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The role of statins in cardioembolic stroke
Journal of Clinical Neuroscience xxx (xxxx) xxx
Contents lists available at ScienceDirect
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Clinical study
The role of statins in cardioembolic stroke Bruno Kusznir Vitturi a,⇑, Rubens José Gagliardi a a
Department of Neurology, Santa Casa de São Paulo School of Medical Sciences, Dr. Cesário Motta Júnior Street 112 01221-020, São Paulo, Brazil
a r t i c l e
i n f o
Article history: Received 9 September 2019 Accepted 16 December 2019 Available online xxxx Keywords: Statins Cardioembolic stroke Ischemic stroke Outcomes
a b s t r a c t Background: Statin therapy has become one of the most important advances in stroke secondary prevention. Nevertheless, statin therapy in patients with cardioembolic stroke has not been supported by clinical evidence yet. This study aimed to investigate the effect of statins on the neurological outcomes after a cardioembolic stroke. Methods: We conducted a prospective cohort study including consecutive patients with cardioembolic stroke. Subjects were classified into non-statin, simvastatin 20 mg, simvastatin 40 mg, and highpotency statin groups. After 2 years, the functional outcome, stroke recurrence, major cardiovascular events, and mortality were assessed. Results: Among the 91 patients included in our cohort, there were 18 (19.8%) patients without statins, 30 (33.0%) with simvastatin 20 mg, 38 (41.7%) with simvastatin 40 mg and 5 (5.5%) with high-potency statins. Using simvastatin 40 mg was associated with a significantly lower incidence of stroke recurrence lower. Patients with simvastatin 40 mg and high-potency statins presented the best functional recovery throughout the follow-up (p < 0.01). Conclusions: The use of statins in patients with cardioembolic stroke may be beneficial in some cases, preventing stroke recurrence and improving functional outcomes. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Statin therapy has become the most important advance in stroke prevention since the introduction of aspirin and blood pressure-lowering therapies [1]. Some clinical trials have evaluated the efficacy and safety of statins after a stroke and their positive results led to an increase in the use of statins for these patients. Nevertheless, cardioembolic stroke patients were never included in most of these studies. In secondary prevention of stroke, statin therapy is highly recommended for patients with non-cardioembolic stroke (class I, level A) [2]. Currently, statin therapy in patients with cardioembolic stroke has not been supported by clinical evidence yet [3]. The heterogeneity of stroke subtypes is also important to guide stroke treatment. Cardiac embolism causes more than a third of all ischemic strokes [4]. As the treatment of hypertension and dyslipidemia improves, cardiac embolism has accounted for an increasing share of strokes all around the world [5,6]. Despite a decrease in the overall incidence of stroke, cardioembolic strokes have tripled during the past few decades and may triple again by 2050 based on projections from the United Kingdom, for example [7]. Clarifying ⇑ Corresponding author. E-mail address: [email protected] (B. Kusznir Vitturi).
whether statins are beneficial in patients with cardioembolic ischemic stroke would assist with a common management dilemma. Based on this knowledge, we investigated the effect of statins for secondary prevention in cardioembolic stroke.
2. Methods 2.1. Study design and cohort population We carried out a prospective cohort study composed of consecutive patients admitted to the Department of Neurology of a university-affiliated, tertiary referral hospital in São Paulo, Brazil, who were under regular clinical follow-up between January 2016 and June 2018. Patients aged 18 years or older with a first-ever ischemic cardioembolic stroke within 24 h of symptom onset were considered eligible for the study. Stroke was defined by World Health Organization criteria as a sudden focal neurologic deficit persisting longer than 24 h and confirmed by brain CT or MRI. We excluded patients who used other lipid-lowering drugs and those that were followed up for < 24 months for any reason. Patients were followed up by telephone interviews and face-toface assessments in the outpatient department for a period of 2 years. The interviews were conducted by senior neurologists who were completely blinded to the study. All participants
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Please cite this article as: B. Kusznir Vitturi and R. José Gagliardi, The role of statins in cardioembolic stroke, Journal of Clinical Neuroscience, https://doi. org/10.1016/j.jocn.2019.12.028
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provided written informed consent before inclusion and the research protocol was approved by our local ethics committee.
2.2. Baseline measures and comorbidities Baseline characteristics of stroke patients were recorded on admission. When the patient was discharged, information about stroke subtype, treatment in hospital, complications, laboratory tests, and CT and/or MRI findings were recorded. The data collectors were not aware of the study. Stroke severity was measured using the NIH Stroke Scale (NIHSS) score on hospital admission. Cardioembolic stroke was classified using the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) system [8]. Statins were prescribed without consideration of the lowdensity lipoprotein cholesterol level. Consecutive patients were distinguished into 4 groups according to the particularities of statin therapy. One group consisted of patients receiving simvastatin 20 mg per day and another group, receiving simvastatin 40 mg per day. Patients receiving atorvastatin 3 40 mg per day or rosuvastatin 3 10 mg per day were regarded as receiving high-intensity statin therapy. 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 greater than 50% [9]. Patients who didn’t use statins were included in a separate group as well. Statin use onset was registered for each patient. Previous statin treatment referred to regular use of statins at least 1 month before the stroke. Treatment in the acute phase was defined as statins initiated within 72 h after stroke onset and late-onset treatment were defined as when it was initiated 3 days after stroke onset. Adherence to statin treatment was evaluated using the 8-item Morisky Medication Adherence Scale (MMAS-8) [10]. Total scores range from 0 to 8 and patients were considered adherent only with scores greater than 6.
3. Main outcomes measures The individuals were followed until death or until 2 years after the stroke onset. If no clinical evaluation could be performed during this period, first the patient was searched in the National Registry of Death to detect a possible death before being excluded from the analysis. The outcome variables include all-cause mortality, stroke recurrence (ischemic or hemorrhagic) and major cardiovascular events. Functional outcome was assessed using the modified Rankin Scale (mRS) at 7 days, 30 days, 6 months and 2 years after hospital admission for ischemic stroke. An unfavorable outcome was defined as an mRS score 3 and a favorable outcome was defined as mRS score 2. Each patient had the mRS calculated by two different doctors, one of whom was blind to the study. In case of discrepancy, the opinion of the head of the stroke outpatient clinic was consulted.
3.1. Statistical analysis Categorical variables were analyzed using the chi-square test or Fisher’s exact test and differences in continuous variables were assessed using the student’s t-test (parametric test) or the MannWhitney test (non-parametric test). Odds ratios (ORs) were derived from a multivariable logistic regression with each outcome categorized by statin exposure. Confounding variables included age, sex, stroke severity, medications, smoking and other comorbidities [11]. The limit for significance was set at 2-tailed p = 0.05. All analyses were conducted using SPSS, version 23.0.
4. Results The crude cohort consisted of 523 S patients of all TOAST types. After the etiological investigation, 102 were classified as cardioembolic strokes. We sequentially excluded 11 patients who fulfilled the exclusion criteria or lost of follow-up (Fig. 1). Finally, data from 91 patients were analyzed (Table 1). There were no differences in baseline characteristics between participants and those patients who were lost to follow-up. The mean age of the participants was 61.0 (SD 16.8) years and 44 (48.3%) were female. There were 18 (19.8%) patients without statins, 30 (33.0%) with simvastatin 20 mg, 38 (41.7%) with simvastatin 40 mg and 5 (5.5%) with high-potency statins. Most enrolled patients were pre-stroke statin non-users (n = 78, 85%). Only 37 (40.6%) of subjects begun statin treatment at stroke onset. Among statin users, there were 10 (13.7%) cases of statin withdrawal and 30 (41.1%) patients presented satisfactory adherence to the treatment. One patient died (simvastatin 20 mg group) and 2 patients had major cardiovascular events (one using high-potency statins and others without statins). There was one case of hemorrhagic stroke, which was a non-statin user. Concerning recurrent stroke, 27 patients had a recurrence (6 from the nonstatin group, 11 from the simvastatin 20 mg group, and 6 from the simvastatin 40 mg and 4 from the high-potency group) during follow-up. Detailed description of the profile of the patient who had another stroke is represented in Fig. 2. The median mRS was 2 and 54 (59.3%) had a favorable functional outcome. Patients who received simvastatin 40 mg presented lower risk of having another stroke during the 2-year follow-up (OR = 0.28, 0.10–0.80; p = 0.02) (Table 2). Those in other subgroups didn’t show any difference regarding the incidence of stroke recurrence. Discontinuing statin therapy was associated with increased odds of having a poor functional outcome (OR = 0.05, 0.006– 0.46; p = 0.002). Furthermore, patients that presented a satisfactory adherence to treatment were more likely to have a good functional outcome (OR = 2.28, 0.82–6.30; p = 0.05). Concerning the trend over the 2-year follow-up, patients with simvastatin 40 mg and high-potency statins presented the best functional recovery compared to other subgroups (p < 0.01) (Fig. 3).
5. Discussion Various aspects of the beneficial effect of statin therapy in patients with previous stroke have been previously reported. However, it should be noted that patients in statins clinical studies were primarily at risk of atherosclerotic carotid or coronary vascular disease. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial [12], patients with a major source of cardioembolic stroke (AF, valvular heart disease, and coronary artery disease) were excluded and therefore the benefits of statin therapy should not be generalized to include nonatherosclerotic stroke patients. Other several observational studies have also shown a beneficial effect of statin therapy on stroke recurrence, mortality, and functional outcome in patients with acute ischemic stroke [13]. However, these studies included patients with all stroke subtypes. As a consequence, currently, it is not clear whether patients with cardioembolic stroke should be treated with a statin. The results from the present study may shed light on this question. Defining whether it is beneficial to prescribe statins for cardioembolic stroke patients can either save them from the costs and adverse effects of medication or ensure that they take advantage of the effects already evident in patients with other types of stroke. Long-term treatment with statins reduces the risk of ischemic stroke, even though hypercholesterolemia is not a strong risk fac-
Please cite this article as: B. Kusznir Vitturi and R. José Gagliardi, The role of statins in cardioembolic stroke, Journal of Clinical Neuroscience, https://doi. org/10.1016/j.jocn.2019.12.028
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Fig. 1. Flow chart illustrating study design and number of patients.
Table 1 Baseline and clinical characteristics of patients according to statin subgroups.
Number Age, years, mean, SD Female sex Hypertension Diabetes Coronary artery disease Atrial fibrillation Previous stroke Dyslipidemia Smoking Alcohol abuse Previous use Congestive cardiac failure Early onset Good adherence Thrombolysis Anticoagulation Carotid stenosis NIHSS, median, (min – max) Discontinuation
Total (n.o., %)
Without statin (no., %)
Simvastatin 20 mg (no., %)
Simvastatin 40 mg (no., %)
High-potency statin
p-value
91 (100) 61.1, 13.0 44 (48.3) 70 (76.9) 25 (27.5) 20 (22.0) 49 (53.8) 20 (22.0) 16 (17.6) 24 (26.4) 12 (13.2) 13 (14.3) 31 (34.1) 33 (32.3) 29 (31.9) 14 (15.4) 61 (67.0) 4 (4.4) 5 (0–32) 9 (9.9)
18 (100) 55.9, 13.0 11 (61.1) 12 (66.6) 4 (22.2) 2 (11.1) 9 (50.0) 4 (22.2) 2 (11.1) 6 (33.3) 0 (0) 0 (0) 4 (22.2) 0 (0) 0 (0) 3 (16.7) 11 (61.1) 0 (0) 6 (0–23) 0 (0)
30 (100) 61.2, 12.2 13 (43.3) 25 (83.3) 11 (36.7) 8 (26.6) 17 (56.7) 6 (20.0) 9 (30.0) 9 (30.0) 3 (10.0) 6 (20.0) 9 (30.0) 14 (46.6) 12 (40.0) 3 (10.0) 16 (53.3) 1 (3.3) 5 (0–30) 4 (13.3)
38 (100) 62.6, 13.0 19 (50.0) 28 (73.7) 8 (21.1) 7 (18.4) 19 (50.0) 10 (26.3) 4 (10.5) 8 (21.0) 9 (23.7) 3 (7.9) 16 (42.1) 17 (44.7) 15 (39.5) 8 (21.0) 30 (78.9) 3 (7.9) 6 (0–28) 4 (10.5)
5 (100) 66.6, 15.7 1 (20.0) 5 (100) 2 (40.0) 3 (60.0) 4 (80.0) 0 (0) 1 (20.0) 1 (20.0) 0 (0) 4 (80.0) 2 (40.0) 2 (40.0) 2 (40.0) 0 (0) 4 (80.0) 0 (0) 8 (2–28) 1 (20.0)
0.23 0.50 0.43 0.59 0.13 0.84 0.81 0.22 0.99 0.07 < 0.001 0.64 0.47 0.56 0.63 0.17 0.71 0.79 0.81
tor for stroke [14]. An explanation for this apparent paradox is becoming clear as the role of statins on neuroprotection is being elucidated. This group of drugs is proven to exert multidirectional effects, including effects on reactive oxygen species development, clot formation, and brain plasticity. Therefore, despite the primary interest and research in statin therapy being about the atherosclerotic pathomechanism of stroke, there has been emerging evidence
of potential beneficial effects of this group of drugs in cardioembolic stroke patients. Lee et al. revealed that statin-users present greater collateral status in cardioembolic stroke, for example [3]. There are several aspects of the beneficial effect of statins in the present study that should be considered. Since AF was the most common source of cardioembolism in the present study, epidemiological studies have shown that patients with AF are more likely
Please cite this article as: B. Kusznir Vitturi and R. José Gagliardi, The role of statins in cardioembolic stroke, Journal of Clinical Neuroscience, https://doi. org/10.1016/j.jocn.2019.12.028
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Fig. 2. Clinical profile of patients with stroke recurrence.
Table 2 Multivariable analysis of the independent clinical predictors of stroke recurrence and good functional outcome expressed in odds ratio (OR) with 95% confidence interval (95% CI). Favourable functional outcomes
Without statin Simvastatin 20 mg Simvastatin 40 mg High-potency statin Previous use Discontinuation Early onset Good adherence
Stroke recurrence
OR (95% CI)
p-value
OR (95% CI)
p-value
0.57 (0.18–1.75) 0.85 (0.32–2.23) 1.9 (0.7–5.08) 0.73 (0.11–4.68) 1.3 (0.36–4.62) 0.05 (0.006–0.46) 2.28 (0.82–6.3) 3.2 (1.07–9.91)
0.49 0.93 0.29 0.87 0.91 0.002 0.16 0.05
1.23 (0.41–3.73) 1.62 (0.63–4.15) 0.28 (0.10–0.80) 2.1 (0.52–8.60) 2.32 (0.70–7.72) 2.19 (0.60–7.93) 1.04 (0.41–2.66) 0.62 (0.22–1.69)
0.9 0.43 0.02 0.49 0.28 0.38 0.88 0.49
Fig. 3. Functional outcome of patients over 2 years after cardioembolic stroke according to statin subgroups.
to have diabetes mellitus, hypertension, myocardial infarction, and congestive heart failure [15,16]. Our findings of an association of simvastatin 40 mg use with reduced stroke recurrence are consonant with some prior studies conducted in general stroke population that strongly suggest that statins are associated with a reduction in the absolute risk of ischemic strokes [17]. It also provides complimentary evidence
against the results from a recent cohort study of stroke patients with atrial fibrillation in which the statin therapy completely failed to reduce recurrent stroke risk [18]. Nevertheless, indeed, not all patients of our cohort benefited from the statin’s power to prevent a second stroke. A reasonable explanation is the contribution of anticoagulation in the secondary prevention of patients with cardioembolic stroke. Only patients receiving simvastatin double dose
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had any real additional benefit in preventing a stroke from the already installed role of anticoagulation. Probably due to the small number of patients included with high potency statins, we had no evidence for this treatment subgroup. Furthermore, high-intensity statin and high dosages of simvastatin proved to be the most effective treatment modality in reducing long-term functional limitations. There were no differences in baseline clinical characteristics that may have influenced stroke prognosis. Therefore, reinforced by multivariate analysis, the most logical explanation for the observed difference in neurological outcomes between the groups is the effect of statins. Our study has shown that only proper and continuous use of statins can offer any benefit in patients with cardioembolic stroke. This is in line with previous studies which demonstrated that the suboptimal use of statin could interrupt the beneficial effects. A recent prospective study demonstrated that adherent use of statin had substantial long-term benefits on the prevention of adverse events after acute ischemic stroke [19]. This is especially important due to the high unsatisfactory adherence rate observed, which is consistent with the rates of a recent study [20]. Besides, we observed that statin therapy discontinuation may imply an increased risk of poor functional outcomes. Indeed, statin withdrawal was already associated with increased risk of early neurological deterioration, dependency after stroke [21] and all-cause mortality [22]. Blanco et al. indicated that statin withdrawal not only suppresses brain protection of previous treatment but causes deleterious effects in comparison with the lack of statin-linked protection at stroke onset [21]. Previous studies indicated that statin beneficial effect is partly lost by an increased risk of hemorrhagic stroke [23]. Theoretically, this issue is even more important in cardioembolic stroke because many patients are anticoagulated. Interestingly, in our cohort, there was no statistical difference between the groups regarding the incidence of hemorrhagic stroke. Nevertheless, the safety of statin therapy in the secondary prevention of cardioembolic stroke needs to be better established in further studies. The strengths of this study include that our study cohort was prospectively followed up and details could be acquired by a comprehensive review of their medical records, by telephone interviews and by face-to-face assessments with neurologists. Also, investigators who prescribed statins and those who verified the outcomes were blinded to the study. In our cohort, patients could receive statins regardless of having dyslipidemia and the TOAST stroke subtype. Many previous observational studies that investigated the effects of statins in stroke were biased due to the selection criteria of patients which compromises the impact of the study. Furthermore, we could perform detailed monitoring of multiple potential confounding factors in our research and rigorous definitions of outcomes were applied. We also compared different doses and types of statin treatments, which is different from many previous studies that just consider the patient ‘‘with or without statin”. This study has also some limitations that need to be acknowledged to better interpret the results. The size of the group could have limited the mortality analysis of our study. Because our study is a single-center, hospital-based study, rather than a communitybased study, it is unclear to what extent findings can be generalized. Nevertheless, there are no restrictions to be admitted to our hospital, and we included all consecutive cases admitted. Besides, the prospective and single-center design allowed us to collect information systematically and to uniformly verify both the qualifying event as well as follow-up information in all patients, which reduces the risk of information bias. The biases inherent in an observational study are also applicable to our research. However, conducting a randomized clinical trial would not currently be
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possible because of the already existing evidence of the benefit of statin therapy for stroke patients. 6. Conclusions The etiology of stroke should always be considered for the adoption of effective secondary prevention strategies. The use of statins in patients with cardioembolic stroke may be beneficial in some cases, preventing stroke recurrence and improving functional outcomes. The recommendation to start on statin treatment after a cardioembolic stroke needs to be investigated in further randomized clinical trials. Acknowledgments None. Conflict of interest The authors declare that they have no competing interests. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.12.028. References [1] Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009;8(5):453–63. https://doi.org/10.1016/S1474-4422(09)70058-4. [2] Ringleb PA, Bousser MG, Ford G, et al. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25 (5):457–507. https://doi.org/10.1159/000131083. [3] Lee MJ, Bang OY, Kim SJ, et al. Role of statin in atrial fibrillation-related stroke: an angiographic study for collateral flow. Cerebrovasc Dis 2014;37(2):77–84. https://doi.org/10.1159/000356114. [4] Ferro JM. Cardioembolic stroke: an update. Lancet Neurol 2003;2(3):177–88. https://doi.org/10.1016/S1474-4422(03)00324-7. [5] Bogiatzi C, Hackam DG, McLeod AI, Spence JD. Secular trends in ischemic stroke subtypes and stroke risk factors. Stroke 2014;45(11):3208–13. https:// doi.org/10.1161/STROKEAHA.114.006536. [6] Kamel H, Healey JS. Cardioembolic Stroke. Circ Res 2017;120(3):514–26. https://doi.org/10.1161/CIRCRESAHA.116.308407. [7] Yiin GSC, Howard DPJ, Paul NLM, et al. Age-specific incidence, outcome, cost, and projected future burden of atrial fibrillation-related embolic vascular events: a population-based study. Circulation 2014;130(15):1236–44. https:// doi.org/10.1161/CIRCULATIONAHA.114.010942. [8] Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 2011;24(1):35–41. https://doi. org/10.1161/01.str.24.1.35. [9] Smith M, Lee N, Haney E, Carson S, Helfand M. Drug class review HMG-CoA reductase inhibitors (statins) and fixed-dose combination products containing a statin. Oregon Heal Sci Univ. 2009. [10] Kusznir Vitturi B, Barreto Cabral F, Mella Cukiert C. Outcomes of pregnant women with refractory epilepsy. Seizure. 2019;69:251–7. https://doi.org/ 10.1016/j.seizure.2019.05.009. [11] Kusznir Vitturi B, Gagliardi José R. Use of CHADS2 and CHA2DS2-VASc scores to predict prognosis after stroke. Rev Neurol (Paris) 2019. https://doi.org/ 10.1016/j.neurol.2019.05.001. pii: S0035-3787(19)30469-2. [12] Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355(6):549–59. https:// doi.org/10.1056/NEJMoa061894. [13] Milionis HJ, Giannopoulos S, Kosmidou M, et al. Statin therapy after first stroke reduces 10-year stroke recurrence and improves survival. Neurology. 2009;96 (5):. https://doi.org/10.1212/WNL.0b013e3181a711cbe5918. [14] Castilla-Guerra L, del Fernandez-Moreno M del C, Leon-Jimenez D, Rico-Corral MA. Statins in ischemic stroke prevention: what have we learned in the postsparcl (the stroke prevention by aggressive reduction in cholesterol levels) decade?. Curr Treat Options Neurol. 2019;21(5)::22. https://doi.org/10.1007/ s11940-019-0563-4. [15] Willeit K, Kiechl S. Atherosclerosis and atrial fibrillation – two closely intertwined diseases. Atherosclerosis 2014;233(2):679–81. https://doi.org/ 10.1016/j.atherosclerosis.2013.11.082.
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[16] Soliman EZ, Safford MM, Muntner P, et al. Atrial fibrillation and the risk of myocardial infarction. JAMA Int Med 2014;174(1):107–14. https://doi.org/ 10.1001/jamainternmed.2013.11912. [17] Tramacere I, Boncoraglio GB, Banzi R, et al. Comparison of statins for secondary prevention in patients with ischemic stroke or transient ischemic attack: a systematic review and network meta-analysis. BMC Med 2019;17(1):67. https://doi.org/10.1186/s12916-019-1298-5. [18] Wu YL, Saver JL, Chen PC, et al. Effect of statin use on clinical outcomes in ischemic stroke patients with atrial fibrillation. Med (United States) 2017;96 (5):. https://doi.org/10.1097/MD.0000000000005918e5918. [19] Kim J, Lee HS, Nam CM, Heo JH. Effects of statin intensity and adherence on the long-term prognosis after acute ischemic stroke. Stroke 2017;48(10):2723–30. https://doi.org/10.1161/STROKEAHA.117.018140.
[20] Chung PW, Yoon BW, Lee YB, et al. Medication adherence of statin users after acute ischemic stroke. Eur Neurol 2018;80(1–2):106–14. https://doi.org/ 10.1159/000493530. [21] Blanco M, Nombela F, Castellanos M, et al. Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology 2007;69 (9):904–10. https://doi.org/10.1212/01.wnl.0000269789.09277.47. [22] Colivicchi F, Bassi A, Santini M, Caltagirone C. Discontinuation of statin therapy and clinical outcome after ischemic stroke. Stroke 2007;38(10):2652–7. https://doi.org/10.1161/STROKEAHA.107.487017. [23] Vergouwen MDI, De Haan RJ, Vermeulen M, Roos YBWEM. Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease. Stroke 2008;39(2):497–502. https://doi.org/10.1161/ STROKEAHA.107.488791.
Please cite this article as: B. Kusznir Vitturi and R. José Gagliardi, The role of statins in cardioembolic stroke, Journal of Clinical Neuroscience, https://doi. org/10.1016/j.jocn.2019.12.028
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
The role of statins in cardioembolic stroke Bruno Kusznir Vitturi a,⇑, Rubens José Gagliardi a a
Department of Neurology, Santa Casa de São Paulo School of Medical Sciences, Dr. Cesário Motta Júnior Street 112 01221-020, São Paulo, Brazil
a r t i c l e
i n f o
Article history: Received 9 September 2019 Accepted 16 December 2019 Available online xxxx Keywords: Statins Cardioembolic stroke Ischemic stroke Outcomes
a b s t r a c t Background: Statin therapy has become one of the most important advances in stroke secondary prevention. Nevertheless, statin therapy in patients with cardioembolic stroke has not been supported by clinical evidence yet. This study aimed to investigate the effect of statins on the neurological outcomes after a cardioembolic stroke. Methods: We conducted a prospective cohort study including consecutive patients with cardioembolic stroke. Subjects were classified into non-statin, simvastatin 20 mg, simvastatin 40 mg, and highpotency statin groups. After 2 years, the functional outcome, stroke recurrence, major cardiovascular events, and mortality were assessed. Results: Among the 91 patients included in our cohort, there were 18 (19.8%) patients without statins, 30 (33.0%) with simvastatin 20 mg, 38 (41.7%) with simvastatin 40 mg and 5 (5.5%) with high-potency statins. Using simvastatin 40 mg was associated with a significantly lower incidence of stroke recurrence lower. Patients with simvastatin 40 mg and high-potency statins presented the best functional recovery throughout the follow-up (p < 0.01). Conclusions: The use of statins in patients with cardioembolic stroke may be beneficial in some cases, preventing stroke recurrence and improving functional outcomes. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Statin therapy has become the most important advance in stroke prevention since the introduction of aspirin and blood pressure-lowering therapies [1]. Some clinical trials have evaluated the efficacy and safety of statins after a stroke and their positive results led to an increase in the use of statins for these patients. Nevertheless, cardioembolic stroke patients were never included in most of these studies. In secondary prevention of stroke, statin therapy is highly recommended for patients with non-cardioembolic stroke (class I, level A) [2]. Currently, statin therapy in patients with cardioembolic stroke has not been supported by clinical evidence yet [3]. The heterogeneity of stroke subtypes is also important to guide stroke treatment. Cardiac embolism causes more than a third of all ischemic strokes [4]. As the treatment of hypertension and dyslipidemia improves, cardiac embolism has accounted for an increasing share of strokes all around the world [5,6]. Despite a decrease in the overall incidence of stroke, cardioembolic strokes have tripled during the past few decades and may triple again by 2050 based on projections from the United Kingdom, for example [7]. Clarifying ⇑ Corresponding author. E-mail address: [email protected] (B. Kusznir Vitturi).
whether statins are beneficial in patients with cardioembolic ischemic stroke would assist with a common management dilemma. Based on this knowledge, we investigated the effect of statins for secondary prevention in cardioembolic stroke.
2. Methods 2.1. Study design and cohort population We carried out a prospective cohort study composed of consecutive patients admitted to the Department of Neurology of a university-affiliated, tertiary referral hospital in São Paulo, Brazil, who were under regular clinical follow-up between January 2016 and June 2018. Patients aged 18 years or older with a first-ever ischemic cardioembolic stroke within 24 h of symptom onset were considered eligible for the study. Stroke was defined by World Health Organization criteria as a sudden focal neurologic deficit persisting longer than 24 h and confirmed by brain CT or MRI. We excluded patients who used other lipid-lowering drugs and those that were followed up for < 24 months for any reason. Patients were followed up by telephone interviews and face-toface assessments in the outpatient department for a period of 2 years. The interviews were conducted by senior neurologists who were completely blinded to the study. All participants
https://doi.org/10.1016/j.jocn.2019.12.028 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
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provided written informed consent before inclusion and the research protocol was approved by our local ethics committee.
2.2. Baseline measures and comorbidities Baseline characteristics of stroke patients were recorded on admission. When the patient was discharged, information about stroke subtype, treatment in hospital, complications, laboratory tests, and CT and/or MRI findings were recorded. The data collectors were not aware of the study. Stroke severity was measured using the NIH Stroke Scale (NIHSS) score on hospital admission. Cardioembolic stroke was classified using the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) system [8]. Statins were prescribed without consideration of the lowdensity lipoprotein cholesterol level. Consecutive patients were distinguished into 4 groups according to the particularities of statin therapy. One group consisted of patients receiving simvastatin 20 mg per day and another group, receiving simvastatin 40 mg per day. Patients receiving atorvastatin 3 40 mg per day or rosuvastatin 3 10 mg per day were regarded as receiving high-intensity statin therapy. 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 greater than 50% [9]. Patients who didn’t use statins were included in a separate group as well. Statin use onset was registered for each patient. Previous statin treatment referred to regular use of statins at least 1 month before the stroke. Treatment in the acute phase was defined as statins initiated within 72 h after stroke onset and late-onset treatment were defined as when it was initiated 3 days after stroke onset. Adherence to statin treatment was evaluated using the 8-item Morisky Medication Adherence Scale (MMAS-8) [10]. Total scores range from 0 to 8 and patients were considered adherent only with scores greater than 6.
3. Main outcomes measures The individuals were followed until death or until 2 years after the stroke onset. If no clinical evaluation could be performed during this period, first the patient was searched in the National Registry of Death to detect a possible death before being excluded from the analysis. The outcome variables include all-cause mortality, stroke recurrence (ischemic or hemorrhagic) and major cardiovascular events. Functional outcome was assessed using the modified Rankin Scale (mRS) at 7 days, 30 days, 6 months and 2 years after hospital admission for ischemic stroke. An unfavorable outcome was defined as an mRS score 3 and a favorable outcome was defined as mRS score 2. Each patient had the mRS calculated by two different doctors, one of whom was blind to the study. In case of discrepancy, the opinion of the head of the stroke outpatient clinic was consulted.
3.1. Statistical analysis Categorical variables were analyzed using the chi-square test or Fisher’s exact test and differences in continuous variables were assessed using the student’s t-test (parametric test) or the MannWhitney test (non-parametric test). Odds ratios (ORs) were derived from a multivariable logistic regression with each outcome categorized by statin exposure. Confounding variables included age, sex, stroke severity, medications, smoking and other comorbidities [11]. The limit for significance was set at 2-tailed p = 0.05. All analyses were conducted using SPSS, version 23.0.
4. Results The crude cohort consisted of 523 S patients of all TOAST types. After the etiological investigation, 102 were classified as cardioembolic strokes. We sequentially excluded 11 patients who fulfilled the exclusion criteria or lost of follow-up (Fig. 1). Finally, data from 91 patients were analyzed (Table 1). There were no differences in baseline characteristics between participants and those patients who were lost to follow-up. The mean age of the participants was 61.0 (SD 16.8) years and 44 (48.3%) were female. There were 18 (19.8%) patients without statins, 30 (33.0%) with simvastatin 20 mg, 38 (41.7%) with simvastatin 40 mg and 5 (5.5%) with high-potency statins. Most enrolled patients were pre-stroke statin non-users (n = 78, 85%). Only 37 (40.6%) of subjects begun statin treatment at stroke onset. Among statin users, there were 10 (13.7%) cases of statin withdrawal and 30 (41.1%) patients presented satisfactory adherence to the treatment. One patient died (simvastatin 20 mg group) and 2 patients had major cardiovascular events (one using high-potency statins and others without statins). There was one case of hemorrhagic stroke, which was a non-statin user. Concerning recurrent stroke, 27 patients had a recurrence (6 from the nonstatin group, 11 from the simvastatin 20 mg group, and 6 from the simvastatin 40 mg and 4 from the high-potency group) during follow-up. Detailed description of the profile of the patient who had another stroke is represented in Fig. 2. The median mRS was 2 and 54 (59.3%) had a favorable functional outcome. Patients who received simvastatin 40 mg presented lower risk of having another stroke during the 2-year follow-up (OR = 0.28, 0.10–0.80; p = 0.02) (Table 2). Those in other subgroups didn’t show any difference regarding the incidence of stroke recurrence. Discontinuing statin therapy was associated with increased odds of having a poor functional outcome (OR = 0.05, 0.006– 0.46; p = 0.002). Furthermore, patients that presented a satisfactory adherence to treatment were more likely to have a good functional outcome (OR = 2.28, 0.82–6.30; p = 0.05). Concerning the trend over the 2-year follow-up, patients with simvastatin 40 mg and high-potency statins presented the best functional recovery compared to other subgroups (p < 0.01) (Fig. 3).
5. Discussion Various aspects of the beneficial effect of statin therapy in patients with previous stroke have been previously reported. However, it should be noted that patients in statins clinical studies were primarily at risk of atherosclerotic carotid or coronary vascular disease. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial [12], patients with a major source of cardioembolic stroke (AF, valvular heart disease, and coronary artery disease) were excluded and therefore the benefits of statin therapy should not be generalized to include nonatherosclerotic stroke patients. Other several observational studies have also shown a beneficial effect of statin therapy on stroke recurrence, mortality, and functional outcome in patients with acute ischemic stroke [13]. However, these studies included patients with all stroke subtypes. As a consequence, currently, it is not clear whether patients with cardioembolic stroke should be treated with a statin. The results from the present study may shed light on this question. Defining whether it is beneficial to prescribe statins for cardioembolic stroke patients can either save them from the costs and adverse effects of medication or ensure that they take advantage of the effects already evident in patients with other types of stroke. Long-term treatment with statins reduces the risk of ischemic stroke, even though hypercholesterolemia is not a strong risk fac-
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Fig. 1. Flow chart illustrating study design and number of patients.
Table 1 Baseline and clinical characteristics of patients according to statin subgroups.
Number Age, years, mean, SD Female sex Hypertension Diabetes Coronary artery disease Atrial fibrillation Previous stroke Dyslipidemia Smoking Alcohol abuse Previous use Congestive cardiac failure Early onset Good adherence Thrombolysis Anticoagulation Carotid stenosis NIHSS, median, (min – max) Discontinuation
Total (n.o., %)
Without statin (no., %)
Simvastatin 20 mg (no., %)
Simvastatin 40 mg (no., %)
High-potency statin
p-value
91 (100) 61.1, 13.0 44 (48.3) 70 (76.9) 25 (27.5) 20 (22.0) 49 (53.8) 20 (22.0) 16 (17.6) 24 (26.4) 12 (13.2) 13 (14.3) 31 (34.1) 33 (32.3) 29 (31.9) 14 (15.4) 61 (67.0) 4 (4.4) 5 (0–32) 9 (9.9)
18 (100) 55.9, 13.0 11 (61.1) 12 (66.6) 4 (22.2) 2 (11.1) 9 (50.0) 4 (22.2) 2 (11.1) 6 (33.3) 0 (0) 0 (0) 4 (22.2) 0 (0) 0 (0) 3 (16.7) 11 (61.1) 0 (0) 6 (0–23) 0 (0)
30 (100) 61.2, 12.2 13 (43.3) 25 (83.3) 11 (36.7) 8 (26.6) 17 (56.7) 6 (20.0) 9 (30.0) 9 (30.0) 3 (10.0) 6 (20.0) 9 (30.0) 14 (46.6) 12 (40.0) 3 (10.0) 16 (53.3) 1 (3.3) 5 (0–30) 4 (13.3)
38 (100) 62.6, 13.0 19 (50.0) 28 (73.7) 8 (21.1) 7 (18.4) 19 (50.0) 10 (26.3) 4 (10.5) 8 (21.0) 9 (23.7) 3 (7.9) 16 (42.1) 17 (44.7) 15 (39.5) 8 (21.0) 30 (78.9) 3 (7.9) 6 (0–28) 4 (10.5)
5 (100) 66.6, 15.7 1 (20.0) 5 (100) 2 (40.0) 3 (60.0) 4 (80.0) 0 (0) 1 (20.0) 1 (20.0) 0 (0) 4 (80.0) 2 (40.0) 2 (40.0) 2 (40.0) 0 (0) 4 (80.0) 0 (0) 8 (2–28) 1 (20.0)
0.23 0.50 0.43 0.59 0.13 0.84 0.81 0.22 0.99 0.07 < 0.001 0.64 0.47 0.56 0.63 0.17 0.71 0.79 0.81
tor for stroke [14]. An explanation for this apparent paradox is becoming clear as the role of statins on neuroprotection is being elucidated. This group of drugs is proven to exert multidirectional effects, including effects on reactive oxygen species development, clot formation, and brain plasticity. Therefore, despite the primary interest and research in statin therapy being about the atherosclerotic pathomechanism of stroke, there has been emerging evidence
of potential beneficial effects of this group of drugs in cardioembolic stroke patients. Lee et al. revealed that statin-users present greater collateral status in cardioembolic stroke, for example [3]. There are several aspects of the beneficial effect of statins in the present study that should be considered. Since AF was the most common source of cardioembolism in the present study, epidemiological studies have shown that patients with AF are more likely
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Fig. 2. Clinical profile of patients with stroke recurrence.
Table 2 Multivariable analysis of the independent clinical predictors of stroke recurrence and good functional outcome expressed in odds ratio (OR) with 95% confidence interval (95% CI). Favourable functional outcomes
Without statin Simvastatin 20 mg Simvastatin 40 mg High-potency statin Previous use Discontinuation Early onset Good adherence
Stroke recurrence
OR (95% CI)
p-value
OR (95% CI)
p-value
0.57 (0.18–1.75) 0.85 (0.32–2.23) 1.9 (0.7–5.08) 0.73 (0.11–4.68) 1.3 (0.36–4.62) 0.05 (0.006–0.46) 2.28 (0.82–6.3) 3.2 (1.07–9.91)
0.49 0.93 0.29 0.87 0.91 0.002 0.16 0.05
1.23 (0.41–3.73) 1.62 (0.63–4.15) 0.28 (0.10–0.80) 2.1 (0.52–8.60) 2.32 (0.70–7.72) 2.19 (0.60–7.93) 1.04 (0.41–2.66) 0.62 (0.22–1.69)
0.9 0.43 0.02 0.49 0.28 0.38 0.88 0.49
Fig. 3. Functional outcome of patients over 2 years after cardioembolic stroke according to statin subgroups.
to have diabetes mellitus, hypertension, myocardial infarction, and congestive heart failure [15,16]. Our findings of an association of simvastatin 40 mg use with reduced stroke recurrence are consonant with some prior studies conducted in general stroke population that strongly suggest that statins are associated with a reduction in the absolute risk of ischemic strokes [17]. It also provides complimentary evidence
against the results from a recent cohort study of stroke patients with atrial fibrillation in which the statin therapy completely failed to reduce recurrent stroke risk [18]. Nevertheless, indeed, not all patients of our cohort benefited from the statin’s power to prevent a second stroke. A reasonable explanation is the contribution of anticoagulation in the secondary prevention of patients with cardioembolic stroke. Only patients receiving simvastatin double dose
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had any real additional benefit in preventing a stroke from the already installed role of anticoagulation. Probably due to the small number of patients included with high potency statins, we had no evidence for this treatment subgroup. Furthermore, high-intensity statin and high dosages of simvastatin proved to be the most effective treatment modality in reducing long-term functional limitations. There were no differences in baseline clinical characteristics that may have influenced stroke prognosis. Therefore, reinforced by multivariate analysis, the most logical explanation for the observed difference in neurological outcomes between the groups is the effect of statins. Our study has shown that only proper and continuous use of statins can offer any benefit in patients with cardioembolic stroke. This is in line with previous studies which demonstrated that the suboptimal use of statin could interrupt the beneficial effects. A recent prospective study demonstrated that adherent use of statin had substantial long-term benefits on the prevention of adverse events after acute ischemic stroke [19]. This is especially important due to the high unsatisfactory adherence rate observed, which is consistent with the rates of a recent study [20]. Besides, we observed that statin therapy discontinuation may imply an increased risk of poor functional outcomes. Indeed, statin withdrawal was already associated with increased risk of early neurological deterioration, dependency after stroke [21] and all-cause mortality [22]. Blanco et al. indicated that statin withdrawal not only suppresses brain protection of previous treatment but causes deleterious effects in comparison with the lack of statin-linked protection at stroke onset [21]. Previous studies indicated that statin beneficial effect is partly lost by an increased risk of hemorrhagic stroke [23]. Theoretically, this issue is even more important in cardioembolic stroke because many patients are anticoagulated. Interestingly, in our cohort, there was no statistical difference between the groups regarding the incidence of hemorrhagic stroke. Nevertheless, the safety of statin therapy in the secondary prevention of cardioembolic stroke needs to be better established in further studies. The strengths of this study include that our study cohort was prospectively followed up and details could be acquired by a comprehensive review of their medical records, by telephone interviews and by face-to-face assessments with neurologists. Also, investigators who prescribed statins and those who verified the outcomes were blinded to the study. In our cohort, patients could receive statins regardless of having dyslipidemia and the TOAST stroke subtype. Many previous observational studies that investigated the effects of statins in stroke were biased due to the selection criteria of patients which compromises the impact of the study. Furthermore, we could perform detailed monitoring of multiple potential confounding factors in our research and rigorous definitions of outcomes were applied. We also compared different doses and types of statin treatments, which is different from many previous studies that just consider the patient ‘‘with or without statin”. This study has also some limitations that need to be acknowledged to better interpret the results. The size of the group could have limited the mortality analysis of our study. Because our study is a single-center, hospital-based study, rather than a communitybased study, it is unclear to what extent findings can be generalized. Nevertheless, there are no restrictions to be admitted to our hospital, and we included all consecutive cases admitted. Besides, the prospective and single-center design allowed us to collect information systematically and to uniformly verify both the qualifying event as well as follow-up information in all patients, which reduces the risk of information bias. The biases inherent in an observational study are also applicable to our research. However, conducting a randomized clinical trial would not currently be
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possible because of the already existing evidence of the benefit of statin therapy for stroke patients. 6. Conclusions The etiology of stroke should always be considered for the adoption of effective secondary prevention strategies. The use of statins in patients with cardioembolic stroke may be beneficial in some cases, preventing stroke recurrence and improving functional outcomes. The recommendation to start on statin treatment after a cardioembolic stroke needs to be investigated in further randomized clinical trials. Acknowledgments None. Conflict of interest The authors declare that they have no competing interests. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.12.028. References [1] Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009;8(5):453–63. https://doi.org/10.1016/S1474-4422(09)70058-4. [2] Ringleb PA, Bousser MG, Ford G, et al. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25 (5):457–507. https://doi.org/10.1159/000131083. [3] Lee MJ, Bang OY, Kim SJ, et al. Role of statin in atrial fibrillation-related stroke: an angiographic study for collateral flow. Cerebrovasc Dis 2014;37(2):77–84. https://doi.org/10.1159/000356114. [4] Ferro JM. Cardioembolic stroke: an update. Lancet Neurol 2003;2(3):177–88. https://doi.org/10.1016/S1474-4422(03)00324-7. [5] Bogiatzi C, Hackam DG, McLeod AI, Spence JD. Secular trends in ischemic stroke subtypes and stroke risk factors. Stroke 2014;45(11):3208–13. https:// doi.org/10.1161/STROKEAHA.114.006536. [6] Kamel H, Healey JS. Cardioembolic Stroke. Circ Res 2017;120(3):514–26. https://doi.org/10.1161/CIRCRESAHA.116.308407. [7] Yiin GSC, Howard DPJ, Paul NLM, et al. Age-specific incidence, outcome, cost, and projected future burden of atrial fibrillation-related embolic vascular events: a population-based study. Circulation 2014;130(15):1236–44. https:// doi.org/10.1161/CIRCULATIONAHA.114.010942. [8] Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 2011;24(1):35–41. https://doi. org/10.1161/01.str.24.1.35. [9] Smith M, Lee N, Haney E, Carson S, Helfand M. Drug class review HMG-CoA reductase inhibitors (statins) and fixed-dose combination products containing a statin. Oregon Heal Sci Univ. 2009. [10] Kusznir Vitturi B, Barreto Cabral F, Mella Cukiert C. Outcomes of pregnant women with refractory epilepsy. Seizure. 2019;69:251–7. https://doi.org/ 10.1016/j.seizure.2019.05.009. [11] Kusznir Vitturi B, Gagliardi José R. Use of CHADS2 and CHA2DS2-VASc scores to predict prognosis after stroke. Rev Neurol (Paris) 2019. https://doi.org/ 10.1016/j.neurol.2019.05.001. pii: S0035-3787(19)30469-2. [12] Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355(6):549–59. https:// doi.org/10.1056/NEJMoa061894. [13] Milionis HJ, Giannopoulos S, Kosmidou M, et al. Statin therapy after first stroke reduces 10-year stroke recurrence and improves survival. Neurology. 2009;96 (5):. https://doi.org/10.1212/WNL.0b013e3181a711cbe5918. [14] Castilla-Guerra L, del Fernandez-Moreno M del C, Leon-Jimenez D, Rico-Corral MA. Statins in ischemic stroke prevention: what have we learned in the postsparcl (the stroke prevention by aggressive reduction in cholesterol levels) decade?. Curr Treat Options Neurol. 2019;21(5)::22. https://doi.org/10.1007/ s11940-019-0563-4. [15] Willeit K, Kiechl S. Atherosclerosis and atrial fibrillation – two closely intertwined diseases. Atherosclerosis 2014;233(2):679–81. https://doi.org/ 10.1016/j.atherosclerosis.2013.11.082.
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Please cite this article as: B. Kusznir Vitturi and R. José Gagliardi, The role of statins in cardioembolic stroke, Journal of Clinical Neuroscience, https://doi. org/10.1016/j.jocn.2019.12.028