Timing of Aneurysm Treatment After Subarachnoid Hemorrhage: Relationship With

Delayed Cerebral Ischemia and Poor Outcome

Sanne M. Dorhout Mees, Andrew J. Molyneux, Richard S. Kerr, Ale Algra and Gabriel J.E.
Rinkel

Stroke. 2012;43:2126-2129; originally published online June 14, 2012;

doi: 10.1161/STROKEAHA.111.639690
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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 Timing of Aneurysm Treatment After
Subarachnoid Hemorrhage
Relationship With Delayed Cerebral Ischemia and Poor Outcome
Sanne M. Dorhout Mees, MD; Andrew J. Molyneux, MD, PhD; Richard S. Kerr, MD, PhD;
Ale Algra, MD, PhD; Gabriel J.E. Rinkel, MD, PhD

Background and Purpose—The ideal timing of coiling or clipping after aneurysmal subarachnoid hemorrhage is unknown.
Within the International Subarachnoid Aneurysm Trial we assessed differences in incidence of delayed cerebral
ischemia and clinical outcome between different timings of treatment.
Methods—The treated 2106 patients randomized to coiling or clipping were divided into 4 categories: treatment ⬍2 days,
on days 3 to 4, on days 5 to 10, and ⬎10 days after the hemorrhage. ORs with 95% CI were calculated with logistic
regression analysis for delayed cerebral ischemia, poor outcome at 2 months, and 1 year for the different timing
categories, with treatment ⬍2 days as reference. Analyses were performed for all patients, and for coiled and clipped
patients separately, and were adjusted for baseline characteristics.
Results—Adjusted ORs of delayed cerebral ischemia for treatment on days 5 to 10 were 1.18 (95% CI, 0.91–1.53) for all
patients, 1.68 (95% CI, 1.17–2.43) after coiling, and 0.79 (95% CI, 0.54 –1.16) after clipping. ORs for poor outcome
at 2 months were 1.16 (95% CI, 0.89 –1.50) for treatment (clipping and coiling combined) at 3 to 4 days, 1.39 (95% CI,
1.08 –1.80) for treatment at 5 to 10 days, and 1.84 (95% CI, 1.36 –2.51) for treatment ⬎10 days. ORs for coiled and
clipped patients separately were in the same range. Results for outcome at 1 year were similar.
Conclusions—Our results support the current practice for early aneurysm treatment in subarachnoid hemorrhage patients.
The risk for poor outcome was highest when treatment was performed after day 10; postponing treatment in patients who
are eligible for treatment between days 5 to 10 after subarachnoid hemorrhage is not recommended. (Stroke. 2012;43:
2126-2129.)
Key Words: subarachnoid hemorrhage 䡲 aneurysm

R ebleeding after aneurysmal subarachnoid hemorrhage

(SAH) dramatically decreases the chances of good
outcome.1,2 To prevent rebleeding, treatment of the ruptured
aneurysm was almost exclusively performed by neurosurgical
clipping before 1995. Over many years, there has been debate
about the most suitable timing of surgery.3–5 In the 1960s and
1970s, most patients were operated on in the late phase 2 or
3 weeks after the hemorrhage. Surgery in the initial 2 weeks
was considered too dangerous, because operating on the
swollen and vulnerable brain tissue led to high rates of
perioperative complications.6 – 8 This especially applied
during the period of maximum vasospasm between days 4
and 10; this was considered a particularly dangerous
period to operate, because of the risk of delayed cerebral
ischemia (DCI). An observational study performed in the
1980s in patients with aneurysmal SAH admitted within 3
days after the ictus suggested that outcome was worst
when patients were operated between 7 and 10 days after
the SAH; early surgery was neither more hazardous nor
more beneficial than was surgery after day 10.9 A Co-
chrane review in 2001 identified only 1 randomized
clinical trial on timing of surgery after aneurysmal SAH.10
In this trial, patients undergoing early surgery (days 0 –3)
tended to have the best outcome, and patients with inter-
mediate surgery (days 4 –7) the worst.11 A systematic
review that included not only this trial, but also 10
observational studies, found that both early (days 0 –3) and
intermediate (days 4 –7) surgical treatment resulted in
better outcome than did late surgery.12
In the early 1990s, endovascular aneurysm occlusion by
means of detachable coils was introduced; this is now an
established method of aneurysm treatment.13 To our knowl-
edge, there are no randomized studies on the optimal timing
of coiling. One observational study including 327 coiled

Received November 2, 2011; accepted April 4, 2012.

From the Rudolf Magnus Institute of Neuroscience, Department of Neurology and Neurosurgery (S.M.M., A.A., G.J.E.R.); Julius Centre for Health
Sciences and Primary Care (A.A.), University Medical Center Utrecht, the Netherlands; and Neurovascular Research Unit (A.J.M., R.S.K.), Nuffield
Department of Surgery, University of Oxford and Oxford Radcliffe Hospitals, National Health Service Trust, Radcliffe Infirmary, Oxford, United
Kingdom.
Correspondence to S.M. Dorhout Mees, Room G03.228, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail
s.m.dorhoutmees@umcutrecht.nl
© 2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.111.639690

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2126
 Dorhout Mees et al Timing of Aneurysm Treatment and Poor Outcome 2127

patients did not find any difference with regard to outcome Table 1. Baseline and Disease Characteristics of the 2106
for early, intermediate, or late treatment.14 Included Patients
Most centers now aim to treat the aneurysm within 2 days Timing of Treatment, Days After SAH
after SAH. For patients who are only eligible for treatment
later than day 2, it is important to know the optimal timing of All 0 –2 3– 4 5–10 ⱖ11
aneurysm treatment: as soon as possible or postponed until N 2106 891 482 474 259
after the 10th day, and whether the treatment modality Age, mean (SD) 52 (12) 51 (11) 51 (12) 52 (12) 55 (12)
influences optimal timing. Women (%) 1321 (63) 562 (63) 300 (62) 285 (60) 174 (67)
Within the International Subarachnoid Aneurysm Trial WFNS 1–3* (%) 1990 (95) 815 (92) 469 (97) 460 (97) 246 (95)
(ISAT), we assessed differences in occurrence of DCI and
Fisher 1–2 (%) 470 (22) 175 (20) 94 (20) 131 (28) 70 (27)
clinical outcome between different timings of treatment for
Admission day, 1 (1–3) 1 (0–1) 2 (1–2) 3 (1–5) 7 (3–1)
coiled and for clipped patients.
median (IQR)
Randomization 2 (1–4) 1 (1–1) 2 (2–3) 5 (4–6) 11 (8–1)
Methods day, median
Patients (SD)
We analyzed the data of patients who participated in the ISAT trial, Days between 1 (0–3) 0 (0–1) 1 (1–1) 1 (1–3) 3 (1–7)
a clinical trial that randomized 2143 patients either to endovascular randomization
coiling treatment or neurosurgical clipping of the ruptured aneurysm. and treatment,
The methods of this trial have been described previously.13 In short, median (SD)
patients were included in the trial if they had a definite subarachnoid
hemorrhage within the previous 28 days and an aneurysm, which DCI (%) 511 (24) 218 (25) 118 (25) 123 (26) 52 (20)
was judged by both the neurosurgeon and the interventional radiol- Rebleeding† (%) 28 (1.3) 6 (0.7) 2 (0.4) 5 (1.1) 15 (5.8)
ogist to be suitable for treatment by either technique, but there was
SAH indicates subarachnoid hemorrhage; WFNS, World Federation of
uncertainty which treatment was most appropriate. Informed consent
Neurological Surgeons scale; IQR, interquartile range; DCI, delayed cerebral
was obtained from the patient or relatives. The majority of included
ischemia.
patients were in good clinical condition at admission and had anterior
circulation aneurysms. For the current study, we analyzed patients *Measured at randomization.
according to the treatment they actually received, and also if †Rebleeding after randomization, but before treatment.
treatment crossover occurred (on treatment analysis).
Of the included patients, age, sex, clinical grade on admission by for age, clinical condition at admission, and amount of blood on
means of the World Federation of Neurosurgical Surgeons (WFNS) initial computed tomography scan.
grading scale,15 amount of blood on the initial computed tomography
according to the Fisher Scale,16 and the occurrence of DCI were Results
recorded. Age was dichotomized at 55 years. The WFNS scale was
The time from admission until randomization did not depend
dichotomized into good clinical condition (WFNS 1–3) or poor
clinical condition (WFNS 4 –5). The Fisher scale was dichotomized on the time from SAH onset until admission (regression
into small amount of blood on computed tomography scan (Fisher coefficient, ⫺0.01; 95% CI, ⫺0.04 to 0.02). Of the 2143
1–2) or large amount of blood on computed tomography scan (Fisher patients randomized in ISAT, 2106 patients received endo-
3– 4). DCI was diagnosed on clinical grounds as delayed ischemic vascular or neurosurgical treatment. Of these patients, 891
neurological deficit, which was not caused by operative factors or
other factors, such as procedural vessel occlusion, hydrocephalus, or
patients were treated on days 0 to 2 after SAH, 482 patients
aneurysmal rebleeding, and the clinicians judged the deterioration to were treated on days 3 to 4, 474 patients between days 5 to
be caused by vasospasm. Clinical outcome was assessed by self- 10, and 259 patients on day 11 or later (Table 1). The median
reported questionnaires with the modified Rankin Scale score at 2 day of randomization in patients treated between 5 to 10 days
months and at 1 year.17 Poor outcome was defined as an modified (day 5) and on day 11 or later (day 11) was higher than in
Rankin Scale score of 3 or higher, or death.
patients treated on days 0 to 2 (day 1) or 3 to 4 (day 2).
Statistical Analyses Patients treated on days 0 to 2 received treatment on a median
First, we analyzed whether there was a relationship between time of 0.3 day after the randomization day, patients treated on day
from SAH until admission and time from admission until random- 3 to 4 or 5 to 10 on a median of 1 day after randomization
ization with linear regression analysis. Patients were then divided day, and patients treated after 10 days on a median of 3 days
into 4 categories according to the timing of treatment after the SAH: after randomization day. Rebleeding before aneurysm treat-
within 2 days, on day 3 or 4, on days 5 to 10, and ⬎10 days. ORs
with 95% CI were calculated with logistic regression analysis for ment, but after randomization, was more frequent in the
DCI, poor outcome at 2 months, and at 1 year for the different timing group treated after day 10.
categories; the first category (treatment within 2 days) was a Data on DCI were available for 2099 patients (99.7%). The
reference. We performed these analyses for all patients, and sepa- risks of DCI for all treated patients, and for patients after
rately for coiled and for clipped patients. With subgroups of 450
coiling and clipping separately, are given in Table 2. Only
patients and a risk of poor outcome of 30%, an absolute risk
difference of 6% would have a 95% CI of 0.2% to 11.8%. Likewise, between days 5 to 10 was there a statistically significant
with similar subgroups and risk of DCI of 25%, an absolute risk interaction between treatment modality and timing, with a
difference of 6% would have a 95% CI of 0.6% to 11.4%. To check lower risk of DCI for clipping during this time period than for
for interaction between treatment modality and the timing category, coiling (P⫽0.01).
the cross-product of clipping and the particular timing category were
entered into the regression analyses. If the probability value of the Data on poor outcome at 2 months and at 1 year are given
cross-product was ⬍0.05, we considered there to be an interaction in Table 3. The risk of poor outcome increased with increas-
between treatment modality and timing. All analyses were adjusted ing time lapse of treatment after SAH. There was no inter-
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2128 Stroke August 2012

Table 2. ORs for DCI for Patients Treated on Days 3– 4, Table 3. ORs for Poor Outcome at 2 Months and 1 Year for
Days 5–10, and Days 11 or Later Compared With Patients Patients Treated on Days 3– 4, Days 5–10, and Day 11 or Later
Treated on Days 0 –2, for All Patients and for Coiled and Compared With Patients Treated on Days 0 –2, for All Patients
Clipped Patients Separately and for Coiled and Clipped Patients Separately
Crude Adjusted Crude Adjusted
n/N (%) OR (95% CI) OR (95% CI)* n/N (%) OR (95% CI) OR (95% CI)*
All Patients Outcome 2 mo
ⱕ2 d 218/886 (25%) Ref Ref All Patients
3–4 d 118/480 (25%) 1.00 (0.77–1.29) 1.04 (0.80–1.36) ⱕ2 d 247/881 (28%) Ref Ref
5–10 d 123/474 (26%) 1.07 (0.83–1.39) 1.18 (0.91–1.53) 3–4 d 138/477 (29%) 1.05 (0.82–1.34) 1.16 (0.89–1.50)
ⱖ11 d 52/259 (20%) 0.77 (0.55–1.08) 0.83 (0.59–1.17) 5–10 d 147/472 (31%) 1.16 (0.91–1.48) 1.39 (1.08–1.80)
Coiled Patients ⱖ11 d 102/257 (39%) 1.69 (1.26–2.26) 1.84 (1.36–2.51)
ⱕ2 d 102/482 (21%) Ref Ref Coiled Patients
3–4 d 58/261 (22%) 1.06 (0.74–1.53) 1.11 (0.77–1.61) ⱕ2 d 115/477 (24%) Ref Ref
5–10 d 68/238 (29%) 1.49 (1.04–2.13) 1.68 (1.17–2.43) 3–4 d 69/262 (26%) 1.13 (0.80–1.59) 1.27 (0.88–1.83)
ⱖ11 d 22/109 (20%) 0.94 (0.56–1.58) 1.01 (0.60–1.72) 5–10 d 57/237 (24%) 1.00 (0.69–1.44) 1.17 (0.79–1.72)
Clipped Patients ⱖ11 d 39/108 (36%) 1.78 (1.14–2.77) 1.73 (1.06–2.81)
ⱕ2 d 116/404 (29%) Ref Ref Clipped Patients
3–4 d 60/219 (27%) 0.94 (0.65–1.35) 0.97 (0.67–1.41) ⱕ2 d 132/404 (33%) Ref Ref
5–10 d 55/236 (23%) 0.75 (0.52–1.09) 0.79 (0.54–1.15) 3–4 d 69/215 (32%) 0.97 (0.68–1.39) 1.03 (0.71–1.49)
ⱖ11 d 30/150 (20%) 0.62 (0.39–0.98) 0.64 (0.41–1.02) 5–10 d 90/235 (38%) 1.28 (0.92–1.78) 1.46 (1.02–2.08)
DCI indicates delayed cerebral ischemia. ⱖ11 d 63/149 (42%) 1.51 (1.03–2.22) 1.61 (1.07–2.41)
*Adjusted for age, clinical condition at admission, and amount of blood on Outcome at 1 y
the initial computed tomography scan.
All Patients
ⱕ2 d 219/883 (25%) Ref Ref
action between treatment modality and timing in any timing
category. 3–4 d 109/473 (23%) 0.91 (0.70–1.18) 1.00 (0.76–1.32)
5–10 d 122/467 (26%) 1.07 (0.83–1.39) 1.27 (0.97–1.66)
Discussion ⱖ11 d 94/258 (36%) 1.74 (1.29–2.34) 1.89 (1.38–2.57)
Our study shows that clinical outcome is worse when aneu- Coiled Patients
rysm occlusion is performed later after SAH, after differences ⱕ2 d 103/480 (21%) Ref Ref
in baseline characteristics have been taken into account. In 3–4 d 55/258 (21%) 0.99 (0.69–1.43) 1.10 (0.78–1.63)
patients who were coiled between 5 to10 days after the SAH,
5–10 d 51/237 (22%) 1.00 (0.69–1.47) 1.17 (0.79–1.75)
the risk for DCI was higher than in other treatment periods,
ⱖ11 d 44/109 (40%) 2.48 (1.60–3.85) 2.50 (1.55–4.03)
but this increased risk did not result in worse outcome either
at 2 months or at 1 year compared with treatment within 2 Clipped Patients
days. Clipped patients had no higher risk of DCI when treated ⱕ2 d 116/403 (29%) Ref Ref
between 5 to 10 days. 3–4 d 54/215 (25%) 0.83 (0.57–1.21) 0.87 (0.59–1.30)
Patients who were randomized and treated after day 10 had 5–10 d 71/230 (31%) 1.11 (0.78–1.57) 1.23 (0.85–1.78)
worse outcome than did patients treated earlier. It is important ⱖ11 d 50/149 (34%) 1.25 (0.84–1.87) 1.31 (0.86–2.00)
to realize that patients were not randomized for the timing of *Adjusted for age, clinical condition at admission, and amount of blood on
treatment, and the worse outcome in this group is probably the initial computed tomography scan.
related to the reasons for postponing treatment, such as poor
clinical condition on admission, early rebleeding, or early worse clinical condition at admission and improved by the
deterioration from other causes. This assumption is supported time of randomization. The occurrence of DCI does not seem
by the fact that patients in this group were randomized on to be the cause of poor outcome, as it was not increased in this
a median of 11 days after the SAH, which suggests that patient group. As might be expected, rebleeding did occur
these patients were only eligible for treatment from day 11 more often in patients treated after day 10, and this is an
onwards. important reason for poor clinical outcome.
The time from admission until randomization did not Because these are observational data, no direct causal
depend on the time of admission since SAH. As soon as effect between timing and clinical outcome can be concluded.
patients were considered eligible for treatment, they could be Also, 92% of patients were in a good clinical condition at the
randomized, and treatment was not postponed because of time of randomization. This means that we cannot extrapolate
randomization. Although the clinical condition (WFNS) did our results to patients who present with poor clinical condi-
not differ between the groups, the grade was measured at time tion. Patients were only randomized when both the neurosur-
of randomization and not at time of presentation at the geon and the interventional neuroradiologist considered the
hospital. Patients treated after day 10 may have been at a aneurysm suitable for treatment, which also limits generaliz-
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 Dorhout Mees et al Timing of Aneurysm Treatment and Poor Outcome
ability. DCI was diagnosed on clinical grounds, and transcra-
nial Doppler or radiographic studies were not used in the
definition. The strengths of this study are the large sample
size in each timing category, and the fact that patients were
randomized for coiling or clipping, giving us the opportunity
to look for differences between these 2 treatment modalities.
Based on our sample size considerations, an absolute risk
difference of 6% between timing subgroups for poor outcome
or DCI would have sufficient precision. This means that
smaller differences could not be detected precisely enough.
Historically, clipping between days 5 to 10 is considered
the worst period for neurosurgery.9,11 Interestingly, in our
study, the risk for DCI was low in patients clipped during this
time, and outcome was not worse when compared with
treatment after day 10. On the basis of the current evidence,
there seems no reason to postpone treatment in patients who
are eligible for treatment at day 5. Ideally, given all the
methodological concerns mentioned above, a new random-
ized trial would be needed to give definite answers to the
ideal timing of aneurysm treatment after SAH; however, such
a trial is not likely to be performed given the observational
evidence for benefit of early treatment. If a randomized trial
on timing of treatment were conducted, we think it should
address the question of when patients who present to the
hospital in poor clinical condition should be treated or about
those who present for treatment later than day 4 after the
hemorrhage. An alternative strategy to study optimal timing
would be to use a Markov decision model.
Conclusion
In conclusion, our results show that aneurysm treatment after
day 10 is associated with worse outcome, regardless of
treatment modality. The results are in line with the latest
literature that advocates treatment of the aneurysm as early as
possible after SAH.10,12,14 Interestingly, clipping between
days 5 to 10 did not lead to a higher chance of DCI, whereas
coiling between days 5 to 10 did increase the chance of DCI,
but not poor outcome. Based on these results, we do not
recommend postponing clipping until day 10 or later in
patients who are candidates for aneurysm treatment between
5 and 10 days after hemorrhage.
Sources of Funding
This study was partly sponsored by the Netherlands Heart Founda-
tion, grant number 2005016.
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2129
Disclosures
None.
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