Effects of Acute Pravastatin Treatment on Intensity of Rescue Therapy, Length of Inpatient Stay, and 6-Month Outcome in Patients After Aneurysmal Subarachnoid Hemorrhage
Background and Purpose— We have previously demonstrated that acute pravastatin therapy after aneurysmal subarachnoid hemorrhage ameliorates vasospasm-related delayed ischemic deficits. This study assesses the effects of pravastatin on the frequency and intensity for rescue therapy, length of inpatient stay, and long-term outcome at 6 months.
Methods— Eighty aneurysmal subarachnoid hemorrhage patients (age 18 to 84 years, onset 1.8±1.3 days) were randomized to receive daily oral pravastatin (40 mg) or placebo for up to 14 days. Clinical events were recorded during the trial. Six-month outcome was assessed using the Short Form 36 and the modified Rankin Scale.
Results— Although no significant difference in the outcome at discharge was found between the trial groups, multivariate analysis showed pravastatin therapy reduced unfavorable outcome by 73% (P=0.041). The benefit persisted at 6 months (P=0.063) and was notable in the physical (P<0.001) and psychosocial (P<0.001) aspects measured using Short Form 36. Furthermore, the acute pravastatin therapy reduced the requirement for triple-H therapy (hypertensive, hypervolemic, hemodilution; P=0.045) and mortality related to vasospasm (P=0.02) and sepsis (P=0.001); no significant difference was found in the length of inpatient stay between the trial groups.
Conclusions— This trial demonstrates that acute statin treatment reduces traditional rescue therapy for vasospasm after aneurysmal subarachnoid hemorrhage. Improvement in early outcome has proved robust at 6 months, particularly in relation to physical and psychosocial (Short Form 36) outcome.
Aneurysmal subarachnoid hemorrhage (aSAH) is of clinical and socioeconomic importance. In the UK, the annual incidence is estimated as 8 per 100 000 people, or around 5000 patients per year.1 Although accounting for only 5% of all strokes, aSAH disproportionately affects the young and has an enormous impact on productive life, most prominently in the psychosocial domain.2 Despite considerable advances in diagnosis and treatment, high rates of death and disability still occur, particularly when cerebral vasospasm results in delayed ischemic deficits (DIDs).3 According to a recent national audit within the UK, in addition to DIDs, the outcome after SAH is determined by clinical events including hydrocephalus, inpatient sepsis, and coexisting morbidities (hypertension, ischemic heart disease).1 After successful intervention, only 47% of patients are discharged directly to home, whereas the majority (53%) need further stays in referring hospital or rehabilitation units. Overall, unfavorable outcome reaches 50% which equates to 2500 patients either dying or sustaining severe disability in Britain every year.1
We have previously demonstrated that acute treatment with pravastatin improves impaired autoregulation, ameliorates cerebral vasospasm, reduces the incidence of DIDs, and decreases mortality after aSAH.4 In this study we assess whether these early beneficial effects have been translated into reductions in the need for rescue therapy, and whether there are impacts on the length of inpatient stay. Finally, we examine the durability of the short-term improvement by assessing long-term outcome at 6 months.
Materials and Methods
Data relating to clinical events were extracted from the pravastatin trial.4 Approval was granted from the Local Research Ethics Committee (LREC No. 03/353) and the Medicines and Healthcare Products Regulatory Agency (MHRA No. MF/8000/13164). Eighty adult aSAH patients (age from 18 to 84 years) admitted to the Department of Neurosurgery, Addenbrooke’s Hospital, were randomized (double-blind) equally to receive either daily pravastatin sodium 40 mg (Lipostat, Bristol-Myers Squibb.) or placebo (lactose) for up to 14 days. Trial medications were commenced within 72 hours of the bleed. Baseline data included age, gender, medical history, and initial aSAH grade according to the World Federation of Neurological Surgeons (WFNS).5 Radiological information included the Fisher grade on CT,6 presence of hydrocephalus or intraventricular hemorrhage, and aneurysm location on cerebral angiography. Exclusion criteria were nonaneurysmal SAH, pregnancy, preictal statin therapy and contraindications to statin use (eg, history of liver or renal dysfunction, alanine aminotransferase >50 U/L).
After admission, the clinical management of each patient was standardized, including 60 mg oral nimodipine every 4 hours and moderate intravenous fluid supplement (0.9% saline 3 L/d). Daily transcranial Doppler was adopted for measuring vasospasm and assessing cerebral autoregulation. When there were clinical indications for continuous bedside monitoring, patients were admitted to the Neurosciences Critical Care Unit (NCCU). Catecholamines, including noradrenaline and dopamine, were used either for triple-H therapy (hypertensive, hypervolemic, hemodilution) during symptomatic vasospasm or for controlling septic shock.7,8 Sepsis was defined prospectively according to the American College of Chest Physicians/Society of Critical Care Medicine Consensus.8 None of the patients underwent endovascular angioplasty for vasospasm. Factors that might have affected the outcome were documented, including ventriculitis, sepsis, modes of aneurysm treatment (endovascular versus clipping), operating neurosurgeons, and immediate postoperative deficits. History of smoking, medications, and chronic systemic illnesses were also recorded.
DIDs were defined as development of focal neurological deficits or a drop in the Glasgow Coma Scale by 2 points or more.9 DIDs were defined as vasospasm-related if it was associated with vasospasm on transcranial Doppler. Other possible conditions causing neurological deterioration (eg, hydrocephalus, intracerebral hemorrhage, surgical complications, metabolic abnormalities, or infection) were excluded by repeated imaging (CT, xenon CT, or cerebral angiography) and metabolic screening.
At discharge, the outcome was assessed according to the modified Rankin Scale (mRS).10 Favorable outcome was defined as mRS 1 or 2, unfavorable outcome mRS 3 to 6. At 6 months, arrangements were made for patients to return to the outpatient clinic where the outcome was assessed by an independent neurosurgeon (P.J.H.) blinded to randomization. Assessment of health-related quality-of-life using the Short Form 36 (SF-36) questionnaire was undertaken at the same time. The SF-36 scores were also divided into 2 broad areas of subjective well-being, namely the physical and the psychosocial health.11,12 At follow-up patients were still blind to their treatment allocations.
All analyses were performed on an intention-to-treat basis, and probability values were 2-sided. Data were presented as mean±SD and 95% CI. Analysis was performed using statistical software, STATA Intercooled 8.0 for Windows. Data were compared between the pravastatin and placebo groups. Pre- and postrandomization characteristics were compared using the χ2 test (the Fisher exact test was used when any number of the cell was <5), except the age, where the t test was used. The incidence of rescue therapy was analyzed as time-to-event and the log-rank test was used. The t test was used to compare the durations of rescue therapy, lengths of inpatient stay, and scores of SF-36.
Stepwise multiple logistic or linear regression analysis was applied to determine the factors that might be considered independent predictors of unfavorable outcome and scores of SF-36, whereas a significance level of 0.05 was chosen for variable entry into the model. The odds ratio (OR) and linear coefficient were calculated and presented with 95% CI. P<0.05 was considered statistically significant.
During the period of 2004, 86 patients with aSAH were approached; 6 of them were excluded because of pregnancy in 1, concurrent statin therapy in 2, abnormal liver function in 2, and refusal to participate in 1. The remaining 80 patients were recruited and randomized.
Patients averaged 52.9 (±12.0) years (range 19 to 84 years), included 36 males (45.0%) and 44 females (55.0%). Most were of good-grade (WFNS grade 1 to 3, 67.5%), Fisher grade 3 or 4 (86.3%), or with hydrocephalus (57.5%). Some had intraventricular hemorrhage (25%). Comorbidities included hypertension (23.8%), diabetes mellitus (5.0%), and history of ischemic heart disease (5.0%). Twenty patients (25.0%) were smokers, including 2 ex-smokers who just quit within 1 year (1 placebo and 1 pravatstain). Four patients (5.0%) were taking angiotensin-converting enzyme inhibitors for controlling hypertension, whereas 10 patients (12.5%) had aspirin for history of ischemic heart disease or deep vein thrombosis (Table 1).
After randomization, 32 patients had insertions of external ventricular drainage, and 19 of them developed ventriculitis. Among the culprit aneurysms, the anterior communicating artery was the most common location (32.5%), followed by the middle cerebral artery (25.0%). Most patients underwent craniotomy for clipping (65.0%), whereas some underwent coiling (16.25%). Very poor grade patients were untreated or received delayed treatment after 2 weeks (18.8%). Twelve patients experienced immediate postoperative deficits. The middle cerebral artery aneurysm had the most frequent surgical complications (mean complication rate 30%; 95% CI, 9.9 to 50.1; P=0.030). Seventeen patients developed sepsis from pneumonia or catheter-related infections (21.25%).
Trial medications were commenced within 1.8±1.3 days (95% CI, 0 to 4.3 days) of the bleed. Thirty-eight patients (47.5%) completed the 14-day trial. Of the remainder, 30 patients (37.5%) were well enough to be discharged early, 10 died (12.5%), and premature withdrawal occurred in 2 patients (2.5%). All 80 patients were included for final analysis.
Prerandomization characteristics, including age, gender, WFNS grade, Fisher grade, hydrocephalus, intraventricular hemorrhage, location of aneurysm, smoking, medications (angiotensin-converting enzyme inhibitors and aspirin), and history of chronic systemic illnesses (systemic hypertension, diabetes mellitus, ischemic heart disease) were well balanced between the trial groups (Table 1). Factors which may have affected the outcome after randomization, including insertions of external ventricular drainage, ventriculitis, interventions, immediate postoperative deficits, operating neurosurgeons, and sepsis, were also well balanced between the trial groups, though there seemed to be more patients in the pravastatin group experiencing external ventricular drainage–related ventriculitis (30.0% compared with 17.5%; P=0.189), immediate postoperative deficits (22.5% compared with 7.5%; P=0.115), or sepsis (27.5% compared with 15.0%; P=0.176). But none of them was significant by the log-rank test (Table 2).
The proportion of patients receiving triple-H therapy in this study was 27.5%. The incidence of receiving the triple-H therapy was significantly reduced from 37.5% (95% CI, 22.5 to 52.5) to 17.5% (95% CI, 5.72 to 29.28; P=0.045, Figure) in the pravastatin group. The average duration of using triple-H therapy was 1.1±2.3 days (95% CI, 0.6 to 1.6 days) with no difference between the trial groups.
The proportions of patients receiving noradrenaline and dopamine were 43.8% and 35.0%, respectively. The average durations of using noradrenaline and dopamine were 2.0±3.3 days (95% CI, 1.2 to 2.7 days) and 1.4±2.6 days (95% CI, 0.8 to 2.0 days), respectively. However, no difference was shown between the trial groups.
Length of Inpatient Stay
Fifty-five patients were admitted to NCCU, an admission rate 68.75%. For the whole study population the average lengths of stay in hospital, NCCU, and ward were 25.0±24.4 (95% CI, 19.6 to 30.4), 10.8±16.5 (95% CI, 7.1 to 14.4), and 15.5±15.8 (95% CI, 12.0 to 19.0) days, respectively. After exclusion of deaths, the average lengths of stay were 27.3±25.2 (95% CI, 21.3 to 33.3), 11.1±17.5 (95% CI, 6.9 to 15.3), and 17.7±15.7 (95% CI, 13.9 to 21.4) days, respectively. There was no difference in the length of stays in hospital, NCCU or ward between the trial groups.
Outcome at Discharge
At discharge, 50 patients were independent and had favorable outcome (62.5%). No significant difference in the mRS scores was found between the trial groups, though there was a tendency toward reduced disability in the pravastatin group. Multivariate analysis identified WFNS grade (OR 2.37/grade; 95% CI, 1.46 to 3.83/grade; P<0.001), immediate postoperative deficits (OR 7.06; 95% CI, 1.06 to 47.16; P=0.044), and sepsis (OR 38.69; 95% CI, 3.66 to 408.52; P=0.002) as variables which increased disability at discharge, whereas pravastatin therapy was associated with a 73% decrease (OR 0.27; 95% CI, 0.08 to 0.95; P=0.041; Table 3, upper).
Ten patients died during hospitalization. Causes of the 8 deaths in the placebo group included 5 from vasospasm-related DIDs. None of the 2 deaths in the pravastatin group were related to vasospasm. In addition to a reduction in mortality for all causes by 75% (log-rank test P=0.037), acute pravastatin therapy reduced mortality related to vasospasm (0 compared with 12.5%, log-rank test P=0.02) or sepsis (6.25% compared with 71.43%, log-rank test P=0.001).
Outcome at 6 Months
At 6 months, 53 patients achieved a favorable outcome (66.25%) and there was no difference between the trial groups. Multivariate analysis identified immediate postoperative deficits (OR 6.04; 95% CI, 1.02 to 35.82; P=0.048), sepsis (OR 11.27; 95% CI, 2.93 to 43.40; P<0.001), and hydrocephalus (OR 4.75; 95% CI, 1.26 to 17.91; P=0.021) as variables which increased disability at 6 months, whereas pravastatin was associated with a 71% reduction (OR 0.29; 95% CI, 0.08 to 1.07; P=0.063; Table 3, lower). Likewise, pravastatin reduced 6-month mortality by 88% (OR 0.12; 95% CI, 0.02 to 0.69; P=0.018), with inpatient sepsis being a durable factor associated with deaths at 6 months (OR 13.25; 95% CI, 2.52 to 69.71; P=0.002).
Results From SF-36 Questionnaire
Sixty questionnaires were completed and returned from the 69 survivors, giving a response rate of 87.0%. When individual dimensions were compared, there was no significant difference between the trial groups. Multivariate analysis revealed that pravastatin therapy was associated with an improved physical (coefficient 0.06, 95% CI, 0.03 to 0.10; P<0.001) and psychosocial score (coefficient 0.19; 95% CI, 0.15 to 0.22; P<0.001; Table 4).
Clinical Benefits From Acute Statin Therapy
We have previously reported that acute pravastatin therapy after aSAH significantly reduced the incidence, duration, and severity of cerebral vasospasm, improving autoregulation. These pathophysiological gains were associated with early improvements in the incidence and intensity of vasospasm-related DIDs and early mortality.4 The current report demonstrates further gains in both the short- and long-term. Although the study design was not powered to detect clinical improvements and the incidence of sepsis, external ventricular drainage–related ventriculitis, and immediate postoperative deficits seemed to be higher in the pravastatin group, multivariate analyses highlighted the pravastatin therapy as the only independent predictor of improved outcome at discharge and at 6 months. Therefore, these complications, frequently seen after invasive procedures or monitoring among aSAH patients,13–16 were more likely to be associated with the randomization effect of this small trial.
Effects on Rescue Therapy
Subarachnoid blood-induced inflammation has been found to play a pivotal role in the pathogenesis of vasospasm and depletes nitric oxide derived from the endothelial nitric oxide synthase.17,18 Furthermore, sepsis and systemic inflammatory response syndromes are known to be associated with the occurrence of vasospasm, and the increased metabolic demand with sepsis potentially aggravates processes of cerebral ischemia.16 Statin therapy may counteract these events by inhibiting the C-reactive protein and lipopolysaccharide-induced inflammatory cascades.19 Furthermore, other pleiotropic effects of statins have been demonstrated to minimize the risk of sepsis-related multiorgan failure.20
Induced hypertension using catecholamines has been used as rescue therapy for cerebral ischemia.3 However, this approach may be followed by serious complications, including pulmonary edema, myocardial infarction, and catheter-related sepsis.21 Recent clinical studies have suggested that pretreatment with statins could reduce the risk and severity of sepsis and therefore could be incorporated into the management in preventing sepsis.20,22,23
Effects on Inpatient Stay and Hospital Resources
Previous analysis in the cost containment for treating patients with aSAH have shown that the highest resource consumption occurs in treating patients with vasospasm and the main expenditures are seen in the intensive care setting.24 Although the overall inpatient stay for survivors was not different between the treatment arms, the implication is that the statin treatment was associated with substantial cost savings by reducing the intensity of inpatient requirements for managing cerebral vasospasm, the key factor extending the stay in the NCCU.
Effects on Long-Term Psychosocial Outcome
The mRS is commonly used as an end point for clinical trials involving stroke or aSAH.25,26 Although assessment using mRS does not require detailed neurological or psychological examinations, it gives disproportionate weight to physical disability relative to cognitive or behavioral impairment. Thus, incorporating a subjective perception of health may be of assistance to address any potential imbalance.27 The SF-36 has both good validity and internal consistency, and also has the advantage of inputting missing data.27–30 Because the ability to return to work is the ultimate aim for any affected population, the SF-36 should strengthen the outcome data on key psychosocial aspects.29,30
Compared with the reference population, we have found that there is a general deterioration in psychosocial-related life-quality among aSAH patients, regardless of the allocated treatment group. Previous studies using SF-36 have shown that a substantial proportion of aSAH patients continue to have problems in their daily lives 6 to 18 months after their illness, even though they have been given the highest graded scale using Glasgow Outcome Scale or mRS.29,30 A high proportion of patients who are able to resume their previous profession has been found to be of low mood.31 These patients have problems with work and other daily activities as a result of physical limitations or emotional stress, or the aSAH may have changed the appreciation of life after recovery from an acute, life-threatening illness.2 In this study the borderline significance in the long-term mRS scores lends support to the positive effects of pravastatin on key SF-36 scores relating to physical and psychosocial well being. The relatively small sample size was not powered to detect a clinical gain, but the findings have provided momentum to the organization of a multicenter phase III trial, the Statins for Aneurysmal Subarchnoid Hemorrhage (STASH) trial (n=1600; http://www.stashtrial.com)
Results from this trial demonstrate that acute pravastatin therapy reduces the need for rescue therapy and shortens inpatient stay, particularly when sepsis complicates the clinical course after aSAH. An associated clinical improvement at discharge also persists at 6 months with notable gains related to physical and psychosocial domains. The STASH trial is designed to address this influence of statin therapy on long-term clinical outcome.
Sources of Funding
This project was sponsored by the Addenbrooke’s Foundation Trust Hospital and the University of Cambridge. Dr Ming-Yuan Tseng was supported by scholarships from the British Council and the Raymond and Beverly Sackler Studentship, University of Cambridge, UK. Mr PJ Hutchinson is supported by the Senior Surgical Scientist Fellowship of the Academy of Medical Sciences/Health Foundation, UK. Dr Marek Czosnyka is on leave from Warsaw University of Technology, Poland.
- Received October 17, 2006.
- Revision received November 19, 2006.
- Accepted December 11, 2006.
Lindsay KW, Langham J, Kirkpatrick PJ, Shaw MDM, Gholkar AR, Molyneux A, Browne J, van der Meulen J, Reeves B, Copley L, Horrocks J. Final report of an audit carried out in 34 neurosurgical units in the UK and Ireland between 14 September 2001 to 13 September 2002. In: National Study of Subarachnoid Hemorrhage. London, UK: The Royal College of Surgeons of England; 2006.
Hop JW, Rinkel GJ, Algra A, van Gijn J. Quality of life in patients and partners after aneurismal subarachnoid hemorrhage. Stroke. 1998; 29: 798–804.
van Gijn J, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain. 2001; 124: 249–278.
Tseng MY, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ. Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: a phase II randomised placebo-controlled trial. Stroke. 2005; 36: 1627–1632.
Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang DA, Nelson R, Richards P, Sinar J, Bailey S, Skene A. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989; 298: 636–642.
Hasan D, Vermeulen M, Wijdicks EF, Hijdra A, van Gijn J. Management problems in acute hydrocephalus after subarachnoid hemorrhage. Stroke. 1989; 20: 747–753.
Solenski NJ, Haley EC Jr, Kassell NF, Kongable G, Germanson T, Truskowski L, Torner JC; Participants of the Multicenter Cooperative Aneurysm Study. Medical complications of aneurismal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Crit Care Med. 1995; 23: 1007–1017.
Yoshimoto Y, Tanaka Y, Hoya K. Acute systemic inflammatory response syndrome in subarachnoid hemorrhage. Stroke. 2001; 32: 1989–1993.
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.
Duncan PW, Jorgensen HS, Wade DT. Outcome measures in acute stroke trials: a systematic review and some recommendations to improve practice. Stroke. 2000; 31: 1429–1438.
Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA, Sandercock P; International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet. 2005; 366: 809–817.
Garratt AM, Ruta DA, Abdalla MI, Buckingham JK, Russell IT. The SF 36 health survey questionnaire: an outcome measure suitable for routine use within the NHS? BMJ. 1993; 306: 1440–1444.
Kim DH, Haney CL, Ginhoven GV. Utility of outcome measures after treatment for intracranial aneurysms: a prospective trial involving 520 patients. Stroke. 2005; 36: 792–796.