Fig. 3.1
Multimodal CT imaging of acute ischemic stroke patient presenting at 4 h of symptom onset, baseline non-contrast CT scan shows early changes of ischemia in the left insula as loss of great and white matter differentiation, CBF (cerebral blood flow) is reduced and MTT (mean transit time) is prolonged in larger area (white arrows) in the left middle cerebral artery (LMCA) territory, CBV (cerebral blood volume) is reduced in small area (white arrow) in LMCA territory, CT angiography shows distal LMCA occlusion and CT angiography map at the level of basal ganglia has an schematic area of penumbra and core based on the perfusion imaging. The follow-up CT scan at 24 h shows left insular involvement alone (white arrow)
Introduction
The only medical therapy shown to improve patient outcome in acute ischemic stroke (AIS) is intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) [1]. A thrombolytic agent aids clot dissolution and timely restoration of the blood flow to the ischemic brain tissue thereby preventing death of neurons and leading to clinical improvement (Fig. 3.2). Due to the success of rtPA, a number of new lytic agents are being tested in clinical trials. Despite evidence from randomized control trials and meta-analyses, the IV thrombolysis rates among all acute ischemic stroke patients presenting within 3 h have been poor (7 %) [2]. The primary reasons for under use of rtPA are a narrow therapeutic window and strict inclusion/exclusion criteria.
Fig. 3.2
Mechanism of action of recombinant tissue plasminogen activator; Step 1 is binding of rtPA molecule to fibrin clot, Step 2 is activation of fibrin bound plasminogen, leads to cleaving of plasmin (serine protease) from plasminogen, Step 3 is fibrinolysis by activated plasmin and Step 4 is clot dissolution and restoration of blood flow. rtPA recombinant tissue plasminogen activator, pmgn plasminogen, p plasmin
In the first half of this chapter, we examine the rationale for use of intravenous thrombolysis in acute ischemic stroke management based on contemporary clinical evidence. Further we delineate practical steps for IV thrombolysis in the emergency setting. In the latter half, we discuss the role antithrombotics in AIS.
Rationale for IV thrombolysis
Acute ischemic stroke is caused by complete or partial occlusion of cerebral artery in approximately 80 % of patients [3]. The occlusion is due to in-situ arterial thrombosis or thromboembolism from cardiac or proximal arterial source and occasionally from the venous source when there is PFO or pulmonary AV fistula.
There is sudden and severe reduction in the cerebral blood flow (CBF) to the cerebral tissue distal to the clot. In elegant primate experiments, Astrup et al. [4] demonstrated that the affected arterial territory has varying reduction in the CBF. The territory can be divided into four zones according to the decreasing cerebral blood flow: zone of normal blood flow, zone of oligemia, zone of penumbra, and zone of infarct (Fig. 3.3). The neuronal and supporting cells in the occluded arterial territory die due to the lack of oxygen and glucose in the zone of infarct.
Fig. 3.3
Zones of differential distribution of cerebral blood flow in the ischemic cerebral hemisphere and effect of low blood flow on the cerebral tissue. CBF cerebral blood flow map, DT delay time map
In the zone of penumbra, the CBF is low but has not reached the critical level to cause neuronal cell death. The volume of the penumbra tissue decreases with time. The fate of penumbral tissue is dependent on the triad of adequacy of cerebral collateral circulation, ischemia tolerance of the cerebral tissue and the clot burden. The clot burden (Fig. 3.4) can be reduced by fibrinolysis and thereby reperfusion to the affected tissue can be achieved. Fibrinolytic agents like streptokinase (ASK [5], MAST-I [6], MAST-E [7] studies), rtPA (NINDS [8], ATLANTIS A [9], ATLANTIS B [10], ECASS [11], ECASS II [12], ECASS III [13]), Tenecteplase (Parson et al.) [14], and Desmoteplase (DIAS [15], DEDAS [16], and DIAS 2 [17]) have been used for stroke thrombolysis.
Fig. 3.4
Triad of determinants of fate of penumbral tissue
Evidence for Efficacy
Recombinant Tissue Plasminogen Activator (rtPA)
The recombinant tissue plasminogen activator (rtPA) is a second-generation thrombolytic agent. It is the only thrombolytic agent approved by US FDA, based on results from the NINDS Stroke Study published in 1996 [8]. Twelve randomized clinical trials have been done to date using rtPA (Table 3.1). All the other abovementioned thrombolytic agents or fibrinolytic agents are categorized as experimental (Table 3.2) and are being used as a part of clinical trial only. The use of IV thrombolysis in AIS is time-dependent and the randomized clinical evidence can be divided into three time periods: 0–3, 3–4.5, and 0–6 h.
Table 3.1
Randomized clinical trials of tissue plasminogen activator for acute ischemic stroke according to symptom onset time
Study | Year | N | Dose | Time of outcome assessment | Outcome |
|---|---|---|---|---|---|
Symptom onset: 0–3 h | |||||
Haley et al. | 1993 | 27 | 0.85 mg/kg | 3 months | NIHSS |
NINDS I | 1995 | 291 | 0.9 mg/kg (max. 90 mg) | 24 h | NIHSS |
NINDS II (Pivotal) | 1995 | 333 | 0.9 mg/kg (max. 90 mg) | 3 months | NIHSS, GOS, BI, mRS |
NINDS I and II | 1995 | 624 | 0.9 mg/kg (max. 90 mg) | 3 months | NIHSS, GOS, BI, mRS |
Symptom onset: 0–6 h | |||||
Mori et al. | 1992 | 34 | 0.6 mg/kg vs. 0.9 mg/kg | 1 month | Reperfusion (A), HSS |
JTSG | 1993 | 98 | 0.6 mg/kg (34 mg) | 1 month | Reperfusion (A), HSS |
ECASS | 1995 | 620 | 1.1 mg/kg (max. 100 mg) | 3 months | mRS, BI |
ECASS II | 1998 | 800 | 0.9 mg/kg (max. 90 mg) | 3 months | mRS 2–6 |
ATLANTIS A | 2000a | 142 | 0.9 mg/kg (max. 90 mg) | 3 months | mRS 2–6, BI, NIHSS |
ATLANTIS B | 1999a | 613 | 0.9 mg/kg (max. 90 mg) | 3 months | mRS 2–6, BI, NIHSS |
Wang et al. | 2003 | 100 | 0.9 mg/kg (max. 90 mg) | 3 months | CSS, BI |
IST-3 | 2012 | 3,035 | 0.9 mg/kg (max. 90 mg) | 6 months | OHS 0–2 |
Symptom onset: 3–4.5 h | |||||
ECASS III | 2008 | 821 | 0.9 mg/kg (max. 90 mg) | 3 months | mRS 0–1 |
Symptom onset: 3–6 h | |||||
EPITHET | 2008 | 101 | 0.9 mg/kg (max. 90 mg) | 3 months | Infarct Growth |
Table 3.2
Randomized clinical trials of other thrombolytic agent for acute ischemic stroke according to symptom onset time
Study | Year | Drug | N | Time Window (hours) | Dose | Time of outcome assessment | Outcome |
|---|---|---|---|---|---|---|---|
MAST-I | 1995 | Streptokinasea | 622 | 0–6 | 1.5 mU | 6 months | mRS |
MAST-E | 1996 | Streptokinasea | 310 | 0–6 | 1.5 mU | 6 months | BI, mRS |
ASK | 1996 | Streptokinasea | 340 | 0–4 | 1.5 mU | 3 months | BI > 60 |
STAT | 2000 | Ancrod | 500 | 0–3 | 0.082–0.167 IU/Kg/h | 3 months | BI ≥ 95 |
DEDAS | 2006 | Desmoteplase | 37 | 3–9 | 90 μg/kg vs. 125 μg/kg | Early | SICH |
DIAS 2 | 2009 | Desmoteplase | 186 | 3–9 | 90 μg/kg vs. 125 μg/kg | 3 months | mRS (0–2), NIHSS ≥ 8, BI 75–100 |
Parsons et al. | 2012 | Tenecteplase vs. Alteplase | 75 | 0–6 | 0.1 mg/kg vs. 0.25 mg/kg (TNK) vs. 0.9 mg/kg (tPA) | 24 h | Tissue reperfusion and NIHSS improvement |
0–3 h
The NINDS stroke study was done in two parts. Part 1 aimed to assess the clinical activity of rtPA at 24 h defined as early improvement, with either complete resolution of neurological deficits or an improvement in NIHSS score of 4 or more. Part 2 aimed to assess the persistent effect of rtPA at 3 months, with the hypothesis that a greater proportion of patients treated with rtPA would have minimal or no deficit compared to patients treated with placebo. The inclusion and exclusion criteria were the same for both parts of the study. Part 1 of the study did not show a significant difference in patients treated with rtPA vs. placebo (47 % vs. 39 %, relative risk (95 % CI), 1.2 (0.9–1.6); p = 0.21) for the primary outcome. On post-hoc analysis there was a difference in the median NIHSS score (8 (3–17) vs. 12 (6–19); p < 0.02) at 24 h.
Part 2 of the study, showed significant differences in several measures of morbidity, with more favorable outcomes in patients treated with rtPA. A modified Rankin scale of 0–1 was observed in 39 % of patients treated with rtPA as compared to 26 % of patients treated with a placebo (Odds Ratio (95 % CI), 1.7 (1.1–2.6); p = 0.019). The combined results of part 1 and 2 showed an absolute difference of 12 % (OR (95 % CI), 1.7 (1–2.6); p = 0.03), and 20 % (2.4 (1.5–3.7); p < 0.001) for favorable outcome as assessed by mRS (0–1) in patients treated with tPA in first 90 min and between 90 min and 180 min, respectively. The number–needed–to-treat (NNT) to have a Barthel index of 95–100 at 3 months is 6.6 in the first 90 min and 5.8 between 90 and 180 min. The observed beneficial effect of rtPA was irrespective of stroke subtype. Despite this overwhelming difference in disability, there was no difference in mortality at 3 months in patients treated with rtPA (17 %) vs. placebo (21 %, p = 0.30). Symptomatic intracerebral hemorrhage (SICH) in the first 36 h after treatment was more common in patients treated with rtPA (6.4 %) vs. placebo (0.6 %, p < 0.001). The number-needed-to –harm (NNH) was 17. The patients with high admission NIHSS score and persistently elevated blood pressure post thrombolysis were more likely to have SICH.
Further follow-up showed persistent benefit (modified Rankin scale 0–1) in patients treated with rtPA compared to placebo at 6 months (41 % vs. 29 %, OR 1.8 (95 % CI, 1.3–2.5); p = 0.001) and 1 year (41 % vs. 28 %, OR 1.8 (1.3–2.5); p = 0.001) [18].
3–4.5 h
The ECASS III trial hypothesized that benefits of IV rtPA could be safely extended up to 4.5 h [13]. A total of 821 patients were enrolled in the study, 418 to the rtPA group and 403 to the placebo group. The inclusion and exclusion criteria were more rigid compared to the NINDS stroke study. Ischemic stroke patients between ages 18–80 years were included; whereas patients with severe stroke based on clinical assessment (e.g., NIHSS > 25) or appropriate imaging (stroke involving >1/3rd of the middle cerebral artery territory), patients with a history of prior stroke and diabetes mellitus and patients on oral anticoagulants (regardless of INR) were excluded.
The study showed that patients with ischemic stroke who had rtPA administered between 3 and 4.5 h of symptom onset had a modest benefit compared to those who received placebo. A total of 52.4 % of patients treated with rtPA had favorable outcome (mRS 0–1) vs. 45.2 % in the placebo group, with absolute improvement of 7.2 % (OR 1.34 95 % CI 1.02–1.76; p = 0.04). The NNT was 13.8 for a favorable outcome. There was no difference in the mortality in patients treated with rtPA (7.7 %) vs. placebo (8.4 %, OR 0.90, 95 % CI 0.54–1.49; p = 0.68). SICH according to the NINDS stroke study definition occurred in 7.9 % patients treated with rtPA vs. 3.5 % (OR 2.38 95 % CI 1.25–4.52; p = 0.006) placebo group, the NNH is 22.7.
A pooled analysis [19] of data from the NINDS stroke study, ECASS, ECASS II, ATLANTIS A and B, ECASS III and EPITHET [20] studies showed a declining effect size with symptom onset to treatment time (n = 3,670). Adjusted odds of a favorable 3-month outcome were 2.55 (95 % CI 1.44–4.52) for first 90 min after symptom onset, 1.64 (1.12–2.4) for 90–180 min, 1.34 (1.06–1.68) for 181–270 min and 1.22 (0.92–1.61) for 271–360 min in favor of the patients treated with rtPA. Benefit was evident up to 4.5 h but not later. The odds of intra-parenchymal hemorrhage type 2 (post-rtPA hemorrhagic transformation occupying more than two-thirds of the ischemic area and/or with mass effect) was not associated with time, though it was persistently higher in patients treated with rtPA, 3.1 % vs. 0 in the first 90 min, 5.6 % vs. 1 % (OR 8.23 95 % CI 2.4–28.3; p < 0.0008) for 90–180 min, 4.3 % vs. 1.2 % (3.61, 1.76–7.38; p < 0.0004) for 181–270 min and 0.9 % vs. 6.8 % (4.3, 2.8–18.9; p < 0.0001) for 271–360 min. The NNT for modified Rankin score of 0 or 1 in the first 90 min was 4.5, 91–180 min was 9, and 181–270 min was 14.1 and 271–360 min was 21.4. The results of this pooled analysis had set the stage for the Third International Stroke Trial (IST-3).
0–6 h
The Third International Stroke Trial (IST-3) [21] was the largest randomized controlled trial involving intravenous thrombolysis in AIS. The primary trial hypothesis was that rtPA given to adult patients of all ages with acute ischemic stroke, within 6 h of symptom onset, increased the proportion of people who were alive and independent at 6 months compared to placebo. It aimed to broaden the inclusion criteria for IV thrombolysis. Patients older than 80 years and severe stroke at presentation were included. At the outset, in the year 2000, researchers planned to recruit 6,000 patients to detect an absolute difference of 3 % in the primary outcome. In the year 2007, the target recruitment was revised to 3,100 patients to detect an absolute difference of 4.7 % in the primary outcome due to slow recruitment. At baseline, 54 % of patients were >80 years of age, one-third of patients were enrolled between 4.5 and 6 h after symptoms onset, 14 % had a NIHSS of >20 and 41 % of patients had signs of acute ischemia on pre-randomization imaging.
The study failed to meet the prespecified end point. At 6 months, 37 % in the rtPA group and 35 % in control group (OR 1.13 95 % CI 0.95–1.35; p = 0.18) were alive and independent. In subgroup analyses, 3.8 % more patients had favorable outcome in the >80 years group vs. −0.7 % in the ≤80 years group, with an Odds ratio of 1.35 (95 % CI, 0.97–1.88) in favor of rtPA. This was the most significant finding of this study. The odds for favorable outcome for patients treated between 0 and 3 h was 1.64 (95 % CI, 1.03–2.62), 3–4.5 h OR was 0.73 (0.5–1.07) and 4.5–6 h OR was 1.31 (0.89–1.93). The lack of benefit for patients treated with rtPA between 3 and 4.5 h was in contradiction to the ECASS III results and may reflect the different population in this study. There was no difference in groups with or without possible evidence of early ischemic changes on the pre-randomization imaging. SICH was observed in 7 % patients treated with rtPA vs. 1 % in the control group (OR 6.94, 95 % CI 4.1–11.8; p < 0.0001), the NNH was 16.6. In a subgroup analysis, there was no difference among patients treated with antiplatelet drugs in previous 48 h.
Following IST-3, a systematic review and meta-analysis of all the randomized tPA trials to date including IST-3 was conducted (n = 7,012) [22]. The aim was to assess the overall effect of IV rtPA when given up to 6 h after stroke. The studies were not differentiated according to the onset to treatment or time of follow-up (Table 3.1). The meta-analysis reported favorable outcome (mRS 0–1) in 34.8 % patients treated with rtPA vs. 29.3 % with placebo (OR 1.29 95 % CI 1.2–1.4; p < 0.0001), with NNT of 18.2 for patients treated up to 6 h after symptom onset. SICH was seen in 7.6 % patients treated with rtPA vs. 1.8 % with placebo (3.72, 2.98–4.64; p < 0.0001), the NNH was 17.2. Patient older than 80 years of age treated with rtPA had persistent benefit at 0–3 h with an odds ratio of 1.68 (95 % CI 1.2–2.3) and at 0–6 h with OR of 1.22 (0.98–1.53). The meta-analysis suggests that there may be benefit in treating patients after 4.5 h of symptom onset but careful patient selection is warranted, as the magnitude of benefit was minimal at best. As this was not a pooled analysis, the results should be interpreted with caution.
Other IV Thrombolytics
Streptokinase (SK)
SK is a first generation thrombolytic agent. As the name suggests, it is derived from streptococci bacteria. It binds to plasminogen in a nonspecific manner thus resulting in more widespread fibrin degradation. All the randomized studies associated with SK were stopped prematurely due to increased risk of intracranial hemorrhage [5–7]. The Australian Streptokinase trial (ASK) [5] observed a trend towards unfavorable outcome (Table 3.2) (relative risk 1.08; 95 % CI, 0.74–1.58) and increased symptomatic hemorrhage (12.6 % vs. 2.4 %, p < 0.01). The authors observed a greater unfavorable outcome in patients treated after 3 h of symptom onset. The Multicentre Acute Stroke Trial—Europe (MAST-E) study [7] noted similar outcomes (mRS ≥ 3 or death) in patients treated with streptokinase vs. placebo (79.5 % vs 81.8 %, p = 0.6) with increased incidence of symptomatic cerebral hemorrhage (21.2 % vs 2.6 %, p < 0.001). In this study, both groups received concomitant heparin therapy, which may account for the increased hemorrhage risk. The Multicentre Acute Stroke Trial—Italy (MAST-I) [6] used aspirin with streptokinase in acute ischemic stroke in a 2 × 2 factorial design. Patients receiving streptokinase with or without aspirin had higher odds 2.7 (95 % CI 1.7–4.3; p < 0.0001) of 10-day fatality.
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