Effects of Acute Treatment With Pravastatin on Cerebral Vasospasm, Autoregulation, and Delayed Ischemic Deficits After Aneurysmal Subarachnoid Hemorrhage

Abstract

Background and Purpose-Statins may improve cerebral vasomotor reactivity through cholesterol-dependent and -independent mechanisms. A phase II randomized controlled trial was conducted to examine the hypothesis that acute pravastatin treatment could improve cerebrovascular autoregulation and reduce vasospasm-related complications after aneurysmal subarachnoid hemorrhage (SAH). Methods-A total of 80 aneurysmal SAH (aSAH) patients (18 to 84 years of age) within 72 hours from the ictus were randomized equally to receive either oral pravastatin (40 mg) or placebo daily for up to 14 days. Primary end points were the incidence, duration, and severity of cerebral vasospasm, and duration of impaired autoregulation estimated from transcranial Doppler ultrasonography. Secondary end points were the incidence of vasospasm-related delayed ischemic deficits (DIDs) and disability at discharge. Results-Prerandomization characteristics were balanced between the 2 groups. No treatment-related complication was observed. The incidences of vasospasm and severe vasospasm were reduced by 32% (Pϭ0.006) and 42% (Pϭ0.044), respectively, and the duration of severe vasospasm was shortened by 0.8 days (Pϭ0.068) in the pravastatin group. These measurements were maximal on the ipsilateral side of ruptured aneurysms. The duration of impaired autoregulation was shortened bilaterally (PՅ0.01), and the incidence of vasospasm-related DIDs and mortality were decreased by 83% (PϽ0.001) and 75% (Pϭ0.037), respectively, in the pravastatin group. Conclusion-Acute treatment with pravastatin after aSAH is safe and ameliorates cerebral vasospasm, improves cerebral autoregulation, and reduces vasospasm-related DID. Unfavorable outcome at discharge was reduced primarily because of a reduction in overall mortality. This is the first demonstration of clinical benefits with immediate statin therapy for an acute cerebrovascular disorder. (Stroke. 2005;36:1627-1632.)

Statins in Traumatic Brain Injury

“…In 2005, Lynch et al 42 found that simvastatin (80 mg daily for 14 days) reduced the incidence of vasospasm and biomarker surrogates of endothelial dysfunction and CNS inflammation. These results were concordant with the study by Tseng et al, 75 who demonstrated that pravastatin (40 mg daily for 14 days) improved surrogate measures of vasospasm and functional outcomes. Two other small prospective studies also demonstrated safety and feasibility of statin use in SAH, but did not show statistically significant improvement in vasospasm, delayed ischemic deficit, or functional outcomes.…”

“…87 However, neuroprotection has been demonstrated even with hydrophilic statins, such as rosuvastatin 67 and pravastatin, 75 presumably due to vascular and anti-inflammatory effects, although breach of the BBB is common after acute brain injury. In fact, the pilot trials evaluating statins in SAH used both lipophilic and hydrophilic statins (simvastatin 42 and pravastatin, 75 respectively), with a similar decrease in cerebral vasospasm. It is not known whether potency or the ability of a particular statin to lower cholesterol is important in the setting of neuroprotection.…”

Microthrombosis after Aneurysmal Subarachnoid Hemorrhage: An Additional Explanation for Delayed Cerebral Ischemia

“…The results of these trials were impressive, as acute statin treatment decreased the incidence of not only vasospasm, but also of DCI and mortality (Lynch et al, 2005;Tseng et al, 2005Tseng et al, , 2007. Statins may be an interesting treatment option in patients with SAH as statins possibly not only decrease the incidence of vasospasm, but also reduce plasma levels of vWF, indicating decreased endothelial activation (Lynch et al, 2005;Tseng et al, 2005). Furthermore, statins have been shown to enhance fibrinolysis and inhibit blood coagulation (Krysiak et al, 2003).…”

Cerebral Autoregulation after Subarachnoid Hemorrhage: Comparison of Three Methods

“…It has been described that cerebral autoregulation may become disturbed after subarachnoid hemorrhage (SAH), [1][2][3][4][5][6][7] which has been associated with development of delayed cerebral ischemia (DCI). 1,2,[5][6][7][8][9] The transient hyperemic response test (THRT) is a transcranial Doppler (TCD) based method, which characterizes the changes in cerebral blood flow velocity (FV) after a brief compression of the common carotid artery. It is a recognized and simple method of testing autoregulation in vivo.…”

“…It is a recognized and simple method of testing autoregulation in vivo. 2,6,8,[10][11][12][13][14][15][16][17][18] It is directly proportional to the static rate of autoregulation, which is the 'gold standard' for measuring autoregulation, 15 and it has been shown to be predictive of DCI after SAH. 2,6 However, other ways of measuring autoregulation that do not require physical or pharmacological blood pressure stimulation have been described.…”