Fig. 7.1
Coagulation cascade. The coagulation cascade has two initial pathways that result in fibrin formation: the contact activation pathway (intrinsic pathway) and the tissue factor pathway (extrinsic pathway). Both pathways cause the same fundamental reactions that produce fibrin. HK high-molecular-weight kininogen, PK prekallikrein, PL phospholipid (Adapted from: Ferguson et al. [5])
In addition to circulating anticoagulants (activated protein C and protein S), the endogenous thrombolytic system including plasmin also regulates thrombus growth. Endogenous tPA is the naturally circulating plasminogen activator that mediates plasmin formation from plasminogen. On the surface of a thrombus, fibrin binds endogenous tPA neighboring its substrate plasminogen, which accelerates plasmin formation and continues thrombus remodeling. Plasmin has a very short half-life of approximately 0.1 s, and endogenous fibrinolysis is controlled by several inhibitors of plasmin, such as α2-antiplasmin, thrombospondin, and plasminogen activator inhibitor-1 (PAI-1). The potential risk for thrombosis is determined according to the relative concentration of these inhibitors and the endogenous tPA. The complex formed by endogenous tPA, fibrin, and plasminogen accelerates the activation of plasminogen and increases the clot-selective fibrinolysis. Therefore, fibrinolysis takes place predominantly within the thrombus, and clot lysis can be achieved with comparatively low bleeding risk when thrombolytic agents (exogenous tPA) are used. All currently used thrombolytic agents are endogenous or exogenous plasminogen activators that act on fibrin and thrombin.
7.3 Drugs for Intravenous Thrombolysis
7.3.1 Tissue Plasminogen Activator (tPA)
Streptokinase and urokinase are first-generation thrombolytic agents. Streptokinase is derived from purified streptococci bacteria. It has no fibrin specificity; therefore, its action is not limited at the location of thrombus formation. Trials of streptokinase in acute ischemic stroke were terminated early owing to high mortality and high hemorrhage rates compared to placebo [6]. Urokinase is formed by the kidney and found in urine. Its clinical use is limited due to fibrinogenesis. In the Prolyse in Acute Cerebral Thromboembolism II trial (PROACT II, 1999), intra-arterial infusion of recombinant prourokinase in 180 patients showed better outcomes at 90 days despite an increased rate of symptomatic intracranial hemorrhage (ICH) [7]. Thus far, the PROACT II study is the only favorable intra-arterial urokinase trial. However, the specificity of streptokinase and urokinase for plasminogen-bound fibrin is much lower than that of second- and third-generation thrombolytic drugs (alteplase, desmoteplase, or tenecteplase).
The tPA is a second-generation thrombolytic agent and a 70-kDa serine proteinase found in endothelial cells of blood vessels. Its plasma half-life is 4–8 min. Figure 7.2 illustrates the amino acid sequence of tPA. It has four domains, and the active site for plasminogen cleavage is in the COOH-terminal serine proteinase domain. tPA for commercial use could be produced through recombinant DNA techniques. Because tPA has fibrin-selective properties, it is classified as a fibrin-specific agent. There are also other fibrin-specific thrombolytic agents, the characteristics of which are compared in Table 7.1. tPA (alteplase) is the only thrombolytic drug currently approved by the US FDA for acute myocardial infarction, acute ischemic stroke, and acute pulmonary embolism.
Table 7.1
A comparison of thrombolytic agents
Agent | Hal-life (min) | Fibrin selectivity | PAI-1 inhibition |
|---|---|---|---|
Urokinase | 15 | − | +++ |
tPA (alteplase) | 4–8 | ++ | +++ |
Tenecteplase | 11–20 | +++ | − |
Desmoteplase | 138 | ++++++ | ? |
7.3.2 Large Clinical Trials on tPA
The National Institute of Neurological Disorders and Stroke (NINDS) tPA trial in 1995 caused a paradigm shift in the management of acute ischemic stroke [10]. It emphasized the importance of rapid assessment and initiation of tPA administration. Six subsequent randomized trials have been conducted to compare tPA and placebo at various time windows of 0–6 h from stroke onset. The benefit of tPA within the 4.5-h time window became evident regardless of stroke severity or patient age; however, the efficacy and safety beyond 4.5 h remained unconfirmed [11]. The tPA studies are summarized in Table 7.2.
Table 7.2
Summary of the tPA studies
Year | Study name | n | Time from onset (h) | No. of patients aged >80 years | tPA (mg/kg) | Outcome (tPA vs. placebo) | Symptomatic ICH (tPA vs. placebo) |
|---|---|---|---|---|---|---|---|
1995 | NINDS | 624 | 0–3 | 54 | 0.9 | 43% vs. 27%a† | 6.4% vs. 0.6% |
1995 | ECASS | 620 | 0–6 | 0 | 1.1 | 45% vs. 40%b | 19.8% vs. 6.5% |
1997 | ECASS II | 800 | 0–6 | 0 | 0.9 | 54% vs. 46%b† | 8.8% vs. 3.4% |
1999 | ATLANTIS-A | 142 | 0–6 | 0 | 0.9 | 35% vs. 25%c | 11.3% vs. 0%† |
1999 | ATLANTIS-B | 547 | 3–5 | 0 | 0.9 | 34% vs. 32%c | 7% vs. 1.1%† |
2008 | EPITHET | 100 | 3–6 | 25 | 0.9 | 47% vs. 41%b | 7.7% vs. 0%† |
2009 | ECASS III | 821 | 3–4.5 | 0 | 0.9 | 52% vs. 45%a† | 2.4% vs. 0.2%† |
2012 | IST-3 | 3,035 | 0–6 | 1696 | 0.9 | 37% vs. 35%d | 7% vs. 1%† |
7.3.2.1 ECASS I
The result of the European Cooperative Acute Stroke Study (ECASS) was reported in 1995. ECASS is the first large, randomized, blinded, placebo-controlled clinical trial on high-dose intravenous tPA, which was designed to investigate if this thrombolytic therapy is beneficial and safe in patients with acute stroke [12]. A total of 620 patients with acute ischemic stroke were enrolled and randomized to treatment with 1.1 mg/kg body weight tPA or placebo within 6 h from the onset of symptoms. However, there was no significant difference in clinical efficacy in the intention-to-treat population analysis, whereas the per-protocol population analysis revealed a significant difference in the modified Rankin Scale (mRS) score in favor of tPA-treated patients. Thus, intravenous thrombolysis was found unacceptable for general use in ischemic stroke within 6 h from symptom onset.
7.3.2.2 NINDS
In 1995, the National Institute of Neurological Disorder and Stroke (NINDS) study was published [10]. This study included ischemic stroke patients within 3 h from the onset of stroke symptoms and used 0.9 mg/kg body weight tPA, which were different from ECASS I. The trial had two parts; 291 patients were enrolled in part 1 and 333 patients were enrolled in part 2. Part 1 investigated whether tPA has a clinical benefit, as defined by an improvement of 4 points from the baseline NIHSS score or the recovery from the neurologic deficits within 24 h after the stroke onset. Part 2 assessed functional outcomes at 3 months, according to the Barthel index, mRS, Glasgow Outcome Scale, and NIHSS scores. In part 1, there was no difference between the tPA and placebo groups in the proportion of patients with neurologic improvement at 24 h. In part 2, the long-term clinical advantage of tPA was observed for the tPA group at 3 months for all four outcome measures. As compared with placebo-treated patients, patients treated with tPA were at least 30% more likely to show minimal or no disability at 3 months on the evaluation of neurological status. The rate of symptomatic ICH occurrence within 36 h after treatment was higher in the tPA group than in the placebo group (6.4% vs. 0.6%); however, the mortality rate was similar between the two groups. Conclusively, the NINDS study showed that treatment with intravenous tPA within 3 h of the onset of symptoms improved clinical outcomes at 3 months despite an increased incidence of symptomatic ICH (Fig. 7.3).
Fig. 7.3
Statistically significant differences between IV tissue plasminogen activator (tPA) and placebo-treated patients on three assessment scales in the National Institute of Neurological and Communicable Diseases and Stroke (NINDS) study, part 2. Values do not total 100% because of rounding. The National Institutes of Health Stroke Scale (NIHSS) score, Barthel index, and modified Rankin Scale (mRS) score at 3 months are shown, and there is a statistically significant improvement in the tPA-treated patients as compared with placebo in each of these categories
7.3.2.3 ECASS II
The ECASS II study assessed the safety and efficacy of intravenous thrombolysis with tPA (0.9 mg/kg body weight) within 6 h of stroke symptom onset, including 800 patients with ischemic stroke and by using computerized tomography (CT) to exclude patients with signs of major infarction [13]. Patients with early ischemic changes on CT in more than one-third of the middle cerebral artery (MCA) territory, stupor and comatose, and hemiplegia with eyeball deviation were excluded. Anticoagulants and antiplatelet agents were not used for the first 24 h after randomization of patient treatment. The results did not confirm a statistical benefit for tPA. One hundred sixty-five (40.3%) tPA-treated patients and 143 (36.6%) placebo-treated patients had favorable mRS (0–1) outcomes (p = 0.277). However, despite the increased risk of intracranial hemorrhage, thrombolysis with tPA (0.9 mg/kg body weight) in selected patients may lead to a clinically relevant improvement in outcome (although statistically not significant).
7.3.2.4 ATLANTIS
In 1999, the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study was published. It was a double-blind, randomized trial assessing the efficacy and safety of 0.9 mg/kg intravenous tPA in patients with acute ischemic stroke within 6 h of symptom onset (part A) [14]. After an interim safety analysis, the time window was changed to 0–5 h, and it was decided to restart enrollment as a separate study (part B) [15]. This trial was terminated prematurely because of the absence of a beneficial effect. In the analysis of part B, the median time to treatment was 4.5 h. The efficacy was not different between the two groups. However, the symptomatic ICH rate was significantly increased in the tPA group. In 2002, a subgroup analysis of ATLANTIS data was released on the clinical outcomes of the 61 patients enrolled in the ATLANTIS study, who were randomized to receive intravenous tPA or placebo within 3 h of stroke symptom onset. The primary end point was the percentage of patients who had complete recovery, as determined by an NIHSS score of ≤1 at 90 days after treatment. Despite a significant increase in the rate of symptomatic ICH, tPA-treated patients had a favorable outcome (NIHSS score ≤1) at 3 months (p = 0.01). These data supported the NINDS-based recommendation to administer intravenous tPA to ischemic stroke patients within 3 h of symptom onset.
7.3.2.5 Pooled Analysis of NINDS, ECASS, and ATLANTIS Data
In 2004, the investigators of the ATLANTIS, ECASS II, and NINDS trials conducted a pooled analysis of six randomized controlled trials on tPA (up to 6 h) to evaluate the effect of time to treatment on functional outcome [16]. This analysis demonstrated a strong association between time to treatment and functional outcome. As the time interval to treatment increased, the odds ratio (OR) of a favorable outcome (mRS <2) decreased (p < 0.005). The ORs were 2.8 for 0–90 min, 1.6 for 91–180 min, 1.4 for 180–270 min, and 1.2 for 271–360 min. Symptomatic ICH occurred in 5.9% of patients treated with tPA compared with 1.1% of placebo-treated patients (p < 0.0001). The results of this study showed a clear association between the time interval to tPA and the treatment efficacy; however, it also suggested a potential benefit beyond 3 h. The most important finding from this pooled analysis was that the odds of favorable outcome decreased with every minute of delay from the stroke symptom onset.
7.3.2.6 ECASS III
In 2008, the ECASS III study assessed the safety and efficacy of tPA administered between 3 and 4.5 h after stroke onset [17]. A total of 821 patients were enrolled in this study and randomly assigned to the tPA (n = 418) and placebo (n = 403) groups. The trial excluded patients older than 80 years old, those with baseline NIHSS >25, and those taking anticoagulants or who had a history of stroke. The median time for the administration of tPA was 3 h 59 min. More patients showed clinical benefits with tPA than with placebo (52.4% vs. 45.2%; p = 0.04). The incidence of ICH was higher with tPA than with placebo (for any type of ICH, 27.0% vs. 17.6%, p = 0.001; for symptomatic ICH, 2.4% vs. 0.2%, p = 0.008). Despite a tenfold increase in symptomatic ICH, there was no significant difference between the tPA and placebo groups in terms of mortality (7.7% vs. 8.4%). ECASS III demonstrated a benefit of intravenous tPA beyond the conventional 3-h time window established in the NINDS trial, effectively extending the window for tPA to 4.5 h (Fig. 7.4).
Fig. 7.4
European Cooperative Acute Stroke Study (ECASS) III trial 3-month outcome intention-to-treat group (modified Rankin Scale [mRS] scores). More patients had a favorable outcome (mRS score ≤1) with tissue plasminogen activator (tPA) than with placebo (52.4% vs. 45.2%; OR, 1.34; 95% confidence interval [CI], 1.02–1.76; p = 0.04)
7.3.2.7 IST-3
The third International Stroke Trial (IST-3) was designed to determine whether more patients might benefit up to 6 h from stroke onset [18]. In this international, multicenter, randomized, open-treatment trial, patients were assigned to either the 0.9 mg/kg intravenous tPA group or the control group. The inclusion criteria were broad, and there was no upper age limit for inclusion; more than half of the 3,035 patients were aged >80 years. The primary outcome was the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0–2, at 6 months. The 3,035 patients were enrolled by 156 hospitals in 12 countries. At 6 months, 554 (37%) patients in the tPA group versus 534 (35%) in the control group were alive and independent (OHS 0–2; adjusted OR, 1.13; 95% CI, 0.95–1.35; p = 0.181). Despite early fatal ICH, tPA within 6 h did not affect the longer-term survival and improved the functional outcome. The benefit was greatest among patients treated within 3 h and did not decrease among elderly patients or those with severe stroke. For every 1,000 patients with tPA within 3 h of stroke, 80 more will live independently than if they had not been given tPA. There was an increased risk of early death due to symptomatic ICH in the first week. These results encourage physicians to consider thrombolytic treatment for a wider range of patients (particularly those aged >80 years), and treat those with more severe neurologic deficits from stroke. It also contributes to the increase in the proportion of ischemic stroke cases treated within 3 h.
7.3.2.8 SITS-MOST and SITS-NEW
In September 2002, the European Agency for the Evaluation of Medicinal Products (EMEA) conditionally approved tPA for the treatment of ischemic stroke within 3 h of onset of symptoms. One of the conditions for this approval was that treatment safety should be monitored in accordance with a study protocol (Safe Implementation of Thrombolysis in Stroke—Monitoring Study [SITS-MOST]) [19]. Under European Union regulations, SITS-MOST was required to evaluate the safety profile of tPA in clinical practice by comparison with results from previous randomized controlled trials. A total of 6,483 patients were enrolled from 285 centers in 14 countries between 2002 and 2006 for this prospective observational study. The baseline clinical characteristics of patients in SITS-MOST were largely similar to those in the pooled randomized controlled trials. At 24 h, the proportion of patients with symptomatic ICH was 1.7%; at 7 days, the proportion with the same condition as per the Cochrane definition was 7.3% compared with 8.6% in the pooled randomized controlled trials. The mortality rate at 3 months in SITS-MOST was 11.3% compared with 17.3% in the pooled randomized controlled trials. This study confirmed that intravenous tPA is beneficial and safe when used within 3 h of stroke onset, even in hospitals with little previous experience with thrombolytic therapy for acute ischemic stroke. In 2014, Safe Implementation of Thrombolysis in Stroke—Non-European Union World (SITS-NEW) was carried out to assess the safety of intravenous tPA in an Asian population by comparison with results from SITS-MOST and pooled analysis of previous randomized controlled trials [20]. The standard dose of intravenous tPA (0.9 mg/kg) was safe and efficacious in the Asian population, as observed in the previous studies, when used in routine clinical practice within 3 h after stroke onset.
7.3.2.9 Trials for Enhancing the Thrombolytic Activity of tPA
Recanalization with tPA treatment cannot be easily achieved in occlusions of more proximal cerebral arteries. The rate of early successful recanalization with tPA was about 25% in cases of proximal MCA occlusion and 10% in cases of internal carotid artery (ICA) occlusion [21]. The rate of reocclusion of a distal artery due to thrombus breakdown and migration was as high as 30% with tPA [22]. Therefore, methods enhancing thrombolytic activity are required to increase the recanalization rate and reduce the reocclusion of distal blood vessels.
Ultrasound-enhanced thrombolysis has been attempted in vitro and in vivo to promote the activity of thrombolytic drugs [23]. The microbubbles in blood vessels generated by ultrasound induce microstreaming of blood to the occlusion as a delivery route for tPA. Ultrasound also enlarges the fibrin mesh, facilitating the binding and penetration of tPA into a thrombus [24]. A continuous transcranial ultrasound at 2 MHz greatly increased the rate of early recanalization in patients treated with tPA [25]. However, these studies did not guarantee the validation in terms of assessing the degree of recanalization, because they used only transcranial Doppler change instead of angiography. A phase III sonolysis trial (CLOTBUST-ER) that combines lysis of thrombus with ultrasound and systemic tPA for emergent revascularization has completed patient enrolment and will commence soon [26]. Intravenous administration of microbubbles as a contrast agent, with the intention of increasing the available volume of microbubbles for ultrasound, is expected to enhance the thrombolytic activity of tPA.
7.3.3 Other Thrombolytic Agents
7.3.3.1 Tenecteplase
Tenecteplase, a noble and genetically engineered mutant tPA, was developed to improve thrombolytic efficacy and safety. Three specific alterations in the original amino acid sequence of the tPA molecule resulted in a longer half-life of 17 ± 7 min, greater specificity for fibrin, and more resistance to endogenous PAI-1. With these properties, tenecteplase appears to be a more effective and safer thrombolytic agent than tPA (alteplase). Two randomized prospective clinical trials have either been conducted or are under way to compare tenecteplase with alteplase for acute ischemic stroke. The first was a small phase 2B open-label blinded outcome trial completed in 2011, randomly assigning 75 patients to receive alteplase (0.9 mg/kg body weight) or tenecteplase (0.1 or 0.25 mg/kg body weight) at <6 h after the onset of ischemic stroke in a 6-h window [27]. The co-primary end points were the proportion of the CT perfusion deficit that was reperfused at 24 h on perfusion-weighted magnetic resonance imaging (MRI) and the extent of clinical improvement at 24 h as assessed on the NIHSS scale. The results were positive for co-primary end points. The two tenecteplase groups with different dosages showed significantly improved reperfusion (p = 0.004) and better clinical outcomes (p < 0.001) at 24 h than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg/kg) was superior to the lower dose and to alteplase for all efficacy outcomes. The following secondary end points were also positive: infarct growth at 24 h and 90 days, complete or partial recanalization at 24 h, major neurological improvement (NIHSS reduction of 8) at 24 h, and excellent or good recovery at 90 days [27]. A phase 3 trial, the Norwegian Tenecteplase Stroke Trial (NOR-TEST), is also ongoing, randomizing 954 patients to identify a 9% or more difference in excellent outcome for intravenous tenecteplase at a dose of 0.4 mg/kg compared with a standard dose of intravenous alteplase [28]. The primary outcome measure for this study is mRS score at 90 days, with secondary end points of NIHSS score and recanalization at 24 h.
7.3.3.2 Desmoteplase
Desmoteplase is a plasminogen activator derived from the saliva of the vampire bat Desmodus rotundus. The DNA sequences of plasminogen activators in vampire bat saliva were completely analyzed in 1991. Of them, alpha 1 (rDSPAα1, desmoteplase) is the most active and shows a 72% homology to human tPA [29]. Desmoteplase has very high fibrin specificity, longer half-life (138 min), and no effect on the blood-brain barrier, making it a promising thrombolytic agent. The first clinical trials on desmoteplase (Desmoteplase in Acute Ischemic Stroke [DIAS]) demonstrated a higher rate of reperfusion and better functional outcome of lower weight-adjusted desmoteplase dose compared with the placebo [30, 31]. The Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS) study also demonstrated the efficacy and safety of 125 μg/kg intravenous desmoteplase in acute ischemic stroke [31, 32]. However, the phase 3 trial, DIAS 2, did not show a beneficial effect of desmoteplase at 3–9 h after stroke onset [31, 33]. The limitations of the study were the small sample size and lack of standardized criteria for image selection. The subsequent analysis of pooled data from DIAS and DIAS 2 revealed that patients with a proximal cerebral artery occlusion or high-grade stenosis showed much greater mismatch tissue volumes and a positive response to desmoteplase in comparison to placebo. In 2009, the DIAS 3 and DIAS 4 phase 3 trials were started, enrolling 400 patients with acute ischemic stroke. The participants were treated with desmoteplase as an intravenous bolus dose of 90 μg/kg within 3–9 h after stroke symptom onset. Only patients with occlusion or high-grade stenosis in proximal large cerebral arteries as assessed by magnetic resonance or CT angiography were selected. Additional perfusion-weighted and/or diffusion-weighted imaging could be performed. However, those two additional phase 3 trials with advanced imaging selection criteria failed to show the benefits of desmoteplase in acute ischemic stroke. DIAS 3 showed no beneficial effect overall when given at 3–9 h after symptom onset to patients with major cerebral artery occlusion, and DIAS 4 was terminated early owing to the result of DIAS 3 [34].
7.3.3.3 Ancrod
Intravenously administered ancrod reduces serum fibrinogen levels, leading to an anticoagulation effect. It decreases blood viscosity and increases blood flow to the ischemic area of the brain. Ancrod, a serine protease, is extracted from the venom of the Malayan viper [35]. It showed beneficial effects in acute ischemic stroke when initiated within 3 h of stroke onset [31, 36, 37]. The Stroke Treatment with Ancrod Trial (STAT), a randomized, double-blind, placebo-controlled trial, was conducted between August 1993 and January 1998. A total of 500 ischemic stroke patients were randomized to receive ancrod (n = 248) or placebo (n = 252) as a continuous 72-h intravenous infusion initiated within 3 h of symptom onset. Favorable functional outcome was achieved by more patients in the ancrod group (42.2%) than in the placebo group (34.4%, p = 0.04), and mortality was not different between the groups. There was a trend toward more symptomatic ICH cases in the ancrod group than in the placebo group (5.2% vs. 2.0%; p = 0.06) [36]. Subsequent studies with an extended treatment window to 6 h from stroke onset have not revealed any significant improvement in clinical outcome [31, 37, 38].
7.3.3.4 Glycoprotein IIb/IIIa Antagonist
Glycoprotein (GP) IIb/IIIa antagonists inhibit activation of platelets, preventing reocclusion and promoting thrombus breakdown [39]. Platelet activation by ADP causes a conformational change in platelet GPIIb/IIIa receptors that induces its binding to fibrinogen. In large clinical trials, GPIIb/IIIa antagonists were effective for the treatment of acute coronary syndromes. However, their safety and efficacy in acute ischemic stroke were uncertain until the Safety of Tirofiban in acute Ischemic Stroke (SaTIS) trial was completed [40]. Tirofiban is a highly selective, fast-acting GPIIb/IIIa platelet receptor inhibitor. A total of 260 patients with acute ischemic stroke (NIHSS score 4–18) were randomized in the SaTIS trial and intravenously received either tirofiban or placebo within 3–22 h after stroke onset for 48 h. The rate of intracerebral hemorrhagic transformation did not differ between the two groups. The mortality rate after 5 months was significantly lower in patients treated with tirofiban. The study confirmed the safety of tirofiban; however, there was no difference in neurological/functional outcome after 5 months between the groups. Another GBIIb/IIIa antagonist, abciximab, was tested for the treatment of acute ischemic stroke within 5 h in the Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). This trial did not show either the efficacy or safety of intravenous administration of abciximab for the treatment of patients with acute ischemic stroke irrespective of the end point or population studied. Instead, there was a significant increase in fatal or symptomatic ICH in the abciximab groups [41]. Eptifibatide is the third inhibitor of GPIIb/IIIa. The efficacy and safety of combined intravenous tPA and eptifibatide compared with intravenous tPA alone were evaluated in the Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke—Enhanced Regimen stroke trial (CLEAR-ER). The combination therapy cohort showed a lower occurrence of symptomatic ICH and a trend for good functional outcome (mRS 0–1, 49.5% vs. 36%) [42].
7.3.3.5 Argatroban
Argatroban is a direct thrombin inhibitor with a relatively short half-life of 45 min. The Argatroban Anticoagulation in Patients with Acute Ischemic Stroke (ARGIS-I) trial has demonstrated its safety, but not its efficacy, in 2003 [43]. Patients within 12 h of stroke onset were enrolled. The rate of symptomatic ICH was not significantly higher in the argatroban groups; however, argatroban did not demonstrate better clinical outcomes than did placebo. The Argatroban with tPA for Acute Stroke (ARTSS) study reported complete recanalization rate of 63% at 24 h with combination treatment with argatroban and tPA [31, 44]. Phase II ARTSS-2 was conducted. It was designed to randomly assign patients to a high or low dose of argatroban infusion for 48 h and intravenous tPA versus tPA alone, and recruitment was completed in 2015 [45]. In patients treated with intravenous tPA, adjunctive argatroban appears safe; however, the observed clinical benefit warrants further study in a future clinical trial.
7.4 Practical Use of Intravenous tPA in Acute Ischemic Stroke
7.4.1 Protocols for Intravenous tPA Therapy
Intravenous tPA (0.9 mg/kg, maximum 90 mg) is recommended for selected patients with acute ischemic stroke who could be treated within 3 h of symptom onset. The exclusion and inclusion criteria for tPA use are listed in Tables 7.3 and 7.4. A recommended treatment plan for patients receiving intravenous tPA is explained in Table 7.5. The beneficial effect of tPA is time dependent; therefore, initiation of tPA should begin as quickly as possible. The door-to-needle time needs to be within 60 min from hospital arrival. For patients who cannot be treated within 3 h, intravenous tPA (0.9 mg/kg, maximum dose 90 mg) should also be considered for eligible patients in the time period of 3–4.5 h after a clearly defined stroke onset (Table 7.4). These are in line with recent guidelines from the American Heart Association (AHA)/American Stroke Association [46]. The eligibility criteria for treatment in this extended time window are the same as those for patients treated within 3 h, except for the following exclusion criteria: (i) patients >80 years old, (ii) those taking oral anticoagulants regardless of the international normalized ratio (INR), (iii) those with a baseline NIHSS score of >25, (iv) those with imaging evidence of ischemic injury involving more than one-third of the MCA territory, or (v) those with a history of both stroke and diabetes mellitus (Table 7.4). In general, blood pressure should be controlled below 185/110 mm Hg with antihypertensive agents before and during intravenous tPA infusion. In patients receiving intravenous tPA, clinicians should pay attention to the potential adverse effects of tPA, such as bleeding problems and angioedema that may lead to airway obstruction. Intravenous tPA could be used in patients with a seizure at the time of stroke onset, if there is supporting evidence that the residual neurologic impairments are due to a stroke and not a postictal state. Intravenous tPA in acute ischemic stroke patients with mild deficits, rapidly improving symptoms, major surgery history within 3 months, and recent myocardial infarction could be considered cautiously, and the risk of tPA use against its benefits should be assessed. Patients with rapidly improving stroke symptoms (RISS) were excluded for tPA use in clinical trials to avoid tPA treatment of transient ischemic attack. However, there is recent consensus that tPA use in RISS should be excluded only for patients who improve to a degree that any remaining deficits seem nondisabling [47]. The therapeutic decision should be made on the basis of close monitoring of neurologic deficits by the physician. Despite limited evidence, patients who regain consciousness with ischemic stroke (unclear onset stroke) and have no early ischemic changes on initial brain CT can also benefit from intravenous thrombolysis [48, 49].
Table 7.3
Inclusion and exclusion criteria of IV tissue plasminogen activator within 3 h from symptom onset
Inclusion criteria |
Diagnosis of ischemic stroke causing measurable neurological deficit |
Onset of symptoms <3 h before beginning treatment |
Age ≥18 years |
Exclusion criteria |
Significant head trauma or stroke in the previous 3 months |
Symptoms suggestive of subarachnoid hemorrhage |
Arterial puncture at a noncompressible site in the previous 7 days |
History of ICH |
Intracranial neoplasm, arteriovenous malformation, or aneurysm |
Recent intracranial or intraspinal surgery |
Elevated blood pressure (systolic >185 mm Hg or diastolic >110 mm Hg) |
Active internal bleeding |
Acute bleeding diathesis, including but not limited to |
Platelet count <100,000/mm3 |
Heparin received within 48 h, resulting in abnormally elevated aPTT greater than the upper limit of normal |
Current use of anticoagulant with INR >1.7 or PT >15 s |
Current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated sensitive laboratory tests (such as aPTT, INR, platelet count, and ECT; TT; or appropriate factor Xa activity assays) |
Blood glucose concentration <50 mg/dL (2.7 mmol/L) |
CT demonstrates multilobar infarction (hypodensity >1/3 cerebral hemisphere) |
Relative exclusion criteria |
Recent experience suggests that under some circumstances—with careful consideration of risk over benefit—patients may receive fibrinolytic therapy despite one or more relative contraindications. Consider the risk-to-benefit ratio of IV rtPA administration carefully if any of these relative contraindications are present: |
Only minor or rapidly improving stroke symptoms (clearing spontaneously) |
Pregnancy |
Seizure at onset with postictal residual neurological impairments |
Major surgery or serious trauma within the previous 14 days |
Recent gastrointestinal or urinary tract hemorrhage (within the previous 21 days) |
Recent acute myocardial infarction (within the previous 3 months) |
Table 7.4
Additional inclusion and exclusion criteria of IV tissue plasminogen activator within 3–4.5 h from symptom onset
Inclusion criteria |
Diagnosis of ischemic stroke causing measurable neurological deficit |
Onset of symptoms within 3–4.5 h before beginning treatment |
Relative exclusion criteria |
Age >80 years |
Severe stroke (NIHSS >25) |
Taking an oral anticoagulant regardless of INR |
History of both diabetes and ischemic stroke |
Table 7.5
Treatment of acute ischemic stroke: intravenous administration of tPA
Infuse 0.9 mg/kg (maximum dose 90 mg) during 60 min, with 10% of the dose given as a bolus for 1 min |
Admit the patient to an intensive care unit or stroke unit for monitoring |
If the patient develops severe headache, acute hypertension, nausea, or vomiting or has worsening neurological findings, discontinue the infusion (if IV rtPA is being administered) and obtain an emergent CT scan |
Measure blood pressure and perform neurological assessments every 15 min during and after IV rtPA infusion for 2 h, then every 30 min for 6 h, and then hourly until 24 h after IV rtPA treatment |
Increase the frequency of blood pressure measurements if the systolic blood pressure is >180 mm Hg or if the diastolic blood pressure is >105 mm Hg; administer antihypertensive medications to maintain blood pressure at or below these levels (Table 7.6)
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