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Armahizer et al
and higher fibrin sensitivity than alteplase, both of which may
confer a benefit for tenecteplase over alteplase. Tenecteplase
is dosed as a single IV bolus of 0.4 mg/kg (max dose: 40 mg).
In a recent open-label randomized controlled trial (n = 1100),
tenecteplase was noninferior to alteplase regarding functional
outcomes at 3 months, defined as a mRS score of 0 to 1 (OR:
1.08; 95% CI, 0.84-1.38).23 No difference in the incidence of
ICH was observed. An ongoing randomized controlled trial
(TEMPO-2) is comparing IV tenecteplase 0.25 mg/kg with
standard of care in minor stroke or transient ischemic attack
(TIA) within 12 hours of onset.24
The EXTEND-IA TNK study compared tenecteplase
0.25 mg/kg (max: 25 mg, n = 101) followed by thrombectomy to alteplase 0.9 mg/kg (max: 90 mg, n = 101) followed by thrombectomy among patients presenting with
large vessel occlusions (LVO).25 The primary outcome of
the study was reperfusion greater than 50% of the affected
territory or absence of thrombus on angiographic assessment, which occurred in more patients in the tenecteplase
arm (22% vs 10%, P < .01 for noninferiority, P < .05 for
superiority). Patients receiving tenecteplase also had a lower
mRS at 90 days (2 vs 3, OR: 1.7; 95% CI, 1.0-2.8; P < .05),
without significant difference in cerebral hemorrhage.
Additional study of tenecteplase will continue in the
EXTEND-IA TNK part 2 trial, assessing a higher dose of
tenecteplase of 0.4 mg/kg.26
Major fibrinolytictrials have been provided in Table 3.

Endovascular Therapy and Mechanical
Thrombectomy
Despite several trials showing benefit of fibrinolysis in patients
presenting with AIS, IV alteplase has demonstrated reduced
efficacy for LVOs, with recanalization occurring in only about
one third of these patients.29-31 Intra-arterial thrombolysis and/
or mechanical thrombectomy with the use of retrievable stents
or "stentrievers" have been of great interest to aid in the treatment of those patients demonstrating persistently occluded
large intracranial arteries despite fibrinolytic therapy. Unfortunately, initial randomized controlled trials of intra-arterial
treatments were unable to show a benefit.32-34
Investigators from the Multicenter Randomized Clinical
Trial of Endovascular Treatment for Acute Ischemic Stroke
in the Netherlands (MR CLEAN) study, published in 2014,
provided the first evidence supporting the efficacy of
endovascular treatment for LVO in AIS.35 MR CLEAN
was a randomized trial evaluating intra-arterial treatments
in addition to usual care versus usual care alone in 500
patients throughout the Netherlands. Randomized patients
were treated within 6 hours of symptom onset and had a
documented anterior cerebral artery occlusion on vessel
imaging. The method of intra-arterial treatment was left to
the discretion of the local interventionalist and patients
could receive intra-arterial alteplase doses up to 90 mg or
urokinase up to 1 200 000 IU, unless previous IV alteplase

was administered, in which case these doses were capped
at 30 mg or 400 000 IU, respectively. Mechanical thrombectomy included thrombus retraction, aspiration, wire
disruption, or retrievable stents. Intra-arterial treatment
demonstrated an improvement in functional independence
at 90 days, as measured by a mRS score 0 to 2, as compared with the control group (32.6% vs 19.1%, adjusted
OR: 2.16; 95% CI, 1.39-3.38), without significant differences in mortality or sICH. Five additional studies evaluating the use of intra-arterial therapy have since been
published, demonstrating similar favorable outcomes.36-40
Recently, the highly anticipated results of the DWI or
CTP Assessment with Clinical Mismatch in the Triage of
Wake-Up and Late Presenting Strokes Undergoing
Neurointervention with Trevo (DAWN) and Endovascular
Therapy Following Imaging Evaluation for Ischemic Stroke
(DEFUSE 3) trials were published, evaluating patients
experiencing previous onset of stroke-like symptoms
between 6 and 24 and 6 and 16 hours, respectively.41,42 The
majority of patients were considered "wake-up" strokes, a
largely unexplored area of practice in relation to endovascular therapies. It is of utmost importance to note that these
studies utilized perfusion-based neuroimaging to determine
the size of brain tissue considered nonsalvageable ischemic
core versus tissue considered to be experiencing reversible
ischemia, referred to as the penumbra. Ischemic core and
penumbral volumes on CT perfusion or MRI diffusion were
calculated using RAPID software, an automated image processing system. The DAWN trial randomized 206 patients
to receive mechanical thrombectomy (n = 107) or usual
care (n = 99) identifying an improvement in the utilityweighted mRS at 90 days of 2 points (95% CI, 1.1-3.0) with
rates of 90-day functional independence being 49% in the
thrombectomy group versus 13% in the usual care group.41
The DEFUSE 3 investigators evaluated 182 patients who
had developed stroke symptoms between 6 and 16 hours
earlier, that were then randomized to endovascular therapy
(n = 92) versus standard medical therapy (n = 90).42
Endovascular therapy plus medical management was associated with a favorable shift in mRS at 90 days (OR: 2.77,
P < .001), a higher percentage of functionally independent
patients (45% vs 17%, P < .001) and a lower mortality rate
(14% vs 26%, P = .05), compared with medical management alone. Based on the results of these trials, among
patients with AIS secondary to LVO with favorable perfusion imaging findings, endovascular therapies between 6
and 24 hours resulted in less disability and improvement in
functional independence at 90 days.41,42

Endovascular Therapy and Blood
Pressure Management
Controversy exists in regards to blood pressure management
following endovascular therapy. Well-defined strategies for
blood pressure control among patients receiving IV fibrinolytic
Hospital Pharmacy - February 2020

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