Safety of Statin Pretreatment in Intravenous Thrombolysis for Acute Ischemic Stroke
Background and Purpose—A recent meta-analysis investigating the association between statins and early outcomes in acute ischemic stroke (AIS) patients treated with intravenous thrombolysis (IVT) indicated that prestroke statin treatment was associated with increased risk of 90-day mortality and symptomatic intracranial hemorrhage. We investigated the potential association of statin pretreatment with early outcomes in a large, international registry of AIS patients treated with IVT.
Methods—We analyzed prospectively collected data from the Safe Implementation of Treatments in Stroke-East registry (SITS-EAST) registry on consecutive AIS patients treated with IVT during an 8-year period. Early clinical recovery within 24 hours was defined as reduction in baseline National Institutes of Health Stroke Scale score of ≥10 points. Favorable functional outcome at 3 months was defined as modified Rankin Scale scores of 0 to 1. Symptomatic intracranial hemorrhage was diagnosed using National Institute of Neurological Disorders and Stroke, European-Australasian Acute Stroke Study-II and SITS definitions.
Results—A total of 1660 AIS patients treated with IVT fulfilled our inclusion criteria. Patients with statin pretreatment (23%) had higher baseline stroke severity compared with cases who had not received any statin at symptom onset. After adjusting for potential confounders, statin pretreatment was not associated with a higher likelihood of symptomatic intracranial hemorrhage defined by any of the 3 definitions. Statin pretreatment was not related to 3-month all-cause mortality (odds ratio, 0.92; 95% confidence interval, 0.57–1.49; P=0.741) or 3-month favorable functional outcome (odds ratio, 0.81; 95% confidence interval, 0.52–1.27; P=0.364). Statin pretreatment was independently associated with a higher odds of early clinical recovery (odds ratio, 1.91; 95% confidence interval, 1.25–2.92; P=0.003).
Conclusions—Statin pretreatment seems not to be associated with adverse outcomes in AIS patients treated with IVT. The effect of statin pretreatment on early functional outcomes in thrombolysed AIS patients deserves further investigation.
Current American Heart Association (AHA) guidelines advocate continuation of statin treatment among acute ischemic stroke (AIS) patients pretreated with statins. This recommendation was based on data from observational studies that indicated an association of statin pretreatment with favorable functional outcome (FFO) in AIS.1
However, conflicting findings have been reported about the association of statin pretreatment with stroke outcomes in patients treated with intravenous thrombolysis (IVT). Certain investigators reported that statin pretreatment or intake during the acute stroke stage was associated with increased rates of symptomatic intracerebral hemorrhage (sICH) after intravenous2 or intra-arterial3 thrombolysis. Moreover, a recent meta-analysis indicated that prestroke statin treatment was associated with increased risk of 90-day mortality in unadjusted analyses. However, the former association did not retain its statistical significance after adjustment for potential confounders, including stroke severity.4 In view of the former considerations, we sought to investigate the potential association of statin pretreatment with early safety and efficacy outcomes in a large, international registry of AIS patients treated with IVT.
We analyzed prospectively collected data from the Safe Implementation of Treatments in Stroke-East registry (SITS-EAST) on consecutive AIS patients treated with IVT during an 8-year period (October 2003–December 2011). SITS-EAST register data were collected on patients treated with IVT using the general SITS-ISTR register platform as previously described.5,6 The participating countries in the SITS-EAST registry were Croatia, Czech Republic, Estonia, Greece, Hungary, Lithuania, Poland, Russia, Slovakia, Slovenia, and Turkey. SITS-EAST registry represents ≈30% of the population of SITS registry. The rates of sICH, FFO, and death are directly comparable between SITS-EAST and SITS registries indicating a similar accuracy and completeness of data collection between the 2 registries.
We included all IVT-treated AIS patients if they had (1) available data on pretreatment with statins and (2) neuroimaging data for sICH evaluation. The safety end points were death and sICH after IVT administration, defined with either the SITS (local or remote parenchymatous hemorrhage type 2 combined with National Institutes of Health Stroke Scale [NIHSS] score increase ≥4 points or leading to death <22–36 hours),6 European-Australasian Acute Stroke Study II (ECASS II; any hemorrhage combined with NIHSS score increase ≥4 points or leading to death ≤7 days),7 or National Institute of Neurological Disorders and Stroke (NINDS; ie, any hemorrhage combined with NIHSS score increase ≥1 point or leading to death ≤7 days) criteria.8 The efficacy end points were FFO (modified Rankin Scale score, 0–1 at 3 months)6 and early clinical recovery (ECR, reduction in the baseline NIHSS score of ≥10 points at 24 hours).9
Statistical comparisons were performed between subgroups of patients using the χ2 test (or the Fisher exact test) and the unpaired t test (or Mann–Whitney U test), where appropriate. Association of statin pretreatment with safety and efficacy end points was evaluated with univariate and multivariate logistic regression models adjusting for potential confounders (demographics, vascular risk factors onset-to-treatment time, baseline NIHSS scores, admission systolic/diastolic blood pressure levels). All statistical analyses were conducted using the Statistical Package for Social Sciences version 11.5 for Windows (SPSS Inc, Chicago, IL).
A total of 8856 patients were treated with IVT in SITS-EAST registry from October 2003 to December 2011. Patients with unavailable data regarding the use of statins (n=7112) were excluded from the present analysis. Table I in the online-only Data Supplement presents the comparative analyses of baseline characteristics between patients with and without available data on statin pretreatment. We also excluded additional 84 patients because of unavailable neuroimaging data on sICH. A total of 15 of these 84 patients died early (within 24 hours from stroke onset) during hospitalization with unavailable neuroimaging data.
A total of 1660 AIS patients treated with IVT (mean age, 67±13 years; 59% men; median NIHSS score on admission 11 points; interquartile range, 5–16) with available data on statin pretreatment and post–tissue-type plasminogen activator neuroimaging at 24 hours were included in the present analyses. Pretreatment with statins was reported on 373 (23%) of the study population. Baseline characteristics of AIS patients with and without statin pretreatment are presented on Table 1. AIS pretreated with statins were older (P=0.002), had higher prevalence of hypertension (P<0.001), diabetes mellitus (P<0.001), atrial fibrillation (P=0.007) as well as congestive heart failure (P<0.001), and presented with higher baseline stroke severity (P=0.019). The association of statin pretreatment with baseline stroke severity did not reach statistical significance after adjustment for AF (unstandardized linear regression coefficient, 0.685; 95% confidence interval [CI], −0.010 to 1.380; P=0.054].
In univariate analyses (Table 2), the rates of sICH, defined using the NINDS (odds ratio [OR], 1.54; 95% CI, 0.99–2.37), ECASS II (OR, 1.22; 95% CI, 0.73–2.06), or SITS criteria (OR, 1.66; 95% CI, 0.78–3.56), did not differ between AIS patients with or without statin pretreatment. Follow-up data at 3 months were available for 788 (47%) patients. Similarly, there was no association between statin pretreatment and the 3-month stroke mortality (OR, 1.30; 95% CI, 0.91–1.85). Statin pretreatment was associated with a lower likelihood of FFO in initial unadjusted analyses (OR, 0.72; 95% CI, 0.54–0.95). Conversely, ECR rate in the first 24 hours after stroke onset was found to be significantly higher in thrombolysed patients pretreated with statins, compared with those who did not receive statin pretreatment (OR, 1.77; 95% CI, 1.25–2.52).
In multivariate analyses adjusting for potential confounders, including demographics (age, sex), vascular risk factors (hypertension, diabetes mellitus, atrial fibrillation, congestive heart failure, current smoking), onset-to-treatment time, baseline NIHSS scores, admission systolic and diastolic blood pressure levels (Table 3), statin pretreatment was not associated with a higher likelihood of sICH (OR [NINDS definition], 1.41; 95% CI, 0.83–2.39; OR, 1.13 [ECASS II definition]; 95% CI, 0.60–2.14; OR [SITS definition], 1.89; 95% CI, 0.75–4.77)], 3-month mortality (OR, 0.92; 95% CI, 0.57–1.49), or 3-month FFO (OR, 0.81; 95% CI, 0.52–1.27). Statin pretreatment was independently related to higher odds of ECR (OR, 1.91; 95% CI, 1.25–1.92). There was no interaction of diabetes mellitus on the association of statin pretreatment with sICH using the NINDS (P for interaction=0.290), ECASS II (P for interaction=0.117), and SITS (P for interaction=0.952) definitions in the adjusted analyses.
Our findings underline the safety of statin pretreatment (in terms of sICH or death) in AIS patients treated with systemic thrombolysis. Although statin pretreatment was not found to have an impact on 3-month functional outcome, it was independently associated with an increased likelihood of ECR during the first hours following tissue-type plasminogen activator–infusion.
Our results are in line with a recent, prospective, multicenter study of 2072 AIS patients treated with systemic thrombolysis, which reported that statin use in the acute phase of stroke after IVT was safe (in terms of the outcome events of sICH and death).10 Moreover, our study findings lend support to an observational study of 11 stroke registries (n=4012) that failed to document any association between statin pretreatment and risk of sICH or early mortality in adjusted analyses.11 Consequently, our experience in 1600 thrombolysed AIS patients coupled with the observations of 2 previous large (>1000 patients) multicenter studies contradict the earlier, single-center, retrospective reports indicating a potential detrimental effect of statin pretreatment on the risk of sICH in AIS treated with thrombolytic therapies.
Furthermore, we did not document any association between statin pretreatment and likelihood of 3-month death in the present analyses adjusted for numerous confounders (OR, 0.92; 95% CI, 0.57–1.49; n=788) in contrast to the unadjusted associations reported in an earlier meta-analysis indicating that statin therapy at stroke onset was associated with increased likelihood of all-cause death at 90 days (pooled OR, 1.25; 95% CI, 1.02–1.52; P=0.03; n=4339 patients).4 Notably, after adjusting for age, stroke severity, and other potential confounding variables, no association was also observed between statin therapy and 90-day death in patients treated with IVT in this meta-analysis (OR, 1.14; 95% CI, 0.90–1.44; n=4012 patients).4
Certain limitations of the present report need to be acknowledged including the absence of central adjudication of outcome events and the unavailability of data on statin dosage. Moreover, it should be noted that we included no neuroimaging parameters (eg, brain microbleeds) as potential confounders in our analyses. Furthermore, patients with unavailable and available data on statin pretreatment differed in terms of age, prevalence of atrial fibrillation and heart failure, onset to treatment time, stroke severity, and systolic blood pressure levels on hospital admission (Table I in the online-only Data Supplement). In addition, autopsy data, recurrent stroke rate, and information about ethnicity were not collected in the SITS registry. Consequently, patients who died early during hospitalization (within 24 hours) without previously undergoing post–tissue-type plasminogen activator neuroimaging evaluation and with no available data on autopsy (n=15) may have been complicated with an undetected sICH. Although the vast majority of SITS-EAST registry patients are white, there is no formal information in the registry about race or ethnicity. Moreover, we did not evaluate early poststroke statin use (during the first 24 hours of AIS) and this needs to be taken into account in the interpretation of the reported associations. However, it should be noted that our results are directly comparable with prior studies that also did not collect information on early poststroke statin use.10,11 Finally, the association between statin pretreatment and ECR did not translate into an improved functional outcome at 3 months and this may be attributed to the unavailable follow-up data in 53% of the study population.
However, we would like to highlight certain strengths of our study including the adequate sample size from an international, multi-center registry with standardized protocol and the use of 3 different definitions for sICH diagnosis. Moreover, in our multivariate analyses, we adjusted for numerous potential confounders, including demographics, vascular risk factors, baseline stroke severity, onset-to-treatment time, and blood pressure levels at hospital admission.
In conclusion, our study findings provide reassurance to clinicians that statin pretreatment does not adversely affect the rates of sICH in AIS patients treated with IVT, whereas further research is needed to evaluate whether the detected association of statin pretreatment with ECR may eventually translate into higher rates of FFO at 3 months.
A part of this study findings has been presented in International Stroke Conference 2014 as podium presentation.
Sources of Funding
Drs Tsivgoulis, Kadlecová, and Mikulik have been supported by European Regional Development Fund – Project St. Anne´s University Hospital, Brno – International Clinical Research Center (FNUSA-ICRC; No. CZ.1.05/1.1.00/02.0123).
Dr Vilionskis discloses honoraria from Boehringer Ingelheim, Inc not related to the current project. The others authors disclose no conflicts.
Guest Editor for this article was Markku Kaste, MD, PhD.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.010244/-/DC1.
- Received June 1, 2015.
- Revision received June 1, 2015.
- Accepted June 10, 2015.
- © 2015 American Heart Association, Inc.
- Jauch EC,
- Saver JL,
- Adams HP Jr,
- Bruno A,
- Connors JJ,
- Demaerschalk BM,
- et al
- Meier N,
- Nedeltchev K,
- Brekenfeld C,
- Galimanis A,
- Fischer U,
- Findling O,
- et al
- Ní Chróinín D,
- Asplund K,
- Åsberg S,
- Callaly E,
- Cuadrado-Godia E,
- Díez-Tejedor E,
- et al
- Mikulík R,
- Kadlecová P,
- Czlonkowska A,
- Kobayashi A,
- Brozman M,
- Svigelj V,
- et al
- Hacke W,
- Kaste M,
- Fieschi C,
- von Kummer R,
- Davalos A,
- Meier D,
- et al