Statins Improve Survival in Patients With Cardioembolic Stroke
Background and Purpose—The objective of this study was to investigate the potential benefits of statin therapy on mortality and stroke recurrence after cardioembolic stroke.
Methods—In this retrospective observational study, we analyzed data from 535 patients with first-ever cardioembolic stroke. Patients were classified into nonstatin, low-potency statin, and high-potency statin groups. The primary outcomes were time to mortality and time to recurrent stroke.
Results—The mean duration of follow-up was 22.2 months. The cumulative mortality rate was 7% at the end of the first year and 10% at the end of the third year. Statin therapy was independently associated with reduced mortality (hazard ratio, 0.237; 95% confidence interval, 0.080–0.703 for nonstatin versus low-potency statin; hazard ratio, 0.158; 95% confidence interval, 0.037–0.686 for nonstatin versus high-potency statin). Statin treatment did not affect the incidence of recurrent stroke in patients with cardioembolic stroke.
Conclusions—Statin therapy could be associated with reduced mortality in patients with cardioembolic stroke.
The beneficial effects of statins in patients with noncardioembolic stroke have been well documented.1,2 However, statin therapy in patients with cardioembolic stroke has not been supported by clinical evidence. Because cardioembolic stroke can be linked to the atherosclerotic disease, either directly in the cases of myocardial infarction and aortic complex atheroma, or indirectly in the cases of atrial fibrillation (AF),3 dilated or congestive cardiomyopathy,4 and thrombus in left ventricular wall,5 statins may also affect the outcomes of cardioembolic stroke. Based on this knowledge, we investigated the effect of statins for secondary prevention in cardioembolic stroke.
The study protocol was approved and supervised by the Institutional Review Boards of Korea University Medical Center. We retrospectively analyzed the data of subjects who were registered in a prospectively collected stroke registry from 3 university hospitals (Korea University Stroke Registry’s Anam, Guro, and Ansan arms) from January 2008 to December 2012. Among the 4175 subjects who were registered in the Korea University Stroke Registry during the study period, 661 first-ever ischemic stroke patients with cardioembolic stroke were initially recruited. We sequentially excluded 70 patients who were lost to follow-up <30 days from discharge, 33 with incomplete data, and 23 who died during admission. Finally, data from 535 patients were analyzed (Figure I in the online-only Data Supplement). All patients had ≥1 potential sources of cardioembolism, and AF was the most common potential source (Table I in the online-only Data Supplement). Because the main exposure of the present study was statin therapy after stroke occurrence, we classified the patients into 2 groups: the statin and nonstatin groups. The statin group was further divided into high-potency and low-potency statin groups. The high-potency statin group was defined by patients who were prescribed a dose and type of statin that was expected to reduce the initial low-density lipoprotein cholesterol level >50% (atorvastatin 40 mg, atorvastatin 80 mg, rosuvastatin 10 mg, rosuvastatin 20 mg, and simvastatin/ezetimibe 20/10 mg or 40/10 mg).6
The primary outcomes in this study were time to mortality from any cause and time to recurrent stroke. Therefore, the association between statin therapy and mortality or recurrent stroke in cardioembolic stroke was analyzed using Kaplan–Meier estimation and univariable and multivariable Cox proportional regression with subgroup analyses. In the multivariable model, variables with significant P values (<0.05) in univariable analysis, including National Institutes of Health Stroke Scale at admission and use of anticoagulants, were included with stepwise method. Finally, the effects of statins in patients with cardioembolic stroke were compared with those in patients with noncardioembolic stroke. For these analyses, we recruited 2116 subjects with noncardioembolic stroke who registered in the Korea University Stroke Registry during the study period (Figure I in the online-only Data Supplement). All statistical analyses were performed using SAS version 9.2 (SAS Institute, Inc, Cary, NC). The details of the methodology are described in the online-only Data Supplement.
Among the 535 patients, 295 (55.1%) were not prescribed a statin, 125 (23.4%) were prescribed a low-potency statin, and 115 (21.5%) were prescribed a high-potency statin. The mean duration of follow-up was 22.2 (median, 17.4; interquartile range, 8.0–34.1) months. Baseline characteristics are described (Table II in the online-only Data Supplement). Forty-two patients died (35 from the nonstatin group, 5 from the low-potency group, and 2 from the high-potency group): 11 from cardiac disease, 11 from recurrent stroke, 13 from other causes (including infection and cancer), and 7 from unknown causes. The cumulative mortality rate was 7% at the end of the first year and 10% at the end of the third year. With regard to recurrent stroke, 40 patients had a recurrence (29 from the nonstatin group, 12 from the low-potency group, and 7 from the high-potency group) during follow-up. The cumulative proportion of patients with recurrent stroke was 5% at the end of the first year and 13% at the end of the third year.
In patients with cardioembolic stroke, statin therapy was independently associated with reduced mortality (Table). Kaplan–Meier estimation shows that either low- or high-potency statin therapy was associated with reduced mortality (log-rank test; P=0.006; Figure). There was no difference in survival between the low- and high-potency statin groups. The relative benefit in terms of mortality of statin therapy showed no heterogeneity according to the demographic, clinical, or laboratory risk factors in subgroup analyses (Figure II in the online-only Data Supplement). However, statin therapy did not show a significant benefit in stroke recurrence (Table III in the online-only Data Supplement).
The beneficial effect of statin therapy for patients with noncardioembolic stroke was similar to the effect in patients with cardioembolic stroke (Table IV in the online-only Data Supplement). Statin therapy significantly reduced mortality in patients with noncardioembolic stroke. The interaction between cardioembolic and noncardioembolic stroke about the benefit of statins on mortality was not significant (P=0.099). However, the beneficial effect of statin therapy on recurrent stroke was also not observed in patients with noncardioembolic stroke.
Various aspects of the beneficial effect of statin therapy in patients with previous stroke have been previously reported. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study showed a 16% relative risk reduction of fatal or nonfatal stroke. Statin therapy was also associated with a reduction in major cardiovascular accidents.1 Subgroup analysis of the Heart Protection Study (HPS) showed statin-induced risk reduction in major coronary and vascular events in patients with previous stroke.2 Results from both studies suggest that patients with a previous stroke may benefit from statins via prevention of stroke and other major vascular events. However, it should be noted that patients in both studies were primarily at risk of atherosclerotic carotid or coronary vascular disease. In the SPARCL trial, patients with a major source of cardioembolic stroke (AF, valvular heart disease, and coronary artery disease [CAD]) were excluded.1 Information about the prevalence of cardiac arrhythmia was not reported in the HPS.2 Several registry-based observational studies have also shown a beneficial effect of statin therapy on stroke recurrence, mortality, and functional outcome in patients with acute ischemic stroke.7,8 However, these studies included patients with all stroke subtypes. As a consequence, it was not clear whether the patients with cardioembolic stroke without known CAD should be treated with a statin. Therefore, the results from the present study may shed light on this question.
In the present study, the effect of statins on mortality did not change according to the potency of the statin, although high-potency statins seemed to be superior. In addition, the effect was not restricted to patient age, total and low-density lipoprotein cholesterol levels, inflammatory condition (C-reactive protein level and white blood cell count), stroke severity (National Institutes of Health Stroke Scale score), anticoagulation therapy, or other previously known cardiovascular risk factors, including hypertension, diabetes mellitus, CAD, and cerebral atherosclerosis. It should be noted, when interpreting our results, that the levels of total and low-density lipoprotein cholesterol and the prevalence of concomitant CAD and cerebral atherosclerosis were lower in patients in the nonstatin group (Table II in the online-only Data Supplement). In other words, patients in the statin group were at greater risk for adverse vascular complications compared with patients who were not treated with statins. It may seem paradoxical that patients at high risk have better outcomes, considering the current guideline for use in the secondary prevention of stroke.9 Therefore, the results of the present study suggest that statin therapy has additional benefits beyond its current indications.
There are several aspects of the beneficial effect of statins in the present study that should be considered. Although AF was the most common source of cardioembolism in the present study, epidemiological studies have shown that patients with AF are more likely to have diabetes mellitus, hypertension, myocardial infarction, and congestive heart failure.3 Importantly, AF has been known to be a risk factor for CAD,10 and the major cause of death in patients with AF is CAD.11 Besides AF, ≈12% of cardioembolic strokes in this study were atherosclerotic in origin, and most of them were from an aortic complex atheroma (Table I in the online-only Data Supplement). However, the prevalence of complex aortic plaques may be higher, considering that complex aortic plaques were reported in ≈25% of patients with AF12 and the underperformance of transesophageal echocardiography in patients with stroke with documented AF. Therefore, the effect of statins on concomitant CAD and aortic complex atheroma13 via modifying lipid metabolism and increasing plaque stabilization mechanisms may be linked to the reduced mortality seen in the present study. Otherwise, the neuroprotective and anti-inflammatory (pleiotropic) effects of statins may also partially have a beneficial effect on mortality.
Stroke recurrence was not different among the groups of cardioembolic stroke in the present study. As a matter of fact, statins may not reduce stroke recurrence in cardioembolic infarction. Although antiplatelet effects of statins have been documented,14 recurrence of stroke in patients with cardioembolic stroke is mostly attributed to AF and is only effectively prevented by anticoagulation.15
This study has some limitations. Because of the retrospective study design, we could not exclude the presence of undetected bias. Furthermore, prescription of statins might not occur in patients with severe neurological deficits (selection bias). However, we attempted to minimize bias by adjusting all obtainable demographic and clinical data. Subgroup analyses also reconfirmed the effect of statins on mortality. Despite these limitations, our study showed a potential benefit of statin therapy in patients with cardioembolic stroke. Large, randomized, controlled studies should be performed to confirm the effect of statins on cardioembolic stroke.
Dr Choi designed the research and drafted the article. Dr Seo supervised the project, designed the study, performed statistical analyses, and drafted the article. Drs Kang, Jung, Cho, Oh, and Yu acquired and interpreted the data and made critical revisions to the article.
Sources of Funding
This work was partially supported by a grant from the Korean Stroke Society Young Investigator’s Award (KSS-2009-003) and by a Korea University Grant (K1032861).
Dr Seo received grants from the Korean Stroke Society and Korea University.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.005518/-/DC1.
- Received March 17, 2014.
- Accepted April 11, 2014.
- © 2014 American Heart Association, Inc.
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