Patterns and Predictors of Discharge Statin Prescription Among Hospitalized Patients With Intracerebral Hemorrhage
Background and Purpose—Many patients hospitalized with intracerebral hemorrhage are at high future risk for ischemic events and may benefit from stain therapy. However, little is known about patterns of statin prescription among patients with intracerebral hemorrhage, especially after the finding of higher hemorrhagic stroke risk in the statin treatment arm of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. We evaluated recent nationwide trends in discharge statin treatment after intracerebral hemorrhage hospitalization.
Methods—Using data from 25 673 patients with hemorrhagic stroke admitted to Get With Guidelines–Stroke participating hospitals between January 1, 2005, and December 31, 2007, we assessed factors associated with discharge statin prescription, including treatment over time and in relation to dissemination of the SPARCL results. Piecewise logistic multivariable regression models were fit to track statin use in various periods.
Results—Mean age was 67.9±15 years, 48.1% female, and discharge statin treatment in 39.5%. Variables independently associated with lower discharge statin use included female sex (OR 0.87, 95% CI, 0.82 to 0.93), prior stroke/transient ischemic attack (OR 0.85, 95% CI, 0.78 to 0.92), academic center (OR 0.87, 95% CI, 0.82 to 0.93), and Midwest region (OR 0.65, 95% CI, 0.56 to 0.80). Statin prescription climbed over the study period from 66.9% to 74.5% (P<0.001) among eligible patients with a decrease during SPARCL reporting (P=0.03) and then a return to prior levels thereafter.
Conclusions—Discharge statin prescription among hospitalized patients with intracerebral hemorrhage has modestly risen over time. The clinical implications of this care pattern among patients with intracerebral hemorrhage require further study.
- clinical trials
- health services
- hemorrhagic stroke
- intracerebral hemorrhage
- practice patterns
It was not until recently that a definitive benefit of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, or “statin,” therapy was proven in patients with prior strokes.1 Indeed, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial revealed that among persons with recent symptomatic cerebrovascular disease, and no established history of known coronary artery disease (CAD), the incidence of cardiovascular events was significantly fewer in those who received intensive statin treatment compared with placebo, but the benefit was slightly offset by a higher incidence of hemorrhagic strokes in the high-dose statin treatment arm.2
SPARCL showed that statins are beneficial in patients with ischemic stroke and transient ischemic attack of atherosclerotic origin,1 and guidelines have been updated to reflect this,3 but there are lingering questions about the role of statins in patients with stroke who are at risk for future hemorrhage by virtue of a past intracerebral hemorrhage (ICH)4 yet are simultaneously at great risk for ischemic events based on their clinical profile.5 Several hospital-based prevention measures are underused in hospitalized patients with hemorrhagic stroke compared with patients with ischemic stroke,6 but patterns of and variables associated with discharge statin prescriptions among patients with hemorrhagic stroke are unknown.
In this study, we aimed to evaluate recent national trends in discharge statin treatment among patients with ICH, investigate whether such treatment changed in response to the dissemination of SPARCL trial results, and determine patient and hospital characteristics associated with discharge use of statins among patients with ICH.
We used data from the Get With The Guidelines–Stroke (GWTG–Stroke) Program, a nationwide registry and quality improvement initiative aimed at facilitating adherence to guideline-based care in patients hospitalized with stroke and transient ischemic attack (TIA).7,8 Participating hospitals use an Internet-based Patient Management Tool (Outcome Sciences Inc, Cambridge, Mass) to enter data, receive decision support, and obtain feedback through on-demand reports of performance on quality measures. GWTG–Stroke participating hospitals record data from successive stroke and TIA hospital admissions but have the choice as to whether they want to specifically record data from consecutive hemorrhagic stroke admissions. Case ascertainment is done by clinical identification during the hospital encounter, retrospective surveillance of International Classification of Diseases, 9th Revision codes, or both. Trained hospital personnel abstract data on demographics, medical history, initial head CT findings, in-hospital treatment and events, and discharge treatment. A performance measure of the GWTG–Stroke Program is that every patients with ischemic stroke or TIA is discharged on lipid-lowering therapy in accord with prevailing expert consensus national guidelines.9 Although patients with ICH are excluded from this measure, discharge use and documented contraindications to statin therapy are collected on each patient.7 Each participating hospital received either human research approval to enroll cases without individual patient consent under the common rule or a waiver of authorization and exemption from subsequent review by their Institutional Review Board.
Factors evaluated for association with discharge use of statins in patients with ICH included sociodemographic and clinical variables at the individual and GWTG–Stroke hospital level previously shown to influence discharge treatment use. These included age, sex, race/ethnicity (analyzed for this article as white, black, Hispanic, or other),9 comorbid medical conditions (atrial fibrillation, prosthetic heart valve, previous stroke/TIA, coronary artery disease, or prior myocardial infarction [CAD/prior myocardial infarction were collected as a single field], carotid stenosis, diabetes, peripheral vascular disease, hypertension, dyslipidemia, and smoking), use of lipid-lowering treatment before admission, and hospital characteristics (bed size, annual number of stroke discharges, academic teaching status, and geographical region). Hospital bed size was used as a continuous variable, whereas annual number of stroke discharges were categorized as 0 to 100, 101 to 300, or >300. Hospital teaching status and hospital region (defined as Northeast, Midwest, South, or West) were determined using statistics published by the American Hospital Association.
In our secondary analysis, we assessed statin use in patients with ICH in the time periods before, during, and after dissemination of the SPARCL trial results.
Our primary outcome of interest was percent discharged on statin treatment. The secondary outcome of interest, analyzed only in an unadjusted manner, was percent discharged on lipid-modifying treatment, which included use of statins, fibrates, or unspecified lipid modifier therapy.
We analyzed the GWTG–Stroke data set from January 1, 2005, to December 31, 2007. For the SPARCL analysis, the time period was further categorized in relation to dissemination of the SPARCL results through conference and print publication: (1) pre-SPARCL reporting, January 2005 to April 2006; (2) during-SPARCL reporting, May 2006 to August 2006 (SPARCL trial results were first presented at an international conference in May 2006 and then published in print form as an article in August 2006); and (3) post-SPARCL reporting, September 2006 to December 2007.
Only patients with ICH were included in this analysis. During the study period, there were 49 324 ICH discharges from 917 hospitals. Patients who died before discharge (n=12 276), discharged to hospice care (n=2599), transferred to another acute care hospital (n=2347), left against medical advice (n=173), or in whom discharge status was missing (n=564) were excluded. Patients with known contraindications to lipid-lowering treatment (n=5378) and those with discharge lipid therapy status missing (n=314) were also excluded. For analyses aimed at assessing how SPARCL influenced clinical practice, we further excluded those with measured low-density lipoprotein cholesterol level <100 mg/dL (unless on cholesterol reducer at admission, n=12 928), history of atrial fibrillation or newly diagnosed atrial fibrillation (n=2260), or with a prosthetic heart valves (n=258) because these patients were excluded from SPARCL. Therefore, for the discharge statin prescription analysis, there were 25 673 patients (52% of overall ICH cohort) eligible patients from 838 sites, whereas for the analyses pertaining to SPARCL, there were 10 341 eligible (21% of overall ICH cohort) patients from 738 sites. The covariate missing rate was relatively low (approximately 3%). Missing data were imputed to the most prevalent category for use in regression modeling.
Univariate changes in discharge treatment use of statins and lipid-modifying treatment over time were tested using the Cochran-Mantel-Haenszel row-mean score test. Patient-level characteristics and hospital-level variables were then compared across the pre-SPARCL, during SPARCL, and post-SPARCL periods. Piecewise logistic multivariable regression models were fit to track statin use at discharge (reported as estimated ORs of a given month compared with the previous month) in the 3 SPARCL time periods. Individual- and hospital-level confounders were also controlled for in the regression models. The generalized estimating equation method with an exchangeable working correlation matrix was used to provide valid inference after accounting for within hospital correlation. Models containing only time effects are referred to as “unadjusted,” whereas models with complete adjustment for patient and hospital characteristics, in addition to the time effects, are referred to as “adjusted.” All probability values are 2-sided. Analyses were performed using SAS Version 9.1.3 (SAS Institute, Cary, NC).
Mean age among the study population of patients hospitalized with ICH was 67.9 years and a slight majority were men (Table 1). Other sociodemographic and clinical characteristics in the overall cohort as well as in the pre-, during-, and post-SPARCL periods are shown in Table 1. Three fourths of the cohort had a baseline history of hypertension, one fourth had diabetes, and mean admission low-density lipoprotein was 108.4 mg/dL. Most hospitals were located in the South and two thirds were academic. Discharge use of lipid-lowering medication was (10 734 of 25 673) 41.8% with statin prescription occurring in (10 135 of 25 673) 39.5% (Table 1). Admission use of lipid-lowering therapy was 32.3%. There were 4479 patients (47.4%) who were not taking lipid-lowering therapy on admission and had measured low-density lipoprotein >100 mg/dL who were newly discharged on a statin. Conversely, there were 8255 patients (15.8%) who were taking lipid-lowering therapy on admission who were not discharged on a statin or other lipid-lowering drug (that is, in whom lipid therapy was discontinued). Discharge statin treatment for patients who were previously not statin treatment on admission in January 2005 was 15.7% and rose to 37.1% in December 2007 (correlation between time and the discharge statin: P<0.0001), whereas discharge statin nontreatment for patients who were on statin treatment on admission in January 2005 was 16.7% and was essentially unchanged at 17.7% in December 2007 (correlation between time and the discharge statin, P>0.05). Comparing hospitals that chose to collect ICH data versus those that did not showed that there were no significant differences geographically, but those that collected ICH data were significantly larger in size and patient volume and were more likely to be academic hospitals.
Table 2 shows individual and hospital characteristics among patients with ICH discharged versus not discharged on statins. Patients with known CAD/prior myocardial infarction, diabetes, hypertension, dyslipidemia, or premorbid lipid modifier use were more likely to be discharged on a statin than not, whereas patients who were younger, female, or with higher admission National Institutes of Health Stroke Scale score were less likely to be discharged on a statin. Variables independently associated with discharge statin prescription in multivariable generalized estimated equation analysis taking into account clustering of data within hospitals are shown in Table 3. Notably, patients without discharge statin prescription were more likely to be admitted to academic hospitals or be admitted to a hospital in the South or Midwest of the country. Patients with known dyslipidemia or taking a cholesterol reducer at the time of admission were substantially more likely to receive discharge statin therapy.
Among 10 341 patients hospitalized with ICH who met criteria for the SPARCL trial, statin prescriptions increased in a linear fashion, from 66.9% to 74.5%, with a trend toward a slight deceleration in the rate of increase during the period of SPARCL reporting and resumption of the prior increase rates thereafter (Figure). Discharge lipid modifier prescription also climbed steadily and linearly over the study period (Figure). Compared with the period before the dissemination of the SPARCL results, during the time when the SPARCL trial result was disseminated, discharge statin use among patients with ICH showed a significant decrease (during SPARCL versus pre-SPAPCL probability value=0.03), which returned to the pre-SPARCL pattern thereafter. Adjusted odds of change in statin use per month among hospitalized patients with ICH during periods related to conference/print dissemination of the SPARCL trial results are shown in Table 4.
We found that use of statin medications at discharge in hospitalized patients with ICH rose modestly from 2005 to 2007. However, SPARCL trial reporting did not contribute significantly to this rise in discharge therapy and, in fact, there was actually a significant decrease in discharge statin therapy during SPARCL trial reporting. This reduction was temporary with a resumption of prior treatment patterns shortly thereafter, yet by 18 months after SPARCL was first reported, 1 in 4 statin-eligible patients (by SPARCL criteria) with hemorrhagic stroke was being discharged from the hospital without a statin. Although patients with ICH are at great risk of future cerebral thromboembolic events due to shared risk factors with ischemic stroke as well as pre-existing atherosclerotic disease,4 and statins may play an important role in lowering cardiovascular risk,10 we are unaware of any prior study that has examined statin prescription patterns among patients with ICH.
The significant but transient decrease in discharge statin therapy during SPARCL trial reporting among patients with ICH, followed by resumption of a slow (but not significant) increase in discharge statin therapy, may reflect initial clinician concerns about the higher incidence of hemorrhagic stroke among those who received high-dose statin treatment in SPARCL2 and concerns perhaps in part later mitigated by editorial commentary.11
Several factors that influence discharge statin prescription in patients with cerebral ischemia12 similarly do so in patients with ICH. Multivariable analyses that investigated odds of being discharged after an ICH on a statin indicated that hospitalized patients with ICH with known CAD/prior myocardial infarction or CAD risk equivalents (diabetes, carotid stenosis), or histories of major traditional vascular risk factor like hypertension, dyslipidemia, and recent smoking, were more likely to leave the hospital on a statin. These findings conflict with other data that suggest patients with polyvascular disease tend to receive less intense secondary prevention therapy.13 Interestingly, however, patients with a history of stroke or TIA were less likely to receive a statin at discharge after another cerebrovascular event, and we speculate that because stroke history is strongly associated with admission ICH severity and discharge outcome,14 clinicians may have been concerned about inadvertently exacerbating hemorrhagic risk through the antithrombotic actions of statins in these patients or they may have been worried about the increased risk of hemorrhage observed in SPARCL. As noted in other studies among hospitalized patients with stroke, being on cholesterol-reducing therapy before admission was the strongest predictor of being sent out of the hospital on 1.15,16
Other factors independently associated with lesser odds of being discharged from the hospital after an ICH on a statin have also been identified in data among patients with ischemic stroke and TIA.15,16 For instance, women who survive an ischemic stroke are generally less likely to receive optimal in-hospital management than their male counterparts, including discharge lipid modifier treatment.17,18 Persons residing in the South region of the United States tend to have poorer stroke outcomes than individuals elsewhere in the country,19 but our study found low discharge statin treatment in the Midwest region as well as the South. Consistent with a similar finding in an analysis of patients with ischemic stroke and TIA,12 academic hospitals participating in GWTG–Stroke were less likely to implement discharge statin treatment when compared with nonacademic hospitals. The reason for this lower treatment use at hospitals that harbor knowledgeable experts in the management of stroke is not immediately clear and will require further study, but in the case of patients with ICH, we speculate that it could reflect caution based on a greater awareness of the inherent risks of statin use in these patients.
Similarities notwithstanding, compared with statin use in hospitalized patients with ischemic stroke and TIA reported in prior studies,12 we found that there was a generally lower rise in statin use among patients with hemorrhagic stroke over the study period, and statins accounted for a higher proportion of the discharge lipid modifier treatment among patients with hemorrhagic strokes. These differences may have been related to concerns about statins not preventing recurrent hemorrhage, perhaps even increasing risk of recurrent hemorrhage, as well as a lack of direct guidance on this issue by disease-specific guidelines.
This study has limitations. First, many of the hospitals were located in the South or were academic, not all hospitals enrolled patients with ICH, and hospitals that signed up to participate in a quality improvement initiative like the GWTG–Stroke program were likely very motivated to improve the quality of their care in the first place, and therefore, the effect of calendar time with global changes in statin use may not necessarily be generalizable. Second, GWTG–Stroke data were obtained based on the medical record and subject to the accuracy and completeness of clinical documentation. Third, we could not investigate the relationship between stroke severity and odds of statin treatment because the National Institutes of Health Stroke Scale is not routinely collected in clinical practice and was thus incompletely available in the registry. Lastly, there were other major fluctuations in discharge statin treatment at other time points unrelated to SPARCL, so we cannot completely exclude chance as an explanation for the decrease observed in statin use during versus pre-SPARCL.
In summary, indications for statin treatment among patients with ICH are frequent and include conditions that confer high future ischemic vascular risk like CAD and diabetes. Our analysis suggests that discharge statin use after ICH is increasing unrelated to the timing of the SPARCL trial. There is a need for an adequately powered randomized trial to better define the benefits and risks of statin therapy in patients with ICH. Pending such a clinical trial, studies of clinical effectiveness to explore the overall and differential effects of statin therapy in “real-world” patients with ICH are warranted.
Sources of Funding
Get With The Guidelines Program (GWTG) is funded by the American Heart Association (AHA) and the American Stroke Association. GWTG is also supported in part by unrestricted educational grants to the AHA by Pfizer, Inc, New York, NY, and the Merck-Schering Plough Partnership (North Wales, Pa). E.E.S. receives research support from the National Institutes of Health (NIH) (National Institute of Neurological Disorders and Stroke [NINDS] R01 NS062028), the Canadian Institutes for Health Research, the Canadian Stroke Network and the Hotchkiss Brain Institute. G.C.F. receives research support from the NIH (significant).
L.H.S. serves as chair of the American Heart Association (AHA) Get With the Guidelines (GWTG) Steering Committee; serves as a consultant to the Research Triangle Institute, CryoCath, and to the Massachusetts Department of Public Health; and has provided expert medical opinions in malpractice lawsuits regarding stroke treatment and prevention. E.E.S. serves as a member of the GWTG Science Subcommittee and receives salary support from the Canadian Institutes for Health Research. A.F.H. is a member of the AHA GWTG analytical center at the Duke Clinical Research Institute and reports receiving research support from Johnson & Johnson, Medtronic, and Merck; honoraria from AstraZeneca; and serving on the speakers’ bureau for Novartis. A.F.H. has made available online a detailed listing of financial disclosures (http://www.dcri.duke.edu/research/coi.jsp). W.P. and D.M.O. are members of the Duke Clinical Research Institute that serves as the AHA GWTG data-coordinating center. G.C.F. serves as a consultant to Pfizer (modest), Merck (modest), and Schering Plough (modest); receives speaker honoraria from AstraZeneca (significant), Pfizer (significant), Merck (significant), Schering Plough (significant), Bristol Myers Squibb (significant), and Sanofi-Aventis (significant). There are no other disclosures to report.
- Received June 14, 2010.
- Accepted June 30, 2010.
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