J Neurosurg / Volume 119 / September 2013

J Neurosurg 119:603–605, 2013

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Subarachnoid hemorrhage and outcome

R. Loch MacdonaLd, M.d., Ph.d.

Division of Neurosurgery, St. Michael’s Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Department of Surgery, University of Toronto, Ontario, Canada

Wilson and coauthors address an issue of fundamen-tal importance to clinical trial design as well as other top-ics such as what we tell our patients about how long it will take them to get better after brain injury (in the pres-ent case, subarachnoid hemorrhage [SAH]).11 Who could summarize the complexities of time better that William Shakespeare, perhaps the best writer ever, when he began Macbeth’s famous soliloquy at the beginning of Scene 5, Act 5: “To-morrow, and to-morrow, and to-morrow, / Creeps in this petty pace from day to day.” We wait and wait for days and days to estimate the extent to which our patients will recover, but at what cost?—the cost of time, of rehabilitation and of psychological stress, and of devel-opment of new treatments?

Wilson et al. reviewed the data from 88 patients who had Hunt and Hess Grade IV or V SAH and who under-went assessment with the modified Rankin Scale (mRS) at discharge and then 6, 12, and 36 months after the hemor-rhage.11 The mean mRS score was 4.3 ± 1.3 at discharge, 3.3 ± 2.1 at 6 months, 3.3 ± 2.2 at 12 months, and 3.2 ± 2.3 at 36 months. Thus, overall, other than the differ-ence between discharge and 6-month scores, there were fairly minor changes in the overall mean mRS scores. If we exclude the 9 patients who died before discharge, the mean discharge mRS score would be 4.1 ± 1.2, so there is still substantial improvement from discharge to 6 months. Even more convincing, when examined on an individual patient basis, 61% of patients had improved mRS scores between discharge and 6 months, and about 1 in 5 pa-tients had improved scores between 6–12 months and 12–36 months. The rough percentage improvement would be 91% at 6 and 91% at 12 months, assuming 3 years is 100% improvement.

The most important factors associated with improve-ment over time were Hunt and Hess Grade IV (as opposed to Grade V), no large (> 4 cm) or eloquent cerebral infarc-

tion, and age greater than 65 years. These factors were identified in a univariate analysis, so whether they each add independent information in a multivariate analysis is not known. Another key finding was that those who improved in the first 6 months were not necessarily those who improved after 6 months.

There are few other data like these in the literature. Greebe et al.3 have shown the trajectory of recovery in patients discharged to a nursing home after SAH is quali-tatively similar to that of the current data, and another group has shown progressive cognitive improvement in predominately good-grade patients over the 1st year af-ter SAH.4 Since this paper was accepted, Navi et al. have reported outcome over time in 52 patients with nontrau-matic SAH whose hemorrhage was Hunt and Hess Grade I–IV.8 The findings corroborate those reported by Wil-son and colleagues. In the Navi et al. study, about 80% of patients improved one or more points on the mRS between discharge and 6 months, and 50% of Hunt and Hess Grade IV or V patients had mRS scores of 0–2 by 6 months compared to 0% at discharge. The factors that showed trends toward predicting improvement were, as in this study, age, clinical vasospasm (which often results in infarction), and hydrocephalus.

I think neurosurgeons, physicians, and other people who have looked after patients with SAH will recognize that we know that improvement occurs for years after SAH. I have usually counseled patients that about 75% of their recovery will occur in the first 3 months, and 25% of their recovery will plateau at 2–4 years. I don’t remember if I was ever taught that; I think I calculated it after asking patients, whom I followed for years, what they thought the numbers were and then summarizing them. These num-bers fit well with the data of Mocco and colleagues, who reported that in poor-grade SAH patients, roughly 80% of the improvement on the telephone interview of cogni-tive status and Barthel index occurred between discharge and 3 months and the remaining 20% between 3 and 12 months.6

Wilson and colleagues discuss 2 reasons their find-ings are important. The first is for counseling patients and their families about what their outcome will be in months or years, helping them to make choices about rehabili-tation and other services. The second reason concerns clinical trials. Most studies assess outcome 3–6 months after SAH. The authors imply that this is because there is not much improvement beyond this point. But there are other reasons. What does longer follow-up mean and

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See the corresponding article in this issue, pp 606–612.

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why would it matter? The longer the follow-up, the more expensive is the study. More random events (death from cancer, myocardial infarction, and so on) occur and can obscure treatment benefit. For some diseases and treat-ments, the technology changes quickly, so longer-dura-tion studies may not have relevant outcomes by the time they are completed. Also, for treatment studies, it only matters if the treatment lines eventually meet or cross. On the other hand, if a treatment makes the patient im-prove faster, this might be advantageous. The shorter time one is disabled the better. Most would agree that if we had a drug that made significantly more patients an mRS score of 0–2 (independent) at 3 months but was no better than placebo at 3 years, we would use the drug. Wilson and coauthors have alluded not to a drug treatment but to randomized trials that compare clipping and coiling of ruptured aneurysms. Such trials differ from a drug treat-ment designed to achieve neuroprotection or some such effect acutely after SAH, because there are not likely to be long-term problems with a short duration of drug treat-ment. In the Barrow Ruptured Aneurysm Trial (BRAT), poor outcome occurred in 36% of clip-treated patients compared to 30% of coil-treated patients, which was not statistically significant. Likewise, the difference in poor outcome was not significant at 5 years in the International Subarachnoid Aneurysm Trial (ISAT; 18% for clipping compared to 17% for coiling).7 In ISAT, death was sig-nificantly more likely at 5 years in the clip-treated group.

Thus, the timing of outcome assessment would de-pend on the treatment question. In the majority of cases, however, 3 months is enough time. The Food and Drug Administration has suggested 30- to 90-day outcome, which is consistent with the majority of stroke and SAH studies.5,10 The National Institutes of Neurological Disor-ders and Stroke Common Data Elements group have also recommended 90 days.9 Longer study durations may be appropriate for more severely affected populations.

The study by Wilson et al. is well done and there are many strengths. The follow-up is excellent, with almost every patient assessed at every time point. Few other data like these appear in the literature, but there are some limi-tations to the study. The number of patients is relatively small, and the analysis included only patients with Hunt and Hess Grade IV or V SAH on presentation. Future studies might grade patients’ status using some version of the Glasgow Coma Scale and indicate when the grading was done, since the Glasgow Coma Scale may have better reliability and the timing of grading matters.1,2 The pa-tients in the present study were a subset of SAH patients who happened to be entered into a randomized clinical trial. The person assessing the mRS score was not blind-ed to previous mRS scores, and one could envision bias to score the patient better; as doctors we always want to help patients, telling them or making them feel like they are getting better. This study defined improvement as re-duction of at least one point on the mRS. Some of these changes may not be clinically relevant.

The main problem with the study, however, is that the authors first assessed outcome at 6 months, but the most common time of outcome assessment in SAH studies is 3 months. While it is likely there is improvement between

3 and 6 months, it is going to be less than the improve-ment between discharge and 6 months seen in the present study. The other point important for clinical trials is that the aggregate mRS score did not change after 6 months, and we don’t know if it would have changed beyond 3 months. Because individual patient outcomes are not the point in clinical trials, whether there are advantages to as-sessing outcome beyond the standard 3 months will have to be carefully considered depending on what the trial is testing and the severity of the disease.(http://thejns.org/doi/abs/10.3171/2013.1.JNS122368)

Disclosure

The author reports no conflict of interest.

References

1. Degen LA, Dorhout Mees SM, Algra A, Rinkel GJ: Interob-server variability of grading scales for aneurysmal subarach-noid hemorrhage. Stroke 42:1546–1549, 2011

2. Giraldo EA, Mandrekar JN, Rubin MN, Dupont SA, Zhang Y, Lanzino G, et al: Timing of clinical grade assessment and poor outcome in patients with aneurysmal subarachnoid hem-orrhage. Clinical article. J Neurosurg 117:15–19, 2012

3. Greebe P, Rinkel GJ, Algra A: Long-term outcome of patients discharged to a nursing home after aneurysmal subarachnoid hemorrhage. Arch Phys Med Rehabil 91:247–251, 2010

4. Haug T, Sorteberg A, Sorteberg W, Lindegaard KF, Lundar T, Finset A: Cognitive outcome after aneurysmal subarachnoid hemorrhage: time course of recovery and relationship to clini-cal, radiological, and management parameters. Neurosurgery 60:649–657, 2007

5. Lees KR, Bath PM, Schellinger PD, Kerr DM, Fulton R, Hacke W, et al: Contemporary outcome measures in acute stroke research: choice of primary outcome measure. Stroke 43:1163–1170, 2012

6. Mocco J, Ransom ER, Komotar RJ, Sergot PB, Ostapkovich N, Schmidt JM, et al: Long-term domain-specific improve-ment following poor grade aneurysmal subarachnoid hemor-rhage. J Neurol 253:1278–1284, 2006

7. Molyneux AJ, Kerr RS, Birks J, Ramzi N, Yarnold J, Sneade M, et al: 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 8:427–433, 2009

8. Navi BB, Kamel H, McCulloch CE, Nakagawa K, Naravetla B, Moheet AM, et al: Accuracy of neurovascular fellows’ prognostication of outcome after subarachnoid hemorrhage. Stroke 43:702–707, 2012

9. Stroke CDE Working Group: Stroke CDE Instrument Rec-ommendations by Outcome Domain and Classification. NINDS Common Data Elements, 2013

10. US Food and Drug Administration: Guidance for Industry and FDA Staff—Pre-Clinical and Clinical Studies for Neurothrombectomy Devices. (http://www.fda.gov/medical devices/deviceregulationandguidance/guidancedocuments/ ucm071403.htm) [Accessed April 25, 2013]

11. Wilson DA, Nakaji P, Albuquerque FC, McDougall CG, Za-bramski JM, Spetzler RF: Time course of recovery follow-ing poor-grade SAH: the incidence of delayed improvement and implications for SAH outcome study design. Clinical ar-ticle. J Neurosurg [epub ahead of print May 31, 2013. DOI: 10.3171/2013.4.JNS121287]

J Neurosurg / Volume 119 / September 2013

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Response

david a. WiLson, M.d., PeteR nakaji, M.d., FeLiPe c. aLbuqueRque, M.d.,

caMeRon G. McdouGaLL, M.d., josePh M. ZabRaMski, M.d., and RobeRt F. sPetZLeR, M.d.

Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona

We appreciate Dr. Macdonald’s thoughtful comments on our manuscript. The question of how long to wait for improvement following SAH is largely unanswered by the current literature, which focuses mostly on outcomes at 3 or 6 months. In the present study, we sought to better define the long-term time course of recovery following SAH. This is a question that has implications for patient caregivers and for the interpretation of SAH clinical tri-als.

Our data suggest that recovery following SAH oc-curs well beyond the 6-month time point and that indi-vidual recovery following SAH is a dynamic, long-term process that may occur over years. While all aggregate improvement of the entire cohort occurred within the first 6 months following SAH, individual improvement was seen in nearly 20% of patients between 6 months and 1 year and again between 1 and 3 years. Younger patients (< 65 years), those presenting with a better Hunt and Hess grade (IV vs V), and those without evidence of large (> 4 cm) or eloquent cerebral ischemia were more likely to improve. Improvement within 6 months did not predict improvement beyond 6 months, with some patients dem-onstrating no improvement until after the 6-month time point.

These data are important on 2 levels. First, the knowledge that some patients have the capacity to im-prove neurologically even more than 1 year after suffer-ing an SAH is significant for caregivers. Our data sug-gest that, unlike aggregate cohort outcomes, individual outcomes following SAH do not follow a clear trajectory. In some patients, improvement is early and subsequently plateaus, whereas in others a plateau may appear early but

a subsequent improvement is then seen. For patients, their families, and their caregivers, the possibility of individual recovery is more important than the trajectory of the co-hort as a whole in making long-term care decisions. Our study represents 1 step in better characterizing the nature of individual recovery following SAH and the factors as-sociated with long-term improvement.

Second, our data do raise some questions regard-ing the design of SAH trials. In the ideal world, the end point of a clinical trial would reflect the final outcome for the patient. If outcomes change substantially follow-ing the end point of a trial, either due to delayed recovery in some patients or the unforeseen long-term effects of a treatment, the validity of the study design may be called into question. Our data suggest that individual outcomes following SAH may change substantially following the 6-month time point. For this reason, at least in theory, an SAH trial based on outcome within 6 months may not reflect ultimate outcomes.

However, clinical trials do not take place in an ideal world, and Dr. Macdonald has pointed out some of the disadvantages of advocating for longer trials. Ultimately, effective trial design represents a trade-off between what is ideal and what is practical. We agree that longer trials may be prohibitively costly and unwieldy to conduct. Fur-thermore, we agree that in a trial comparing 2 treatments, a longer trial period would only matter if the treatment lines eventually crossed at some point. Our data did not demonstrate that the method of aneurysm treatment influ-enced the capacity for long-term recovery. However, it is also important to note, as Dr. Macdonald mentioned, that the initial differences in outcome between aneurysm clip-ping and coiling seen in ISAT and BRAT did not hold up over the long term. This reinforces the fact that examin-ing outcome at 6 months, or even 1 year, as the final mea-sure of treatment success or failure may be nearsighted. Ultimately, we agree that the optimal timing of outcome assessment depends on several factors, especially the spe-cific treatment question being addressed.

Please include this information when citing this paper: pub-lished online May 31, 2013; DOI: 10.3171/2013.1.JNS122368.