Pharmacologic Agents in Stroke Prevention,
Acute Stroke Therapy, and Interventional
J.J. Connors, III, MD
Pharmaceutical agents have moved far beyond just the aspirin and heparin that were the mainstays of stroke and
interventional therapy as recently as 10 to 15 years ago. Our understanding of the mechanisms of thrombus formation
and vascular response to damage as well as our armamentarium has tremendously improved in the past decade. Direct
thrombin inhibitors, powerful antiplatelet agents, new fibrinolytic agents, and statins now allow far greater manip-
ulation of the intraprocedural and postprocedural clot cascade and atherogenesis. It is mandatory that current-day
interventionists understand the correct and appropriate use of these agents to achieve the desired outcomes of therapy.
J Vasc Interv Radiol 2004;
AbESTT ϭ Abciximab in Emergent Stroke Treatment Trial, FDA ϭ Food and Drug Administration, HERO ϭ Hirulog and Early Reperfusion or
Occlusion, INR ϭ International Normalized Ratio, MI ϭ myocardial infarction, NINDS ϭ National Institute of Neurological Disorders and Stroke, PROACT ϭProlyse in Acute Cerebral Thromboembolism, TIA ϭ transient ischemic attack, tPA ϭ tissue-type plasminogen activator, WARRS ϭ Warfarin versus Aspirin inRecurrent Stroke Study, WASID ϭ Warfarin versus Aspirin for Symptomatic Intracranial Disease.
THE CONCEPT OF
and can be thought of as blood sludge.
posed of platelets. Injury to the endothe-
Platelets adhere to these matrix proteins,
factor initiates coagulation and leads to
mechanical damage secondary to in-dwelling central venous catheters and
tent platelet stimulant, stimulates plate-
lets to adhere to the site of vascular in-
to fibrin, which stabilizes these platelet
From the Department of Interventional Neuroradi-
thrombotic events that can be fatal.
ology, Miami Cardiovascular Institute, Baptist Hos-pital, 8900 North Kendall Drive, Miami, Florida
activated by adhesion factors (eg, colla-
33176. Received March 11, 2003; revision requested
April 23; final revision received October 9; accepted
October 10. Address correspondence to
The author has not identified a potential conflict of
S88 • Pharmacologic Agents in Stroke Management
thrombin that is already in the clot.
compared with unfractionated heparin.
Unfractionated Heparin and Low-
been shown to be of clinical benefit.
Connors • S89
nists (27,28). Hirudin also is better than
Bivalirudin is a 20-
vantageous in lower-risk individuals.
Heparin and Low-molecular-weight Hep-
Heparin has adverse effects.
utes, it is prolonged in patients withhepatic dysfunction (25).
Direct Thrombin Inhibitors
Thrombin Inhibitors over Heparin.—
Di-rect thrombin inhibitors have poten-
not cleared by the plasma proteins).
be effective in clinical trials of patients
agents is approved by the FDA as yet.
Future Directions Concerning Throm-
On the basis of ran-
going coronary angioplasty (23,27,28).
S90 • Pharmacologic Agents in Stroke Management
ered to have failed aspirin therapy.
Clopidogrel is in the
event. For patients with atrial fibrilla-
effect is irreversible for the life of the
The inhibition of the en-
regimen should be in this situation.
other pathways of platelet activation.
might be statistically insignificant.
unclear. Results of earlier trials led to
Extended-release Dipyridamole Plus
ied within 3 months of stroke or TIA.
Connors • S91
one crucial exception: atrial fibrillation
(46,47). Atrial fibrillation results in a
with an average annual risk of 5% (48).
malized Ratio [INR], 2.0 –3.0) (48). For
nosis) or for arterial dissection, nor, to
vention in an elderly population (51).
stroke (ie, the cervical carotid artery is
(INR, 1.4 –2.8) have equivalent effects
warfarin. Initial effects of warfarin ad-
but peak effects may take 3 to 5 days.
A single dose lasts for 2 to 5 days.
efit from warfarin than from aspirin.
200 to 500 mL of fresh frozen plasma.
that the design of the trial did not test
There is lit-
temporary practice (INR, 2.0 –3.0).
the antiplatelet agents listed earlier.
S92 • Pharmacologic Agents in Stroke Management
stroke therapy, no study has es-
indications for warfarin
tion of stroke in all patients with isch-
been “presumed” to be “best medical
therapy” for years. In a trial of warfa-
rin versus aspirin specifically for intra-
particularly in the “large vessel” cate-
tures essentially all serum cholesterol.
the difference was not statistically sig-
effect is about 10%). Thus, statins are a
stantial reduction in stroke risk. In the
agent as described earlier in relation to
tion trial (58), investigators studied the
(“dual”) antiplatelet medication is bet-
tirely separate from their effects on se-
lesterol levels—is still present (56). For
Connors • S93
tial financial gain from production.
are other vascular risk factors present.
ACUTE STROKE THERAPY
Alteplase (Activase; Ge-
tered and then traveling to the clot like
efficacy for this clinical situation.
performed, all with uniform failure.
influence the “systemic lytic state.”
well as its antigenicity. Its serum half-
This agent is not ap-
large-vessel occlusion (61). Direct local
intraarterial infusion of the fibrinolytic
S94 • Pharmacologic Agents in Stroke Management
alteplase is the most difficult to use of
trials as well as acute stroke trials, the
in the presence of N
(69). Also, an early trial of vampire bat
alteplase for intraarterial therapy is its
Considerations Regarding Stroke
Intraarterial Lytic Infusion for
Emergency Stroke Therapy
FDA with that one trial, the trial itself
had positive results (P
ϭ .04), with a
Connors • S95
concentrations do indeed slow lysis.
mate of the lysing ability of alteplase is
is capable of dissolving 4 g of clot (not
Complications Associated with Lytic
tially fill the entire femoral artery (20
this setting would be about 1.6 U (80).
(79,80,81) have indicated that there is a
tually slow down lysis considerably.
The hypothesis of “plasminogen steal”
uated in detail in the field of oncology,
als range from 0.7% to 2.0% (85,86).
ies that this is the case. Both higher and
bolus regimen, and total infusion time.
with reteplase (88), but at least some of
this difficulty in the interventional ra-
Heparin and Bleeding.—
of any lytic agent is still an issue. Only
action of certain lytic agents if used in
to be effective in the range of 0.01 to 20
g/mL (77). MI trials (83,84) have useful anywhere from 0.1–10 U/h; bleeding episodes than in those whodemonstrated the bell-shaped curve of
activity for certain fibrin-specific lytic
S96 • Pharmacologic Agents in Stroke Management
tors, are capable of “disaggregation”
direct clinical indicator of this fact.
anticoagulation during therapy (78).
pletely by these agents than by lytics.
Glycoprotein IIb/IIIa Inhibitors
interest in the role of glycoprotein IIb/
and thrombolysis in general (90 –92).
Glycoprotein IIb/IIIa Receptor Inhibi-
tors in Interventional Cases.—
be of value, reversibility is also an is-
its effects can be reversed with platelet
transfusion (98). The reversal of eptifi-
later time to treatment (average, 5 h).
increased risk of intracranial bleeds (or
layer forms at the injury site; this is the
rapid binding to platelets (Ͻ1 min).
is not fully elucidated. There is a small
Connors • S97
platelet and lytic agent use specifically
for stroke therapy is in its infancy. Pre-
Combination Therapy for Acute
result in increased fibrinolytic activity
Combination Therapy for
is the case, the initial target of therapy
lytic agents, including urokinase (100).
early results, no substantial benefit has
with intraarterial lytic infusion. A pos-
with glycoprotein IIb/IIIa inhibitors.
form at sites of vessel injury. “White”
S98 • Pharmacologic Agents in Stroke Management
sis. Following statistical analysis of the
improve patient outcomes by (a
on patient outcomes; (b
) evaluating the
cellular biology of blood coagulation.
ally and collectively; and (c
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Sundhedsvæsenets Patientklagenævn Ambulancebehandlere Fuldmægtig, cand. jur. Stine Kenneth Larsen Sundhedsvæsenets Patientklagenævn Patientklagenævnet har udgivet nedenstående Sammenfatninger af nævnets praksis: • Kliniske tandteknikere. 1999-2001. November 2002 • Lægeerklæringer. 1998-2002. Februar 2003 • Identifikation, mærkning og glemte ting. 2000-2001. F
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