Hospital Pharmacy - February 2020 - 19

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Armahizer et al
lipoprotein (LDL) goals with statin benefit groups.
Statins primarily exert their benefit through inhibition of
hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase.
Although this mechanism is primarily recognized as the
nidus for significant serum LDL reduction, the downstream
pleiotropic effects of statin therapy may have additional neuroprotective benefit in AIS, including increased synthesis of
endothelium-derived nitric oxide, improvements in endothelial dysfunction, attenuation of the acute inflammatory
response, mediation of oxidative stress, and modulation of
angiogenesis and prothrombotic factors.80-82
Previous large, prospective, randomized trials conducted
in patients with ASCVD or risk factors for vascular disease
have established the role of statin therapy in the prevention
of stroke, with a collective relative risk reduction (RRR)
ranging from 19% to 48% on the incidence of nonfatal and
fatal stroke.83-86 The Stroke Prevention by Aggressive
Reduction in Cholesterol Levels (SPARCL) trial provides
the strongest support for statin use for secondary prevention
of AIS and TIA.87 In 4731 patients with an ischemic stroke,
hemorrhagic stroke, or TIA within 1 to 6 months of randomization, atorvastatin 80 mg once daily significantly reduced
the incidence of recurrent nonfatal and fatal stroke (HR:
0.84; 95% CI, 0.71-0.9; P = .03) when compared with placebo. This reduction in recurrent stroke came at the cost of
an increased incidence of hemorrhagic stroke; however, this
did not translate to increased death from ICH. A post hoc
analysis of the SPARCL trial showed that patients with LDL
reductions of ⩾50% had a 31% reduction in the combined
risk of nonfatal and fatal stroke (HR: 0.69; 95% CI, 0.550.87; P = .004) without an increase in hemorrhagic stroke
(HR: 1.04; 95% CI, 0.61-178; P = .89).88 Achievement of an
LDL < 70 mg/dL translated to a 28% reduction in the risk of
stroke (P = .0018).88 The results of this post hoc analysis,
and those from a large stroke registry database, indicate that
there may still be merit in targeting significant reduction in
LDL ⩾50% or <70 mg/dL in patients at high-risk for recurrent cerebrovascular disease.89
The potential for neuroprotection has inspired investigators to identify additional roles for statin therapy outside of
stroke risk reduction. Several retrospective analyses and
prospective cohort studies have demonstrated that pretreatment and acute treatment with both moderate-intensity and
high-intensity statin therapy improves baseline stroke severity (NIHSS ⩽ 5), improves functional outcomes (mRS 0-2),
and results in improved reperfusion.90-92 Despite these early
promising results, the utility of acute administration of statin
therapy following ischemic stroke remains controversial.
The Administration of Statin on Acute Ischemic Stroke
Patient (ASSORT) trial randomized 257 patients to receive
either early (within 24 hours of presentation) or delayed (on
day 7) statin therapy following AIS.93 At 90 days, there was
no difference between the early and delayed treatment in
patient disability, determined by mRS (OR: 0.84; 95% CI,
0.53-1.3; P = .46). However, this study was limited by mild

baseline stroke severity and suboptimal statin dosing. Two
additional trials, FASTER and EUREKA, also demonstrated
no clear benefit of statin administration in AIS; however,
both were terminated early due to poor recruitment.94,95 The
NeuSTART2 trial is an ongoing study assessing the efficacy
of high-dose lovastatin 640 mg for 3 days in AIS.96 Although
the timing of initiation of statin therapy in AIS remains controversial, a randomized controlled trial of patients on
chronic statin therapy presenting with an ischemic stroke
showed that withdrawal of statin therapy for only 3 days
results in worse functional outcomes (mRS > 2), larger
infarct volume, and a 4.66-fold increase in the risk of death.97
Statin therapy remains a cornerstone of primary and secondary ischemic stroke prevention. These benefits have been
highlighted through numerous prospective, placebo-controlled trials, and as a part of an aggressive risk factor management protocol.65 The appropriate utilization of statin
therapy in AIS management still remains largely unanswered,
although, potential benefits largely outweigh known harm.

Venous Thromboembolic Prophylaxis
Incidence of venous thromboembolism (VTE) following AIS
is estimated to be between 20% and 42%, with immobilization
being a main risk factor.98,99 In a recent population study (n =
30 002), the highest risk for VTE was within the first month
(HR: 19.7; 95% CI, 10.1-38.5) and then 1 to 3 months following stroke (HR: 10.6; 95% CI, 5.0-22.5).98 Use of intermittent
pneumatic compression (IPC) devices is a well-established
strategy to reduce incidence of deep venous thromboembolism (DVT).2,99 Chemoprophylaxis with heparin products
poses some controversy due to bleeding risk.2 This is exemplified in a meta-analysis, which found prophylactic heparin and
LMWH to be associated with fewer DVTs (OR: 0.21; 95% CI,
0.15-0.29) and symptomatic pulmonary embolisms (OR: 0.60;
95% CI, 0.44-0.81), but an increased incidence of sICH (OR:
1.68; 95% CI, 1.11-2.55).71 A randomized controlled trial (n =
1762) found enoxaparin 40 mg once daily to reduce risk of
VTE by 43% compared with heparin 5000 units twice daily
with a similar occurrence of bleeding.100 Despite these findings, heparin is often initiated at a dose of 5000 units 3 times
daily due to concern for enoxaparin's longer half-life with
bleeding risk, although these approaches have not been
directly compared. Pharmacologic prophylaxis is reasonable
in AIS patients with high VTE risk, but must be weighed
against the risks of bleeding.

Management of Adverse Events Related
to the Administration of Alteplase
Angioedema
Orolingual angioedema (OA) is a potentially life-threatening
complication of IV alteplase that occurs in between 1.3% and
5.1% of patients.101,102 Angioedema is hypothesized to be
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