Intravenous Thrombolysis

Up until now, the only thrombolytic agent licensed in Europe for the treatment of ischemic stroke is recombinant tissue plasminogen activator (rtPA), alteplase. The evidence for its use has evolved over the last 20 years and originated from several randomized clinical trials (RCTs): the Alteplase Thrombolysis for Acute Non-interventional Therapy in Ischemic Stroke (ATLANTIS) trials A and B [6], the European Cooperative Acute Stroke Study (ECASS) [7], ECASS II [8] and ECASS III [9], the two-part National Institute of Neurological Disorders and Stroke (NINDS) rtPA study [10], and the third International Stroke Trial (IST-3) [11]. These studies varied in timing and dose of rtPA, which may account for some of the differences in outcomes reported in each of the trials. One other major factor for the different observations is the change of the overall treatment of stroke patients, especially the introduction of stroke units. For instance, the placebo group of the ECASS-II patients had the same rate of good clinical outcome as the rtPA group of the NINDS study. The NINDS rtPA study demonstrated an odds ratio of 1.7 (95% CI 1.2–2.6) for a favorable outcome at 3 months with rtPA treatment when administered within 3 hours of ischemic stroke onset. The absolute benefit of 14% could be translated into a number needed to treat of 7 to achieve a favorable outcome. In contrast, the ECASS studies (I and II) did not confirm a significant benefit of rtPA. However, in these trials rtPA was given within 6 hours after symptom onset and another endpoint was used. Analyzing the subgroup of patients treated early and using the combined NINDS-endpoint, these studies would also have been positive [12]. Initially, regulatory authorities placed an upper limit of 3 hours for routine use of alteplase after stroke, although the evidence showed benefit extending beyond 3 hours. The SITS register, introduced to monitor routine clinical use of rtPA [13], demonstrated that treatment at an average of 3 hours 15 minutes and until 4.5 hours after stroke onset remains as safe as earlier treatment in routine clinical practice [14]. Safety and efficacy of rtPA in the 3–4.5-hour time window was also examined in the ECASS-III study. This placebo-controlled RCT revealed a 34% higher chance (95% CI 1.02–1.76) for good clinical outcome (modified Rankin Score [mRS] 0–2 after 3 months) with a rate of symptomatic intracranial hemorrhage of 2.4%. The third International Stroke Trial (IST-3) sought to determine whether a greater range of patients may benefit from intravenous thrombolysis, especially those not fulfilling the strict European licensing criteria [11]. Investigators randomized patients to receive intravenous rtPA or control up to 6 hours from stroke onset with no upper age limit to recruitment. More than 3 000 patients were included, across 12 countries. Overall, 2 581 (95%) of 2 714 patients with data (data for some relevant variables were not collected in the initial phase) did not meet the prevailing EU-license-approval criteria. Fifty-three percent of patients in IST-3 were older than 80 years. The trial was neutral on its primary endpoint, but on secondary outcomes, thrombolysis was associated with functional benefit despite significant increases in early symptomatic intracranial hemorrhage (7% vs. 1%) and death (11% vs. 7%) within the first 7 days of stroke. By 6 months, mortality was similar in each group.

To reveal sufficient numbers for subgroup and time-dependent analysis, investigators and sponsors of the RCTs agreed to perform combined analysis of individual patients’ data [15]. After a recent update, the database consisted of 3 670 patients, 1 850 of those treated with rtPA within a 6-hour time window [16]. The odds of a favorable outcome were clearly inversely associated with delay from stroke onset to treatment, with those patients treated earliest following their stroke having the most favorable outcome (Figures 19.1 and 19.2). Favorable outcome at 3 months was defined as an mRS of 0 or 1. The analysis identified an adjusted odds ratio for favorable outcome at 3 months of 2.55 (95% CI 1.44–4.52) for patients treated within the first 90 minutes of stroke, 1.64 (95% CI 1.12–2.40) when treatment was commenced 91–180 minutes following onset, 1.34 (1.06–1.68) in the time window of 181–270 minutes. In the latest quartile there was no significant difference between rtPA and placebo (OR 1.11, 95% CI 0.92–1.61). The benefits of thrombolysis are therefore without doubt largest when treatment is initiated early and minimizing delays to treatment is imperative in improving patient outcome. These benefits have been demonstrated without a significantly increased risk of death, but the proportion of patients with significant parenchymal hemorrhage, defined as dense blood clot exceeding 30% infarct volume with significant space-occupying effect, was larger in rtPA-treated patients (5.6% vs. 1.0% in those who received treatment between 91 and 180 minutes following stroke onset). Of clinical importance, the proportion of patients suffering secondary parenchymal hemorrhage was associated with increasing age, but not with time from onset to treatment or baseline National Institutes of Health Stroke Scale (NIHSS) score.

Figure 19.1 Relation of stroke onset to start of treatment (OTT) with treatment effect after adjustment for prognostic variables assessed by (A) day 90 modified Rankin score 0–1 vs. 2–6 (interaction p = 0.0269); (B) global test that incorporates modified Rankin score 0–1 vs. 2–6, Barthel Index score 95–100 vs. 90 or lower and NIHSS score 0–1 vs. 2 or more (interaction p = 0.0111); (C) mortality (interaction p = 0.0444); and (D) parenchymal hemorrhage type 2 (interaction p = 0.4140). For each graph, the adjusted odds ratio is shown with the 95% CIs.

Source: Reprinted from Lees et al. [16], with permission from Elsevier.

Figure 19.2 Distribution of modified Rankin scores by onset to start of treatment (OTT) interval. The alteplase vs. placebo distributions were compared within each interval by Cochran-Mantel-Haenszel test without adjustment for prognostic factors: 0–90 min, p = 0.354; 91–180 min, p = 0.0522; 181–270 min, p = 0.0308; 271–360 min, p = 0.4537.

Source: Reprinted from Lees et al. [16], with permission from Elsevier.

Based on the RCTs intravenous thrombolysis with rtPA within a 3-hour time window is a Class 1, Level of Evidence 1A recommendation in international guidelines [1, 2]. For the time window of 3.0–4.5 hours it is also a level 1A recommendation in Europe, but only a 1B recommendation in the USA. Because of the time-dependent efficacy, door-to-needle time should be within 60 minutes (Class 1, Level of Evidence 1A).

The European label consists of several contraindications for thrombolytic stroke therapy with rtPA (an overview is listed in Table 19.1). For instance, it is contraindicated in patients with seizure at stroke onset due to the possibility of confusion with Todd’s paresis, which may be present as a stroke mimic, although its use can be considered if the neurological deficit is due to acute cerebral ischemia. Patients with severe hypertension at the time of admission were excluded from the trials of thrombolysis. Therefore, a blood pressure below 185/110 mmHg before and for the first 24 hours after thrombolytic therapy is recommended. Severe hypertension increases the risks of hemorrhagic transformation following thrombolysis. The dose of alteplase is weight-dependent at 0.9 mg/kg up to a maximum dose of 90 mg. Ten percent of the total dose is administered as an intravenous bolus, with the remaining 90% delivered over 1 hour.

Prior anti-platelet treatment is associated with an increased risk of intracranial hemorrhage [17]. Aspirin and other anti-platelets or anti-coagulants should therefore be avoided for 24 hours following thrombolysis, as should arterial puncture at a non-compressible site. Prophylaxis of deep vein thrombosis using a low dose of a low molecular weight heparin (LMWH) is possible.

Having identified patients who are potential candidates for intravenous thrombolysis, systems must be in place to ensure their timely transfer to an appropriate medical facility and rapid access to assessment and imaging once admitted. The exact structure of a stroke service will vary depending on local factors. Structuring thrombolysis services in places where patient populations are spread over large rural areas can be particularly challenging. The structure of such a service will differ depending on local needs and no single model can be claimed to be superior to another. Technologies such as telemedicine can facilitate the thrombolysis rate in local hospitals without 24/7 neurological service [18].

Beside rtPA other thrombolytic substances like desmoteplase and tenecteplase have been evaluated in RCTs. Possible advantages of those substances are higher plasminogen specificity and longer half-life times, which makes single shot therapy possible. The DEDAS and DIAS trials aimed to prove the benefit of desmoteplase in a cohort of stroke patients in an extended time window (beyond the time window with rtPA approval) and with existing penumbra (see Chapter 3). DEDAS, DIAS-1, and DIAS-2 focused on patients with MRI evidence of perfusion/diffusion mismatch of the infarct core and hypoperfusion in a 4.5–9-hour time window [19–21]. After promising results of the phase 2 studies, the DIAS-2 study did not show a benefit of desmoteplase given 3–9 hours after the onset of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in NIHSS score of at least 8 points or an NIHSS score of 1 point or less, a modified Rankin Scale score of 0–2 points, and a Barthel index of 75–100. The clinical response rates at day 90 were 47% (27 of 57) for 90 µg/kg desmoteplase, 36% (24 of 66) for 125 µg/kg desmoteplase, and 46% (29 of 63) for placebo; without any significant difference. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. The DIAS-3 study aimed to assess the safety and efficacy of desmoteplase given between 3 and 9 hours after symptom onset in patients with occlusion or high-grade stenosis in major cerebral arteries, found on CTA or MRA. Four hundred and ninety two patients were randomized in 77 centers in 17 countries. Median time from stroke onset to treatment was 6.9 hours for placebo and 7.0 hours for desmoteplase. The primary endpoint (mRS 0–2 at day 90) occurred in 51% of the desmoteplase patients as compared to 50% of the placebo patients (adjusted OR 1.20, 95% CI 0.79–1.81). Symptomatic intracranial hemorrhage occurred in six (3%) of the desmoteplase and five (2%) of the placebo patients [22].

Tenecteplase is approved for thrombolytic therapy as a single bolus injection in myocardial infarction patients. It has been evaluated in stroke patients, for instance in a small phase 2B RCT in Australia [23] and in the NOR-TEST trial [24]. To enhance the selection of patients most likely to benefit from thrombolytic therapy, the eligibility criteria for the Australian trial were a perfusion lesion at least 20% greater than the infarct core on CT perfusion and an associated vessel occlusion on CT angiography. The co-primary endpoints were the proportion of the perfusion lesion that was reperfused at 24 hours on perfusion-weighted magnetic resonance imaging and the extent of clinical improvement at 24 hours as assessed with the NIHSS. Patients within a 6-hour time window were randomized into two tenecteplase and one alteplase arm. Together, the two tenecteplase groups had greater reperfusion (p = 0.004) and clinical improvement (p <0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events [23]. The NOR-TEST trial aimed to investigate the safety and efficacy of tenecteplase versus alteplase in patients with acute stroke who were eligible for intravenous thrombolysis. It was done as a phase 3, randomized, open-label, blinded endpoint, superiority trial in 13 Norwegian stroke units. Those enrolled were adults suspected of acute ischemic stroke who were eligible for thrombolysis and admitted within 4.5 hours of symptom onset or within 4.5 hours of awakening with symptoms, or who were eligible for bridging therapy before thrombectomy. The primary outcome was excellent functional outcome defined as mRS of 0 or 1 at 3 months. One thousand one hundred patients were randomly assigned to the tenecteplase (n = 549) or alteplase (n = 551) arm. Most of the patients had mild strokes with a median NIHSS of 4 (IQR 2–8) at randomization. Excellent 3-month outcome was achieved by 64% of patients in the tenecteplase group and 63% of patients in the alteplase group (OR 1.08, 95% CI 0.84–1.38) [24]. Thus, tenecteplase was not superior to alteplase in a cohort of patients with predominantly mild strokes and should still be used only in clinical trials, but not in clinical routine.

Intra-Arterial Thrombolysis

Although some evidence exists to support the use of intra-arterial thrombolysis for proximal occlusions of the middle cerebral artery (MCA) within 6 hours of onset, it is not currently established as a routine treatment option in most centers. The PROACT II trial randomized 180 patients with acute ischemic stroke due to proven occlusion of the MCA and without hemorrhage or major early infarction signs on CT scan to heparin and intra-arterial pro-urokinase – which is not available in Europe – or heparin alone. Forty percent in the intervention arm achieved a good outcome compared with 25% in the control arm [25]. Even if this approach did not reach routine clinical use, it was an important step in the development of mechanical thrombectomy.

See also Chapter 20.

Mechanical Thrombectomy

The combined analysis of the RCTs has demonstrated that thrombolytic therapy with rtPA is also effective in patients with severe stroke. However, it is of limited absolute benefit: only 10% of the patients with an NIHSS score of 16 or more had an excellent clinical outcome (mRS 0–1) [26] (Figure 19.3).

Figure 19.3 Effect of alteplase on excellent stroke outcome (mRS 0–1) by stroke severity. Estimates were derived from a logistic regression model stratified by trial. (Modified from Emberson et al. [26].)

This small benefit can at least in part be explained by the limited ability of rtPA in removing large clots [27]. Furthermore, early recanalization is generally less than 30% for carotid, proximal MCA, or basilar artery occlusion [28]. Therefore, re-introduction of mechanical thrombectomy (MT) devices was a major step in the treatment of patients with large-vessel occlusion. Technical evolution of those systems is explained in detail in Chapter 20, and an example is displayed in Figure 19.8.

A major setback for thrombectomy occurred in 2013 when three RCTs failed to show efficacy of endovascular clot retrieval compared with standard clinical treatment, including intravenous thrombolysis [29–31]. However, the design of these studies was heavily criticized because of several limitations, including patient selection without pre-interventional vessel examination, use of older technology (only very few stent retriever devices), and a long delay between stroke onset and intervention. Nevertheless, in a post-hoc subgroup analysis of patients with CT angiogram-proven large-vessel occlusion, there was a statistical benefit from endovascular treatment within 90 minutes of i.v. rtPA [32].

In October 2015, results of the MR CLEAN trial (Multicenter Randomized Clinical trial of Endovascular Treatment in the Netherlands) were presented [33]. In this trial 500 patients were enrolled in 16 medical centers in the Netherlands. Patients with proven major vessel occlusion not rapidly improving from rtPA treatment were randomized to endovascular stroke therapy or standard of care. Stent retrievers were used in 97% of the EVT cases. This was the first trial showing a clear benefit of endovascular therapy up to 6 hours after stroke onset in the proximal anterior circulation in addition to best medical therapy (IVT up to 4.5 hours in most patients). The endovascular procedure was associated with a shift to improved function at 90 days, as reflected in more patients in the lower mRS categories, with an adjusted common odds ratio (acOR) of 1.67 (95% CI 1.21–2.30). Secondary outcome parameters (NIHSS score at 24 hours and 1 week, recanalization at 24 hours, and final infarct at 1 week) were all statistically significant, favoring the intervention group. Treatment effect was consistent in all predefined subgroups.

Subsequently several other ongoing studies had to be stopped prematurely, but their results consistently confirmed the MR-CLEAN results [34–38]. Note that, unlike the previous equivocal trials, these trials all selected patients with proven large artery occlusion using CT angiography and, mostly, randomized patients within 6 hours of stroke onset. Details of the studies regarding design, patient’s baseline data, and results are summarized in Table 19.2 and Figure 19.4.

Figure 19.4 Functional outcome of patients with ischemic stroke in trials of endovascular thrombectomy. Rates of independent functional outcome at 90 days after treatment (mRS of 0–2) are shown for selected trials of endovascular thrombectomy. Relative risk (with 95% CI) of achieving mRS 0–2 at 90 days is also shown. (Modified from Campbell et al. [39].)

Important evidence about the safety and efficacy of MT also comes from the “Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials” (HERMES) collaboration meta-analysis of the first five positive studies [40]. In a pooled cohort of 1 287 patients, HERMES showed that the proportions of patients achieving a good (independent) functional outcome (mRS 0–2 at 90 days) were 46.0% (mechanical thrombectomy) compared to 26.5% (best medical treatment); see Figure 19.5.

Figure 19.5 Distribution of the modified Rankin Scale in the HERMES analysis. (Modified from Goyal et al. [40].)

RtPA was given to 83% of patients in the thrombectomy population and 87% of those in the control population. The number needed to treat for patients to achieve a reduction of 1 or more points on mRS was 2.6. Reassuringly, mortality at 90 days and risk of symptomatic intracerebral hemorrhage (ICH) did not differ between patients receiving i.v. rtPA and thrombectomy versus i.v. rtPA alone. A major advantage of the HERMES meta-analysis is the option to examine the efficacy of MT in subgroups that were too small to be investigated in the – mostly prematurely stopped – individual trials. The benefit remained in subgroups of patients >80 years of age and those who did not receive i.v. rtPA. Thrombectomy led to a consistent benefit across NIHSS scores, from milder to more severe strokes. Although there was no statistical heterogeneity of effect by the degree of early brain ischemia measured by the Alberta Stroke Program Early CT score (ASPECTS), there was clear benefit only for ASPECTS >5 (indicating a limited extent of early ischemic tissue injury). However, there were only a few patients with ASPECTS <5 included. Other subgroup analyses can be found in Figure 19.6.

Figure 19.6 Forest plot showing adjusted treatment effect for the modified Rankin Scale at 90 days in pre-specified subgroups in the HERMES analysis. (Modified from Goyal et al. [40].)

Other recent meta-analyses, including more trials, have confirmed the key findings from HERMES. The systematic review of Church et al. [41] described 20 randomized trials for endovascular acute stroke treatment. The meta-analysis for the endpoint mRS 0–2 at 90 days of any trial showed a benefit of endovascular treatment, OR 1.69 (95% CI 1.31–2.19), with a rather large number needed to treat (NNT) of 31. However, heterogeneity for this analysis was substantial with I² = 71%. Restricting the analysis to the six grade-1 trials using predominantly stent retrievers, the OR increased to 2.44 (95% CI 1.77–3.36). The NNT for stent retriever studies was eight for the endpoint mRS 0–2 and heterogeneity was moderate with I² = 35% in the limited analysis (see Figure 19.7).

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Related posts:

Chapter 4 – Imaging for Prediction of Functional Outcome and for Assessment of Recovery Chapter 8 – Cardiac Diseases Relevant to Stroke Chapter 12 – Intracerebral Hemorrhage Chapter 17 – Ischemic Stroke in the Young and in Children Chapter 22 – Management of Acute Ischemic Stroke and its Late Complications Chapter 21 – Intensive Care of Stroke

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