Published online before print December 22, 2005, doi: 10.1161/01.STR.0000199666.44942.41
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(Stroke. 2006;37:335.)
© 2006 American Heart Association, Inc.
Letters to the Editor |
Is There an Interaction Between Pravastatin and Clinical Events Other Than Vasospasm in Patients With Aneurysmal Subarachnoid Hemorrhage?
Division of Neurosurgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong
To the Editor:
We would like to congratulate Tseng et al1 for the article titled "Effects of acute treatment with Pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: A phase II randomized placebo-controlled trial". The authors hypothesized that statins might improve cerebral vasomotor activity through cholesterol-dependent and -independent mechanisms. They randomized aneurysmal subarachnoid hemorrhage patients (18 to 84 years of age) within 72 hours from the ictus to receive either oral pravastatin (40 mg) or placebo daily for up to 14 days. They were able to show a decrease in incidence of vasospasm, duration of severe vasospasm, duration of impaired autoregulation, incidence of vasospasm-related delayed ischemic deficits and mortality with pravastatin treatment impressively in this 80-patient study.
The authors’ center had a clipping to coiling ratio of 4 to 1 for patients with aneurysmal subarachnoid hemorrhage. The authors reported a ventriculitis rate of 30% in statin group versus 17.5% in the placebo group, an immediate postoperative deficit of 22.5% in statin group versus 7.5% in placebo group, as well as a sepsis rate of 27.5% in the statin group versus 15% in the placebo group. The events seemed to double in all 3 categories in the statin group though not reaching statistical significance in this 80-patient study. That raised the puzzle whether it would be related to use of statins or other unspecified factors. Studies2,3 had suggested that prior statin-use might be related to a lower in-hospital infection rate and a lower C-reactive protein level. Little is known about the acute effect on sepsis after initiating statins. Would it actually be more sepsis? Clarification of the clinical events above may provide information to suggest a possible similar, neutral, or contradictory effect on sepsis.
The authors noted a significant higher mortality rate of 20% in the placebo group versus 5% in the statin group. It would be of interest to know contributing causes of the mortality, whether it would be related to vasospasm or other events as sepsis or cardiovascular events. A secondary analysis to see a relationship between total and LDL cholesterol levels on presentation and outcome might also be helpful to indicate the direction of statin research in aneurysmal subarachnoid hemorrhage in the future.
References
- Tseng MY, Czosnyka M, Richards H, Pickard J, Kirkpatrick PJ. Effects of acute treatment with Pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: a phase II randomized placebo-controlled trial. Stroke. 2005; 36: 1627–1632.
[Abstract/Free Full Text] - Albert MA, Danielson E, Rifai N, Ridker PM; PRINCE Investigators. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomised trial and cohort study. JAMA. 2001; 286: 64–70.
[Abstract/Free Full Text] - Almog Y, Shefer A, Novack V, Maimon N, Barski L, Eizinger M, Friger M, Zeller L, Danon A. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation. 2004; 110: 880–885.
[Abstract/Free Full Text]
Response:
Department of Neurosurgery, Addenbrooke’s Hospital, University of Cambridge, United Kingdom
We would like to thank Dr Wong and Professor Poon for addressing the detrimental factors (immediate postoperative deficits, sepsis, and ventriculitis) which affected clinical outcome during the trial. Because immediate postoperative deficits and ventriculitis were closely associated with invasive neurosurgical procedures,1,2 we believe that the imbalance between the pravastatin and placebo groups was a consequence of a relatively small sample size rather than any side effect of medication.
Although the severity of infection was not quantified, sepsis was more frequent in the pravastatin group.3 However, the duration of noradrenaline use for sepsis-related hypotension seemed shorter in the pravastatin group (placebo versus pravastatin, 7.0±5.3. versus 3.7±3.2 days; P=0.07) indicating a more rapid resolution of profound sepsis. These features did not raise major concern as to the potential for statin therapy to increase the incidence of significant sepsis. However, septic complications will need to be carefully scrutinized as part of a clinical phase III trial.
Our results also showed that acute pravastatin treatment reduced overall mortality in patients with subarachnoid hemorrhage.3 The causes of the 8 deaths in the placebo group included 5 cases of cerebral infarction caused by vasospasm-related delayed ischemic deficits. None of the 2 deaths in the pravastatin group were related to vasospasm, and acute pravastatin therapy seemed to reduce vasospasm-related mortality (placebo versus pravastatin, 12.5% versus 0, log-rank test P=0.02). However, there is little doubt in our minds that despite these encouraging findings, issues such as those raised in this discussion need to be addressed by conducting a large (Phase III) trial.
References
- Ogilvy CS, Carter BS, Kaplan S, Rich C, Crowell RM. Temporary vessel occlusion for aneurysm surgery: risk factors for stroke in patients protected by induced hypothermia and hypertension and intravenous mannitol administration. J Neurosurg. 1996; 84: 785–791.[Medline] [Order article via Infotrieve]
- Hasan D, Vermeulen M, Wijdicks EF, Hijdra A, van Gijn J. Management problems in acute hydrocephalus after subarachnoid hemorrhage. Stroke. 1989; 20: 747–753.
[Abstract/Free Full Text] - Tseng MY, Czosnyka M, Richards H, Pickard J, Kirkpatrick PJ. Effects of acute treatment with Pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: A phase II randomized placebo-controlled trial. Stroke. 2005; 36: 1627–1632.
[Abstract/Free Full Text]
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