Keywords:
Statin - Ischemic stroke - Outcomes - Prevention
Palavras-chave:
Estatinas - Acidente vascular cerebral isquêmico - Desfechos - Prevenção
INTRODUCTION
Stroke is the second leading cause of death and disability in Latin American countries
and worldwide[1]. The absolute number of people with incident strokes has significantly increased
by 81% from 1990 to 2017, the number of people who survived by 95%, and the number
of those who died from stroke by 40%[2]. Given these numbers, the importance of adopting effective secondary prevention
strategies is paramount[3]. Statin therapy has become an essential advance in stroke prevention since the introduction
of aspirin and blood pressure-lowering therapies[4]. Positive results from clinical trials have already evaluated the efficacy and safety
of statins in stroke, leading to an increase in the use of statins for these patients[5].
However, since then, no real-world study has ever been conducted in a stroke population.
Besides, the vast majority of studies on statins and stroke have been performed in
populations with notably different scenarios from developing countries[6]. In Brazil, for example, there is no previous research regarding the role of statins
in the outcomes of stroke patients. Patients who receive treatment in the real world
can differ in important ways from the patients enrolled in the clinical trials for
that treatment. Randomized clinical trials are usually limited to the assessment of
a single therapeutic intervention, and they have severe inclusion and exclusion criteria,
which often distances the outcome of the neurologist's reality. Moreover, real-world
studies can help us better understand how the treatment is used in everyday clinical
practice[7].
Furthermore, many questions regarding the use of statins in stroke have not yet been
answered by clinical trials. Providing appropriate management to patients with acute
stroke depends on the underlying etiology of stroke. Nevertheless, no previous studies
compared the effects of statins on different types of stroke, so current evidence
only supports the use of statins to atherothrombotic stroke patients[8]. Also, it is still unknown whether prior use of statins influences neurological
outcomes after a stroke. Similarly, the equivalence of statin types and doses is still
uncertain, and the real consequences of discontinuing statin therapy lack clarity[9].
To date, evidence from real-world data for evaluating detailed associations between
secondary prevention of stroke and statin use is lacking. Therefore, we performed
this study to address most of these issues.
METHODS
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,
who were under regular clinical follow-up between January 2014 and August 2018. Patients
aged 18 years or older with a first-ever ischemic stroke were considered eligible
for the study. Stroke was defined according to the World Health Organization as a
sudden focal neurologic deficit persisting longer than 24 hours 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-to-face assessments in the outpatient department for two years. Senior neurologists
who were utterly blinded to the study conducted the interviews. All participants provided
written informed consent before inclusion, and the research protocol was approved
by our local ethics committee.
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.
Statins were individually prescribed without consideration of the low-density lipoprotein
cholesterol level. Consecutive patients were distinguished into four 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 40 mg per day or rosuvastatin 10 mg per day were regarded as
receiving high-intensity statin therapy. The high-potency statin group was defined
by patients who have prescribed a dose and type of statin that was expected to reduce
the initial low-density lipoprotein cholesterol level by more than 50%[10]. Patients who did not 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 one month before the stroke. Treatment in the acute phase
was defined as statins initiated within 72 hours after stroke onset, while late-onset
treatment was defined as when it was initiated three days after stroke onset. Adherence
to statin treatment was evaluated using the 8-item Morisky Medication Adherence Scale
(MMAS-8)[11]. Total scores range from 0 to 8, and patients were considered adherent only with
scores higher than 6.
Main outcomes measures
The individuals were followed until death or until two 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 primary outcome was the post-stroke functional limitations
that were assessed using the modified Rankin Scale (mRS) at 7 days, 30 days, 6 months,
and 2 years after hospital admission for ischemic stroke. We defined an unfavorable
outcome as mRS score≥3, and a favorable outcome 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.
Secondary outcomes included all-cause mortality, stroke recurrence (ischemic or hemorrhagic),
and major cardiovascular events.
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 Mann-Whitney 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[12]. The limit for significance was set at 2-tailed p=0.05. All analyses were conducted
using SPSS, version 23.0.
RESULTS
Five hundred forty-six patients were identified as having an ischemic stroke during
the study period. Of this group, 33 were excluded because of exclusion criteria or
loss of follow-up, leaving 513 patients for analysis ([Figure 1]). Of those analyzed, 417 (81.3%) were exposed to a statin, and 96 (18.7%) were not.
There were 169 (32.9%) with simvastatin 20 mg, 202 (39.3%) with simvastatin 40 mg,
and 46 (9.0%) with high-potency statins. The mean age of the participants was 56.7
(SD 15.1) years, and 236 (46.4%) were female. The demographics and clinical features
of the cohort are presented in [Table 1]. There were no significant differences in sex, history of the previous stroke, NIHSS,
atrial fibrillation, smoking, alcohol abuse, carotid stenosis, and anticoagulation
therapy. Older patients, patients with cardiovascular factors (coronary heart disease,
dyslipidemia, diabetes, hypertension), and those who
Table 1
Baseline and clinical characteristics of patients according to statin subgroups.
|
Total (no., %)
|
Without statin (no., %)
|
Simvastatin 20 mg (no., %)
|
Simvastatin 40 mg (no., %)
|
High-potency statin
|
p-value
|
|
Number
|
513 (100)
|
96 (100)
|
169 (100)
|
202 (100)
|
46 (100)
|
|
|
Age, years, mean, SD
|
56.7, 15.1
|
48.6, 17.2
|
57.4, 15.0
|
48.6, 17.2
|
62.5, 11.8
|
<0.001
|
|
Female sex
|
238 (46.4)
|
51 (53.1)
|
75 (44.4)
|
87 (43.1)
|
25 (54.3)
|
0.33
|
|
Hypertension
|
357 (69.6)
|
54 (56.2)
|
124 (73.4)
|
141 (69.8)
|
38 (82.6)
|
0.002
|
|
Diabetes
|
141 (27.5)
|
17 (17.7)
|
46 (27.2)
|
57 (28.2)
|
21 (45.6)
|
0.008
|
|
Coronary artery disease
|
72 (14.0)
|
3 (3.1)
|
21 (12.4)
|
32 (15.8)
|
16 (34.8)
|
<0.001
|
|
Atrial fibrillation
|
61 (11.9)
|
10 (10.4)
|
20 (11.8)
|
23 (11.4)
|
6 (13.0)
|
1.0
|
|
Previous stroke
|
97 (18.9)
|
15 (15.6)
|
37 (21.9)
|
39 (19.3)
|
6 (13.0)
|
0.59
|
|
Dyslipidemia
|
113 (22.0)
|
9 (9.4)
|
49 (29.0)
|
39 (19.3)
|
16 (34.8)
|
<0.001
|
|
Smoking
|
177 (34.5)
|
22 (22.9)
|
62 (36.7)
|
75 (37.1)
|
18 (39.1)
|
0.08
|
|
Alcohol abuse
|
68 (13.2)
|
8 (8.3)
|
20 (11.8)
|
36 (17.8)
|
4 (8.7)
|
0.1
|
|
Congestive cardiac failure
|
46 (9.0)
|
5 (5.2)
|
12 (7.1)
|
23 (11.4)
|
6 (13.0)
|
0.25
|
|
Thrombolysis
|
45 (8.8)
|
2 (2.1)
|
11 (6.5)
|
29 (14.3)
|
3 (6.5)
|
0.003
|
|
Anticoagulation
|
106 (20.7)
|
28 (29.2)
|
32 (18.9)
|
37 (18.3)
|
9 (19.6)
|
0.20
|
|
Antiplatelets
|
391 (76.2)
|
89 (92.7)
|
135 (79.9)
|
163 (80.7)
|
35 (76.1)
|
0.03
|
|
Carotid stenosis
|
65 (12.7)
|
5 (5.2)
|
21 (12.4)
|
27 (13.4)
|
9 (19.6)
|
0.09
|
|
NIHSS, median, (min-max)
|
5 (0-32)
|
6 (0-23)
|
5 (0-30)
|
6 (0-28)
|
8 (2-28)
|
0.79
|
|
TOAST
|
|
|
|
|
|
<0.001
|
|
Large-artery atherosclerosis
|
119 (23.2)
|
12 (12.5)
|
39 (23.1)
|
47 (23.3)
|
21 (45.6)
|
|
|
Cardioembolism
|
103 (20.1)
|
20 (20.8)
|
33 (19.5)
|
42 (20.8)
|
8 (17.4)
|
|
|
Small-vessel oclusion
|
36 (7.0)
|
7 (7.1)
|
13 (7.7)
|
13 (6.4)
|
3 (6.5)
|
|
|
Stroke of other determined cause
|
102 (19.9)
|
38 (39.6)
|
34 (20.1)
|
23 (11.4)
|
7 (15.2)
|
|
|
Stroke of undetermined cause
|
153 (29.8)
|
19 (19.8)
|
50 (29.6)
|
77 (38.1)
|
7 (15.2)
|
|
|
Discontinuation
|
51 (9.9)
|
N/A
|
25 (14.8)
|
21 (10.4)
|
5 (10.9)
|
0.41
|
|
Good adherence of statin
|
150 (29.2)
|
N/A
|
50 (29.6)
|
80 (39.6)
|
20 (43.5)
|
0.07
|
|
Early onset of statin
|
206 (40.1)
|
N/A
|
75 (44.4)
|
110 (54.4)
|
21 (45.6)
|
0.13
|
|
Previous use of statin
|
72 (14.0)
|
0 (0.0)
|
25 (14.8)
|
29 (14.4)
|
18 (39.1)
|
<0.001
|
*not applicable.
Figure 1 Flow chart illustrating study design and number of patients.
We registered 11 (2.1%) deaths during follow-up, and 25 (4.9%) patients had major
cardiovascular events. There were four (0.8%) cases of hemorrhagic stroke as well
(two were without statins, one with simvastatin 40 mg, and other with a high-potency
statin). Concerning recurrent stroke, 104 (20.3) patients had a recurrence during
follow-up. A detailed description of the profile of the patient who had another stroke
is represented in [Figure 2]. Patients with statins had a lower risk of major cardiovascular events (OR=0.3;
0.1–0.7; p=0.01). Regarding mortality, there was no difference according to statin
use (OR=0.6; 0.1-2.3; p=0.73). The median mRS was 2, and 307 (59.8%) had a favorable
functional outcome.
Figure 2 Clinical profile of patients with stroke recurrence.
Most enrolled patients were pre-stroke statin non-users (n=441; 86.0%). However, no
benefit related to previous statin use was found ([Table 2]). Only 209 (40.7%) of subjects begun statin treatment at stroke onset. Early-onset
of statin use was associated with better neurofunctional outcomes and a lower chance
of stroke recurrence (p<0.01). Among statin users, there were 54 (10.5%) cases of
statin withdrawal, and only 154 (30.0%) patients presented satisfactory adherence
to the treatment. Poor adherence and treatment discontinuation were also associated
with a worse functional outcome and a higher chance of having another stroke (p<0.01).
Table 2
Multivariable analysis of the independent clinical predictors of stroke recurrence
and good functional outcome expressed in Odds Ratio with 95% confidence interval.
|
Favorable functional outcomes
|
Stroke recurrence
|
|
OR (95%CI)
|
p-value
|
OR (95%CI)
|
p-value
|
|
Without statin
|
0.4 (0.2-0.7)
|
0.004
|
2.1 (1.3-3.5)
|
0.005
|
|
Simvastatin 20 mg
|
0.9 (0.6-1.3)
|
0.61
|
1.5 (1.0-2.3)
|
0.09
|
|
Simvastatin 40 mg
|
1.7 (1.2-2.4)
|
0.007
|
0.3 (0.2-0.5)
|
<0.001
|
|
High-potency statin
|
1.4 (0.7-2.7)
|
0.34
|
1.3 (0.6-2.6)
|
0.65
|
|
Previous use
|
1.1 (0.7-1.9)
|
0.71
|
1.1 (0.6-2.1)
|
0.77
|
|
Discontinuation
|
0.4 (0.2-0.7)
|
0.004
|
3.1 (1.7-5.7)
|
<0.001
|
|
Early onset
|
1.9 (1.3-2.8)
|
<0.001
|
0.5 (0.3-0.8)
|
0.003
|
|
Good adherence
|
4.2 (2.7-6.6)
|
<0.001
|
0.2 (0.1-0.5)
|
<0.001
|
OR: Odds Ratio; 95%CI: 95% confidence interval.
Patients who received no statin treatment had higher functional limitations and greater
chances of having another stroke (p<0.01). Patients with simvastatin 40 mg best benefited
from the effects of therapy, whereas results from patients treated with simvastatin
20 mg and high-intensity statins did not reach sufficient statistical significance
to demonstrate the benefit of statins in the context of secondary prevention. Specifically,
considering the comparative improvement of patients' functionality after stroke, patients
with simvastatin 40 mg and high-powered statins had the best functional recovery over
one year (p<0.05) ([Figure 3]). Statins were effective in preventing recurrence of another stroke in cases of
large-artery atherosclerosis, small-vessel occlusion, and stroke of undetermined cause
([Table 3]). Interestingly, in the case of stroke classified as cardioembolic or with other
determined causes, there was no advantage in the use of statins.
Figure 3 Functional outcome of patients over 2 years after stroke according to statin subgroups.
Table 3
Multivariable analysis of the effect of statin use in stroke recurrence and good functional
outcome according to TOAST classification. Data are expressed in Odds Ratio with 95%
confidence interval.
|
TOAST
|
Favorable functional outcomes
|
Stroke recurrence
|
|
OR (95%CI)
|
p-value
|
OR (95%CI)
|
p-value
|
|
Large-artery atherosclerosis
|
11. 6 (1.4-93.3)
|
0.01
|
0.3 (0.08-0.99)
|
0.09
|
|
Cardioembolism
|
2.1 (0.8-5.5)
|
0.23
|
0.8 (0.3-2.3)
|
0.88
|
|
Small-vessel oclusion
|
13.3 (11.4-127.6)
|
0.02
|
0.08 (0.01-0.6)
|
0.02
|
|
Stroke of other determined cause
|
1.4 (0.6-3.2)
|
0.56
|
0.5 (0.1-1.6)
|
0.35
|
|
Stroke of undetermined cause
|
2.4 (0.9-6.4)
|
0.11
|
0.3 (0.1-0.7)
|
0.002
|
OR: Odds Ratio; 95%CI: 95% confidence interval.
DISCUSSION
In our study, the use of statins was correlated with a reduced risk of stroke recurrence
and better functional outcomes. In line with previous studies, being without statins
turned out to be at higher risk for a worse prognosis[6]. Although statins were designed to reduce cholesterol levels, the ideal use of these
agents and the mechanism by which they protect against cerebrovascular events have
been a source of controversy[8]. Recent studies are advocating for a possible role of statins on neuroprotection,
improving disabilities[13]. This group of drugs is proven to exert multidirectional effects, interfering with
reactive oxygen species development, clot formation, endothelial function, and brain
plasticity[14]. Therefore, despite the primary interest and research in statin therapy being about
the atherosclerotic pathophysiological mechanism of stroke, there has been emerging
evidence of multiple potential beneficial effects of this group of drugs in patients
with stroke.
To our knowledge, we provide the first description of statin prescription from a developing
country. Among post-stroke statin users, high-intensity use accounted for the smallest
part of the patients, which is different from other countries, although the proportion
of patients without any statin was similar[15]. Current guidelines do not yet determine the best dose and statin in a stroke setting.
In our cohort, high dosages of simvastatin proved to be the most effective treatment
modality in improving stroke prognosis. Indeed, the benefit appears to be dose dependent[16]. Interestingly, high-powered statins have not shown significant evidence of interfering
with stroke prognosis. One possible reason may come from the fact that they are expensive
medications not offered for free in our public health system so that the patient may
more quickly, for financial reasons, have poor adherence, delay the onset, or spend
a few days without continuous use of the drug. Nevertheless, particularly, simvastatin
in the double dose and high-intensity statins showed the most significant ability
to recover functional gain in our population, possibly suggesting that such drugs
may be preferentially indicated in more severe stroke patients with more significant
functional impairment. Our results reflect a worldwide trend that many patients with
ischemic stroke may be under-treated[15],[17].
Our study provides a pioneering analysis regarding the comparison of the effect of
statins considering the etiology of stroke. Considering the stratification of patients
according to TOAST, statins showed positive results for the majority of patients:
in cases of large-artery atherosclerosis, small-vessel occlusion, and stroke of undetermined
cause. However, our study also suggests that cardioembolic stroke and stroke with
other determined cause may not benefit from statin therapy in the same way or at least
be less cost-effective. One possible explanation may come from the inherent heterogeneity
in these groups of stroke patients. Another pertinent consideration refers to the
fact that many of these patients are also anticoagulated, to raise the question of
whether statins would add any additional benefit in secondary prevention compared
to the use of anticoagulants, for example. In fact, no previous study evaluated the
role of statins in post-stroke outcomes in these types of patients, since patients
enrolled in statins clinical trials were primarily at risk of atherosclerotic carotid
or coronary vascular disease[18]. Indeed, current guidelines restrict the recommendation for post-stroke statin prescription
basically to atherosclerotic stroke patients[19]. Defining whether it is beneficial to prescribe statins for all 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[20]. We believe that our results may shed light on this question.
In agreement with previous observations, our study demonstrated that statins are effective
in preventing cardiovascular events in stroke victims[18],[21]. However, in our study, statins were ineffective in preventing mortality. Possibly,
the impact on mortality could be seen in population studies with prolonged follow-up,
although a recent meta-analysis corroborated our study indicating that statins do
not alter the mortality risk[21]. Hemorrhagic stroke is a controversial possible adverse event that has been associated
with statin therapy in some studies[22]. However, in our follow-up, a small prevalence of hemorrhagic stroke was detected
that is similar to other observational studies[23], which cannot be correctly attributed to the use of statins.
Our results regarding are in agreement with previous studies that showed that statin
therapy at stroke onset is associated with better outcomes[6]. It seems that time is brain also for statin prescribing. Regarding prior statin
use, our results are in line with other studies suggesting the benefit of prior statin
use is controversial and may be effective only for restricted patients[24],[25].
Our study has also shown that only proper and continuous use of statins can offer
any benefit in stroke patients. We found that patients with poor adherence to treatment
present poor prognosis after stroke, which is in line with some previous studies that
demonstrated that the suboptimal use of statin in all stroke patients could interrupt
the beneficial effects[26]. This is especially important due to the high unsatisfactory adherence rate observed,
which is consistent with the rates of a recent study[27]. Besides, we observed that statin therapy discontinuation might imply an increased
risk of poor functional outcomes. Indeed, statin withdrawal was already associated
with increased risk of early neurological deterioration, dependency after stroke,
and all-cause mortality[28],[29]. 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[28].
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.
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[20]. 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". We are not
aware of another study examining statins and multiple long-term outcomes after an
ischemic stroke in Brazil.
Some limitations need to be acknowledged to interpret the results better. Because
our study is a single-center, hospital-based study, rather than a community-based
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.
It is possible that some variables with an impact on outcomes were not included in
our registry, for example. However, conducting a randomized clinical trial would not
currently be possible because of the already existing evidence of the benefit of statin
therapy for stroke patients. Also, an indication bias may be applicable in our study
since the prescription of statins is currently done in an individual and personalized
way, since the current guidelines only recommend with precision the use of these drugs
in patients with high atherothrombotic risk[30], which is not necessarily the reality of most patients with stroke.
Overall, this work suggests that statins play an essential role in the treatment of
ischemic stroke, preventing stroke recurrence and cardiovascular events, and improving
functional performance. Proper adherence to statin therapy, not interrupting treatment,
is critical for treatment success. Simvastatin 40 mg seems to be the best option considering
the cost-benefit. Additional randomized prospective studies are needed to confirm
the effect of statins in the stroke population according to the etiology.
