ORIGINAL RESEARCH ARTICLE Preadmission Statin Use Does Not Improve Functional Outcomes or Prevent Delayed Ischemic Events in Patients with Spontaneous Subarachnoid Hemorrhage Bryan D. Lizza,1* Adam Kosteva,2 Matthew B. Maas,3 Neil F. Rosenberg,4 Eric Liotta,3 James Guth,3 Kimberly E. Levasseur-Franklin,1 and Andrew M. Naidech,3 1
Department of Pharmacy, Northwestern Medicine, Chicago, Illinois; 2Department of Neurology, Northwestern Memorial Faculty Foundation, Chicago, Illinois; 3Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; 4Department of Neurology, Intermountain Medical Center, Murray, Utah
STUDY OBJECTIVE To determine whether preadmission statin use in patients with spontaneous subarachnoid hemorrhage (SAH) is associated with improved functional outcomes and a lower incidence of delayed cerebral ischemic events compared with statin-naive patients with SAH. DESIGN Prospective cohort study. SETTING Neurosciences intensive care unit of a tertiary care hospital. PATIENTS A total of 295 consecutive patients with SAH admitted between March 2006 and May 2013 who had complete medication histories; of these patients, 41 reported taking a statin prior to admission, and 254 were statin naive. INTERVENTION All patients received clinical management for SAH according to hospital protocol for standard care that included acute statin therapy with enteral pravastatin 40 mg/day on hospital day 1 for up to 21 days. MEASUREMENTS AND MAIN RESULTS Functional outcomes were assessed by using the modified Rankin Scale (mRS) at 14 days, 28 days, and 3 months. Delayed cerebral ischemia was assessed by using clinical evaluation and computed tomography. Patients taking statins prior to admission were more likely to have a history of diabetes mellitus, hypertension, coronary artery disease, and stroke. No significant difference in favorable neurologic outcome (mRS score 0–3) at 3 months was observed between the preadmission statin group compared with the statin-naive group (56.3% vs 72.4%, p=0.095). In multivariate logistic regression analysis, only age, severity of rupture, and coronary artery disease were less likely to predict a favorable neurologic outcome. No significant difference in the development of delayed cerebral ischemic events was observed between groups (p=0.48). CONCLUSION Statin use prior to admission did not improve functional outcomes or prevent delayed cerebral ischemic events in patients with SAH. Age, severity of rupture, and coronary artery disease were less likely to predict a favorable neurologic outcome at 3 months after discharge. KEY WORDS statin, subarachnoid hemorrhage, ischemia, vasospasm, functional outcome. (Pharmacotherapy 2014;**(**):**–**) doi: 10.1002/phar.1436
Presented as a poster at the Society of Critical Care Medicine 43rd Critical Care Congress, San Francisco, California, January 9–13, 2014. *Address for correspondence: Bryan D. Lizza, Clinical Pharmacist–Critical Care, Northwestern Medicine, 251 E Huron Street, Feinberg Pavilion, LC-700, Chicago, IL 60611; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
Delayed cerebral ischemia (DCI) related to arterial vasospasm remains a significant cause of morbidity and mortality in patients with spontaneous subarachnoid hemorrhage (SAH); up to 70% of these patients may develop death or severe disability. The development of vasospasm typically occurs between 4 and 10 days after
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hemorrhage and occurs more frequently in patients with a higher severity of rupture. The etiology of arterial vasospasm following SAH is complex, and many therapeutic strategies to reverse vasospasm-related deficits exist including nimodipine, hyperdynamic therapy, and intraarterial vasodilators.1–5 Inhibitors of 3-hydroxy-3methylglutaryl coenzyme A reductase (statins) have also been theorized to be beneficial in preventing DCI related to arterial vasospasm. Statins possess pleiotropic effects that may increase cerebral blood flow and improve vasomotor reactivity through upregulation of endothelial nitric oxide synthase.6, 7 Clinical trials evaluating the use of acute statin therapy following SAH have demonstrated inconsistent results and have focused on recruiting primarily statin-naive patients.8–12 Little data are available regarding prehemorrhage use of statins, but available information suggests that preadmission treatment may prevent cerebral vasospasm and improve functional outcomes in SAH.13, 14 Thus the objective of our study was to determine whether preadmission statin use is associated with improved functional outcomes and a lower incidence of delayed cerebral ischemic events compared with statin-naive patients presenting with SAH. Methods Study Design, Setting, and Patient Population The study was approved by the Northwestern University institutional review board (IRB). Written informed consent to collect data and clinical outcomes was obtained from the patient or a legally authorized representative in all cases except when the patient died in a hospital or no representative could be located for an incapacitated patient. In that case, the IRB approved collection of data in a registry without consent. We enrolled consecutive patients with SAH who were admitted to our neurosciences intensive care unit between March 2006 and May 2013. All patients were diagnosed by a board-certified neurologist, with confirmation of SAH by computed tomography (CT) or xanthochromia of the cerebrospinal fluid if the CT was nondiagnostic. Patients with SAH attributable to trauma, arteriovenous malformation rupture, vasculitis, or other structural lesions were excluded. Clinical data, laboratory data, and follow-up were prospectively recorded.
Clinical Management Diagnostic catheter or CT angiography and aneurysm obliteration with surgical clipping or endovascular coiling were performed as soon as possible. Nimodipine was administered unless the systolic blood pressure was less than 120 mm Hg according to hospital protocol. All patients were treated on hospital day 1 with enteral pravastatin 40 mg/day for up to 21 days as part of routine care.10, 11 Transcranial Doppler (TCD) sonography was performed daily by a certified technician. We prospectively recorded the presence of vasospasm as diagnosed by the following: mean TCD flow velocity at two thresholds of greater than 120 or 200 cm/second, development of clinical signs or symptoms (new focal neurologic deficit or depressed mental status without other explanation), or arterial stenosis on angiography. Patients with vasospasm were treated with hyperdynamic therapy (hypervolemia, hypertension, hemodilution). Diagnostic angiography was performed with balloon angioplasty of vasospastic arteries and/or intraarterial vasodilators if clinically appropriate. Medication Reconciliation and Cohort Designation As part of a mandatory process, medication reconciliation was performed by a dedicated pharmacist on admission to our neurosciences intensive care unit. The medication history was reviewed with the patient (if able to provide this information) or next of kin. We prospectively recorded the use of statins prior to admission including drug, dose, and frequency. Patients with incomplete medication histories were excluded from analysis. Patients who reported taking a statin on their admission medication history were considered preadmission statin users, and those who denied using a statin were considered statin-naive patients. Data Collection Clinical variables were prospectively recorded until death or hospital discharge. Laboratory values and laboratory reports were retrospectively retrieved by using electronic data extraction. We collected baseline demographics and medical history data onto standardized forms. Neurologic status on admission was assessed with the World Federation of Neurological Surgeons (WFNS) scale, which is graded as 1 (best, Glasgow Coma
PRIOR STATIN USE AND OUTCOMES FOLLOWING SAH Lizza et al
Scale [GCS] score of 15), 2 (GCS score 13–14, no motor deficit), 3 (GCS score 13–14, motor deficit present), 4 (GCS score 7–12), and 5 (worst, GCS score 3–6). Severity of hemorrhage was assessed using the Hunt-Hess scale, National Institutes of Health Stroke Scale (NIHSS), and CT score. Stroke or delayed cerebral infarction was prospectively recorded during the hospital stay by study staff as a new hypodensity on CT not present on admission or due to postoperative changes or resolving edema, or on magnetic resonance imaging (MRI) of the brain as a new area of increased intensity on B1000 with decreased intensity on apparent diffusion coefficient maps. Number and location were classified as previously described. Functional outcomes were obtained at 14 days, 28 days, and 3 months by a trained study coordinator not involved in the clinical care of the patient by using the modified Rankin Scale (mRS), which ranges in score from 0 (no symptoms) to 6 (death). We categorized a poor functional outcome as an mRS score of 4–6 and a favorable neurologic outcome as an mRS score of 0–3. We used a validated questionnaire to ascertain the mRS after discharge.15, 16 The primary outcome of our analysis was the percentage of patients who experienced a favorable neurologic outcome. Secondary outcomes included the prevalence of delayed ischemic events, vasospasm, and need for rescue therapy. Statistical Analysis Continuous data are presented as mean SD for normally distributed variables or median (interquartile range [IQR]) for nonnormally distributed variables. Normally distributed variables were analyzed by using the Student t test or Mann-Whitney U test for nonnormally distributed variables. Categoric data were compared with the Pearson v2 or Fisher exact test as appropriate. For our multivariate analysis of favorable outcome at 3 months (mRS score 0–3), we used logistic regression with a threshold for model inclusion of p≤0.2. A p value less than 0.05 was considered statistically significant. Variables with point estimates greater than 1.0 with a significant 95% confidence interval were considered to be predictive of experiencing a favorable neurologic outcome. Variables with point estimates less than 1.0 with a significant 95% confidence interval were interpreted as less likely to predict a favorable neurologic outcome based on our method of coding. Statistical
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analyses were conducted using SPSS statistical software, v.21.0 (SPSS Inc., Chicago, IL). Results A total of 335 patients were identified from our database query. We excluded 40 patients on the basis of either incomplete medication histories (24 patients [60%]) or lack of representation to provide informed consent (16 patients [40%]), leaving 295 patients identified as having complete medication histories. Table 1 presents the baseline demographics of these patients. Briefly, most of the patients were female and nonsmokers, and received surgical clipping. A total of 41 patients (14%) reported using statins for various indications prior to aneurysm rupture, with a median statin dose in simvastatin equivalents of 20 mg (IQR 20–40 mg). The most commonly prescribed statins were atorvastatin followed by simvastatin, which constituted most of the statin users (Table 2). Patients who were receiving statins prior to admission were older and more likely to have a history of diabetes mellitus, hypertension, stroke, and coronary artery disease. No significant differences between preadmission statin users and statin-naive patients were observed in terms of severity of presentation as assessed by the WFNS scale, Hunt-Hess grade, admission GCS, admission NIHSS, or CT score were noted. The incidence of vasospasm as diagnosed by TCD greater than 120 cm/second (p=0.451), TCD greater than 200 cm/second (p=0.855), angiography (p=0.539), and clinically (p=0.737; Table 3) did not significantly differ between preadmission statin users and statin-naive patients. Patients in the preadmission statin group received a similar rate of treatment for vasospasm by angioplasty (p=0.45), intraarterial vasodilators (p=0.733), and hyperdynamic therapy (p=0.462) compared with statin-naive patients. No significant difference in the occurrence of delayed ischemic events or stroke was noted between the groups (p=0.48). A similar proportion of patients in both groups experienced a positive neurologic outcome at 14 days, 28 days, and 3 months (Table 4). Data for mRS at 3 months were available for 84.4% of the study cohort. After adjustment for differences in baseline characteristics, multivariable logistic regression analysis revealed the presence of multiple comorbidities as predictors of a poor neurologic outcome (Table 5). Higher severity of aneurysm
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Table 1. Baseline Demographic and Clinical Characteristics of the Study Patients Characteristic Age, yrs Male Hunt-Hess scale WFNS grade GCS score on admission NIHSS score on admission CT score Hydrocephalus History of ICH History of stroke Coronary artery disease Atrial fibrillation Hypertension Diabetes mellitus Family history of aneurysm Smoking history External ventricular drain Cerebral angiography Computed tomography angiography Procedure performed Coil Clip None Location of aneurysm ICA/PCOM MCA ACA/ACOM VB/Basilar/Posterior Other Perimesencephalic/subtruncal Aneurysm diameter, mm
All patients (n=295) 53.5 91 2 1 15 1 3 46 3 13 22 3 139 28 32 125 176 199 277
15.1 (30.8) (2–3) (1–3) (13–15) (0–4) (1–3) (15.6) (1.0) (4.4) (7.5) (1.0) (47.1) (9.5) (10.8) (42.4) (59.7) (67.5) (93.9)
Preadmission statin users (n=41) 62.2 15 2 2 14 1 3 3 1 5 13 1 32 12 4 17 25 27 39
18.4 (36.6) (2–3) (1–2) (14–15) (0–4) (2–3) (7.3) (2.4) (12.2) (31.7) (2.4) (78.0) (29.3) (9.8) (41.5) (61.0) (65.9) (95.1)
79 (26.8) 157 (53.2) 59 (20.0)
6 (14.6) 24 (58.5) 11 (26.8)
73 43 83 38 5 53 7.0
10 6 7 6 1 11 7.8
(24.7) (14.5) (28.1) (12.9) (1.8) (18.0) 4.7
(24.4) (14.6) (17.1) (14.6) (2.4) (26.8) 4.6
Statin-naive patients (n=254) 52.1 76 2 1 15 1 3 43 2 8 9 2 107 16 28 108 151 172 238
p value
14.1 (29.9) (2–3) (1–3) (13–15) (0–4) (1–3) (16.9) (0.8) (3.1) (3.5) (0.8) (42.1) (6.3) (11.0) (42.5) (59.4) (67.7) (93.7)
< 0.001 0.39 0.99 0.33 0.60 0.82 0.76 0.12 0.33 0.009 < 0.001 0.33 < 0.001 < 0.001 0.81 0.90 0.85 0.81 0.72
73 (28.7) 133 (52.4) 48 (18.9)
0.24
63 (24.8) 37 (14.6) 76 (29.9) 32 (12.6) 4 (1.6) 42 (16.5) 6.9 4.7
0.490
0.41
Data are mean SD, no. (%) of patients, or median (interquartile range). ACA = anterior cerebral artery; ACOM = anterior communicating artery; CT = computed tomography; GCS = Glasgow Coma Scale; ICA = internal carotid artery; ICH = intracerebral hemorrhage; MCA = middle cerebral artery; NIHSS = National Institute of Health Stroke Scale; PCOM = posterior communicating artery; VB = vertebrobasilar system; WFNS = World Federation of Neurological Surgeons.
rupture, age, and coronary artery disease were less likely to predict a favorable neurologic outcome.
Table 2. Specific Statin Use Among the 41 Preadmission Statin Users Statin
Discussion In our study of 295 patients diagnosed with SAH, preadmission statin use was not associated with improved functional outcomes and did not protect against vasospasm or DCI. Statin users were also more likely to be older and have a higher rate of cardiovascular and metabolic disorders. In our regression analysis, only age, severity of aneurysm rupture, and coronary artery disease were less likely to predict a favorable neurologic outcome. As expected, more severe aneurysm rupture, older age, and history of coronary artery disease are more likely to predispose patients to a higher rate of neurologic damage and the development of neurogenic stunned myocardium, which may lead to a poor
Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin Median dose, mg, in simvastatin equivalents (interquartile range)
No. (%) of patients 17 1 3 2 4 14 20
(41.4) (2.4) (7.3) (4.9) (9.8) (34.1) (20–40)
prognosis.17, 18 Based on these findings, the prognostic significance of preadmission statin use in patients treated with acute statin therapy after SAH is limited and is more likely a surrogate for patients who have a greater number of comorbid disease states. Another explanation may be related to the differences in clinical man-
PRIOR STATIN USE AND OUTCOMES FOLLOWING SAH Lizza et al Table 3. Analysis of Clinical Outcomes and Vasospasm Diagnosis and Treatment Preadmission Statin-naive patients statin users (n=254) p value (n=41) Transcranial Doppler > 120 cm/sec Transcranial Doppler > 200 cm/sec Angiographic evidence Symptoms present Rescue therapy Angioplasty Intraarterial vasodilators Hyperdynamic therapy Stroke
20 (48.8)
140 (55.1)
0.45
6 (14.6)
40 (15.7)
0.86
7 (17.1) 7 (17.1)
54 (21.3) 49 (19.3)
0.54 0.74
1 (2.4) 9 (22.0)
13 (5.1) 62 (24.4)
0.45 0.73
8 (19.5)
63 (24.8)
0.46
1 (2.4)
16 (6.3)
0.48
Data are no. (%) of patients.
Table 4. Favorable Functional Outcomes According to Modified Rankin Scale Score 0–3
Time point
Preadmission statin users (n=41)
Statin-naive patients (n=254)
p value
14 days 28 days 3 months
15 (36.6) 17/38 (44.7) 18/32 (56.3)
115 (45.3) 143/236 (60.6) 157/217 (72.4)
0.31 0.077 0.095
Data are no. (%) of patients.
Table 5. Multivariate Logistic Regression Analysis: Favorable Neurologic Outcome at 3 Monthsa Point 95% confidence estimate interval p value Age, yrs Severity of aneurysm rupture, WFNS grade History of stroke Coronary artery disease Hypertension Diabetes mellitus
0.967 0.428
0.94–0.99 0.34–0.54
0.007 < 0.001
0.430 0.242 0.530 1.026
0.08–2.29 0.07–0.82 0.26–1.09 0.34–3.10
0.323 0.022 0.083 0.964
Variables with point estimates > 1.0 with a significant 95% confidence interval were considered to be predictive of experiencing a favorable neurologic outcome. Variables with point estimates < 1.0 with a significant 95% confidence interval were interpreted as less likely to predict a favorable neurologic outcome. Variables considered in the initial model were age, preadmission statin use, history of stroke, coronary artery disease, hypertension and/or diabetes mellitus, and WFNS grade. WFNS = World Federation of Neurological Surgeons. a Indicated by modified Rankin Scale score of 0–3.
agement among institutions where the risk of statin withdrawal is obviated by acute treatment with pravastatin. In one case-control analysis, a significant portion of statin users (36%) had their statin agent discontinued after admission, and a portion of controls (11%) started statin therapy after onset of SAH.14 This may limit our
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ability to compare their results with ours because acute statin withdrawal is associated with an increased risk of SAH.19 Our results are consistent with those of another study that found no association between the risk of vasospasm and use of statins prior to hemorrhage after adjusting for potential confounders.13 It is worth noting that the authors reported the primary end point as a composite (clinical symptoms, TCD threshold, and/or angiographic evidence), whereas we reported the individual components. The authors also reported that most of the patients (73.1%) had their statin therapy discontinued on admission. Neither study incorporated a clinical care protocol of initiating or continuing statin therapy following hemorrhage, which is an important distinction.13, 14 The theoretical benefit of acute statin therapy following hemorrhage remains controversial.20, 21 Independent of their lipid-lowering effects, statins improve cerebral autoregulation by upregulation of endothelial nitric oxide synthase, increasing availability of nitric oxide.6, 7 In addition, plasma levels of markers of endothelial injury and astrocyte activation were markedly reduced following treatment with simvastatin.9 In prospective trials, acute statin treatment was associated with a reduced rate of delayed ischemic deficits and improved functional outcomes.8–11, 22–24 Pooled results of clinical trials of posthemorrhage statin use have shown conflicting results, which are likely limited by the small cohort analyzed (190 patients) or the differences in treatment used (pravastatin 40 mg vs simvastatin 80 mg).12, 25, 26 The results of the recently completed phase III trial Statins for Aneurysmal Subarachnoid Hemorrhage (STASH) will investigate this limitation because projected enrollment is expected to include nearly 800 patients. In other disease states such as acute coronary syndrome, the pleiotropic effects of statins on inflammatory mediators have been closely correlated with relative statin potency yet remain independent of their lipid-lowering effects.27–29 Based on this observation, it is reasonable to expect that statin potency may be correlated with treatment outcome in patients with SAH. Our analysis has a number of limitations. First, we observed a small percentage of patients who reported using a statin prior to admission (14%), consistent with previous analyses,13, 14 which likely predisposes our study to a type II error. We were also unable to ascertain the
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duration of statin use prior to admission or patient compliance, which may limit our findings. Despite these limitations, our analysis indicates that statin use prior to admission did not improve clinical and functional outcomes when acute therapy with pravastatin was used. Given the relatively low severity of SAH at our facility, the possibility for selection bias may be considered. Our institution is a tertiary care referral center and accepts advanced cases of intracranial hemorrhage. On further examination, our database enrolls more than 95% of all patients presenting with intracranial hemorrhage and thus is unlikely to be affected by selection bias.
8. 9. 10.
11.
12.
Conclusion Patients treated with statins prior to admission for SAH experienced similar neurologic outcomes compared with statin-naive patients. Statin use at the time of aneurysm rupture may confer little added protection, and early initiation of statin therapy after hemorrhage may provide sufficient pharmacologic benefit by the time subsequent pathologic processes such as vasospasm and related delayed ischemic injury manifest. The results of the recently completed STASH trial will further support or refute the benefit of statin therapy following SAH. Further, preadmission statin use may not confound the results of future studies of acute statin therapy for SAH. References 1. Kronvall E, Undren P, Romner B, Saveland H, Cronqvist M, Nilsson OG. Nimodipine in aneurysmal subarachnoid hemorrhage: a randomized study of intravenous or peroral administration. J Neurosurg 2009;110:58–63. 2. Choi HA, Ko SB, Chen H, et al. Acute effects of nimodipine on cerebral vasculature and brain metabolism in high grade subarachnoid hemorrhage patients. Neurocrit Care 2012;16:363–7. 3. Dankbaar JW, Slooter AJ, Rinkel GJ, Schaaf IC. Effect of different components of triple-H therapy on cerebral perfusion in patients with aneurysmal subarachnoid haemorrhage: a systematic review. Crit Care 2010;14:R23. 4. Egge A, Waterloo K, Sjoholm H, Solberg T, Ingebrigtsen T, Romner B. Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled study. Neurosurgery 2001;49:593–605. 5. Musahl C, Henkes H, Vajda Z, Coburger J, Hopf N. Continuous local intra-arterial nimodipine administration in severe symptomatic vasospasm after subarachnoid hemorrhage. Neurosurgery 2011;68:1541–7. 6. McGirt MJ, Lynch JR, Parra A, et al. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke 2002;33:2950–6. 7. Sabri M, Ai J, Marsden PA, Macdonald RL. Simvastatin recouples dysfunctional endothelial nitric oxide synthase in
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experimental subarachnoid hemorrhage. PLoS ONE 2011;6: e17062. Chou SH, Smith EE, Badjatia N, et al. A randomized, doubleblind, placebo-controlled pilot study of simvastatin in aneurysmal subarachnoid hemorrhage. Stroke 2008;39:2891–3. Lynch JR, Wang H, McGirt MJ, et al. Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial. Stroke 2005;36:2024–6. 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 randomized placebo-controlled trial. Stroke 2005;36:1627–32. Tseng MY, Hutchinson PJ, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ. Effects of acute pravastatin treatment on intensity of rescue therapy, length of inpatient stay, and 6-month outcome in patients after aneurysmal subarachnoid hemorrhage. Stroke 2007;38:1545–50. Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB. Effect of statin treatment on vasospasm, delayed cerebral ischemia, and functional outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis update. Stroke 2010;41:e47–52. Moskowitz SI, Ahrens C, Provencio JJ, Chow M, Rasmussen PA. Prehemorrhage statin use and the risk of vasospasm after aneurysmal subarachnoid hemorrhage. Surg Neurol 2009;71:311–7. Parra A, Kreiter KT, Williams S, et al. Effect of prior statin use on functional outcome and delayed vasospasm after acute aneurysmal subarachnoid hemorrhage: a matched controlled cohort study. Neurosurgery 2005;56:476–84. Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke 2007;38:1091–6. Wilson JT, Hareendran A, Grant M, et al. Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the modified Rankin scale. Stroke 2002;33:2243–6. Liang CW, Chen R, Macri E, Naval N. Preadmission betablockers are associated with decreased incidence of neurogenic stunned myocardium in aneurysmal subarachnoid hemorrhage. J Stroke Cerebrovasc Dis 2013;22:601–7. Shivalkar B, Van Loon J, Wieland W, et al. Variable effects of explosive or gradual increase of intracranial pressure on myocardial structure and function. Circulation 1993;87:230–9. Risselada R, Straatman H, van Kooten F, et al. Withdrawal of statins and risk of subarachnoid hemorrhage. Stroke 2009;40:2887–92. Rabinstein AA. Vasospasm and statin therapy: yet another cautionary tale. Neurocrit Care 2010;12:310–2. Sandercock P. “Yes” or “no” to routine statins after subarachnoid hemorrhage to prevent delayed cerebral ischaemia, vasospasm, and death? A cautionary tale of 2 meta-analyses. Stroke 2010;41:e1–2. Kramer AH, Gurka MJ, Nathan B, Dumont AS, Kassell NF, Bleck TP. Statin use was not associated with less vasospasm or improved outcome after subarachnoid hemorrhage. Neurosurgery 2008;62:422–7. McGirt MJ, Garces Ambrossi GL, Huang J, Tamargo RJ. Simvastatin for the prevention of symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage: a single-institution prospective cohort study. J Neurosurg 2009;110:968–74. Vergouwen MD, Meijers JC, Geskus RB, et al. Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled randomized trial. J Stroke Cerebrovasc Dis 2009;29:1444–53. Kramer AH, Fletcher JJ. Statins in the management of patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. Neurocrit Care 2010;12:285–96. Sillberg VA, Wells GA, Perry JJ. Do statins improve outcomes and reduce the incidence of vasospasm after aneurysmal subarachnoid hemorrhage: a meta-analysis. Stroke 2008;39: 2622–6.
PRIOR STATIN USE AND OUTCOMES FOLLOWING SAH Lizza et al 27. Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G, Montinaro A. Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) randomized trial. J Am Coll Cardiol 2009;54:558–65. 28. Gibson CM, Pride YB, Hochberg CP, et al. Effect of intensive statin therapy on clinical outcomes among patients undergoing percutaneous coronary intervention for acute coronary syn-
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drome. PCI-PROVE IT: A PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22) substudy. J Am Coll Cardiol 2009;54:2290–5. 29. Kim JS, Kim J, Choi D, et al. Efficacy of high-dose atorvastatin loading before primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: the STATIN STEMI trial. JACC Cardiovasc Interv 2010;3:332–9.
Department of Pharmacy, Northwestern Medicine, Chicago, Illinois; 2Department of Neurology, Northwestern Memorial Faculty Foundation, Chicago, Illinois; 3Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; 4Department of Neurology, Intermountain Medical Center, Murray, Utah
STUDY OBJECTIVE To determine whether preadmission statin use in patients with spontaneous subarachnoid hemorrhage (SAH) is associated with improved functional outcomes and a lower incidence of delayed cerebral ischemic events compared with statin-naive patients with SAH. DESIGN Prospective cohort study. SETTING Neurosciences intensive care unit of a tertiary care hospital. PATIENTS A total of 295 consecutive patients with SAH admitted between March 2006 and May 2013 who had complete medication histories; of these patients, 41 reported taking a statin prior to admission, and 254 were statin naive. INTERVENTION All patients received clinical management for SAH according to hospital protocol for standard care that included acute statin therapy with enteral pravastatin 40 mg/day on hospital day 1 for up to 21 days. MEASUREMENTS AND MAIN RESULTS Functional outcomes were assessed by using the modified Rankin Scale (mRS) at 14 days, 28 days, and 3 months. Delayed cerebral ischemia was assessed by using clinical evaluation and computed tomography. Patients taking statins prior to admission were more likely to have a history of diabetes mellitus, hypertension, coronary artery disease, and stroke. No significant difference in favorable neurologic outcome (mRS score 0–3) at 3 months was observed between the preadmission statin group compared with the statin-naive group (56.3% vs 72.4%, p=0.095). In multivariate logistic regression analysis, only age, severity of rupture, and coronary artery disease were less likely to predict a favorable neurologic outcome. No significant difference in the development of delayed cerebral ischemic events was observed between groups (p=0.48). CONCLUSION Statin use prior to admission did not improve functional outcomes or prevent delayed cerebral ischemic events in patients with SAH. Age, severity of rupture, and coronary artery disease were less likely to predict a favorable neurologic outcome at 3 months after discharge. KEY WORDS statin, subarachnoid hemorrhage, ischemia, vasospasm, functional outcome. (Pharmacotherapy 2014;**(**):**–**) doi: 10.1002/phar.1436
Presented as a poster at the Society of Critical Care Medicine 43rd Critical Care Congress, San Francisco, California, January 9–13, 2014. *Address for correspondence: Bryan D. Lizza, Clinical Pharmacist–Critical Care, Northwestern Medicine, 251 E Huron Street, Feinberg Pavilion, LC-700, Chicago, IL 60611; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
Delayed cerebral ischemia (DCI) related to arterial vasospasm remains a significant cause of morbidity and mortality in patients with spontaneous subarachnoid hemorrhage (SAH); up to 70% of these patients may develop death or severe disability. The development of vasospasm typically occurs between 4 and 10 days after
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hemorrhage and occurs more frequently in patients with a higher severity of rupture. The etiology of arterial vasospasm following SAH is complex, and many therapeutic strategies to reverse vasospasm-related deficits exist including nimodipine, hyperdynamic therapy, and intraarterial vasodilators.1–5 Inhibitors of 3-hydroxy-3methylglutaryl coenzyme A reductase (statins) have also been theorized to be beneficial in preventing DCI related to arterial vasospasm. Statins possess pleiotropic effects that may increase cerebral blood flow and improve vasomotor reactivity through upregulation of endothelial nitric oxide synthase.6, 7 Clinical trials evaluating the use of acute statin therapy following SAH have demonstrated inconsistent results and have focused on recruiting primarily statin-naive patients.8–12 Little data are available regarding prehemorrhage use of statins, but available information suggests that preadmission treatment may prevent cerebral vasospasm and improve functional outcomes in SAH.13, 14 Thus the objective of our study was to determine whether preadmission statin use is associated with improved functional outcomes and a lower incidence of delayed cerebral ischemic events compared with statin-naive patients presenting with SAH. Methods Study Design, Setting, and Patient Population The study was approved by the Northwestern University institutional review board (IRB). Written informed consent to collect data and clinical outcomes was obtained from the patient or a legally authorized representative in all cases except when the patient died in a hospital or no representative could be located for an incapacitated patient. In that case, the IRB approved collection of data in a registry without consent. We enrolled consecutive patients with SAH who were admitted to our neurosciences intensive care unit between March 2006 and May 2013. All patients were diagnosed by a board-certified neurologist, with confirmation of SAH by computed tomography (CT) or xanthochromia of the cerebrospinal fluid if the CT was nondiagnostic. Patients with SAH attributable to trauma, arteriovenous malformation rupture, vasculitis, or other structural lesions were excluded. Clinical data, laboratory data, and follow-up were prospectively recorded.
Clinical Management Diagnostic catheter or CT angiography and aneurysm obliteration with surgical clipping or endovascular coiling were performed as soon as possible. Nimodipine was administered unless the systolic blood pressure was less than 120 mm Hg according to hospital protocol. All patients were treated on hospital day 1 with enteral pravastatin 40 mg/day for up to 21 days as part of routine care.10, 11 Transcranial Doppler (TCD) sonography was performed daily by a certified technician. We prospectively recorded the presence of vasospasm as diagnosed by the following: mean TCD flow velocity at two thresholds of greater than 120 or 200 cm/second, development of clinical signs or symptoms (new focal neurologic deficit or depressed mental status without other explanation), or arterial stenosis on angiography. Patients with vasospasm were treated with hyperdynamic therapy (hypervolemia, hypertension, hemodilution). Diagnostic angiography was performed with balloon angioplasty of vasospastic arteries and/or intraarterial vasodilators if clinically appropriate. Medication Reconciliation and Cohort Designation As part of a mandatory process, medication reconciliation was performed by a dedicated pharmacist on admission to our neurosciences intensive care unit. The medication history was reviewed with the patient (if able to provide this information) or next of kin. We prospectively recorded the use of statins prior to admission including drug, dose, and frequency. Patients with incomplete medication histories were excluded from analysis. Patients who reported taking a statin on their admission medication history were considered preadmission statin users, and those who denied using a statin were considered statin-naive patients. Data Collection Clinical variables were prospectively recorded until death or hospital discharge. Laboratory values and laboratory reports were retrospectively retrieved by using electronic data extraction. We collected baseline demographics and medical history data onto standardized forms. Neurologic status on admission was assessed with the World Federation of Neurological Surgeons (WFNS) scale, which is graded as 1 (best, Glasgow Coma
PRIOR STATIN USE AND OUTCOMES FOLLOWING SAH Lizza et al
Scale [GCS] score of 15), 2 (GCS score 13–14, no motor deficit), 3 (GCS score 13–14, motor deficit present), 4 (GCS score 7–12), and 5 (worst, GCS score 3–6). Severity of hemorrhage was assessed using the Hunt-Hess scale, National Institutes of Health Stroke Scale (NIHSS), and CT score. Stroke or delayed cerebral infarction was prospectively recorded during the hospital stay by study staff as a new hypodensity on CT not present on admission or due to postoperative changes or resolving edema, or on magnetic resonance imaging (MRI) of the brain as a new area of increased intensity on B1000 with decreased intensity on apparent diffusion coefficient maps. Number and location were classified as previously described. Functional outcomes were obtained at 14 days, 28 days, and 3 months by a trained study coordinator not involved in the clinical care of the patient by using the modified Rankin Scale (mRS), which ranges in score from 0 (no symptoms) to 6 (death). We categorized a poor functional outcome as an mRS score of 4–6 and a favorable neurologic outcome as an mRS score of 0–3. We used a validated questionnaire to ascertain the mRS after discharge.15, 16 The primary outcome of our analysis was the percentage of patients who experienced a favorable neurologic outcome. Secondary outcomes included the prevalence of delayed ischemic events, vasospasm, and need for rescue therapy. Statistical Analysis Continuous data are presented as mean SD for normally distributed variables or median (interquartile range [IQR]) for nonnormally distributed variables. Normally distributed variables were analyzed by using the Student t test or Mann-Whitney U test for nonnormally distributed variables. Categoric data were compared with the Pearson v2 or Fisher exact test as appropriate. For our multivariate analysis of favorable outcome at 3 months (mRS score 0–3), we used logistic regression with a threshold for model inclusion of p≤0.2. A p value less than 0.05 was considered statistically significant. Variables with point estimates greater than 1.0 with a significant 95% confidence interval were considered to be predictive of experiencing a favorable neurologic outcome. Variables with point estimates less than 1.0 with a significant 95% confidence interval were interpreted as less likely to predict a favorable neurologic outcome based on our method of coding. Statistical
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analyses were conducted using SPSS statistical software, v.21.0 (SPSS Inc., Chicago, IL). Results A total of 335 patients were identified from our database query. We excluded 40 patients on the basis of either incomplete medication histories (24 patients [60%]) or lack of representation to provide informed consent (16 patients [40%]), leaving 295 patients identified as having complete medication histories. Table 1 presents the baseline demographics of these patients. Briefly, most of the patients were female and nonsmokers, and received surgical clipping. A total of 41 patients (14%) reported using statins for various indications prior to aneurysm rupture, with a median statin dose in simvastatin equivalents of 20 mg (IQR 20–40 mg). The most commonly prescribed statins were atorvastatin followed by simvastatin, which constituted most of the statin users (Table 2). Patients who were receiving statins prior to admission were older and more likely to have a history of diabetes mellitus, hypertension, stroke, and coronary artery disease. No significant differences between preadmission statin users and statin-naive patients were observed in terms of severity of presentation as assessed by the WFNS scale, Hunt-Hess grade, admission GCS, admission NIHSS, or CT score were noted. The incidence of vasospasm as diagnosed by TCD greater than 120 cm/second (p=0.451), TCD greater than 200 cm/second (p=0.855), angiography (p=0.539), and clinically (p=0.737; Table 3) did not significantly differ between preadmission statin users and statin-naive patients. Patients in the preadmission statin group received a similar rate of treatment for vasospasm by angioplasty (p=0.45), intraarterial vasodilators (p=0.733), and hyperdynamic therapy (p=0.462) compared with statin-naive patients. No significant difference in the occurrence of delayed ischemic events or stroke was noted between the groups (p=0.48). A similar proportion of patients in both groups experienced a positive neurologic outcome at 14 days, 28 days, and 3 months (Table 4). Data for mRS at 3 months were available for 84.4% of the study cohort. After adjustment for differences in baseline characteristics, multivariable logistic regression analysis revealed the presence of multiple comorbidities as predictors of a poor neurologic outcome (Table 5). Higher severity of aneurysm
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Table 1. Baseline Demographic and Clinical Characteristics of the Study Patients Characteristic Age, yrs Male Hunt-Hess scale WFNS grade GCS score on admission NIHSS score on admission CT score Hydrocephalus History of ICH History of stroke Coronary artery disease Atrial fibrillation Hypertension Diabetes mellitus Family history of aneurysm Smoking history External ventricular drain Cerebral angiography Computed tomography angiography Procedure performed Coil Clip None Location of aneurysm ICA/PCOM MCA ACA/ACOM VB/Basilar/Posterior Other Perimesencephalic/subtruncal Aneurysm diameter, mm
All patients (n=295) 53.5 91 2 1 15 1 3 46 3 13 22 3 139 28 32 125 176 199 277
15.1 (30.8) (2–3) (1–3) (13–15) (0–4) (1–3) (15.6) (1.0) (4.4) (7.5) (1.0) (47.1) (9.5) (10.8) (42.4) (59.7) (67.5) (93.9)
Preadmission statin users (n=41) 62.2 15 2 2 14 1 3 3 1 5 13 1 32 12 4 17 25 27 39
18.4 (36.6) (2–3) (1–2) (14–15) (0–4) (2–3) (7.3) (2.4) (12.2) (31.7) (2.4) (78.0) (29.3) (9.8) (41.5) (61.0) (65.9) (95.1)
79 (26.8) 157 (53.2) 59 (20.0)
6 (14.6) 24 (58.5) 11 (26.8)
73 43 83 38 5 53 7.0
10 6 7 6 1 11 7.8
(24.7) (14.5) (28.1) (12.9) (1.8) (18.0) 4.7
(24.4) (14.6) (17.1) (14.6) (2.4) (26.8) 4.6
Statin-naive patients (n=254) 52.1 76 2 1 15 1 3 43 2 8 9 2 107 16 28 108 151 172 238
p value
14.1 (29.9) (2–3) (1–3) (13–15) (0–4) (1–3) (16.9) (0.8) (3.1) (3.5) (0.8) (42.1) (6.3) (11.0) (42.5) (59.4) (67.7) (93.7)
< 0.001 0.39 0.99 0.33 0.60 0.82 0.76 0.12 0.33 0.009 < 0.001 0.33 < 0.001 < 0.001 0.81 0.90 0.85 0.81 0.72
73 (28.7) 133 (52.4) 48 (18.9)
0.24
63 (24.8) 37 (14.6) 76 (29.9) 32 (12.6) 4 (1.6) 42 (16.5) 6.9 4.7
0.490
0.41
Data are mean SD, no. (%) of patients, or median (interquartile range). ACA = anterior cerebral artery; ACOM = anterior communicating artery; CT = computed tomography; GCS = Glasgow Coma Scale; ICA = internal carotid artery; ICH = intracerebral hemorrhage; MCA = middle cerebral artery; NIHSS = National Institute of Health Stroke Scale; PCOM = posterior communicating artery; VB = vertebrobasilar system; WFNS = World Federation of Neurological Surgeons.
rupture, age, and coronary artery disease were less likely to predict a favorable neurologic outcome.
Table 2. Specific Statin Use Among the 41 Preadmission Statin Users Statin
Discussion In our study of 295 patients diagnosed with SAH, preadmission statin use was not associated with improved functional outcomes and did not protect against vasospasm or DCI. Statin users were also more likely to be older and have a higher rate of cardiovascular and metabolic disorders. In our regression analysis, only age, severity of aneurysm rupture, and coronary artery disease were less likely to predict a favorable neurologic outcome. As expected, more severe aneurysm rupture, older age, and history of coronary artery disease are more likely to predispose patients to a higher rate of neurologic damage and the development of neurogenic stunned myocardium, which may lead to a poor
Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin Median dose, mg, in simvastatin equivalents (interquartile range)
No. (%) of patients 17 1 3 2 4 14 20
(41.4) (2.4) (7.3) (4.9) (9.8) (34.1) (20–40)
prognosis.17, 18 Based on these findings, the prognostic significance of preadmission statin use in patients treated with acute statin therapy after SAH is limited and is more likely a surrogate for patients who have a greater number of comorbid disease states. Another explanation may be related to the differences in clinical man-
PRIOR STATIN USE AND OUTCOMES FOLLOWING SAH Lizza et al Table 3. Analysis of Clinical Outcomes and Vasospasm Diagnosis and Treatment Preadmission Statin-naive patients statin users (n=254) p value (n=41) Transcranial Doppler > 120 cm/sec Transcranial Doppler > 200 cm/sec Angiographic evidence Symptoms present Rescue therapy Angioplasty Intraarterial vasodilators Hyperdynamic therapy Stroke
20 (48.8)
140 (55.1)
0.45
6 (14.6)
40 (15.7)
0.86
7 (17.1) 7 (17.1)
54 (21.3) 49 (19.3)
0.54 0.74
1 (2.4) 9 (22.0)
13 (5.1) 62 (24.4)
0.45 0.73
8 (19.5)
63 (24.8)
0.46
1 (2.4)
16 (6.3)
0.48
Data are no. (%) of patients.
Table 4. Favorable Functional Outcomes According to Modified Rankin Scale Score 0–3
Time point
Preadmission statin users (n=41)
Statin-naive patients (n=254)
p value
14 days 28 days 3 months
15 (36.6) 17/38 (44.7) 18/32 (56.3)
115 (45.3) 143/236 (60.6) 157/217 (72.4)
0.31 0.077 0.095
Data are no. (%) of patients.
Table 5. Multivariate Logistic Regression Analysis: Favorable Neurologic Outcome at 3 Monthsa Point 95% confidence estimate interval p value Age, yrs Severity of aneurysm rupture, WFNS grade History of stroke Coronary artery disease Hypertension Diabetes mellitus
0.967 0.428
0.94–0.99 0.34–0.54
0.007 < 0.001
0.430 0.242 0.530 1.026
0.08–2.29 0.07–0.82 0.26–1.09 0.34–3.10
0.323 0.022 0.083 0.964
Variables with point estimates > 1.0 with a significant 95% confidence interval were considered to be predictive of experiencing a favorable neurologic outcome. Variables with point estimates < 1.0 with a significant 95% confidence interval were interpreted as less likely to predict a favorable neurologic outcome. Variables considered in the initial model were age, preadmission statin use, history of stroke, coronary artery disease, hypertension and/or diabetes mellitus, and WFNS grade. WFNS = World Federation of Neurological Surgeons. a Indicated by modified Rankin Scale score of 0–3.
agement among institutions where the risk of statin withdrawal is obviated by acute treatment with pravastatin. In one case-control analysis, a significant portion of statin users (36%) had their statin agent discontinued after admission, and a portion of controls (11%) started statin therapy after onset of SAH.14 This may limit our
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ability to compare their results with ours because acute statin withdrawal is associated with an increased risk of SAH.19 Our results are consistent with those of another study that found no association between the risk of vasospasm and use of statins prior to hemorrhage after adjusting for potential confounders.13 It is worth noting that the authors reported the primary end point as a composite (clinical symptoms, TCD threshold, and/or angiographic evidence), whereas we reported the individual components. The authors also reported that most of the patients (73.1%) had their statin therapy discontinued on admission. Neither study incorporated a clinical care protocol of initiating or continuing statin therapy following hemorrhage, which is an important distinction.13, 14 The theoretical benefit of acute statin therapy following hemorrhage remains controversial.20, 21 Independent of their lipid-lowering effects, statins improve cerebral autoregulation by upregulation of endothelial nitric oxide synthase, increasing availability of nitric oxide.6, 7 In addition, plasma levels of markers of endothelial injury and astrocyte activation were markedly reduced following treatment with simvastatin.9 In prospective trials, acute statin treatment was associated with a reduced rate of delayed ischemic deficits and improved functional outcomes.8–11, 22–24 Pooled results of clinical trials of posthemorrhage statin use have shown conflicting results, which are likely limited by the small cohort analyzed (190 patients) or the differences in treatment used (pravastatin 40 mg vs simvastatin 80 mg).12, 25, 26 The results of the recently completed phase III trial Statins for Aneurysmal Subarachnoid Hemorrhage (STASH) will investigate this limitation because projected enrollment is expected to include nearly 800 patients. In other disease states such as acute coronary syndrome, the pleiotropic effects of statins on inflammatory mediators have been closely correlated with relative statin potency yet remain independent of their lipid-lowering effects.27–29 Based on this observation, it is reasonable to expect that statin potency may be correlated with treatment outcome in patients with SAH. Our analysis has a number of limitations. First, we observed a small percentage of patients who reported using a statin prior to admission (14%), consistent with previous analyses,13, 14 which likely predisposes our study to a type II error. We were also unable to ascertain the
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duration of statin use prior to admission or patient compliance, which may limit our findings. Despite these limitations, our analysis indicates that statin use prior to admission did not improve clinical and functional outcomes when acute therapy with pravastatin was used. Given the relatively low severity of SAH at our facility, the possibility for selection bias may be considered. Our institution is a tertiary care referral center and accepts advanced cases of intracranial hemorrhage. On further examination, our database enrolls more than 95% of all patients presenting with intracranial hemorrhage and thus is unlikely to be affected by selection bias.
8. 9. 10.
11.
12.
Conclusion Patients treated with statins prior to admission for SAH experienced similar neurologic outcomes compared with statin-naive patients. Statin use at the time of aneurysm rupture may confer little added protection, and early initiation of statin therapy after hemorrhage may provide sufficient pharmacologic benefit by the time subsequent pathologic processes such as vasospasm and related delayed ischemic injury manifest. The results of the recently completed STASH trial will further support or refute the benefit of statin therapy following SAH. Further, preadmission statin use may not confound the results of future studies of acute statin therapy for SAH. References 1. Kronvall E, Undren P, Romner B, Saveland H, Cronqvist M, Nilsson OG. Nimodipine in aneurysmal subarachnoid hemorrhage: a randomized study of intravenous or peroral administration. J Neurosurg 2009;110:58–63. 2. Choi HA, Ko SB, Chen H, et al. Acute effects of nimodipine on cerebral vasculature and brain metabolism in high grade subarachnoid hemorrhage patients. Neurocrit Care 2012;16:363–7. 3. Dankbaar JW, Slooter AJ, Rinkel GJ, Schaaf IC. Effect of different components of triple-H therapy on cerebral perfusion in patients with aneurysmal subarachnoid haemorrhage: a systematic review. Crit Care 2010;14:R23. 4. Egge A, Waterloo K, Sjoholm H, Solberg T, Ingebrigtsen T, Romner B. Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled study. Neurosurgery 2001;49:593–605. 5. Musahl C, Henkes H, Vajda Z, Coburger J, Hopf N. Continuous local intra-arterial nimodipine administration in severe symptomatic vasospasm after subarachnoid hemorrhage. Neurosurgery 2011;68:1541–7. 6. McGirt MJ, Lynch JR, Parra A, et al. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke 2002;33:2950–6. 7. Sabri M, Ai J, Marsden PA, Macdonald RL. Simvastatin recouples dysfunctional endothelial nitric oxide synthase in
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PRIOR STATIN USE AND OUTCOMES FOLLOWING SAH Lizza et al 27. Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G, Montinaro A. Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) randomized trial. J Am Coll Cardiol 2009;54:558–65. 28. Gibson CM, Pride YB, Hochberg CP, et al. Effect of intensive statin therapy on clinical outcomes among patients undergoing percutaneous coronary intervention for acute coronary syn-
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drome. PCI-PROVE IT: A PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22) substudy. J Am Coll Cardiol 2009;54:2290–5. 29. Kim JS, Kim J, Choi D, et al. Efficacy of high-dose atorvastatin loading before primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: the STATIN STEMI trial. JACC Cardiovasc Interv 2010;3:332–9.
