STASH: Simvastatin in Aneurysmal Subarachnoid Hemorrhage (2017)

“Among patients with aneurysmal subarachnoid hemorrhage, the use of simvastatin did not improve clinical outcomes at 6 months. These findings do not support the use of simvastatin for aneurysmal subarachnoid hemorrhage.”

— The STASH Investigators

1. Publication Details

  • Trial Title: Effect of Statin Treatment on Neurological Outcome in Patients With Aneurysmal Subarachnoid Hemorrhage: The STASH Randomized Clinical Trial.
  • Citation: Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD; for the STASH Collaborators. Effect of Statin Treatment on Neurological Outcome in Patients With Aneurysmal Subarachnoid Hemorrhage: The STASH Randomized Clinical Trial. JAMA. 2017;317(6):577-585. doi:10.1001/jama.2016.20336.
  • Published: February 14, 2017, in The Journal of the American Medical Association (JAMA).
  • Author: Peter J. Kirkpatrick, F.R.C.S.(SN).
  • Funding: The Stroke Association and the British Heart Foundation.

2. Keywords

Aneurysmal Subarachnoid Hemorrhage (aSAH), Simvastatin, Statins, Vasospasm, Delayed Cerebral Ischemia, Neurocritical Care.

3. The Clinical Question

In adult patients with aneurysmal subarachnoid hemorrhage (aSAH) (Population), does treatment with simvastatin (Intervention) compared to placebo (Comparison) improve functional neurological outcome at 6 months (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Delayed cerebral ischemia (DCI) due to vasospasm is a major cause of morbidity and mortality after aSAH. Statins, with their pleiotropic anti-inflammatory and endothelial-stabilizing effects, were thought to have the potential to prevent vasospasm and improve outcomes.
  • Knowledge Gap: Previous smaller trials and a meta-analysis had suggested a potential benefit of statin therapy in aSAH, but the evidence was inconclusive. A large, definitive, multicenter randomized trial was needed to confirm or refute this hypothesis.
  • Proposed Hypothesis: The authors hypothesized that treatment with simvastatin would improve long-term functional outcomes in patients with aSAH.

5. Study Design and Methods

  • Design: A prospective, multicenter, international, randomized, double-blind, placebo-controlled trial.
  • Setting: 35 neurosurgical centers in the United Kingdom, United States, Canada, and other countries.
  • Trial Period: Enrollment from May 2007 to February 2015.
  • Population:
    • Inclusion Criteria: Adult patients (18-65 years) with a CT-confirmed aneurysmal subarachnoid hemorrhage, able to start the trial drug within 96 hours of the ictus.
    • Exclusion Criteria: Known contraindications to statins, severe liver disease, or pre-existing dependency (modified Rankin Scale score >2).
  • Intervention: Simvastatin 40 mg, administered orally or via nasogastric tube once daily for up to 21 days.
  • Control: Matching placebo administered once daily.
  • Management Common to Both Groups: All patients received standard of care for aSAH, including aneurysm treatment (coiling or clipping) and nimodipine for vasospasm prophylaxis.
  • Power and Sample Size: The trial was powered to detect an 8% absolute difference in the rate of favorable outcomes, requiring 800 patients.
  • Outcomes:
    • Primary Outcome: Favorable functional outcome at 6 months, defined as a modified Rankin Scale (mRS) score of 0-2.
    • Secondary Outcomes: Included mortality, incidence of delayed cerebral ischemia, need for rescue therapy for vasospasm, and distribution of mRS scores.

6. Key Results

  • Enrollment and Baseline: 803 patients were randomized (393 to simvastatin, 410 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the rate of favorable functional outcome (mRS 0-2) at 6 months between the simvastatin and placebo groups (63.0% vs 65.5%; P=0.47).
  • Secondary Outcomes: There were no significant differences between the groups in mortality, the incidence of delayed cerebral ischemia, or the need for rescue therapy.
  • Adverse Events: The rates of adverse events, including elevated liver enzymes and creatine kinase, were similar between the two groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a logistic regression model, adjusted for key prognostic factors.
  • Primary Outcome Analysis: The proportion of patients with a favorable mRS score at 6 months was compared between the two groups.
  • Key Statistic(s) Reported: Adjusted Odds Ratio (aOR) for favorable outcome with simvastatin: 0.92 (95% CI, 0.67 to 1.25; P=0.58).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR): An aOR of 0.92 suggests a slight (8%) but non-significant decrease in the odds of a favorable outcome with simvastatin.
    • Confidence Interval (CI): The 95% CI widely crosses 1.0 (from a 33% reduction to a 25% increase in odds), indicating no statistically significant difference.
    • P-value: The p-value of 0.58 confirms the lack of a statistically significant difference.
  • Clinical Impact Measures: Not applicable as no benefit was shown for the primary outcome.
  • Subgroup Analyses: No significant treatment effects were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, international, multicenter, randomized, double-blind, placebo-controlled trial, representing the highest level of evidence.
  • Generalizability: The inclusion of 35 diverse neurosurgical centers increases the external validity of the findings.
  • Patient-Centered Outcomes: The primary outcome of 6-month functional status (mRS) is the standard, patient-centered endpoint for this type of trial.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The trial excluded patients over the age of 65, which may limit the generalizability of the findings to an older population.
  • Other: The rate of favorable outcomes in the placebo group was higher than anticipated, which can make it more difficult to show a benefit from an intervention.

10. Conclusion of the Authors

“Among patients with aneurysmal subarachnoid hemorrhage, the use of simvastatin, 40 mg/d, did not improve clinical outcomes at 6 months. These findings do not support the use of simvastatin for aneurysmal subarachnoid hemorrhage.”

11. To Summarize

  • Impact on Current Practice: This was a definitive “negative” trial that effectively ended the practice of routinely prescribing statins to patients with aSAH for the purpose of preventing vasospasm and improving outcomes. It demonstrated that, despite a plausible biological mechanism and promising smaller studies, this intervention was not effective.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute aneurysmal subarachnoid hemorrhage.
    • Actionable Intervention: Do not initiate simvastatin (or other statins) for the specific indication of improving neurological outcomes after aSAH.
    • Expected Benefit: No benefit was demonstrated.
  • What This Trial Does NOT Mean: This trial does not mean that patients who are already on a statin for a pre-existing condition (e.g., hyperlipidemia) should have it stopped after an aSAH. The trial only addressed the initiation of statins for the acute event.
  • Implementation Caveats: The findings provide a clear recommendation against a specific, previously common off-label practice.

12. Context and Related Studies

  • Building on Previous Evidence: The STASH trial was designed to be the definitive study to confirm or refute the promising but inconclusive findings from a 2007 Cochrane meta-analysis of smaller, single-center trials.
  • Influence on Subsequent Research: As a large and methodologically robust negative trial, STASH has largely closed the door on this specific line of inquiry. Future research into secondary injury after aSAH has shifted to focus on other mechanisms, such as cortical spreading depolarization and neuroinflammation.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Does statin therapy have any role in older patients (>65 years) with aSAH, who were excluded from this trial?
  • Future Directions: The search for effective therapies to prevent delayed cerebral ischemia and improve outcomes after aSAH continues, but the focus has moved away from statins.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, testing a widely available and inexpensive drug for a devastating neurological condition.
  • Methods: The study’s design was of the highest quality: a large, international, multicenter, double-blind, placebo-controlled RCT.
  • Results: The trial had a clear and robustly negative result for its primary, patient-centered outcome. There was no signal of benefit in any secondary outcome or subgroup.
  • Conclusions and Applicability: The authors’ conclusion is a direct and definitive interpretation of the data. The results are highly applicable to the care of aSAH patients under 65 and provide a strong evidence-based recommendation to abandon this practice.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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