Off-label thrombolysis versus full adherence to the current European Alteplase license: impact on early clinical outcomes after acute ischemic stroke

Abstract

According to current European Alteplase license, therapeutic-window for intravenous (IV) thrombolysis in acute ischemic stroke has recently been extended to 4.5 h after symptoms onset. However, due to numerous contraindications, the portion of patients eligible for treatment still remains limited. Early neurological status after thrombolysis could identify more faithfully the impact of off-label Alteplase use that long-term functional outcome. We aimed to identify the impact of off-label thrombolysis and each off-label criterion on early clinical outcomes compared with the current European Alteplase license. We conducted an analysis on prospectively collected data of 500 consecutive thrombolysed patients. The primary outcome measures included major neurological improvement (NIHSS score decrease of ≤8 points from baseline or NIHSS score of 0) and neurological deterioration (NIHSS score increase of ≥4 points from baseline or death) at 24 h. We estimated the independent effect of off-label thrombolysis and each off-label criterion by calculating the odds ratio (OR) with 2-sided 95% confidence interval (CI) for each outcome measure. As the reference, we used patients fully adhering to the current European Alteplase license. 237 (47.4%) patients were treated with IV thrombolysis beyond the current European Alteplase license. We did not find significant differences between off- and on-label thrombolysis on early clinical outcomes. No off-label criteria were associated with decreased rate of major neurological improvement compared with on-label thrombolysis. History of stroke and concomitant diabetes was the only off-label criterion associated with increased rate of neurological deterioration (OR 5.84, 95% CI 1.61-21.19; p = 0.024). Off-label thrombolysis may be less effective at 24 h than on-label Alteplase use in patients with previous stroke and concomitant diabetes. Instead, the impact of other off-label criteria on early clinical outcomes was not different compared with current European Alteplase license.

Intravenous Thrombolysis for Stroke Recurring Within 3 Months From the Previous Event

“…Although the study is not a randomized trial, it clearly indicates that patients with early recurrence may benefit from thrombolysis and provides an important argument for not withholding the treatment in everyday clinical practice. It is also in line with 2 analyses of general off-label r-tPA use that found no associations with sICH and mortality, and poor outcomes 10,11 and in several case reports. 20,[29][30][31]36 However, not all previous studies are confirmatory.…”

“…20,[28][29][30][31][32] In our cohort, representative of real-life stroke care in Central and Eastern Europe, only 2% of patients treated with r-tPA had previous stroke ≤3 months, which is in line with other studies. 4,[9][10][11]28 Therefore, our findings indirectly confirm that patients with previous stroke constitute potentially large and undertreated group. According to our data, patients with a history of previous stroke ≤3 months were more burdened with vascular risk factors and had worse prestroke functional status compared with those with first-ever stroke, which is partially consistent with observations in unselected stroke cases.…”

“…1,2 Its increasing use over the years allowed to accumulate a considerable amount of data supporting off-label treatment in particular situations, [3][4][5][6][7][8][9][10][11] including patients with previous stroke or preexisting…”

Changes in European Label and Guideline Adherence After Updated Recommendations for Stroke Thrombolysis

“…12,[14][15][16] Many patients receive off-label IVT after physician assessment that the benefit outweighs the risk of serious adverse effects, such as intracranial or systemic bleeding. Reported off-label IVT treatment ranges from 34% to 51% of the total IVT-treated population in experienced centers [17][18][19][20] and large registry cohorts including, SITS-Central and Eastern Europe (SITS-EAST) 21 and Virtual International Stroke Trials Archive (VISTA). 22 The aim of this study was to compare nonadherence to label and guideline contraindications for IVT in European hospitals registering patients in the SITS registry both before and after the release of ESO 2008/2009 guidelines.…”

“…[17][18][19][20][21][22] Table 3 shows a full comparison across time periods and with various publications.…”