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Nerovascon sash trial-oct-2011
1. SIMVASTATIN IN ANEURYSMAL
SUBARACHNOID HEAMORRHAGE
(SASH) TRIAL
Sumit Sinha
Department of Neurosurgery, All India Institute of Medical Sciences,
New Delhi, India
6. SASH TRIAL
Aims-
To assess the role of simvastatin
•in preventing and ameliorating vasospasm
and ischemic sequelae after aneurysmal
SAH;
•improving the functional outcome in these
patients at follow up.
7. SASH TRIAL
Material and Methods
•STUDY DESIGN
Prospective, randomized, double-blind,
placebo-controlled pilot trial
Institutional Ethical committee approval taken
Period of Study – December 2008- July 2010
8. SASH TRIAL
Material and Methods (Contd.)-
Inclusion Criteria
•> 18 years
•SAH on CT at admission.
•Saccular aneurysm proven by 3D-DSA/ CTA
•Surgical aneurysm obliteration.
•< 96 hours of ictus.
•Informed consent available
9. SASH TRIAL
Material and Methods (Contd.)
Exclusion criteria
•Contra-indication for Simvastatin use.
•Hunt and Hess Grade V.
•Vasospasm on Initial diagnostic DSA.
•Patients already on HMG-CoA reductase inhibitor.
•Severe chronic renal failure (S Creat >3/ BUN > 40),
elevated liver function tests (>3 times normal) and h/o
liver disease or active liver disease.
•Re-exploration because of ischemic sequelae.
•Pregnancy
10. SASH TRIAL
Material and Methods (Contd.)
Patient randomization
•by the Biostatistics department
•Patients received either the placebo or Simvastatin- 80 mg
once a day for 14 days.
•Both the drug and placebo were prefilled into similarly
appearing capsules by personnel not involved in the study
group, and packaged in similar envelopes numbered
consecutively according to the randomization charts.
•All the treating neurosurgeons and the investigators
blinded to the treatment group.
11. SASH TRIAL
Material and Methods (Contd.)
•All the patients were operated by
neurosurgeons with more than five years of
surgical experience in aneurysm surgery
12. SASH TRIAL
Material and Methods (Contd.)
Work up
•All routine investigations
•Liver transaminases and creatine phosphokinase
(CPK)- once at admission and weekly
•Drug induced hepatitis- S alanine
aminotransferase or aspartate aminotransferase
>3-fold normal (>180 U/L)
•Drug induced myositis- S CPK > 1000 U/L.
13. SASH TRIAL
Material and Methods (Contd.)
Primary outcome measures-
•Clinical vasospasm-
– new ischemic neurologic deficits
– angiographic vasospasm
– TCD velocities >160m/sec.
Secondary outcome measures-
•Glasgow Outcome Score (GOS), Modified Rankin Scale
(MRS) and Barthel Index Score (MBI) at follow up at 1,
3 and 6 months.
14. SASH TRIAL
Trial tree 150 patients screened for study
eligibility
38 patients randomized
19 patients randomized
to simvastatin group
19 patients randomized
to placebo group
Drug discontinued in 2
patients due to > 3
fold rise in SGOT/PT
Drug discontinued in
1 patient due to > 3
fold rise in SGOT/PT
17 patients completed
14 day drug trial and 6
month follow up
18 patients completed
14 day drug trial and 6
month follow up
15. SASH TRIAL
Patient characteristic Group 1 (Drug) Group 2 ( Control) p- value
No of patients 17 18
Mean age (yrs) 48.94 48.61 0.1
No of females (%) 7 (41.2 %) 8 (44.4%) 0.85
No of patients with GCS score 15 at the
time of admission
15 16 0.39
No of patients with motor deficit at the
time of admission
0 0 0
Coexistent unruptured aneurysm 0 1 (5.6%) 0.32
No of patients with ictal loss of
consciousness
5 (29.4%) 10 (55.6%) 0.12
HTN 7 (41.2%) 7 (38.9%) 0.89
DM 0 2 (11.1%) 0.23
COPD 0 0 0.22
Intracerebral hematoma 1 0
RESULTS- Patient Data
18. SASH TRIAL
Group 1 (Drug)
(n=17)
Group 2
( Control)
(n=18)
P value Relative
Risk (RR)
Neurological
deterioration
5 (29.4%) 8 (44.4%) 0.36 0.65
Mortality 1 3 0.23 0.29
High MCA velocity 3 (17.6%) 5 (27.8%) 0.48 0.64
No of days with velocity
> 160 cm/sec
5 +/- 1.6 19 +/- 2.3 0.17
RESULTS- Clinical vasospasm and Neurological deterioration
19. SASH TRIAL
Parameter 1 month 3 month 6 months
GOS Group 1 (Drug) N=17 4.18 +_1.015 4.29 +_ 1.047 4.47 +_ 1.057
Group 2 (Control) N=18 3.61 +_1.406 4.06 +_ 1.425 4.13 +_ 1.519
P value .144 .627 .131
1 month 3 month 6 month
MRS Group 1 (Drug) N=17 1.13 +_ .885 1.07+_ .223 .86 +_1.18
Group 2 (Control) N=18 1.67+_ .404 1.19 +_ .911 1.00 +_ .033
P value .082 .497 .885
1 month 3 month 6 month
MBI Group 1 (Drug) N=17 80.56 +_12.23 82.56 +_10.62 85.59+_10.589
Group 2 (Control) N=18 73.80+_22.174 82.07+_12.55 84.43+_13.11
P value .075 .871 .838
Comparison of functional outcome parameters in
two groups
20. SASH TRIAL
Author/ year Statin Used Sample size Statin effect
McGirt et al; 2002 SVS Mice- 34/36 increased MCA
diameter,
fewer deficits
McGirt et al., 2006 SVS Rabbit- 5/5 increased BA
diameter
Bulsara et al., 2006 SVS Dogs- 4/5 increased BA diameter
DISCUSSION-
Animal Studies
21. SASH TRIAL
DISCUSSION-
Retrospective cohort studies
Author/ year Statin Used Sample size Statin effect
Parra et al., 2005 any/multiple 20/40 decreased incidence sx VSP
Singhal et al., 2005 any/multiple 37/478 no effect on incidence sx VSP
McGirt et al., 2006 any/multiple 15/100 decreased incidence sx VSP
Moskowitz et al.,
2008
any/multiple 26/282 non-significant decreased incidence
sx VSP
Kramer et al., 2008 any/multiple 71/79 no effect on incidence sx VSP
22. SASH TRIAL
DISCUSSION-
Prospective Study
•Simvastatin did not reduce the incidence of
symptomatic cerebral vasospasm, death, or poor
outcome in patients with aSAH.
•Simvastatin was well tolerated, but its benefit may
be less than has been previously reported.
*McGirt MJ et al. J Neurosurg 2009 May;110(5):968-74
23. SASH TRIAL
DISCUSSION-
Randomized trials
Author/ year Statin Used Sample size Statin effect
Lynch et al., 2005 SVS 19/20 decreased incidence sx VSP
Tseng et al., 2005 PVS 40/40 decreased incidence sx VSP
Chou et al; 2008 SVS 19/20 no clear support for benefit. larger
study is needed
24. SASH TRIAL
DISCUSSION-
Meta-Analysis/ Systematic Review
•*Statins reduce vasospasm, DCI and mortality in
aSAH
•**No statistically significant support of beneficial
effect of statins in aSAH
*Sillberg VA et al. Stroke. 2008;39:2622-2626
**Vergouwen MDI et al. Stroke. 2010;41:e47-e52
25. SASH TRIAL
STASH TRIAL
•Multi-centre placebo controlled double blinded
phase III trial assessing the clinical benefit of
SimvaSTatin in Aneurysmal Subarachnoid
Haemorrhage (STASH).
Total patients enrolled 460
Further patients required 340
26. SASH TRIAL
Conclusions
•The incidence of vasospasm, neurological
deterioration, mortality and functional outcome is
lower in statin group, in absolute numbers
•A possible benefit of statins cannot be excluded
•In future, large scale Phase III studies needed to
provide definite answer
