Role of heparin in stroke management
The author: Professor Yasser Metwally
HEPARIN IN THE TREATMENT OF ACUTE STROKE
The fiftieth anniversary of the first publication on the clinical use of heparin for the prevention of thrombosis was marked in 1991. 19 In several medical fields the indications for heparin have been well defined throughout the years, but there is still considerable debate and confusion as to the indications and possible benefits of this treatment in neurology, as shown in a recent survey of US neurologists. 25 Many of the studies suggesting a beneficial role for heparin are quite old and have significant methodological flaws. The widespread use of computed tomography (CT) scans in stroke patients probably contributes to the continuing use of heparin because CT largely alleviates the fear of missing intracerebral bleeding, the most significant side effect and contraindication to heparin.
As many as one third of stroke patients admitted to the hospital experience neurologic worsening within a few days. 28 The clinician is often faced with the frustrating situation of seeing the demise of a patient whose death he was unable to prevent. This has led to experimentation with several drugs to restore function or prevent deterioration including corticosteroids, low molecular weight dextran, glycerol, mannitol, and many others. The main purpose of the use of these agents is to reduce intracranial pressure and edema and thus improve the chances for viability of neurons in the penumbra region. In general, the results of these studies are not particularly promising.
Another approach is to use drugs that act on intravascular processes, particularly anticoagulants. The aim of these agents is to prevent deterioration resulting from extension of the thrombus. Because drugs of the warfarin (Coumadin) group act rather slowly, many attempts were made to employ, heparin in the acute stages of stroke.
The high rate of morbidity and mortality due to strokes places the physician in a difficult situation when faced with a patient who has a higher risk for stroke. This patient may have cardiac disease or may have had a transient ischemic event (TIA) due to carotid artery disease. The goal for the physician in these patients is stroke prevention. This goal is even more acute in the case of a patient who has completely or partially recovered from a previous stroke and in whom secondary prevention is desired. Logical considerations and empirical evidence have suggested several lines of therapy. Some of these methods, such as the use of aspirin, have been widely upheld. 4a, 13a, 16 Other methods, such as the external carotid-internal carotid (EC-IC) bypass procedure, have been practically abandoned as a result of a large and complicated multicenter study. 11 Additional medical and surgical approaches are still being evaluated. Significantly, however, very little data are available concerning the efficacy of the oldest method, anticoagulant therapy. Theoretically, anticoagulants are the most logical treatment against arterial thrombosis in the brain and elsewhere. Still, theory and logic do not always agree with actual results. For many years cardiologists have recommended the use of heparin in acute myocardial infarction, but this type of therapy has been totally discarded. Among neurologists, opinions are divided about the use of heparin in stroke because of a lack of concrete data relating to the risk-benefit ratio. 25
Anticoagulation in patients who have undergone embolic strokes of cardiac origin is of particular importance because of the considerable risk of recurrent embolization, which amounts to 1% per day. 8 Yatsu et al, 42 have defined the precautions and methods of administering heparin to these patients.
Deep vein thrombosis is relatively common following stroke particularly in patients who are immobile due to the severity of the stroke, 4, 40 in the obese, and in those with other associated conditions. This complication carries a significant morbidity, particularly from pulmonary emboli, although many cases are unrecognized. Several pulmonary vascular occlusions can be seen in previously asymptomatic cases at autopsy. Massive pulmonary emboli are much more likely to be recognized and may contribute to death or actually cause it. Several reports suggest that low-dose heparin is an effective prophylactic measure, although available studies are relatively small, and assessments were not blind. 15, 27
Although the main target of heparin treatment is to prevent neurologic deterioration, it should be recalled that not all progressive impairment is due to propagated thrombus formation. Other factors possibly leading to this type of deterioration (Table 1) include systemic factors that can impair the cerebral circulation such as hypotension, low cardiac output, and fever, as well as respiratory and acid-base derangements. Intracranial factors, particularly local edema and generalized increased intracranial pressure, may also contribute to deterioration and in fact may be responsible for about 4% mortality within 1 month after an ischemic stroke. 37 When these complicating factors exist, the volume of the infarcted tissue may increase. These effects are not related to propagated thrombus formation and therefore are not expected to improve following otherwise successful anticoagulation. Because the relative contribution of these factors to neurologic deterioration following strokes (as opposed to propagated thrombus formation) is not clear, the theoretical expected benefit from heparin administration is an educated guess at best.
Table 1. CAUSES OF NEUROLOGIC DETERIORATION FOLLOWING ISCHEMIC STROKES
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Table 2. FACTORS PREDISPOSING HEPARINIZED STROKE PATIENTS TO HEMORRHAGE
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A hypercoagulative state has been described immediately following a stroke, manifesting as elevated levels of fibrinogen, 12, 20 fibrinopeptides, 24 decreased fibrinolysis, 20 and plasminogen activator. 39 This may theoretically justify the use of heparin. Although these observations can explain how heparin could work, however, they do not prove that it does.
Several side effects have been attributed to heparin. Some of these side effects, such as osteoporosis, appear only with chronic therapy. The cardinal risk, however, is obviously hemorrhage. Hemorrhage can occur in every patient treated with heparin, particularly if an excessive dose is given (Tables 2 and 3), and may appear in any organ. Administration of heparin after a thrombotic event entails a far greater risk, however. Following occlusion of a major vessel in the brain, such as the middle cerebral artery, damage occurs not only to brain tissue but also to the vessel wall, particularly the endothelium. If recanalization occurs within a short period, the weakened arterial wall may not be able to withstand the high intravascular pressure, resulting in the transformation of an ischemic to a hemorrhagic infarction. This process, which is particularly common in embolic strokes, may be of different degrees. The spontaneous transformation can become a catastrophic event in an anticoagulated patient.
Thrombocytopenia of a mild degree (up to 20% reduction of platelet count) occurs frequently in heparinized patients and probably has little or no clinical significance. An immunomediated severe thrombocytopenia is quite rare. This is a reversible phenomenon that requires monitoring for early detection, because when heparin is not withdrawn hemorrhage can occur in spite of activated partial thromboplastin time (APTT) within the desired range. Paradoxic thrombocytopenia and thrombosis have been increasingly diagnosed over the last decade. Heparin-induced thrombosis can occur in any arterial or venous vessel but is of particular concern if it involves the brain, because these patients were first given heparin to defend the brain against thrombosis. Fortunately this complication is quite rare.
Table 3. CLINICAL MANIFESTATIONS SUGGESTING HEMORRHAGIC TRANSFORMATION
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Intracranial hemorrhage is the most frequent serious complication of heparin seen by neurologists. Depending on the extent of the hemorrhage, it can carry a grave prognosis. Naturally, it is difficult to be sure whether the anticoagulants are actually responsible for hemorrhagic transformation or have merely contributed to its progression. The treatment of such a bleed is also a formidable task. Although the anticoagulant effects of heparin can be antagonized instantaneously by the administration of prolamine, this is unlikely to affect the progression of intracranial bleeding, which, in any case is limited. Surgical intervention is an option for extracerebral collection and sometimes also for cerebellar or other parenchymatous hemorrhages, but the risks should be weighed carefully. The risk of developing intracranial hemorrhage in a stroke patient or of hemorrhagic transformation obviously depends on good control of aPTT. In many patients who have,bled, however, aPTT values were within the desired range of less than twice the upper normal limit. Other risk factors were also considered, although consensus does not always exist. These factors include the size of the stroke, embolus as an underlying cause, hypertension, age, and the existence of intracranial tumor. 2,5,31,41
INDICATIONS FOR ADMINISTRATION
The modern use of heparin is mainly through intravenous administration, and therefore treatment with heparin following acute stroke requires hospitalization. There are three indications for heparin use:
1. In patients with stroke-in-evolution, to prevent progression.
2. In patients with recent transient ischemic attack (TIA) or reversible ischemic neurologic disability (RIND), to prevent recurrence.
3. In bedridden patients, to prevent pulmonary thromboembolism.
The question of the efficacy of anticoagulants should, of course, be answered separately for each nosologic stroke entity. In cases with embolic stroke, the main endpoint is stroke recurrence in the same or different arterial territory, whereas in patients with established stroke the endpoint is extension of the thrombus. Therefore, patients presenting with TIA, completed stroke, or stroke-in-evolution should be evaluated separately. Also, the extent of the lesion on presentation must be taken into account. Obviously, patients with only TIA on presentation, or alternatively, those with completed stroke in the total distribution of a major blood vessel (e.g., middle cerebral artery) are not likely to progress. In addition, different results in patients with ischemia of the posterior circulation and in the carotid territory are to be expected. These two groups, therefore, should be analyzed separately.
Heparin may be employed in stroke patients as prophylaxis against recurrent emboli. These emboli are rather frequent, and available data suggest that they are particularly common shortly after the first embolic episode. 18 Therefore, heparin may be the logical drug to use, superior to oral anticoagulants that have a long latent period. Several studies have attempted to assess the efficacy of heparin in preventing stroke recurrence following TIA. Probably the largest report is a recent compilation of the Mayo Clinic records. 21 This retrospective analysis demonstrated a slight, and statistically nonsignificant, difference favoring heparin over no treatment. The patients were seen over a 25-year period, however, and the criteria for heparinization or not are not known. There probably was a selection bias, by which patients with a higher risk of complication were not given heparin. Therefore, the results of this analysis, although not final, argue that heparin may not be efficacious after a TIA.
Stroke extension is believed to be caused by thrombus formation, a process which is, at least theoretically, amenable to heparin treatment. Unfortunately, the available studies have not established whether this logical treatment is really effective. 33 Several studies have been conducted, but all have had serious limitations. 16
It is therefore not surprising that conflicting views exist about the indications for anticoagulation in acute ischemic stroke and that several authorities take a negative view of this treatment. 29,30,35,36 In spite of negative reports, 10,17,38, there is a significant trend among clinicians to favor studies with a positive heparin effect.
One of the most frequently quoted references involving heparin use is that of the Cerebral Embolism Study Group. 6 This multicenter study had an open, not blinded design. Although initially the inclusion of many more patients was planned, the study was terminated prematurely without achieving the original endpoints. Altogether, 45 patients were randomly allocated into immediate heparinization or nonanticoagulated groups. The authors concluded that the data support immediate anticoagulation of nonhypertensive patients with embolic brain infarction, although differences in outcome were small and not statistically significant. 6
There are several obvious deficiencies in this study. Most notable is the very small number of patients included (particularly because five major centers were involved). The difficulty of recruiting a sufficiently large number of cases to fulfill strict research criteria for a clinical trial is highlighted by this observation. Nevertheless, the small number of patients can cause both type I and type 11 errors.
Another problem with the study of the Cerebral Embolism Study Group is that the patients were heparinized on the average 32 hours following the stroke. Many physicians feel that this is a rather long time period, and if benefits were to be seen, all patients should have been treated within 24 hours. Had the number of patients been greater, stratification according to the time until treatment initiation could have been performed. The long delay reflects practical difficulties that are not easy to overcome, primarily the need for expert decision as to the correct diagnosis and the need to obtain a CT scan to rule out the possibility of intracranial hemorrhage.6
The term heparinized, used in the original article, 6 is problematic. It inadvertently delivers the message that the patients received an adequate loading dose of heparin (such as the terms digitalization or phenytoinization). In fact, patients received a bolus of 5,000 to 10,000 units initially, followed by continuous infusion at a rate adjusted to prolong the partial thromboplastin time (PTT) 1.5 to 2.5 times the pretreatment level PTT was monitored daily.
This regimen is likely to achieve sufficient anticoagulation during the first 24 hours in a significant number of patients but definitely not in all patients because many physicians are unsatisfied with PTT values lower than twice the control value. Furthermore, individual patients may be resistant to standard doses of heparin. 28 1n the study conducted by Furlan et al, 14 the target anticoagulation was achieved belatedly but usually within 6 days in 44% of anticoagulated patients. Three patients reported in the Cerebral Embolism Study Group received the first heparin dose only 60 to 70 hours after the stroke occurred. The title of the paper, Immediate anticoagulation of Embolic Stroke, is therefore misleading. Unfortunately, it is impossible to know the likelihood of progression in those patients who had better anticoagulation. (It should be recalled, however, that in a recent study Slivka and Levy, 38 failed to find a correlation between the degree of anticoagulation and the likelihood of progression in their patients.).
Although the aim of the Cerebral Embolism Study Group was to evaluate the efficacy of early anticoagulation in embolic strokes, the investigators recognized the difficulty of establishing the diagnosis of stroke due to embolism. Atrial fibrillation was found in 28 of the 45 cases, but it is not clear to what extent atrial fibrillation constitutes a risk factor for stroke. 22 Moreover, atrial fibrillation can sometimes be a consequence of stroke. 23 In patients with embolic stroke, different effects of heparin can be seen, depending on the source of the emboli (atrial, valvular, mural thrombus, or carotid artery), because each source may have different underlying mechanisms of embolus formation.
CLINICAL TRIALS: WHAT DO WE NEED?
The foregoing discussions have pointed out the degree of controversy and ignorance that still prevails concerning the use of heparin. Recognizing these difficulties, several authors have suggested a multicenter study to establish whether heparin is efficacious. 13, 32 Such clinical trials are not easy to perform, however, and have to satisfy certain requirements.
The endpoints of treatment with heparin should be made clear in any clinical trial. The main goal of treatment is either prevention of stroke progression or prevention of new events. A secondary endpoint could be survival, because this can be effected by heparin (through its cerebroprotective effect, by prevention of pulmonary emboli, and so on). Finally, calculation of the risk to benefit ratio demands detailed attention to possible complications (Table 4). 34 The question of whether to heparinize or not to heparinize is of considerable importance due to the potential complications involved in this treatment, which are associated with significant morbidity and mortality. It would become easier to lessen the risk to benefit ratio if the complication rates were better defined for specific types of patients and disorders. 34
The number of aspects that need to be controlled in clinical trials of heparin in stroke is large. This can increase the cost of carrying out a truly comprehensive trial. Although partial answers regarding heparin may be forthcoming (and will be welcomed), it is quite possible that we shall never know how effective heparin is in preventing stroke extension or recurrence. Like other old theories, the idea that heparin is effective in stroke may never be disproven, even if it is wrong. Its use will probably die naturally once newer therapies with fewer side effects become available. 3,26
Table 4. SIDE EFFECTS OF HEPARIN
| Side Effect | Risk Factor |
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In light of the opposing views, it is likely that there is no clear-cut advantage to the use of heparin in patients following acute stroke. In other words, it is possible that although some patients may benefit from heparin, others should not be given this treatment because of a greater likelihood of side effects. The prudent neurologist will try to evaluate the following parameters prior to the administration of heparin.
1. Establish that the neurologic deficit is due to focal brain ischemia. Other causes, particularly reduced cardiac output, are probably not an indication for anticoagulation.
2. Establish that the patient had an ischemic event and not an intracranial bleed. In other words, a CT scan is mandatory prior to initiation of therapy.
3. Establish whether the patient has other intracranial lesions. Single case reports have documented bleeding into intracranial tumors in anticoagulated patients, although these are extremely rare.
4. Evaluate the size and location of the brain infarction. A very large hemispheric infarction is probably more likely to bleed when flow is re-established. Lacunar subcortical infarctions are less likely to progress and may not respond to anticoagulation. 9
5. Rule out the following potential causes of bleeding: uncontrolled hypertension, bleeding diathesis, esophageal varices, and other likely sources of bleeding. Although old age per se is not a contraindication for heparin, bleeding in non-neural sites is more likely to occur in older subjects.
Although low-dose heparin (10,000 to 20,000 U/24 h, intravenously or subcutaneously) is recommended for prophylaxis against deep vein thrombosis or pulmonary embolism, this dose is probably insufficient to prevent stroke extension or recurrence. Thus in various studies, a range of 25,000 to 50,000 U/ d has been employed. The following widely used regimen employs intravenous administration which is superior to subcutaneous administration:
1. Initial bolus of 5,000 to 10,000 U.
2. Continuous infusion of 1,000 U/h.
3. Determination of the aPTT at least every 12 hours, and adjustment of the infusion rate to achieve an aPTT of between 1.5 and 2 times the control. A more frequent estimation of individual requirements is recommended initially.
4. Heparin should be continued for 48 hours and then replaced by oral anticoagulants if needed.
References
1. Atkinson JLD, Sundt TM, Kazmier Fj, et al: Heparin-induced thrombocytopenia and thrombosis in ischemic stroke. Mayo Clin Proc 63:353, 1988
2. Babikian, Kase CS, Pessin MS, et al: Intracerebral hemorrhage in stroke patients anticoagulated with heparin. Stroke 20:1500, 1989
3. Bfller J, Massey EW, Marler JR,et al: A dose escalation study of ORG 10172 in stroke. Neurology 39:262, 1989
4. Bornstein NM, Norris JW: Deep vein thrombosis after ischemic stroke: Rationale for a therapeutic trial. Arch Phys Med Rehabil 69:955, 1988
4a. Bousser MG, Eschwege E, Haguenau M, et al: AICLA controlled trial of aspirin and dipyridamole in the secondary prevention of atherothrombotic cerebral ischemia. Stroke 14:5, 1983
5. Cerebral Embolism Study Group: Cardiogenic stroke, early anticoagulation, and brain hemorrhage. Arch Intern Med 147:636, 1987
6. Cerebral Embolism Study Group: Immediate anticoagulation of embolic stroke: A randomized trial. Stroke 14:668, 1983
7. Cerebral Embolism Study Group: Immediate anticoagulation of embolic stroke: Brain hemorrhage and management options. Stroke 15:779, 1984
8. Cardiac Embolism Task Force: Cardiogenic brain embolism. Arch Neurol 43:71, 1986
9. Dobkin BH: Heparin for lacunar stroke in progression. Stroke 14:421, 1983
10. Duke Rj, Block RF, Turpie AGG, et al: Intravenous heparin for the prevention of stroke progression in acute partial stable stroke: A randomized controlled trial. Ann Intern Med 105:825-828, 1986
11. EC/IC Bypass Study Group: Failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke. N Engl J Med 313:1191, 1985
12. Elliott FA, Bucknell M: Fibrinogen changes in relation to cerebrovascular accidents. Neurology 10:120, 1960
13. Estol Cj, Pessin MS: Anticoagulation: Is there still a role in atherothrombotic stroke? Stroke 21:820-824, 1990
13a. Fields WS, Lemak NA, Frankowski RF, et al: Controlled trial of aspirin in cerebral ischemia. Stroke 8:301, 1977
14. Furlan Aj, Cavalier Sj, Hobbs RE, et al: Hemorrhage and anticoagulation after nonseptic embolic brain infarction. Neurology 32:280-282, 1982
15. Gelmers Hj: Effects of low-dose subcutaneous heparin on occurrence of deep vein thrombosis in patients with ischemic stroke. Acta Neurol Scand 61:313, 1980
16. Genton E, Barnett HJM, Fields WS, et al: Cerebral ischemia: The role of thrombosis and antithrombotic therapy. Stroke 8:150, 1977
17. Haley EC, Kassell NF, Yorner JC: Failure of heparin to prevent progression in progressing ischemic infarction. Stroke 19:10, 1988
18. Hart RG, Coull BM, Hart D: Early recurrent embolism associated with nonvalvular atrial fibrillation. Stroke 14:688, 1983
19. Hedenius P: The use of heparin in internal diseases. Acta Med Scand 107:170, 1941
20. Hossmann V: Coagulation disturbances in cerebrovascular disorders. In Zuch Kj (ed): Brain and Heart Infarct. Berlin, Springer Verlag, 1977, pp 81-92
21. Keith DS, Phillips Sj, Whisnant JP, et al: Heparin therapy for recent transient focal cerebral ischemia. Mayo Clin Proc 62:1101, 1987
22. Kopecky SL, Gersh Bj, McGoon AB, et al: The natural history of lone atrial fibrillation: A population-based study over three decades. N Engl J Med 317:669, 1987
23. Korczyn AD: Respiratory and cardiac abnormalities in brain stem ischaemia. j Neurol Neurosurg Psychiatry 38:187, 1975
24. Lane DA, W(;If S, Ireland M, et al: Activation of coagulation and fibrinolytic systems following stroke. Br J Haematol 52:655, 1983
25. Marsh EE, Adams HP, Biller J, et al: Use of antithrombic drugs in the treatment of acute ischemic stroke: A survey of neurologists in practice in the United States Neurology 39:1631, 1989
26. Massey EW, Biller J, Davis JN, et al: Large dose infusion of heparinoid ORG 10172 in ischemic stroke. Stroke 21:1289, 1990
27. McCarthy ST, Robertson D, Turner jj, et al: Low-dose heparin as prophylaxis against deep-vein thrombosis after acute stroke. Lancet 2:800, 1977
28. Miller VT, Hart RG: Heparin anticoagulation in acute brain ischemia. Stroke 19:403, 1988
29. Phillips Sj: An alternative view of heparin anticoagulation in acute focal brain ischemia. Stroke 20:295, 1989
30. Phillips Sj: Heparin in acute stroke. Stroke 20:1284, 1989
31. Ramirez-Lassepas Mi Quinones MR: Heparin therapy for stroke: Hemorrhagic complications and risk factors for intracerebral hemorrhage. Neurology 34:114, 1984
32. Ramirez-Lassepas M, Quinones MR, Nino HH: Treatment of acute ischemic stroke: Open trial with continuous intravenous heparinization. Arch Neurol 43:386, 1986
33. Sage JL: Stroke: The use and overuse of heparin in therapeutic trials. Arch Neurol 42:315, 1985
34. Schaffert A, Winogrod M: Heparin therapy for stroke. Neurology 34:1619, 1984
35. Scheinberg P: Heparin anticoagulation. Stroke 20:173, 1989
36. Scheinberg P: Heparin in acute stroke. Stroke 20:1284-1285, 1989
37. Silver FL, Norris JW, Lewis Aj, et al: Early mortality following stroke: A prospective review. Stroke 15:492, 1984
38. Slivka A, Levy D: Natural history of progressive ischemic stroke in a population treated with heparin. Stroke 21:1657, 1990
39. Wahlberg TB, Blomback M, Overmark 1: Blood coagulation studies in 45 patients with ischemic cerebrovascular disease and 44 patients with venous thromboembolic disease. Acta Med Scand 207:385, 1980
40. Warlow C, Ogston D, Douglas AS: Deep venous thrombosis of legs after strokes. BMJ 1:1178, 1976
41. Wolf MW: Intracranial hemorrhage during systemic anticoagulation in patients with cerebral metastasis. Arch Itern Med 148:1878, 1988
42. Yatsu FM, Hart RG, Mohr JP, et al: Anticoagulation of embolic strokes of cardiac origin: An update. Neurology 38:314, 1988
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