Heparin and heparinoids in stroke

David G. Sherman, MD

Article abstractAnticoagulation with heparin has a valuable place in prevention and management of deep venous
thrombosis. However, the benefit of heparin in acute ischemic stroke and transient ischemic attack remains unclear
despite its widespread use for these indications. Heparin also carries several risks, including unpredictable anticoagula-
tion effects, bleeding, and thrombocytopenia. Low-molecular-weight heparins (LMWHs) and heparinoids have several
advantages over heparin, such as higher bioavailability, more predictable anticoagulant effects, and less interaction with
platelets. Heparin, LMWHs, and heparinoids have been studied in acute ischemic stroke with variable results. Of three
recent, large, controlled clinical trials, only one documented a net benefit of treatment. Fewer patients treated with an
LMWH within 48 hours of stroke were dead or disabled at 6 months compared with placebo-treated patients. The largest
randomized clinical trial of heparin in acute stroke (the International Stroke Trial) showed that heparin was associated
with a significant excess in bleeding complications but no clinical benefit at 6 months. Interim analysis of the TOAST
(Trial of ORG 10172 in Acute Stroke Treatment) study also showed an excess number of bleeding complications in the
treated group without a corresponding benefit on stroke outcome a t 3 months. Therefore, although heparin, LMWHs, and
heparinoids continue to be used in the management of patients with acute ischemic stroke, their value in recurrent stroke
prevention and in the treatment of stroke-in-progress remains unsettled. Ongoing studies may help to clarify the use of
LMWHs and heparinoids in these patients.
NEUROLOGY 1998;51(S~ppl3):S56-S58

Heparin and heparinoids are anticoagulants com- also increases the risk for immune-mediated throm-
monly prescribed for prevention of recurrent brain bocytopenia (IMT),Swhich is aggravated by the fre-
emboli, stroke progression, systemic embolism, deep quent dosing heparin requires because of its low
venous thrombosis (DVT), and pulmonary embolism bioavailability after subcutaneous (SC) administra-
in patients with ischemic The use of these tion and its short elimination half-life.'O High-risk
agents in treating patients with stroke emerged after patients receiving heparin must undergo frequent
their successful use for prevention of thromboem- measurements of activated partial thromboplastin
bolic events in high-risk patients (e.g., those who had time to regulate the level of anticoagulation.lO,"
undergone surgery, were paralyzed or immobilized, Some of the dosing complications and side effects
or had experienced acute myocardial infar~tion).~-@ associated with larger-sized heparins can be elimi-
However, although they tend t o prescribe heparin, nated with low-molecular-weight heparins (LMWHs)
more than 50%of surveyed neurologists question the and heparinoids. LMWHs are fragments of larger
efficacy of this agent in patients with stroke, many heparins, between 4,000 and 8,000 Da.5J2 Heparin-
citing safety as a primary concern.2 oids are sulfated GAGS similar in size to LMWHS.~."
The anticoagulant benefits of heparin for patients Both LMWHs and heparinoids act similarly to hepa-
with stroke appear to be offset by the risk for intra- rin, inhibiting clotting factor Xa activity after bind-
cerebral hemorrhage (ICH). This discussion provides ing antithrombin 111. However, whereas heparins of
an overview of heparins and heparinoids and sum- >5,000 Da inhibit factor IIa, LMWHs and heparin-
marizes three large, well-controlled clinical trials ini- oids with very low concentrations of larger chains
tiated to determine the actual risk:benefit ratios of exhibit only limited anti-factor IIa activity. As a re-
low-dose heparin and heparinoids in treatment of sult, LMWHs and heparinoids suppress platelet ag-
ischemic stroke. gregation only minimally,11J2thereby reducing the
incidence of bleeding. The smaller size of both
Characteristics of heparins and heparinoids. LMWHs and heparinoids increases their absorption
The benefits and risks of heparin agents depend pri- (to almost 100% after SC administration) and in-
marily on their sites of action. Unfractionated hepa- creases their elimination half-lives (- 1.4-5.9 hours
rin (UFH), a mixture of glycosaminoglycan (GAG) for LMWHs and up to 17-28 hours for heparinoids),
chains of variable length (5,000-30,000 Da), will allowing these compounds to be administered only
bind to the native anticoagulant enzyme antithrom- once or twice daily.'O-12 Similarly, although the re-
bin III.5 The UFH-antithrombin I11 complex inhibits ported incidence of IMT is highly variable, it appears
clotting factors IIa (thrombin) and Xa, thereby pro- to be reduced with LMWHs and heparinoids (0-376)
moting its anticoagulant activity but also placing a compared with that associated with UFH (1-50/0).9J1
patient at risk for bleeding. Heparin administration Unfortunately, in patients with previous IMT,
From the Division of Neurology, University of Texas Health Science Center at San Antonio, TX.
Address correspondence and reprint requests to Dr. David G. Sherman, Division of Neurology, University of Texas Health Science Center a t San Antonio,
Department of Medicine, 7703 Floyd Curl Drive, San Antonio, TX 78284-7883.
S56 Copyright 0 1998 by the American Academy of Neurology
Table 1 Patient outcomes at 6 months in the nadroparin trial
Treatment Groups
High-dose Low-dose
nadroparin (Ti) nadroparin (%) Placebo (%)
Outcome (n = 306) (n = 100) (n = 101)
Deaths 13 17
Independence
Total recovery 26 25
Partial recovery 26 22
Dependence 33 37
Death or dependence 45 52
LMWHs have been found to cross-react with circu-
lating antibodies, potentiating IMT.3 Heparinoids
appear to be safe for anticoagulant therapy in pa-
tients with IMT."
Clinical trials of heparin, LMWHs, and danap-
aroid (a heparinoid) have been conducted to deter-
mine their efficacy in preventing DVT in patients
with Early trials enrolled fewer than 300
patients and did not statistically assess the risk for
bleeding. Three larger trials are discussed below.
Clinical trials. Nadroparin trial. Nadroparin
calcium, an LMWH, was evaluated in two doses in
this randomized, double-blind, controlled clinical tri-
al.13 Patients 80 years of age or younger and diag-
nosed with acute ischemic stroke within the previous
48 hours were enrolled, regardless of stroke severity.
Patients were excluded if they had evidence of hem-
orrhage on a baseline CT scan, if they lacked neuro-
logic deficits, or if they were considered t o have no
chance of survival.
A total of 308 patients received either high-dose
nadroparin (4,100 IU anti-factor Xa SC every 12
hours), low-dose nadroparin (4,100 IU alternating
with placebo every 12 hours), or placebo (every 12
hours) for 10 days. Patients were evaluated at 10
days, 3 months, and 6 months. Primary end points
were death or dependency at 6 months (assessed by
interview with patients or caregivers). Secondary
end points were death, hemorrhagic transformation,
or other complications (e.g., bleeding, recurrent
stroke, DVT) at 10 days and death or dependency at
3 months. Baseline characteristics were similar
across treatment groups, with one exception. More
patients with total anterior circulation infarcts (the
most severe subtype) were enrolled in the placebo
group (21 patients) than in the high-dose (14 pa-
tients) or low-dose (18 patients) nadroparin groups.
Results of the study revealed that high-dose na-
droparin significantly lowered the risk for death or
dependency at 6 months (45%) compared with pla-
cebo (65%;p = 0.005);risk with low-dose nadroparin
was reduced but not significantly (52%) (table 1).
Differences at 3 months were not significant (53%,
60%, and 64% for high-dose nadroparin, low-dose
Table 2 Patient outcomes at 6 months in the Znternational
Stroke Trial
Treated with Not treated with
heparin (%) heparin (%)
Outcome (n = 9,641) (n = 9,644)
(n = 105)
Recovery 17.2 17.0
19 Dependence 40.4 41.3
Death 22.5 21.5
18 Death or dependence 62.9 62.9
16
Adapted from the International Stroke Trial Collaborative
47 Group, with permi~sion.'~
65
nadroparin, and placebo, respectively). The investi-
gators attributed the change in outcomes between 3
and 6 months to progressive recovery in the
nadroparin-treated patients, who were alleged to
have smaller infarct volumes as a result of treat-
ment, which was presumed to maintain blood flow in
the ischemic penumbra. The placebo group had a
greater number of patients with severe stroke.
International Stroke Trial (IST). The IST was
designed as a 2 X 3 factorial study to evaluate the
benefit of heparin alone and in combination with
aspirin (ASA) after a 14-day treatment period.14The
ASA dose was 300 mg daily and heparin doses were
5,000 IU (low dose) and 12,500 IU (high dose) twice
daily.
A total of 19,435 patients were randomized openly
into one of six treatment groups: ASA alone, ASA
plus low-dose heparin, ASA plus high-dose heparin,
low-dose heparin alone, high-dose heparin alone, and
no study medication. Inclusion and exclusion criteria
were similar to those in the nadroparin trial. Pri-
mary end points were death resulting from any
cause within 14 days and death or dependency a t 6
months as determined by follow-up examination, in-
terview, or written questionnaire. Secondary out-
come events included hemorrhagic stroke within 14
days, recurrent ischemic stroke within 14 days, ma-
jor extracranial hemorrhage within 14 days, and pul-
monary embolism within 14 days.
Results of this study showed a nonsignificant
trend toward fewer deaths within 14 days among
heparin-treated patients compared with patients not
treated with heparin (9% vs 9.3%). The numbers of
deaths resulting from hemorrhagic stroke or ex-
tracranial bleeding were significantly greater with
heparin treatment. Heparin-treated patients exhib-
ited fewer recurrent ischemic strokes (2.9% vs 3.8%;
2p = 0.005) and fewer pulmonary emboli (0.5% vs
0.8%; 2p = 0.02) than those not treated with hepa-
rin. Hemorrhagic strokes (1.2% vs 0.4%; 2p =
0.00001) and fatal or nonfatal episodes of extracra-
nial bleeding (1.3% vs 0.4%; 2p = 0.00001) were in-
creased with heparin treatment. At 6 months, the
percentage of patients dead or dependent was identi-
cal (62.9%) in the groups treated with heparin and
not treated with heparin (table 2). Therefore, treat-
ment with heparin within 48 hours after an ischemic
September 1998 NEUROLOGY 51(Suppl3) 567
Table 3 Patient outcomes in the TOAST trial
ORG 10172 (%) Placebo (%)
Outcome (n = 641) (n = 634)
Favorable outcome at 3 months 75.2 73.7
Favorable outcome at 7 days 59.2 54.3
Mortality at 3 months 6.6 6.0
Recurrent stroke or systemic 1.2 1.6
embolus within 7 days
TOAST = Trial of ORG 10172 in Acute Stroke Treatment.
stroke prevented nine recurrent strokes per 1,000
patients at the expense of eight ICHs, and treatment
with ASA prevented eight recurrent strokes at the
expense of one ICH.
Trial of ORG 10172 in Acute Stroke Treatment
(TOAST). This randomized, double-blind trial was
designed t o assess the efficacy and safety of ORG
10172 (danaparoid sodium), a heparinoid, in patients
with acute ischemic stroke.l5 Patients (n = 1,281)
received either ORG 10172 intravenously (dose ad-
justed to yield 0.6-0.8 anti-factor Xa U/mL) or pla-
cebo for 7 days. The primary outcome was favorable
status at 3 months after stroke onset, as defined by
the Glasgow Outcome Scale (score of I or 11) and
Modified Barthel Index (score of 212). Secondary
outcome measures included mortality at 7 days and
3 months and recurrent stroke or systemic embolus
(e.g., DVT, pulmonary embolism) within 7 days. In-
clusion criteria were age between 18 and 85 with a
diagnosis of acute ischemic stroke that occurred
within the previous 24 hours and a prestroke Bar-
the1 Index score of at least 12. Exclusion criteria
were essentially the same as those in the nadroparin
trial and IST.
Intention-to-treat analysis showed no significant
differences among treatment groups in the primary
and secondary outcome measures (table 3). Safety
analysis indicates that the risk for major bleeding
complications was higher in the treated group, in
which 32 patients experienced a major bleeding
event during the first 10 days compared with 10
in the placebo group ( p < 0.005). Similarly, major
ICH was more prevalent in the treated group (14
patients) than in the placebo group (four patients;
p < 0.05).
Conclusions. Heparin, LMWHs, and heparinoids
clearly reduce the incidence of DVT in patients with
~troke.',~J*
However, there appears to be no net long-
term benefit with heparin treatment for patients
with stroke, as determined by the IST. The smaller
S58 NEUROLOGY Sl(Suppl3) September 1998
nadroparin trial does suggest a long-term benefit
with LMWH treatment, but the delay that occurs
before any benefit is detectable casts doubt on
whether the effects are the direct result of LMWH
treatment. The results of TOAST indicate that treat-
ment with heparinoids offers no net benefit to the
stroke patient. An important next step will be to
determine whether certain specific populations of pa-
tients with stroke exhibit greater benefit from anti-
coagulant therapy with LMWH or heparinoids.
References
1. Turpie AGG. Prophylaxis of venous thromboembolism in
stroke patients. Semin Thromb Hemost 1997;23:155-157.
2. Marsh EE 111, Adams HP J r , Biller J , et al. Use of antithrom-
botic drugs in the treatment of acute ischemic stroke: a survey
of neurologists in practice in the United States. Neurology
1989;39:1631-1634.
3. Kappelle LJ,Adams HP Jr, Torner JC, Bendixen BH. Physi-
cian attitudes towards acute stroke-a comparison of primary
care physicians in Iowa and the Netherlands. Cerebrovasc Dis
1993;3:364-369.
4. Sandercock PAG, van den Belt AGM, Lindley RI, Slattery J.
Antithrombotic therapy in acute ischaemic stroke: an over-
view of the completed randomised trials. J Neurol Neurosurg
Psychiatry 1993;56:17-25.
5. Nurmohamed MT, ten Cate H, ten Cate JW.Low molecular
weight heparin(oid)s: clinical investigations and practical rec-
ommendations. Drugs 1997;53:736-751.
6. Stein B, Fuster V. Antithrombotic therapy in acute myocar-
dial infarction: prevention of venous, left ventricular and cor-
onary artery thromboembolism. Am J Cardiol 1989;64:33B-
40B.
7. Harenberg J, Roebruck P, Heene DL, on behalf of the Heparin
Study in Internal Medicine Group. Subcutaneous low-
molecular-weight heparin versus standard heparin and the
prevention of thromboembolism in medical inpatients. Haemo-
stasis 1996;26:127-139.
8. Clagett GP, Reisch JS. Prevention of venous thromboembo-
lism in general surgical patients: results of meta-analysis.
Ann Surg 1988;208:227-240.
9. Warkentin TE, Levine MN, Hirsh J , et al. Heparin-induced
thrombocytopenia in patients treated with low-molecular-
weight heparin or unfractionated heparin. N Engl J Med
1995;332:1330-1335.
10. Lutomski DM, Bottorff M, Sangha K. Pharmacokinetic op-
timisation of the treatment of embolic disorders. Clin Pharma-
cokinet 1995;28:67-92.
11. Skoutakis VA. Danaparoid in the prevention of thromboem-
bolic complications. Ann Pharmacother 1997;31:876-887.
12. Hirsh J , Levine MN. Low molecular weight heparin. Blood
1992;79:1-17.
13. Kay R, Wong KS, Yu YL, et al. Low-molecular-weight heparin
for the treatment of acute ischemic stroke. N Engl J Med
1995;333:1588-1593.
14. International Stroke Trial Collaborative Group. The Interna-
tional Stroke Trial (IST): a randomised trial of aspirin, subcu-
taneous heparin, both, or neither among 19 435 patients with
acute ischaemic stroke. Lancet 1997;349:1569-1581.
15. The Publications Committee for the Trial of ORG 10172 in
Acute Stroke Treatment (TOAST) Investigators. Low molecu-
lar weight heparinoid, ORG 10172 (danaparoid), and outcome
after acute ischemic stroke. A randomized controlled trial.
JAMA 1998;279:1265-1272.