Renal Impairment Reduces the Efficacy of Thrombolytic Therapy in Acute Ischemic Stroke

Abstract

Background: Renal impairment is a potent risk factor for stroke, which remains a leading cause of death and disability. Thrombolysis for acute ischemic stroke has transformed patient outcomes, although the safety and efficacy of this approach remain poorly characterized in patients with renal dysfunction, who manifest a higher risk of bleeding due to uremia. We therefore examined the impact of renal impairment on clinical outcomes with thrombolysis within the current 4.5-hour therapeutic window. Methods: This retrospective multicenter cohort study (2009–2011) examined 229 stroke patients receiving thrombolysis with alteplase (0.9 mg/kg; mean age 70 ± 13 years; 59% male, 24% diabetic). Sixty-five patients had an estimated glomerular filtration rate (eGFR) <60 ml/min. The primary outcome was the improvement in National Institutes of Health Stroke Scale (NIHSS) score at 24 h. Secondary outcomes included the NIHSS score at 7 days, the incidence of symptomatic and asymptomatic intracranial hemorrhage (ICH), extracranial bleeding and death during the index hospitalization. Univariate and multivariate regression analyses were performed to determine the association between demographic characteristics and comorbid factors of interest and outcomes. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Results: There was no significant difference in mean time to thrombolysis between the groups (221 ± 66 vs. 220 ± 70 min from symptom onset; p = 0.9). An eGFR <60 ml/min was independently associated with a statistically significant reduction of the therapeutic effect of alteplase at 24 h on multivariate regression [coefficient –2.3, 95% confidence interval (CI) –3.7 to –0.9; p = 0.002], and this persisted at 7 days (coefficient –3.5, 95% CI –5.3 to –1.7; p < 0.001). On modeling eGFR as a continuous variable, every 10 ml/min decline in eGFR was associated with a 0.40 diminution in NIHSS score improvement with alteplase (95% CI 0.07–0.74; p = 0.02). Older age and a higher presenting NIHSS score were associated with a greater therapeutic effect (p = 0.04 and p < 0.001, respectively). In-patient mortality was 5%, with no significant differences between groups. Renal impairment was not associated with a higher rate of ICH (6.2 vs. 6.7%; p = 0.9). Greater NIHSS score at presentation was the only factor associated with a greater risk of death (odds ratio 1.24, 95% CI 1.10–1.40; p < 0.001) and ICH (odds ratio 1.12, 95% CI 1.03–1.23; p = 0.004). Conclusions: Our results suggest that renal impairment is associated with reduced efficacy of thrombolysis in acute ischemic stroke without any excess hemorrhagic complications. This may relate to diminished fibrinolysis in the uremic milieu or differences in infarct anatomy. Longer-term prospective studies are required to characterize and improve functional outcomes following stroke in a manifestly high-risk group.

Chronic Kidney Disease and Bleeding Complications After Intravenous Thrombolytic Therapy for Acute Ischemic Stroke

“…16,17 Data from previously published studies that have examined this issue were based on patient populations numbering less than a 1000 and revealed differing results. [5][6][7][8][9][10][11] A retrospective study of 578 Japanese patients showed that among patients with ischemic stroke treated with IV tPA renal dysfunction was associated with early intracranial bleeding and poor outcomes, 5 a study of 740 patients in Germany revealed that only severe renal impairment was associated with sICH after IV tPA treatment, 6 another study (n=196) found that patients with ischemic stroke treated with IV tPA who had impaired renal function tended (P=0.096) to have more sICH, 7 and finally a single center retrospective analysis of 224 patients showed increased odds of sICH with kidney impairment but serum creatinine, not GFR was the index of renal function. 8 However, 2 other studies indicated that IV tPA treatment in ischemic stroke patients with CKD was not associated with increased risk of ICH, poor functional outcome, or in-hospital death.…”

“…Downloaded from http://ahajournals.org by on March 22, 2019 (versus normal function) experienced reduced improvement in NIHSS score at 24 hours but had similar rates of ICH. 11 Our study with >44 000 ischemic stroke cases treated at 1326 hospitals, by far the largest to date on this issue, with its ability to also examine the relationships of specific stages of CKD to several end points including a major complication of IV tPA treatment (sICH), 2,3 an incontrovertible outcome (mortality), and an outcome primarily used in several defining trials of IV tPA (independent functional status), 2,3 may make it possibly the most definitive report thus far.…”

“…[5][6][7][8][9][10] These studies have generally been of modest sample size, based on patients from a single center, or evaluated only biomarker outcomes. [5][6][7][8][9][10][11] Furthermore, none of these studies examined the association of the various clinical categories of CKD severity with thrombolytic outcomes among patients with AIS or assessed an end point of systemic hemorrhage.…”

IV thrombolysis and renal function

“…These discrepancies may be attributable to the relatively small sample sizes (n 5 74, 196, 229, and 578 patients). [9][10][11][12] Renal impairment independently predicted poor functional outcome in 3 studies [9][10][11] and death in 2 studies. 9,10 A fourth study could not confirm these findings.…”

“…12 Furthermore, in one study, sICH occurred significantly more often in patients with low GFR, 10 whereas 3 other studies could not find such an association. 9,11,12 This large multicenter study with 4,780 IVT-treated patients had the power to address this lack of information: renal function is a strong predictor for poor functional outcome, death, and sICH. In patients with GFR ,60 mL/min/1.73 m 2 , the risk of poor functional outcome (mRS scores 3-6) increased by 34% at 3 months compared with patients with normal GFR (GFR 60-120 mL/min/1.73 m 2 ).…”