Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke

Lauren Lipscomb, Mercer University College of Pharmacy

According to the American Heart Association/American Stroke Association (AHA/ASA) guidelines, intravenous alteplase is recommended at a maximum dose of 90 mg (0.9 mg/kg) for eligible patients within 3 to 4.5 hours of the onset of an ischemic stroke. In patients eligible for this treatment, it is recommended that the door-to-needle time (time of bolus administration) should be within 60 minutes of arrival at the hospital. [1]


Title: Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke [2]

Design International, multicenter, prospective, randomized, open-label trial with blinded outcome evaluation; N= 3,310
Objective To determine whether the low dose alteplase would be noninferior to the standard dose
Study Groups Standard dose of intravenous alteplase (n= 1,643);

Low dose of intravenous alteplase (n= 1,654)

Methods Standard dose of intravenous alteplase: 0.9 mg per kilogram of estimated, or measured, body weight; 10% as a bolus and 90% as an infusion over a period of 60 minutes; maximum dose, 90 mg;

Low dose of intravenous alteplase: 0.6 mg per kilogram, 15% as a bolus and 85% as an infusion over a period of 60 minutes; maximum dose, 60 mg

Duration March 2012 to August 2015
Primary Outcome Measure Combined end point of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale
Baseline Characteristics Variable Low-dose alteplase (n= 1,654) Standard-dose alteplase (n = 1,643)
Median Age, year 68 67
Female sex, n (%) 634 (38.3) 614 (37.4)
Asian race, no/total no (%) 1,043/1,651 (63.2) 1,036/1,640 (63.2)
Hypertension, no/total no (%) 1,031/1,648 (62.6) 1,034/1,640 (63.0)
Systolic blood pressure, (mmHg) 149 +/- 20 150 +/-20
Diastolic blood pressure, (mmHg) 84 +/- 13 85 +/- 13
Modified Rankin scale score of zero (no symptoms) before stroke no/total no (%) 1,349/1,647 (81.9) 1,325/1,639 (80.8)
Time from stroke onset to alteplase administration, min 170 170
Any alteplase give to patients; no (%)
Bolus dose, mg 6.2 +/- 1.2 6.3 +/-2.1
Infusion dose, mg 35.5 +/- 7.3 56.0 +/- 11.3
Results Outcome Low dose alteplase

(n= 1,654)

Standard dose alteplase (n= 1,643) Odds ratio with low-dose alteplase (95% CI) p-value for noninferiority
Death or disability no/total no (%) 855/1,607 (53.2) 817/1,599 (51.5) 1.09 (0.95 to 1.25) 0.51
Score on modified Rankin scale no/total no (%)
1.00 (0.89 to 1.13) 0.04
0 403/1,607 (25.1) 397/1,599 (24.8)
1 349/1,607 (21.7) 385/1,599 (24.1)
2 250/1,607 (15.6) 225/1,599 (14.1)
3 211/1,607 (13.1) 181/1,599 (11.3)
4 165/1,607 (10.3) 154/1,599 (9.6)
5 89/1,607 (5.5) 87/1,599 (5.4)
6 140/1,607 (8.7) 170/1,599 (10.6)
Adverse Events Common Adverse Events: N/A
Serious Adverse Events: intracerebral hemorrhage: 8.2% low dose alteplase group, 9.3% standard dose alteplase group; ischemic stroke: 7.1% low dose alteplase group 5.9% standard dose alteplase group [3]
Percentage that Discontinued due to Adverse Events: 0%
Study Author Conclusions In a group of predominantly Asian patients with acute ischemic stroke who were eligible for thrombolysis reperfusion therapy, a dose of alteplase of 0.6 mg per kilogram was not shown to be noninferior to the standard dose of 0.9 mg per kilogram with respect to the primary outcome of death and disability. Fewer patients treated with low-dose alteplase than with standard-dose alteplase (1% vs. 2%) had the secondary outcome of symptomatic intracerebral hemorrhage.

 

According to this study, a low dose of alteplase (0.6 mg/kg) was less efficacious than the current standard of practice (0.9 mg/kg). However, the low dose group had less occurrences of intracerebral hemorrhage but had an increased occurrence of ischemic stroke within 90 days. A more comprehensive study with an evenly distributed racial population would be more applicable for a majority of healthcare providers. A fully blinded trial would also eliminate any bias that would be present with an open-label trial.

References

[1] Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947.

[2] Anderson CS, Robinson T, Lindley RI, et al. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. N Engl J Med. 2016;

[3] Anderson CS, Robinson T, Lindley RI, et al. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. N Engl J Med. 2016 (Suppl): S45-46.

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