Keywords:
stroke - statins - intensive care unit - mortality
Palavras-chave:
acidente vascular cerebral - estatina - unidade de terapia intensiva - mortalidade
Stroke is a prevalent cause of death, especially in intensive care units (ICU) and
disabling sequelae in adults worldwide. Among the 15 million worldwide people who
have a stroke each year, five million die, and another five million are permanently
disabled[1]
,
[2]
,
[3].
Dyslipidemia is a risk factor for stroke, and statins are used for secondary prevention
during the chronic phase of the disease[4].
The Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) study
evaluated patients with chronic ischemic stroke (IS) and hemorrhagic stroke (HS),
and observed a reduction in the incidence of new cerebrovascular events among statin
users[5]. However, the hypothesis of a higher incidence of hemorrhagic transformation associated
to statin use proposed by Cordenier et al. indicated that statins should be avoided
during the acute phase of stroke[6]. Therefore, to test this hypothesis, Blanco et al.[7] evaluated the effect of withdrawal of statins on mortality during the acute phase
of stroke. They found that, as opposed to expectations, the withdrawal of statins
increased the probability of death in these patients.
No clinical trial or observational study has yet evaluated the impact of statins during
the acute phase of IS in Latin America, particularly in patients admitted to intensive
care units (ICU). Therefore, the objective of the present study was to evaluate the
association between statin use and all-cause mortality in patients with acute IS during
their ICU stay.
METHODS
In this study, we performed a post-hoc analysis of previous observational and prospective
data (CTN: 86920) to evaluate the association between the use of statins and mortality
during the acute phase of stroke.
Inclusion criteria were as follows: age ≥18, stroke diagnosis, and admission to the
ICUs of the Clinical Hospital of Botucatu Medical School - Universidade Estadual Paulista
“Júlio de Mesquita Filho” (UNESP). We excluded patients with missing medical record
data.
The following medications were administered to patients during the first 7 days of
hospitalization (or according to hospital discharge or death): statins, insulin, noradrenaline,
diuretics, beta blockers, sympatholytics, angiotensin converting enzyme inhibitors
(ACEI), and sodium nitroprusside. Previous use of these medications was also recorded;
the following variables were assessed: age; gender; skin color (self-described by
patients); National Institute of Health Stroke Scale (NIHSS) score; blood pressure
at admission and every 2 hours thereafter; incidence of acute myocardial infarction
(AMI), hemorrhagic transformation, diabetes, high blood pressure, and smoking; These
are traditionally associated to worse outcomes.
Data were collected after the informed consents, which were also obtained from the
patient’s legally authorized representative if the patient could not consent. This
study was approved by the Ethics Committee of the Botucatu Medical School.
Statistical analysis
Sample size was calculated to detect a 30% difference in lethality rate, with an alpha
error of 0.05 and statistical power of 0.8, thus resulting in an estimated required
sample size of 92 patients. Data were analyzed using descriptive statistics, and parametric
variables are described as mean±standard deviation. The outcome of/ interest was defined
as death by any cause in the first week after ICU admission. Data from patients with
and without the outcome were compared using the t-test and chi-square test. Variables
with p<0.1 were included in the multiple logistic regression analysis as confounders.
The dependent variable was the primary outcome, and the association with statin use
was adjusted for confounders. Statistical significance was set at p<0.05 for regression
analysis.
RESULTS
There were 1,432 admissions for stroke in our hospital from March 2012 to April 2016.
A total of 260 patients required treatment in the ICU. Among the intensive care patients,
48 patients refused to give their informed consent; there were also difficulties obtaining
some informed consents. We screened 212 patients, and 66 patients were excluded due
to incomplete records. The final sample included 97 patients with ischemic stroke
after the exclusion of 49 with hemorrhagic stroke.
The mortality rate among patients who used statins during the acute IS phase [14%
(9/63)] was significantly lower than that of among patients who did not use statins
[41% (14/34); p=0.007]. After logistical regression and correction for cofounders,
we found an Odds Ratio of 0.19 [p=0.018, 95%CI 0.05-0.75] for statin use and death in the first 7 days.
No significant difference in mortality rates was found between patients who used statins
prior to the acute phase [(21%) 4/19] and those who had not used statins previously
[24% (19/78); p=1.000]. Statin was discontinued in 4 patients during the acute phase,
none of whom died (0%), whereas 24% (23/93) of patients without statin discontinuation
died (p=0.570). The mortality rate for patients who received statins [10% (5/48)]
was significantly lower than that of patients who did not receive them [37% (18/49);
p=0.005]. All patients were on mechanical ventilation at ICU admission. No patient
was undergoing full anticoagulation. All had prophylaxis for deep venous thrombosis
with low-molecular-weight heparin.
The incidence of hemorrhagic transformation was 9% (3/34) among patients who did not
take statins, whereas 24% (15/63) of patients who received statins experienced cerebral
bleeding (p=0.124). When analyzing only those who received thrombolytic therapy, there
were no significant differences in hemorrhagic transformation rates between groups
with or without statins.
The following factors were significantly associated to mortality: older age, a higher
incidence of AMI on arrival or during hospitalization, higher NIHSS score and lower
systolic blood pressure (SBP) at admission, and lower mean SBP during the first 48
hours after admission. Skin-color, hemorrhagic transformation, and pre-existing diabetes
mellitus or arterial hypertension were not associated to mortality. Data regarding
variables analyzed and their relationship with mortality are shown in [Table 1]. Male patients were selected for multiple logistic regression analysis because such
gender was associated to a higher incidence of mortality, with a p<0.1. When considering
only deaths from cardiovascular causes, there was none in the statin group and 4 in
patients who did not received statins, with statistical significance, p=0.01.
Table 1
Clinical characteristics of patients with ischemic stroke according to the mortality
outcome.
|
Primary outcome (death)
|
|
|
No (n=74)
|
Yes (n=23)
|
p-value
|
|
Age (years)
|
65±12.3
|
75±12.6
|
0.002
|
|
Male gender, n (%)
|
45 (60.8)
|
09 (39.1)
|
0.070
|
|
White skin color, n (%)
|
63 (85.1)
|
22 (95.6)
|
0.300
|
|
SBP at admission
|
163±36
|
130±27
|
0.000
|
|
Median SBP 48h
|
138±15
|
127±16
|
0.003
|
|
NIHSS score
|
15±6.1
|
20±7.2
|
0.008
|
|
AMI, n (%)
|
05 (6.6)
|
07 (30.4)
|
0.002
|
|
DM, n (%)
|
25 (32.4)
|
08 (34.7)
|
0.931
|
|
AH, n (%)
|
58 (78.3)
|
16 (69.5)
|
0.390
|
|
Smoking, n (%)
|
39 (52.7)
|
09 (39.1)
|
0.178
|
|
Hemorrhage, n (%)
|
15 (20.2)
|
03 (13)
|
0.441
|
SBP: systolic blood pressure; NIHSS: National Institute of Health Stroke Scale; AMI:
acute myocardial infarction during hospitalization or admission; DM: history of diabetes
mellitus; AH: history of arterial hypertension. All data were expressed in numbers
and percentage, or numbers and standard deviation, when they had a normal distribution.
We also observed that the prevalence of statin and ACEI use was significantly higher
among survivors, even after adjusting for confounders. Noradrenaline use was directly
associated to higher mortality rates. The use of insulin and beta-blockers was also
associated to better outcomes (p<0.1); therefore, these variables were selected for
multiple logistic regression analysis. The results of this analysis are shown in [Table 2], which describes the use of medications during ICU admission according to mortality.
Table 2
Medication usage during ICU stay in patients with ischemic stroke, according to mortality
outcome.
|
Primary outcome (death)
|
|
|
Medications
|
No (n=74)
|
Yes (n=23)
|
p-value
|
|
Statins, n (%)
|
54 (72.9)
|
09 (39.1)
|
0.007
|
|
Insulin, n (%)
|
33 (44.6)
|
16 (69.5)
|
0.064
|
|
Noradrenaline, n (%)
|
36 (48.6)
|
19 (82.6)
|
0.009
|
|
Diuretics, n (%)
|
40 (54)
|
10 (43.5)
|
0.517
|
|
Beta blockers, n (%)
|
22 (29.7)
|
02 (8.7)
|
0.078
|
|
Sympatholytics, n (%)
|
08 (10.8)
|
02 (8.6)
|
0.919
|
|
ACEI, n (%)
|
33 (44.5)
|
02 (8.6)
|
0.004
|
|
Nitroprusside, n (%)
|
18 (24.3)
|
05 (21.7)
|
0.979
|
ACEI: angiotensin converting enzyme inhibitors. ICU: Intensive Care Unit. All data
were expressed in numbers and percentage.
Logistic regression analysis with progressive exclusion of variables showed that NIHSS
score and age were directly associated to mortality ([Table 3]). This analysis also revealed that the use of ACEI and statins during hospitalization
was inversely associated to death in the first 7 days of ICU admission ([Table 3]).
Table 3
Results of multiple logistic regression analysis (stepwise backward method) of data
on mortality in the first week after ischemic stroke, with the variables selected
in univariate analysis.
|
Odds Ratio
|
95% confidence interval
|
p-value
|
|
Lower
|
Upper
|
|
1st Step
|
|
|
Age (years)
|
1.02
|
0.94
|
1.10
|
0.591
|
|
Male gender
|
0.28
|
0.05
|
1.47
|
0.133
|
|
SBP at admission (mmHg)
|
0.98
|
0.96
|
1.01
|
0.233
|
|
NIHSS score
|
1.10
|
0.96
|
1.267
|
0.151
|
|
Median SBP at 48 h (mmHg)
|
0.99
|
0.93
|
1.05
|
0.736
|
|
AMI
|
4.06
|
0.32
|
50.25
|
0.275
|
|
NOR
|
2.00
|
0.25
|
15.90
|
0.510
|
|
ACEI
|
0.22
|
0.02
|
2.77
|
0.243
|
|
Beta blockers
|
0.34
|
0.02
|
4.94
|
0.431
|
|
Statins
|
0.13
|
0.02
|
0.80
|
0.028
|
|
Insulin
|
4.38
|
0.61
|
31.38
|
0.141
|
|
5th Step
|
|
|
Age (years)
|
1.07
|
1.01
|
1.14
|
0.030
|
|
NIHSS score
|
1.11
|
0.99
|
1.24
|
0.054
|
|
ACEI
|
0.13
|
0.02
|
0.78
|
0.025
|
|
Statins
|
0.19
|
0.05
|
0.75
|
0.018
|
NIHSS: National Institute of Health Stroke Scale; SBP: systolic blood pressure; ACEI:
Angiotensin converting enzyme inhibitors; AMI: acute myocardial infarction.
DISCUSSION
In the current observational study, we found that statin use was associated with a
lower mortality rate in the first week after IS. Some authors believed that statin
use in the acute phase of IS could be hazardous, because some preliminary data indicated
that statin use was associated with hemorrhagic transformation. However, in the present
study, the use of statins was not associated to a significant increase in the occurrence
of hemorrhagic transformation, even among patients who were receiving thrombolytic
therapy. Moreover, we found that statins were associated to a reduction in deaths
from all causes, even after correcting cofounders, for deaths from neurologic and
cardiovascular causes, when analyzed alone. This is probably not related to effects
on cholesterol, but rather to other effects related to statins in endothelial and
inflammatory homeostasis.
Statins are often used for secondary prophylaxis of stroke; however, evidence that
it has effects on endothelial function, hemostasis, inflammation, coronary and cerebral
blood flow suggested a potential benefit in acute stroke[8]. Experimental studies in mice, in which statin was used before or as an acute treatment
for experimental stroke, showed a reduction in infarct core and in neuronal injury[9]
,
[10]. The mechanism for this neuroprotective effect is not believed to be dependent on
the cholesterol metabolism and action that statins have on it. Chen et al.[11] found angiogenesis and synaptogenesis after atorvastatin use initiated one day after
experimental stroke, which suggested better neuroplasticity associated to statin[11]. A clinical trial found better scores in neurological examination at 3 days after
stroke, although not sustained at 90 days, and another trial found worse clinical
outcomes associated to statins withdrawal[7]
,
[12]. However these data were not confirmed in other trials and small studies.
Older age, higher NIHSS score at admission, lower SBP, and AMI were significantly
associated to a higher incidence of all-cause mortality; these data are consistent
with those from previous sudies[13]
,
[14]. Even when the statin use was adjusted for these confounding variables, the association
with improved outcomes remained statistically significant. The use of antihypertensives
(ACE inhibitors) was associated to lower mortality. The use of beta-blockers was not
associated to lower mortality.
Stroke patients with a history of hypertension experience a rightward shift in their
cerebral blood flow self-regulation curve. Thus, reductions of more than 20% in their
diastolic blood pressure should be avoided, because they may compromise brain perfusion.
In such cases, the use of ACEI may be advantageous, seen that these drugs can preserve
the cerebral blood flow self-regulation[15]. The efficacy of ACEI in the prevention of stroke after the acute phase has been
previously demonstrated[16]. Notably, the final logistic regression analysis in the current study revealed that
the use of ACEI was associated to lower mortality, which suggests a protective effect
of this class of drugs in the acute phase as well. However, this hypothesis needs
to be confirmed in future interventional studies.
The main limitation of the current study is its observational design. In addition,
this study constitutes a post-hoc analysis of an observational study designed to evaluate
the association between blood pressure and lethality, and is, therefore, subject to
the inherent bias of this type of analysis. These two listed limitations imply the
need to confirm data in interventional studies. Another limitation is that the TOAST
classification, the circulation or topography of the stroke and if it was a malignant
one were not considered in the multivariate analyses. Sample size, although small,
was enough to demonstrate the statistical associations that were investigated.
In conclusion, the use of statins and ACEI during the acute phase of IS in patients
admitted to the ICU was associated to a lower mortality rate, even after adjusting
age, NIHSS score, and ACEI use. Randomized, controlled trials with a larger sample
size are warranted to determine the efficacy of statins in reducing mortality during
the acute phase of stroke.
