Effect of In-Hospital Initiation of Lipid-Lowering Therapy on Six-Month Outcomes in Patients With Acute Ischemic Stroke or Transient Ischemic Attack

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1 Effect of In-Hospital Initiation of Lipid-Lowering Therapy on Six-Month Outcomes in Patients With Acute Ischemic Stroke or Transient Ischemic Attack Poh-Shiow Yeh, MD a,, Huey-Juan Lin, MD, MPH a,, Chyi-Huey Bai, PhD b, Fang-I Hsieh, PhD b, Der-Shin Ke, MD, PhD a, Yi-Heng Li, MD, PhD c, *; the Taiwan Stroke Registry Early lipid-lowering therapy (LLT) has demonstrated clinical benefits in patients with acute coronary syndrome; however, little is known about early LLT in patients with stroke. We evaluated the effect of in-hospital initiation of LLT on the clinical outcomes of patients with stroke. The Taiwan Stroke Registry prospectively collected data from patients with acute ischemic stroke or transient ischemic attack. By July 31, 2008, 16,704 adult patients without previous LLT had been admitted and survived to discharge. The study end point was the composite outcome of recurrent stroke, ischemic heart disease, and all-cause death. We examined the effect of LLT at discharge on the clinical outcomes of these patients. A propensity analysis was done to adjust for selection biases in the prescription of LLT. At discharge, 4,032 patients (24%) had received LLT. At 6 months, 206 patients (5.1%) in the LLT group and 964 patients (7.6%) in the non-llt group had developed >1 component of the composite end point (p <0.0001). On multivariate Cox regression analysis, after adjustment for the potential confounders, LLT use at discharge was associated with a lower rate of the composite end point at 6 months (hazard ratio 0.78, 95% confidence interval 0.61 to 0.98, p 0.013). In conclusion, our data have indicated that LLT has been underused in patients with stroke. In-hospital initiation of LLT was associated with a better clinical outcome in patients with ischemic stroke or transient ischemic attack Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105: ) Lipid-lowering therapy (LLT) with statins reduces the incidence of cardiovascular events. Survivors of ischemic stroke have a significantly greater risk of recurrent stroke and myocardial infarction during follow-up. 1 3 The objectives of the present study were to use the data from a nationwide hospital-based stroke registry to describe the use of LLT at discharge among patients admitted because of ischemic stroke or transient ischemic attack (TIA) and to evaluate the influence of in-hospital initiation of LLT on the prognosis of these patients. The Taiwan Stroke Registry, launched on May 1, 2006 and engaged in 37 hospitals around Taiwan, prospectively collected the data of patients who had developed acute ischemic stroke or TIA and were hospitalized within 10 days after onset. The patients fulfilling the following criteria were recruited for the present analysis: age 18 years, no LLT use before admission, and surviving until discharged from the hospital. The data were systematically collected according to predetermined registry protocols and included demographic data, vascular risk factors, medications before admission, laboratory test results, treatments during admission, and follow-up information after discharge. The National Institutes of Health Stroke Scale score was used to evaluate the stroke severity at admission. Patients with ischemic stroke or TIA underwent etiology evaluations at the discretion of their attending physicians. The typical evaluations included blood examinations for fasting blood sugar and lipid panels (i.e., total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), carotid ultrasonography, neuroimaging studies (i.e., computed tomography or magnetic resonance imaging with angiography), and cardiac studies (i.e., electrocardiography, transthoracic or transesophageal echocardiography). Hypertension or diabetes was considered present when a patient had either received antihypertensive or antidiabetic treatment before admission or hypertension or diabetes mellitus was diagnosed during the hospital stay. Ischemic heart disease was defined as a history of physia Department of Neurology, Chi-Mei Medical Center, Tainan, Taiwan; b Chi-Chin Huang Taiwan Stroke Registry, Taipei, Taiwan; and c Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan. Manuscript received May 30, 2009; revised manuscript received and accepted July 14, This work was supported in part by grants from the Bureau of Health Promotion, Department of Health, Taiwan (DOH95-HP-1102, DOH96- HP-1105, DOH97-HP-2102, DOH98-HP-1102). Additional supports were from the Ministry of Education Topnotch Stroke Research Center at Taipei Medical University; Department of Health Clinical Trial and Research Center of Excellence at Wan-Fang Hospital (DOH-TD-B ) and Dr. Chi-Chin Huang Research Foundation. TSR is dedicated to Dr. Chi-Chin Huang and family for their generous support of this nation-wide initiative for surveillance of quality in stroke care and prevention. *Corresponding author: Tel: ( 886) , ext. 2392; fax: ( 886) address: heng@mail.ncku.edu.tw (Y.-H. Li). Drs. Yeh and Lin contributed equally to this work. Methods /10/$ see front matter 2010 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 Miscellaneous/In-Hospital Lipid-Lowering Therapy and Ischemic Stroke 1491 Table 1 Clinical patient characteristics Variable LLT at Discharge (n 4,032) No LLT at Discharge (n 12,672) p Value Age (years) Men 2,305 (57%) 7,719 (61%) Hypertension 3,223 (80%) 9,629 (76%) Diabetes mellitus 1,820 (45%) 4,642 (37%) Current smoker 1,275 (32%) 3,650 (29%) Previous ischemic stroke 929 (23%) 3,313 (26%) Previous hemorrhagic 102 (3%) 334 (3%) stroke Ischemic heart disease 426 (11%) 1,518 (13%) Atrial fibrillation 280 (7%) 1,964 (16%) Lipid profile Total cholesterol (mg/dl) Triglycerides (mg/dl) Low-density lipoprotein (mg/dl) High-density lipoprotein (mg/dl) Low-density lipoprotein/ high-density lipoprotein ratio Stroke subtype Large artery 1,177 (30%) 3,107 (27%) atherosclerosis Small vessel occlusion 1,791 (47%) 4,558 (39%) Cardiac embolism 242 (6%) 1,417 (12%) Other specific etiology 31 (1%) 177 (2%) Undetermined 607 (16%) 2,402 (20%) National Institutes of 5 (2 7) 6 (2 9) Health Stroke Scale score at admission Discharge medications Antiplatelet drugs 3,670 (90%) 10,466 (82%) Warfarin 264 (7%) 1,071 (9%) Antihypertensive drugs 2,120 (53%) 5,847 (46%) Antidiabetic drugs 1,548 (38%) 3,530 (28%) Propensity score 0.3 ( ) 0.2 ( ) Data are presented as mean SD or numbers of patients (%); National Institutes of Health Stroke Scale score and propensity score are presented as median (interquartile range). cian-diagnosed coronary heart disease, myocardial infarction, angina pectoris, or unstable angina. Atrial fibrillation was diagnosed when present on the admission electrocardiogram. According to their clinical symptoms and the laboratory data, the patients cerebral ischemia etiology was categorized according to the Trial of ORG in Acute Stroke Treatment (TOAST) classification 4 as large artery atherosclerosis, small vessel occlusion, cardiac embolism, or other specific etiologies. The medication prescribed for long-term use after discharge was categorized as medication at discharge. Antiplatelet drug use at discharge was defined as documentation that the patient was given aspirin, clopidogrel, dipyridamole, or ticlopidine, alone or in combination. Antihypertensive drug use at discharge was defined as documentation that the patient was given a diuretic, calcium antagonist, angiotensin-converting enzyme inhibitor, angiotensin receptor antagonist, or blocker, alone or in combination. Antidiabetic drug use at discharge was defined as documentation that the patient was given sulfonylurea, metformin, thiazolidinedione, an -glucosidase inhibitor, or insulin, alone or in combination. LLT use at discharge was defined as documentation that the patient was taking a statin, fibrate, nicotinic acid, cholestyramine, or ezetimibe, alone or in combination. After discharge, the patients were followed up at the original hospital outpatient clinics or by telephone interview by trained research assistants if they could not attend the clinic visits. The outcomes of interest for the present study were a composite end point of all-cause mortality, recurrent stroke, or the occurrence of ischemic heart disease, whichever came first. Recurrent stroke was defined as the sudden appearance of a new neurologic deficit indicating different vascular territories or a worsening of previous neurologic deficits and fitting the definition of TIA or ischemic or hemorrhagic stroke. All the recurrences were verified by neurologists. The diagnosis of ischemic heart disease included physician-diagnosed myocardial infarction, unstable angina, or angina requiring hospitalization for a coronary revascularization procedure. The medical information was obtained from all available medical records. When death occurred outside a hospital or the medical records for the death were unobtainable, death certificates were used. Continuous variables are presented as the mean SD or median and interquartile ranges, and categorical variables are presented as numbers and percentages. The clinical characteristics of the groups were compared using a chisquare test for categorical variables and an unpaired Student t test or Mann-Whitney rank sum test for continuous variables. To adjust for the bias inherent to the decision to provide LLT at discharge, a propensity analysis 5 was performed using logistic regression analysis to determine the probability of a patient receiving LLT at hospital discharge. The variables included in the propensity score model are listed in Table 1. The c-statistic was calculated to estimate the goodness-of-fit of the propensity score model. The propensity score was compared between patients with and without LLT at discharge and subsequently forced as a continuous variable into a Cox model, along with other predictive variables associated with the outcome of interest. Kaplan-Meier curves were constructed and stratified by LLT use at discharge. The comparison was made using the log-rank test. Univariate and multivariate Cox proportional hazards models were used to examine the association between the clinical characteristics and LLT with the composite end point. Collinearity between LLT use at discharge with the use of other medications at discharge was assessed with Spearman s rank correlation. Univariate Cox regression analysis was performed of all baseline characteristics. The predictors with p 0.15 on univariate analysis were then entered into a multivariate model using a forward stepwise selection algorithm with a threshold of For the multivariate analyses, LLT and the propensity score were forced into the model. The hazard ratios and their 95% confidence intervals (CIs) were calculated. A 2-tailed p value of 0.05 was considered statistically significant. The statistical analyses were performed using Statistical Analysis Systems, version 9.1 (SAS Institute, Cary, North Carolina).

3 1492 The American Journal of Cardiology ( Table 2 Distribution of composite end point at 6 months of follow-up Variable Overall (n 16,704) LLT Use at Discharge (n 4,032) No LLT Use at Discharge (n 12,672) Composite end point 1,170 (7.0%) 206 (5.1%) 964 (7.6%) All-cause mortality 672 (4.0%) 80 (2.0%) 592 (4.7%) Ischemic heart disease 32 (0.2%) 5 (0.1%) 27 (0.2%) Stroke 507 (3.0%) 127 (3.2%) 380 (3.0%) Data are presented as numbers of patients (%). Table 3 Univariate Cox proportional hazards analyses for composite end point at 6 months Variable HR 95% CI p Value Age (per year) Gender (male vs female) Hypertension (yes vs no) Diabetes (yes vs no) Current smoker (yes vs no) Cholesterol on admission ( 200 vs mg/dl) Previous ischemic stroke (yes vs no) Previous hemorrhagic stroke (yes vs no) Previous ischemic heart disease (yes vs no) Arial fibrillation (yes vs no) Stroke subtype (LAA vs non-laa) National Institutes of Health Stroke Scale score at admission (per 1 unit) Antiplatelet drugs at discharge (yes vs no) Warfarin at discharge (yes vs no) Antihypertensive drugs at discharge (yes vs no) Antidiabetic drugs at discharge (yes vs no) LLT at discharge (yes vs no) HR hazard ratio; LAA large artery atherosclerosis. Table 4 Multivariate Cox proportional hazards analyses for composite end point at 6 months Variable HR 95% CI p Value Age (per year) Diabetes (yes vs no) National Institutes of Health Stroke Scale score at admission (per 1 unit) Arial fibrillation (yes vs no) LLT at discharge (yes vs no) Abbreviations as in Table 3. Figure 1. Kaplan-Meier curve for probability of being event free at 6 months stratified by LLT at discharge. Results During the study period to July 31, 2008, 16,704 subjects with ischemic stroke or TIA qualified for the present study. Their mean age was 68.3 years (range 19 to 101), and 60% were men. Of these 16,704 patients, 4,032 (24%) had received LLT before hospital discharge. The baseline clinical characteristics are listed in Table 1. The serum levels of cholesterol, triglycerides, and low-density lipoprotein and the low-density lipoprotein/high-density lipoprotein ratio were greater in the patients receiving LLT at discharge. The LLT group also was more likely to be prescribed concomitant antiplatelet, antihypertensive, and antidiabetic drugs at discharge. According to the propensity score analysis, the decision to initiate LLT during the hospitalization was independently associated with hypertension (95% CI 1.08 to 1.32, p ), large artery atherosclerosis (95% CI 1.15 to 1.46, p ), small vessel occlusion (95% CI 1.11 to 1.40, p ), and concomitant therapy with an antiplatelet drug (95% CI 1.60 to 2.17, p ), antihypertensive drug (95% CI 1.05 to 1.24, p 0.002), or antidiabetic drug (95% CI 1.20 to 1.56, p ). The c-statistic for goodness-of-fit of the propensity score model was 0.64, indicating that the propensity model discriminated satisfactorily between patients who were prescribed LLT at discharge and those who were not. The follow-up rate was 94.2% at 6 months. During follow-up, 1,170 patients (7%) had developed one of the components of the composite end point, including 206 patients (5.1%) and 964 patients (7.6%) with and without LLT at discharge, respectively (p ; Table 2). The 6-month cumulative risk of the composite end point was 2.1% (95% CI 1.5% to 2.8%) for the LLT group and 4.8% (95% CI 4.3% to 5.3%) for the non-llt group. The Kaplan-Meier analysis showed a significant benefit associated with using LLT at discharge (Figure 1). The univariate Cox proportional hazards analyses revealed a significant reduction in the risk of the composite end point at 6 months of follow-up in patients who received LLT at discharge (hazard ratio 0.66, 95% CI 0.57 to 0.77; Table 3). In the multivariate analyses, after adjusting for the clinical variables and the propensity score, age, diabetes, National In-

4 Miscellaneous/In-Hospital Lipid-Lowering Therapy and Ischemic Stroke 1493 stitutes of Health Stroke Scale score at admission, and atrial fibrillation were selected as independent predictors of the composite end point. However, LLT at discharge was significantly associated with a lower rate of the composite end point, with an adjusted hazard ratio of 0.78 (95% CI 0.61 to 0.98; Table 4). No clinically relevant interaction terms improved the multivariate model; accordingly, it was judged that no significant interaction was present between LLT at discharge and age, diabetes, or the National Institutes of Health Stroke Scale score at admission. The Spearman correlation coefficients between LLT and the other concomitant drugs (antiplatelet drugs, warfarin, antihypertensive drugs, and antidiabetic drugs) was to Therefore, the issue of collinearity, i.e., high correlation between two variables to hinder the separate effect assessment of each variable on the outcome, was neglected. Discussion Recently, the use of LLT, especially statins, for the treatment of ischemic stroke has received much attention. Statins confer a neuroprotective effect by increasing nitric oxide bioavailability, which, in turn, regulates cerebral perfusion and improves endothelial function. 6 However, it remains uncertain clinically whether early statin initiation is beneficial after an ischemic stroke event. Several studies have reported that patients who were receiving treatment with statins before or during an acute ischemic stroke had a less severe stroke and experienced reduced post-stroke mortality. 7 9 A recent animal study demonstrated that intravenous statin injection immediately after middle cerebral artery occlusion in mice resulted in decreased brain infarction and better functional recovery. 10 However, the results from a recent human clinical trial showed that very early statin use, within the 3 to 12 hours after symptom onset of acute ischemic stroke, produced no reduction of inflammatory biomarkers and a nonsignificant increase in post-stroke mortality. 11 Currently, no specific studies have addressed the effect of in-hospital initiation of statins on the clinical outcomes after acute ischemic stroke. The current American Heart Association/American Stroke Association guidelines have suggested that statins should be initiated during hospitalization for a first ischemic stroke 12 ; this was largely based on clinical trial data from patients with acute coronary syndrome but not acute stroke. Our prospective and largescale study cohort has allowed us to evaluate the effects of in-hospital initiation of LLT on the clinical outcomes of patients with acute ischemic stroke and TIA. A significant influence of LLT on the composite end point was observed at 6 months after discharge. The Kaplan-Meier curve (Figure 1) continued to separate during follow-up, indicating the importance of the early initiation of LLT during hospitalization and that the delay of LLT initiation might result in lost opportunities to reduce the events in the composite end point. The in-hospital initiation of LLT has also enhanced long-term adherence during follow-up in patients with stroke. 13 From the currently available data and our study results, it might be more important for all patients with acute ischemic stroke and TIA to start LLT during their hospital stay, rather than emphasizing the immediate use of LLT during the very acute stage of the stroke. Our study also demonstrated that LLT was underused in this nationwide sample of patients hospitalized for acute ischemic stroke or TIA. In the whole study cohort, only 24% of patients had received LLT at discharge. Among the patients with cerebral ischemia etiologies of large artery atherosclerosis and small vessel occlusion, 27% of patients had LLT initiated during hospitalization. Even in the highrisk patients with an ischemic heart disease history, only 12% had LLT initiated at discharge. The underuse of LLT in patients admitted because of acute ischemic stroke is a common phenomenon that has also been observed in other studies. In the Vienna Stroke Registry, only 23% patients with ischemic stroke or TIA had received statin treatment at discharge, 14 and in the Michigan Statewide Stroke Registry, only 12.9% of the patients with ischemic stroke or TIA had received LLT during hospitalization. 15 The benefits of in-hospital initiation of LLT in patients with an ischemic stroke or TIA found in the present study highlight the need to increase the LLT prescription rate during hospitalization. These data have also reaffirmed that the established guidelines should be carefully followed to improve patient prognosis. Our study had several potential limitations. After 2000, statins became the most commonly used LLT in Taiwan. 16,17 However, we did not have specific data on the percentage of statin use in the LLT medications for whole study population. One of the participating hospitals for which the medication data at discharge could be obtained showed that 94% of the LLT at discharge was statins. Second, we did not have information on the contraindications to LLT use in the study population; thus, the definite percentage of eligible patients for LLT at discharge was unknown. Third, our design was an observational study, not a randomized controlled trial. Additional adequately powered prospective randomized clinical trials are necessary to confirm our findings. Finally, we did not collect information on the LLT prescription rate among the different hospitals. Previous studies have shown that hospital variation is an important factor in determining the use of LLT at discharge. 14,15 Therefore, it was difficult to investigate the reason the LLT prescription rate at discharge was so low in our study. 1. Dennis MS, Burn JP, Sandercock PA, Bamford JM, Wade DT, Warlow CP. 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