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 anticoagulation 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

also increases the risk for immune-mediated thromHeparin and heparinoids are anticoagulants commonly prescribed for prevention of recurrent brain bocytopenia (IMT),Swhich is aggravated by the freemboli, stroke progression, systemic embolism, deep quent dosing heparin requires because of its low venous thrombosis (DVT), and pulmonary embolism bioavailability after subcutaneous (SC) administrain 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 thromboemmeasurements 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 elimiHowever, 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 Heparinciting 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 hepawith stroke appear to be offset by the risk for intrarin, inhibiting clotting factor Xa activity after bindcerebral 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 heparinmarizes three large, well-controlled clinical trials inioids 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 relow-dose heparin and heparinoids in treatment of sult, LMWHs and heparinoids suppress platelet agischemic stroke. gregation only minimally,11J2thereby reducing the incidence of bleeding. The smaller size of both LMWHs and heparinoids increases their absorption Characteristics of heparins and heparinoids. (to almost 100% after SC administration) and inThe benefits and risks of heparin agents depend pricreases their elimination half-lives (- 1.4-5.9 hours marily on their sites of action. Unfractionated heparin (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 once or twice daily.'O-12 Similarly, although the rebind to the native anticoagulant enzyme antithrombin III.5 The UFH-antithrombin I11 complex inhibits ported incidence of IMT is highly variable, it appears clotting factors IIa (thrombin) and Xa, thereby proto 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 (%) (n = 100) (n = 101) (n = 105)
13 26 26 33 45 17 25 22 37 52 19 18 16 47 65

Table 2 Patient outcomes at 6 months in the Znternational Stroke Trial

Treated with heparin (%) (n = 9,641)
17.2 40.4 22.5 62.9

Outcome Recovery

Not treated with heparin (%) (n = 9,644)

17.0 41.3 21.5 62.9

Outcome (n Deaths

306)

Dependence Death Death or dependence

Independence Total recovery Partial recovery Dependence Death or dependence

Adapted from the International Stroke Trial Collaborative Group, with permi~sion.'~

LMWHs have been found to cross-react with circulating antibodies, potentiating IMT.3 Heparinoids appear to be safe for anticoagulant therapy in patients with IMT." Clinical trials of heparin, LMWHs, and danaparoid (a heparinoid) have been conducted to determine 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 trial.13 Patients 80 years of age or younger and diagnosed with acute ischemic stroke within the previous 48 hours were enrolled, regardless of stroke severity. Patients were excluded if they had evidence of hemorrhage on a baseline CT scan, if they lacked neurologic 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 patients) or low-dose (18 patients) nadroparin groups. Results of the study revealed that high-dose nadroparin significantly lowered the risk for death or dependency at 6 months (45%) compared with placebo (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

nadroparin, and placebo, respectively). The investigators 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 treatment, 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. Primary 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, interview, or written questionnaire. Secondary outcome events included hemorrhagic stroke within 14 days, recurrent ischemic stroke within 14 days, major extracranial hemorrhage within 14 days, and pulmonary 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 extracranial bleeding were significantly greater with heparin treatment. Heparin-treated patients exhibited 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 heparin. Hemorrhagic strokes (1.2% vs 0.4%; 2p = 0.00001) and fatal or nonfatal episodes of extracranial bleeding (1.3% vs 0.4%; 2p = 0.00001) were increased with heparin treatment. At 6 months, the percentage of patients dead or dependent was identical (62.9%) in the groups treated with heparin and not treated with heparin (table 2). Therefore, treatment with heparin within 48 hours after an ischemic
September 1998 NEUROLOGY 51(Suppl3) 567

Table 3 Patient outcomes in the TOAST trial Outcome Favorable outcome at 3 months Favorable outcome at 7 days Mortality at 3 months Recurrent stroke or systemic embolus within 7 days ORG 10172 (%) (n = 641) 75.2 59.2 6.6 1.2 Placebo (%) (n = 634) 73.7 54.3
6.0

1.6

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 treatment with heparinoids offers no net benefit to the stroke patient. An important next step will be to determine whether certain specific populations of patients with stroke exhibit greater benefit from anticoagulant therapy with LMWH or heparinoids.

TOAST = Trial of ORG 10172 in Acute Stroke Treatment.

References
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 adjusted to yield 0.6-0.8 anti-factor Xa U/mL) or placebo 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. Inclusion criteria were age between 18 and 85 with a diagnosis of acute ischemic stroke that occurred within the previous 24 hours and a prestroke Barthe1 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).
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 antithrombotic 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. Physician 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 overview of the completed randomised trials. J Neurol Neurosurg Psychiatry 1993;56:17-25. Low molecular 5. Nurmohamed MT, ten Cate H, ten Cate JW. weight heparin(oid)s: clinical investigations and practical recommendations. Drugs 1997;53:736-751. 6. Stein B, Fuster V. Antithrombotic therapy in acute myocardial infarction: prevention of venous, left ventricular and coronary artery thromboembolism. Am J Cardiol 1989;64:33B40B. 7. Harenberg J, Roebruck P, Heene DL, on behalf of the Heparin Study in Internal Medicine Group. Subcutaneous lowmolecular-weight heparin versus standard heparin and the prevention of thromboembolism in medical inpatients. Haemostasis 1996;26:127-139. 8. Clagett GP, Reisch JS. Prevention of venous thromboembolism 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-molecularweight heparin or unfractionated heparin. N Engl J Med 1995;332:1330-1335. 10. Lutomski DM, Bottorff M, Sangha K. Pharmacokinetic optimisation of the treatment of embolic disorders. Clin Pharmacokinet 1995;28:67-92. 11. Skoutakis VA. Danaparoid in the prevention of thromboembolic 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 International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous 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 molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke. A randomized controlled trial. JAMA 1998;279:1265-1272.

Conclusions. Heparin, LMWHs, and heparinoids clearly reduce the incidence of DVT in patients with ~troke.',~J* However, there appears to be no net longterm benefit with heparin treatment for patients with stroke, as determined by the IST. The smaller

S58

NEUROLOGY Sl(Suppl3) September 1998