In broad, relatively unselected patients with acute ischaemic stroke, immediate high-dose anticoagulation therapy to avert early stroke progression or recurrence reduces recurrent ischaemic stroke compared with control during the treatment period but this benefit is offset by an increase in intracranial haemorrhage (ICH) and extracranial haemorrhage (ECH). Immediate antiplatelet therapy has similarly efficacy as anticoagulation in averting early stroke progress or recurrence, and is safer when used as an immediate agent (see Chapter 9). In acute ischaemic stroke patients with atrial fibrillation, after start of antiplatelet therapy on presentation, early switchover to anticoagulation therapy 2 -14 days after stroke onset is reasonable, but caution should be taken in certain subgroups of patients with high risk of bleeding. In broad, relatively unselected ischaemic stroke patients, low-dose, venous prophylaxis anticoagulation compared with control reduces the occurrence of asymptomatic deep venous thrombosis (DVT) and shows a tendency to reduce pulmonary embolism, but also shows off-setting tendencies to increase ICH and ECH, without conferring a clear net clinical benefit. Low-molecular-weight heparins (LMWH) or heparinoids, compared with unfractionated heparin, appear to further decrease the occurrence of DVT and PE but potentially further increase ICH, but there are too few data to provide reliable information.
The purpose of anticoagulation in patients with ischaemic stroke and transient ischaemic attack (TIA) is to prevent recurrent ischaemic stroke and other serious vascular events (by preventing arterial thromboembolism and cardiogenic embolism) and to prevent venous thromboembolism. The current chapter will review evidence of the effects of anticoagulants in the acute phase and in long-term secondary prevention in relatively unselected ischaemic stroke patients, as well as the effects of anticoagulants in the acute phase of ischaemic stroke with atrial fibrillation (AF). For the effects of anticoagulants in long-term secondary prevention of selected stroke patients with cardioembolic risks, please refer to Chapter 18.
The risk of early recurrence in patients with ischaemic stroke or TIA has been lowered substantially in recent years, due to the development and dissemination into clinical practice of multiple advances in evidence-based treatment strategies. In a large, international observational study of patients with minor ischaemic stroke and TIA, recurrent stroke rates were 2% within 1 week, 3% within 1 month, 4% within 3 months, and 5% within 1 year (Amarenco et al., 2016). However, the risk of early recurrent stroke is much higher in certain subgroups of patients. Among a broad group of acute cerebral ischaemia patients, the hazard for early recurrent stroke was doubled for patients with large artery atherosclerosis as ischaemic mechanism and doubled in patients with multiple acute cerebral infarctions on brain imaging (Amarenco et al., 2016). Similarly, multicentre series have found risks of recurrence by 3 months of up to 15–20% in patients with cervical carotid stenosis (Rothwell, 2008; Johansson and Wester, 2014), and over 10% in patients with intracranial arterial stenosis (Chimowitz et al., 2011; Liu et al., 2015). In contrast, the risk of recurrence in ischaemic stroke or TIA patients with presumed cardioembolism was reported to be up to 3–7% at 90 days (Ay et al., 2010; Paciaroni et al., 2015).
Theoretically, both anticoagulants and antiplatelet drugs should be at least somewhat effective in reducing recurrent ischaemic strokes that are due to thrombus propagation or recurrent thromboembolism, though not events due to haemodynamic and collateral failure, provided they can be administered safely. Anticoagulants inhibit the formation of predominantly ‘red’, erythrocyte and fibrin-rich clots in areas of very reduced and stagnant blood flow, such as in cardiac chambers with impaired contractility (e.g. AF, akinetic left ventricle) and in veins (e.g. paralysed leg). Antiplatelet drugs inhibit the formation of predominantly ‘white’, platelet-rich clots in areas of high shear stress such as in stenotic arteries (e.g. cervical and intracranial large artery atherothrombosis). Because the vascular lesions that cause ischaemic stroke are very heterogeneous, it is unlikely that any one drug or strategy will be dramatically effective in all aetiological subtypes of ischaemic stroke.
A few decades ago, without venous thromboembolism prophylaxis, among patients with hemiplegia after stroke, up to 75% would develop deep vein thrombosis (DVT) and up to 20% pulmonary embolism (PE, including fatal PE in 1–2%) (Sherman et al., 2007). In recent trials with mechanical and pharmacological thromboprophylaxis, DVT develops in up to 10% of acute ischaemic stroke patients, but is mostly asymptomatic, and PE occurs in less than 1% of acute ischaemic stroke patients (Sherman et al., 2007; Dennis et al., 2016).
Acute Ischaemic Stroke
A systematic review identified 24 randomized controlled trials (RCTs) comparing anticoagulant therapy with control in the early treatment (started within 2 weeks of stroke onset) of a total of 23,748 patients with acute ischaemic stroke (Sandercock et al., 2015). One trial enrolled patients within 12 hours of stroke onset, 2 within 24 hours, 10 within 48 hours, and the rest within 14 days. The quality of the trials varied considerably.
The anticoagulants used were standard unfractionated subcutaneous heparin (six trials); standard unfractionated intravenous heparin (two trials); low-molecular-weight heparins (LMWHs) (eight trials: two dalteparin, two nadroparin, one tinzaparin, one fraxiparin, one parnaparin, and one CY 222); subcutaneous heparinoid (two trials: one danaparoid and one mesoglycan); intravenous heparinoid (one danaparoid trial); oral vitamin K antagonists (two trials); and thrombin inhibitors (three trials: two MD805 trials, one argatroban).
Fifteen trials routinely performed a computerized tomography (CT) head scan in all patients to rule out haemorrhage before randomization (Cerebral Embolism Study Group, 1983; Duke et al., 1986; Tazaki et al., 1986; Turpie et al., 1987; Cazzato et al., 1989; Prins et al., 1989; Elias et al., 1990; Sandset et al., 1990; Tazaki, 1992; FISS, 1995; Kwiecinski et al., 1995; Pambianco et al., 1995; Hommel and FISS-bis Investigators Group, 1998; TOAST Investigators, 1998; LaMonte et al., 2004). Three trials performed CT in most patients (Duke et al., 1983; Vissinger, 1995; International Stroke Trial Collaborative Group, 1997). In the International Stroke Trial (IST), 67% of patients were scanned before randomization and 29% after randomization, so that, overall, 96% of patients were scanned. The IST has provided more than 80% of the overall data in this systematic review. It is therefore likely that a small proportion of patients with intracerebral haemorrhage are included in the main analyses of this review, which may have biased the results to mildly underestimate the net beneficial effects in patients with acute cerebral ischaemia.
Eight RCTs involving a total of 22,125 patients found no evidence that anticoagulants reduced the odds of being dead or dependent at the end of follow-up (more than 1 month after randomization) compared with control (odds ratio [OR]: 0.99, 95% confidence interval [CI]: 0.93–1.04; I² = 47.7%) (Figure 10.1).
Figure 10.1 Forest plot showing the effects of any anticoagulant vs control in acute ischaemic stroke on death or dependency at the end of follow-up (if longer than 1 month).
There was substantial heterogeneity in the analysis of the outcome of death and dependency (I2 = 47.7%) between studies with different anticoagulant treatment regimens, which was chiefly attributed to the non-significant trends to benefit in studies with LMWH (OR: 0.82, 95% CI: 0.64–1.04) and heparinoid (OR: 0.81, 95% CI: 0.29–2.27), and the non-significant trend to harm in the study with direct thrombin inhibitor (OR: 1.28, 95% CI: 0.62–2.62).
Pre-specified sensitivity analyses showed that the effect of anticoagulants versus control for death and dependency was consistent among studies with low fixed-dose (OR: 1.00, 95% CI: 0.92–1.08), medium fixed-dose (OR: 0.98, 95% CI: 0.91–1.06), or adjusted-dose anticoagulants (OR: 0.95, 95% CI: 0.75–1.20); and also consistent if data from IST were included (OR: 0.99, 95% CI: 0.94–1.05) or excluded (OR: 0.92, 95% CI: 0.78–1.09).
Based on 11 trials involving a total of 22,776 patients, there was no evidence that anticoagulant therapy reduced the odds of death from all causes (OR: 1.05, 95% CI: 0.98–1.12; I² = 28.5%) at the end of follow-up (more than 1 month after randomization) (Figure 10.2). There was no significant heterogeneity between the included studies with different anticoagulant regimens (Figure 10.2).
Figure 10.2 Forest plot showing the effects of any anticoagulant vs control in acute ischaemic stroke on death at the end of follow-up.
Ischaemic Stroke during the Treatment Period
Eleven trials in 21,605 patients indicated that anticoagulant therapy for acute ischaemic stroke was associated with a statistically significant reduction in recurrent ischaemic stroke (OR: 0.76, 95% CI: 0.65–0.88; I² = 0), from 3.6% (388/10739) with control to 2.7% (300/10866) with anticoagulants, which translated into a number needed to treat to benefit (NNTB) of 108 (95% CI: 74–266) (Figure 10.3). The majority of the data (95%) were obtained from one trial (IST, 1997).
Figure 10.3 Forest plot showing the effects of any anticoagulant vs control in acute ischaemic stroke on recurrent ischaemic/unknown stroke during the treatment period.
Sixteen trials in 22,943 patients indicated that immediate anticoagulant therapy was associated with a statistically significant increase in symptomatic intracranial haemorrhage (ICH) by more than 2-fold (OR: 2.55, 95% CI: 1.95–3.33; I² = 0), from 0.5% (54/11,242) with control to 1.4% (168/11,701) with various types of anticoagulants, which represented a number needed to treat to harm (NNTH) of 131 (95% CI: 88–213) (Figure 10.4). The majority of the data (76%) were obtained from one trial (IST, 1997).
Figure 10.4 Forest plot showing the effects of any anticoagulant vs control in acute ischaemic stroke on symptomatic ICH during the treatment period.
Indirect comparisons of different types of anticoagulants indicated that there was no significant heterogeneity in the number of excess haemorrhages with different agent classes (see Figure 10.4).
There was a dose-related increase in major ICH in patients treated with anticoagulants in the IST, with an increase in the absolute risk of bleeding from 0.3% to 0.7% to 1.8% for control, low-dose (5000 U bid [twice a day]), and medium-dose (12,500 U bid) subcutaneous unfractionated heparin (UFH), respectively (IST, 1997).
There was possibly bias within the data, since the threshold for rescanning patients with clinical deterioration might be lower, if they were known to be using anticoagulants in trials that were not blinded – for instance, the IST trial. Even in blinded trials, the clinicians could be unblinded if they observed bruising at heparin injection sites. Systematic studies with CT scans before initiation of treatment as well as at the end of the treatment period to detect intracranial haemorrhage in all survivors, and autopsy in all patients who died during the study, may allow unbiased assessment of the effects of anticoagulants on the occurrence of ICH. Five trials in the Cochrane review made a systematic attempt to detect both symptomatic and asymptomatic ICH in this way (Cerebral Embolism Study Group, 1983; Prins et al., 1989; Sandset et al., 1990; FISS, 1995; LaMonte et al., 2004). The numbers of patients and events in these trials was small (symptomatic plus asymptomatic haemorrhages occurring in 20/266 [7.5%] patients allocated anticoagulant vs 27/264 [10.2%] patients allocated control). The estimate of risk of ‘symptomatic plus asymptomatic’ haemorrhage in these few small trials of anticoagulation with control is imprecise and inconclusive (OR: 0.76, 95% CI: 0.38–1.52).
Recurrent Stroke of Any Type during the Treatment Period or Follow-up
Eleven RCTs involving 21,605 patients indicated that anticoagulation was not associated with a net reduction in the odds of the composite of any recurrent ischaemic stroke or any symptomatic intracranial haemorrhage during the treatment period (OR: 0.97, 95% CI: 0.85–1.11; I² = 31.3%) (Figure 10.5). The majority of the data (93.6%) were obtained from one trial (IST, 1997). Only three relatively small trials provided data regarding the risk of recurrent stroke of any type at final follow-up, in which there were too few events for reliable analyses.
Figure 10.5 Forest plot showing the effects of any anticoagulant vs control in acute ischaemic stroke on recurrent stroke of any type during the treatment period or at the end of follow-up.
Eighteen trials included data from 22,255 randomized patients (93.7% of patients included in the overall review) in whom data on major extracranial haemorrhage (ECH) (defined as bleeding serious enough to cause death or require hospitalization or transfusion) were recorded. Anticoagulation was associated with a significant 3-fold increase in major ECH (OR: 2.99, 95% CI: 2.24–3.99; I² = 4%), from 0.4% (42/11,000) with control to 1.3% (143/11,255) with anticoagulation (Figure 10.6), which indicated an NNTH of 128 (95% CI: 85–204).
Figure 10.6 Forest plot showing the effects of any anticoagulant vs control in acute ischaemic stroke on major extracranial haemorrhage during the treatment period.
In the meta-analysis combining trials of high-dose and low-dose anticoagulation, 10 RCTs contained data from 916 randomized patients (only 3.9% of patients included in the overall review) in whom the effect of anticoagulants on the occurrence of ‘symptomatic or asymptomatic DVT’ at the end of the treatment period was sought by (1) I-125 fibrinogen scanning (Sandercock et al., 2015; Pince, 1981; Duke et al., 1983; McCarthy and Turner, 1986; Turpie et al., 1987; Prins et al., 1989; Elias et al., 1990; McCarthy et al., 1977); (2) B mode and Doppler ultrasound (Pambianco et al., 1995); or (3) x-ray contrast venography (Sandset et al., 1990; Vissinger, 1995).
Despite the small numbers of patients studied, anticoagulation was associated with a highly significant reduction in the odds of DVT (OR: 0.21, 95% CI: 0.15–0.29; I² = 71.5%), from 44.3% (204/460) with control to 15.1% (69/456) with anticoagulation (Figure 10.7). This result was equivalent to an NNTB of 9 (95% CI: 9–10). However, the majority of DVTs detected were subclinical and asymptomatic.
Figure 10.7 Forest plot showing the effects of any anticoagulant vs control in acute ischaemic stroke on DVT during the treatment period.
There was significant heterogeneity in the results of the trials (I² = 71.5%). This appeared to be related to three trials that did not show any clear effect of anticoagulation on the odds of DVT (Sandset et al., 1990; Pambianco et al., 1995; Vissinger, 1995), and two trials that did (McCarthy and Turner, 1986; Elias et al., 1990). The three negative trials were the only trials that did not use I-125 fibrinogen scanning. One used ultrasound assessment (Pambianco et al., 1995); the other two used venography (Sandset et al., 1990; Vissinger, 1995). These trials also possessed different features, for instance, in the onset-to-randomization intervals and in the study quality of the concealment.
In the meta-analysis combining trials of high-dose and low-dose anticoagulation, 14 RCTs included data from 22,544 patients (95.7% of patients included in the overall review) in which fatal and non-fatal symptomatic PEs were reported, but no trial systematically sought asymptomatic PE by performing ventilation–perfusion scans or computed tomography angiograms (CTAs) in all patients at the end of the treatment period (Sandercock et al., 2015). Anticoagulation was associated with a significant reduction in the odds of symptomatic PE (OR: 0.60, 95% CI: 0.44–0.81; I² = 13.7%), from 1.0% (104/11,074) with control to 0.6% (69/11,470) with anticoagulants (Figure 10.8), which translated into an NNTB of 127 (95% CI: 91–268).
Figure 10.8 Forest plot showing the effects of any anticoagulant vs control in acute ischaemic stroke on symptomatic PE during the treatment period.
Low-dose Prophylactic Anticoagulation
In a later systematic review confined to prophylactic, low-dose anticoagulant regimens, data were available in 14 randomized trials, including 5 trials of UFH, 8 trials of LMWH, and 1 trial of a heparinoid (Dennis et al., 2016). About 90% of the data were contributed by the IST 1 trial of UFH, in which patients were enrolled regardless of mobility status. The occurrence of any (predominantly asymptomatic) DVT was reported in 9 small trials enrolling 605 patients, and was reduced with prophylactic anticoagulation, OR 0.21 ((95% CI: 0.15–0.29). Rates of PE showed heterogeneity of effect by anticoagulation agent class, with less effect in the trial testing UFH regardless of patient mobility. In 7 trials of LMWH enrolling 1090 patients, PE was reduced, 1.3% versus 3.9%, OR 0.34 (95% CI: 0.16–0.71). Rates of symptomatic intracranial haemorrhage and extracranial bleeding were increased with anticoagulation, but nominally less so with LMWH. In 7 trials of LMWH enrolling 970 patients, rates of symptomatic intracranial haemorrhage were 7.7% versus 1.9%, OR 1.36 (95% CI: 0.58–3.18); in 5 LMWH trials enrolling 429 patients, no effect on extracranial bleeding was observed, 0.5% versus 0.5%, OR 1.04 (95% CI: 0.06–16.75). However, although death was not altered across all trials, in 6 LMWH trials enrolling 479 patients, mortality was non-significantly increased, 11.2% versus 6.5%, OR 1.72 (95% CI: 0.92–3.37).
The data from RCTs indicate that routine immediate anticoagulation (with UFH, LMWH, heparinoid, or a thrombin inhibitor) does not provide any net short- or long-term reduction in death or disability (Table 10.1), in relatively broadly selected patients with acute ischaemic stroke.