so obviously the better treatment and therefore it was unethical to randomise patient on the basis of clinical equipoise- which did not exist and those that argued that the technique was too young to undergo such scrutiny. The neurosurgical community was supportive or silent.
For Interventional Neuroradiology the ending of patient recruitment and the trial result should have solved all the problem of resources to take on a new service and the difficult issue associated with resource shifts. But before discussing this problem, it is worth reviewing the comments that ISAT caused to be published. Since ISAT published in October 2002, 8 editorial commentaries were published in 6 mainstream journals4-11, the Lancet published 4 letters12-14 including comments commentaries14-15, "Position Statements" were issued by 3 medical societies (the American Association of Neurological Surgeons (AANS)16, the American Society of Neuroradiology17 and the German Society of Neurorsurgery11 and an article had appeared in the New York Times18. Not to mention several descriptive and critical articles printed in a range of small circulation publications sponsored by commercial companies, Much of this interest carne from neurosurgeons in the United States of America.
Ten days after the ISAT results were published Drs. Harbaugh, Heros and Hadley issued a document on behalf of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons which draws attention to the fact that 20% of patients admitted to participating hospitals were randomised, that only one centre was in the United States of America and that the treated aneurysms were a highly selected subset16, The statement goes on to imply that the standard of neurorsurgery in European centres was less than patients might expect from neurosurgeons in the United States of America, where the degree of sub-specialisation is different and to point out, along with most other commentators, that the long-term protection against rebleeding provided by EVT is unknown and that the results should not be interpreted as applying to all aneurysm patients. In an extraordinary statement they go on "Media reports have attributed a 22,6% risk reduction to endovascular coiling compared to craniotomy for aneurysm clipping, The figure of 22.6%, the overall study relative risk reduction, suggests there was a dramatic reduction in the number of poor outcomes among patients whose aneurysms were treated with coiling as compared to those whose aneurysms were surgically clipped. This is not the case. It is the absolute risk reduction that is of greatest importance to patients. Importantly, the absolute risk reduction of 6.9% reported by the ISAT authors should not be inappropriately generalized". I can only agree with the statement's precision and accept that the statement was addressed to a non-medical audience, but I,m not sure that the 53 patients, who, after allocation to neurosurgery, were dependant or dead at one year and constitute these statistical differences would see the distinction.
But what do we do with the results of properly conducted international clinical research. Repeat the study in the United States of America? Not ethical, I hear the pre-ISAT critics chorus. My view is that the data can be applied logically and is well put by several neurosurgical commentators. Mr K. W. Lindsay in a thoughtful article5 points out that what underlies the AANS response is the pressure from the consumer patient for less invasive surgery and argues that despite the lack of evidence of long-term efficacy that "neuroradiologists should now play an important role in the neurovascular team, not just as a diagnostician, but as an interventionalist, participating in management decisions of all patients with aneurysmal subarachnoid haemorrhage".
What is going to happen to Interventional Neuroradiology now? Will we be forced to abandon Radiology and become a component of a neurovascular team? Medical specialty and turf disputes are not the ultimate issue because in the end, the important goal is that we provide patients with the best treatment as competently as possible. The UK is relatively well provided at the moment with trained Endovascular Therapists but the implications of ISAT are that hospitals accepting patients with acute aneurysmal SAH should be able to provide EVT on an emergency basis. Thus each centres will need 2-3 trained endovascular therapists to provide a service and cover for weekends and out-of-hours treatments. We certainly don,t have that volume of interventional manpower yet. The solution may lie in rationalising centres or training neurosurgeons. The former would risk creating second-class neurosurgical units and the latter, potentially, the end of the interventional neuroradiology.
Will neurosurgeons now train to provide their patients with the choice ofendo or extra vascular surgery?
I think this is unlikely because the required technical skills are different, though there almost certainly will be individuals who want to accept the challenge. Internationally there are a number of "hybrid" surgeons and a strong push is detectable in the United States of America for neurosurgeons to train. It could happen here but currently the consensus amongst UK interventional neuroradiologists is that the skills needed to perform EVT need regular practice. To maintain adequate skill in both clipping and coiling would be difficult. I hope I am right, If I were able to control how this interesting and exciting new branch of medicine develops, I would like to see an independent subspecialty. It is still young but with ISAT the innocence of youth has been lost and if a subspecialty of individuals, exploiting the endovascular route under x-ray guidance can avoid energy sapping demarcation disputes for a little longer its full potential to treat neurovascular diseases would be better realised. What it,s called and where it sits in relation to radiology and neurosurgery is not going to deflect the pressure from patients for minimally invasive surgery.

James V. Byrne
Dept. of Neuroradiology, Racliffe Infirmary Woodstock Road, Oxford OX2 6HE

References

1. Intemational 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; 360: 1267-74.
2. Hilal SK, Khandji AG, Chi TL, Stein BM, Bello JA, Silver AJ. Synthetic fiber-coated platinum coils successfully used for the endovascular treatment of arteriovenous malformations, aneurysms and direct arteriovenous fistulas of the CNS. AJNR Am J Neuroradiol 1988; 9: 1030.
3. Byrne JV, Molyneux AJ, Brennan RP, Renowden SA, Embolisation of recently ruptured intracranial aneurysms, Joumal of Neurology, Neurosurgery and Psychiatry 1995; 59(6): 616-20.
4. Nichols DA, Brown RD, Meyer FB. Coils or clips in subarachnoid haemorrhage? Lancet 2002; 360: 1262-3.
5. Lindsay KW. The impact of the international subarachnoid aneurysm treatment trial (ISAT) on neurosurgical practice. Acta Neurochir 2003; 145:97-9.
6. Ausman JI. ISAT study: Is coiling better than clipping? Surg Neurol 2003; 59: 173-5.
7. Kirkpatrick PJ, Kirollos RW, Higgins N, Matta B. Lessons to be learned from the international subarachnoid haemorrhage trial (ISAT). Br J Neurosurg 2003; 17(1): 5-7.
8. Lasjaunias P. ISAT: A randomised trial to arbitrate a debate between sciences and culture. Journal of Neuroradiology 2003; 30(5): 283-5.
9. Dormont D, Bonafe A, Cognard C, Deramond H, Herbreteau D Pierot L, Pruvo JP, Flandroy P. What about the ISAT results? J Neuroradiol 2003; 30(5): 286-8.
10. Hernesniemi J Koivisto T, Comments on "The impact of the Intemational Subarachnoid Aneruysm Treatment Trial (ISAT) on neurosurgical practice", Acta Neurocir 2003; 146(2): 203-8.
11. Van den Berg R, Rinkel GJ, Vandertop WP. Treatment of ruptured intracranial aneurysms: implications of the ISAT on clipping versus coiling. European J Radiol 2003; 46(3): 172-7.
12. Leung CHS, Poon WS, Yu LM. The ISAT trial. Lancet 2003; 361: 430-1.
13. Britz GW, Newell DW, West GA, LamA. The ISAT trial. Lancet 2003; 361: 431-2.
14. Sellar R, Whittle I. The ISAT trial. Lancet 2003; 361: 432-3.
15. Harbaugh RE, Heros RC, Hadley MN. More on ISAT. Lancet 2003; 361: 783-4.
16. Harbaugh RE, Heros RC, Hadley MN. Position statement on the international subarachnoid aneurysm trial (ISAT). American Association of Neorological Surgeons 2002; www. neurosurgery. org/ health /news /
17. Derdeyn CP, BarrJD, Berenstein A, ConnorsJJ, Dion JE, Duckwiler GR, Higashida RT, Strother CM, Tomsick TA, Turski P. The International Subarachnoid Aneurysm Trial (ISAT): a position statement from the executive committee of the American Society of Interventional and Therapeutic Neuroradiology and the American Society of Neuroradiology. Am J Neuroradiol 2003; 24: 1404-8.
18. McNeil DG Jnr. Fixing aneurysms without surgery. New York Times. Nov 12, 2002.
19. Maurice-Williams RS, Aneurysm surgery alter the International Subarachnoid Aneurysm Trial (ISAT). Joumal of Neurology, Neurosurgery and Psychiatry 2004; 75: 807-8. (v)

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