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Review

Intravenous thrombolysis in acute ischemic stroke: standard and potential future applications Expert Rev. Neurother. Early online, 1–14 (2014)

Michal Harsˇa´ny1–3, Georgios Tsivgoulis1,4 and Andrei V Alexandrov*5 1 International Clinical Research Center, St. Anne’s University Hospital, Brno, Czech Republic 2 Department of Neurology, St. Anne’s University Hospital and Medical Faculty of Masaryk University, Brno, Czech Republic 3 Comprehensive Stroke Center, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA 4 Second Department of Neurology, University of Athens, School of Medicine, “Attikon” University Hospital, Athens, Greece 5 Department of Neurology, The University of Tennessee Health Science Center, Memphis, TN, USA *Author for correspondence: [email protected]

Acute ischemic stroke is a medical emergency requiring urgent treatment. Randomized clinical trial and Phase IV data have provided unequivocal evidence that intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) improves early functional outcomes by restoring brain perfusion. Moreover, these studies have shed substantial light on the factors which are associated with more favorable outcome with tPA and are related to the highest benefit-to-risk ratio. Stroke physicians should consider vascular imaging techniques to aid decision making with thrombolytic therapy. The presence of intracranial occlusion is the target of treatment with early recanalization being the goal. Successful use of intravenous thrombolysis depends on a sound understanding of the decision-making process and organization of the treating team who strives for early treatment initiation and strict adherence to the protocol. Intravenous rt-PA within 4.5 h of onset should now be a standard treatment of acute disabling ischemic stroke throughout the world. This review also summarizes intravenous thrombolysis contraindications as well as the safety of novel reperfusion therapies including tenecteplase, sonothrombolysis and the combination of alteplase with direct thrombin inhibitors or glycoprotein IIb/IIIa receptor antagonists. KEYWORDS: acute ischemic stroke • outcomes • systemic thrombolysis • recanalization • tPA

Intravenous thrombolysis in acute ischemic stroke Safety & efficacy of intravenous thrombolysis: randomized clinical trials

Recombinant tissue plasminogen activator (rt-PA) was first approved by the US FDA in 1996 for intravenous (iv.) application within 3 h of acute ischemic stroke (AIS) onset, which was based on the results of National Institute of Neurological Disorders and Stroke (NINDS) I & II trials in 624 stroke patients [1]. Afterwards, two clinical trials with iv. rt-PA administered within 6 h of symptom onset [2,3] and a systematic review of 3156 patients [4,5] provided more data, thus in 2002, rt-PA was also licensed in Europe for the use within 3 h of ischemic stroke onset in patients younger than 80 years who still have a neurological deficit, no severe changes on CT scan and no general contraindication. In 2004, a pooled analysis of six trials with rt-PA given as informahealthcare.com

10.1586/14737175.2014.934676

late as 6 h after onset indicated a potential benefit in terms of clinical outcomes with extension of the time window to 4.5 h [6]. This hypothesis was confirmed in 2008 by the European Cooperative Acute Stroke Study III (ECASS III) trial that randomized patients younger than 80 years and treated between 3.0 through 4.5 h after stroke onset [7,8]. The current license is based on the original criteria from the NINDS trial, although many of the contraindications lack scientific evidence, thus rendering reduced the number of eligible patients. In fact, there are still many issues that remain uncertain including extension of the time window, the treatment of patients aged above 80 years with severe deficits, minor deficits or early recovery with extended early computed tomography changes, etc. As of today, many patients from these subgroups have either not been treated, that is, in accordance with the license or treated as off-label based on clinician’s decision [9].


2014 Informa UK Ltd

ISSN 1473-7175

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Review

´ ny, Tsivgoulis & Alexandrov Harsˇa

Several recent studies provide data to some of these questions. The Third International Stroke trial (IST-3) enrolled acute stroke patients of all ages within 6 h of onset in order to assess efficacy and safety of rt-PA treatment in patients who did not exactly meet the license criteria [10]. IST-3 is the largest trial of iv. thrombolysis in patients with acute cerebral ischemia [11]. Moreover, about three-quarters of patients in IST-3 were recruited after 3 h of onset and half of all patients were older than 80 years. The primary end point of the trial was the proportion of patients who were alive and independent (defined by Oxford Handicap Score of 0–2) at 6 months after stroke. Although the increase in the number of patients treated with rt-PA who were alive or independent at 6 months did not reach statistical significance (absolute increase 14/1000; 95% CI: -20 to 48), a secondary ordinal analysis showed a significant shift in Oxford Handicap Scores (common odds ratio [OR]: 1.27; 95% CI: 1.10–1.47; p = 0.001). Fatal or non-fatal symptomatic intracranial hemorrhage (SICH) within 7 days occurred in 7% patients treated with rt-PA compared with 1% in the control group (adjusted OR: 6.94; 95% CI: 4.07–11.8). More patients died within 7 days in the rt-PA group than in the control group (11 vs 7%; adjusted OR: 1.60; 95% CI: 1.22–2.08; p = 0.001). On the other hand, between 7 days and 6 months there were fewer deaths in the rt-PA group. In total, after 6 months there were similar case-fatality rates in both groups (27 vs 27%) [11]. Contrary to the expectations [12], a subgroup analysis showed a significantly greater adjusted effect of rt-PA treatment in patients older than 80 years than in patients aged 80 years or younger (p = 0.027). According to this subanalysis, thrombolytic treatment seems to be at least as effective in patients aged above 80 years as in younger patients. In addition, significant trends toward larger effects of treatment with rt-PA were observed in patients with more severe stroke. The benefit was greatest in patients treated within 3 h of onset, although there was insufficient power to examine the decay of benefit with time [11]. The IST-3 trial data support the notion of treating patients as soon as possible and also justify thrombolytic treatment in patients older than 80 years of age. Safety & efficacy of iv. thrombolysis: meta-analyses

Since IST-3 trial enrolled only half the number of patients originally intended due to many changes in the regulatory environment that precluded the participation of several countries, the trial was underpowered for the primary outcome and also to reliably detect subgroup effect. Hence, an updated systematic review and meta-analysis of 12 trials with 7012 stroke patients has been published [13]. This systematic review and metaanalysis showed that patients treated with rt-PA have significantly increased odds of being alive and independent (modified Rankin scale [mRS] 0–2) at the end of follow-up (46.3 vs 42.1%; OR: 1.17; 95% CI: 1.06–1.29; p = 0.001; absolute increase of 42 per 1000 patients treated) and favorable outcome defined as mRS 0–1 (34.8 vs 29.3%; absolute increase of 55 per 1000 patients treated). Fatal intracranial hemorrhage doi: 10.1586/14737175.2014.934676

within 7 days occurred in 3.6% patients treated with rt-PA compared with 0.6% in the control group. Besides intracranial hemorrhage, there was no other cause rendering increased death rate within 7 days in rt-PA-treated patients. This indicates that the excess of deaths in acute phase of stroke in patients treated with rt-PA is mostly from fatal intracranial hemorrhage. In addition, the meta-analysis showed that 11.5% of patients treated with rt-PA and 13.6% patients in the control group died in the period between 7 days and the end of follow-up. In other words, early hazards in rt-PA group were offset by a reduction of the death rate between 7 days and the end of follow-up. As a consequence, there was apparently no effect on deaths from all causes and the rate of patients with mRS 3–5 was reduced. Patients given rt-PA within 3 h of onset achieved mRS 0–1 in 31.6% compared with 22.9% in the control group (OR: 1.61; 95% CI: 1.30–1.99; p < 0.0001). Likewise, patients treated with rt-PA within 3 h had higher rate of mRS 0–2 (40.7 vs 31.7%; OR: 1.53; 95% CI: 1.26–1.86; p < 0.0001). Among patients treated between 3 and 6 h of stroke onset, 47.5% rt-PA-treated patients and 45.7% controls achieved mRS 0–2 (OR: 1.07; 95% CI: 0.96–1.20; p = 0.24), but the difference did not achieve statistical significance. Meanwhile, only three trials included patients aged above 80 years (n = 1711) [1,10,14]. Patients older than 80 years treated within 6 h of onset achieved mRS 0–2 at higher rate in rt-PA group (27.2 vs 23.4%; p = 0.07). Among patients aged below 80 years and treated within 6 h, 52.5% rt-PA-treated patients and 48.3% controls had mRS 0–2 at the end of follow-up (p = 0.009). Among patients treated within 3 h of onset, of those aged above 80 years, 28.9% rt-PA treated and 19.3% controls were alive and independent (mRS 0–2) at the end of follow-up (p = 0.003) compared with 49.6% rt-PA treated and 40.1% controls (p = 0.001) who were aged below 80 years. Among patients aged below 80 years and treated between 3 and 6 h of onset, 52.6% rt-PA treated and 50.3% controls achieved mRS 0–2 compared with 25.9% rt-PA treated and 26.4% controls aged above 80 years old. In conclusion, in patients older than 80 years is rt-PA treatment of benefit at least as large as in the younger patients, particularly if treated early within 3 h of onset (OR: 1.68; 95% CI: 1.20–2.34). Finally, a recent pooled analysis of individual patient data from nine randomized controlled trials (NINDS I &II, ECASS I, II & III, ATLANTIS A & B, EPITHET, IST-3) that was presented at the 2014 International Stroke Conference indicated that the benefit of systemic thrombolysis is time dependent and unrelated to age and admission stroke severity (TABLE 1) [15]. These two updated reviews and meta-analyses brought further insights in thrombolytic treatment. First, patients treated with rt-PA had fewer deaths between 7 days and late follow-up in IST-3 trial. This implies that the excess hazard with rt-PA is notably attributable to SICH within 7 days and patients who survive the acute phase without intracranial hemorrhage benefit. Presumably, more disabled stroke survivors have an ongoing higher risk of death [16], and by shifting the balance toward Expert Rev. Neurother.

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iv. thrombolysis in AIS

Review

better functional outcome, rt-PA reduces Table 1. Effect of onset-to-treatment time, age and baseline stroke the risk of death in the long term. More severity on favorable functional outcome (modified Rankin Scale of specifically, if 100 AIS patients were 0–1) in an individual patient-data meta-analysis of 9 Randomized treated with iv. thrombolysis 10 more Controlled Trials (n = 6.756 patients) [15]. would have achieved favorable functional Variable Control group rt-PA group OR (95% CI) NNT outcome at 3 months in comparison to control subjects, but two more would OTT have died within the first week of symp£180 min 176/762 (23%) 259/787 (33%) 1.75 (1.35–2.27) 10 tom onset due to SICH [15]. Second, 181–270 min 432/1437 (30%) 485/1375 (35%) 1.26 (1.05–1.51) 20 patients with severe and milder strokes 357/1166 (31%) 401/1229 (33%) 1.15 (0.95–1.40) Not applicable benefited from rt-PA treatment. Third, as >270 min suggested by the non-randomized studAge ies [17,18], the relative and absolute bene£80 853/2515 (34%) 990/2512 (39%) 1.25 (1.10–1.42) 20 fits of rt-PA were at least as large in older >80 112/850 (13%) 155/879 (18%) 1.56 (1.17–2.08) 20 as in younger people. Fourth, the new data supported the evidence that benefit Baseline NIHSS-score was greatest when rt-PA was given within 189/321 (59%) 237/345 (69%) 1.48 (1.07–2.06) 10 3 h. Hence, efforts to reduce treatment 0–4 delays are underway. The American 5–10 538/1252 (43%) 611/1281 (48%) 1.22 (1.04–1.44) 20 Heart Association has implemented 11–15 175/808 (22%) 198/794 (25%) 1.24 (0.98–1.58) 33 ‘Target: Stroke’, a multidimensional ini55/671 (8%) 77/662 (12%) 1.50 (1.03–2.17) 25 tiative to improve the timeliness of tPA 16–21 administration, by elevating clinical ‡22 8/313 (3%) 22/309 (7%) 3.25 (1.42–7.47) 25 performance in the care of AIS and faciliNIHSS: NIH Stroke Scale; OTT: Onset-to-treatment time. tating the more rapid integration of evidence into clinical practice using a systematic 10-step approach Likely, pre-existing cognitive impairment may theoretically modulate the efficacy of rt-PA. Nonetheless, many patients (TABLE 2). Interestingly, Fonarow et al. reported in the 2014 International Stroke Conference that this initiative has resulted in a included in IST-3 probably had cognitive impairment, which substantial increase (from 29.6 to 53.3%) in the proportion of did not prevent the trial from showing a benefit of rt-PA for patients treated with a door-to-needle time (DNT) £60 min functional outcome. Hence, the influence of pre-existing cognitive impairment on outcome in large cohorts needs to be across North-American tertiary care stroke centers [19]. assessed and this factor is currently being investigated in France and Japan in the OPHELIE-COG study [31]. iv. thrombolysis in the oldest old With aging population, the proportion of AIS patients older than 80 years treated with iv. tPA is increasing. The main risk iv. thrombolysis in patients with rapidly improving stroke factors for cardiovascular and cerebrovascular diseases in the symptoms oldest old include atrial fibrillation, chronic renal disease and Since the FDA approval of rt-PA for AIS treatment in 1996, it congestive heart failure [20]. In the future, further research has become clear that several criteria used for exclusion from might provide more insights in cognitive status in relation to therapy were not based on actual data or operationally defined iv. thrombolysis for AIS [21,22]. In a retrospective study, acute for use in clinical practice. Historically, the intent of this exclustroke patients with dementia treated with rt-PA had no sion criterion within the NINDS rt-PA Stroke Trial was to increased risk of intracranial hemorrhage and death compared avoid treatment of transient ischemic attacks (TIAs), which with patients without dementia [23]. More importantly, patients would have recovered completely without treatment [32]. with prestroke dementia receiving rt-PA had an increased in- Nevertheless, in clinical practice, dubiosity regarding rapidly hospital mortality, and were less likely to have a favorable dis- improving stroke symptoms (RISS) has arisen, therefore, The charge from hospital; however, the small sample size and lack Re-examining Acute Eligibility for Thrombolysis Task Force of important predictors of outcome precluded statistical signifi- comprising members of the original NINDS rt-PA Stroke Trial cance of the results [24]. In general, patients with pre-existing Steering Committee [1] has been established in order to assess cognitive decline often have white-matter lesions [21], silent clinical experience since the NINDS study and current clinical infarcts and brain microbleeds [21,22,25] that can predispose to practice patterns. In addition, a recent multicenter study has hemorrhagic transformation [26,27]. Besides an increased risk of indicated that iv. thrombolysis is safe and effective for AIS bleeding, elderly patients could be more sensitive to the toxic occurring following hospitalization for TIA [33]. According to effect of rt-PA on ischemic tissue [28], in particular if they have the data from various reports [34–38], it has been implied that cognitive impairment, due to dysfunction of the neurovascular RISS is one of the most common reasons for excluding unit [29] and increased sensitivity to any kind of injury [30]. otherwise eligible patients from rt-PA treatment. Moreover, informahealthcare.com

doi: 10.1586/14737175.2014.934676

Best practice

Advance hospital notification by EMS

Rapid triage protocol and stroke team notification

Single-call activation system

Stroke tools

Rapid acquisition and interpretation of brain imaging

Rapid laboratory testing (including point-of-care testing if indicated)

Mix tPA medication ahead of time

Rapid access to intravenous tPA

Team-based approach

Prompt data feedback

Strategy

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[19].

doi: 10.1586/14737175.2014.934676 Accurately measuring and tracking your hospital’s door-to-needle times, IV tPA treatment rates in eligible patients and performance on other stroke performance/quality measures equip the stroke team to identify areas for improvement and take appropriate action. A data-monitoring and feedback system includes using the Get With The Guidelines-Stroke Patient Management Tool (PMT) and creating a process for providing timely feedback on a case-by-case basis and in hospital aggregate. This system helps identify specific delays, set targets and monitor progress on a case-by-case basis

The team approach based on standardized stroke pathways and protocols has proven to be effective in increasing the number of eligible patients treated and reducing time to treatment in stroke. An interdisciplinary collaborative team is also essential for successful stroke performance improvement efforts. The team should meet frequently to review your hospital’s processes, care quality, patient safety parameters and clinical outcomes, as well as to make recommendations for improvement

Once eligibility has been determined and intracranial hemorrhage has been excluded, intravenous tPA should be promptly administered. tPA should be readily available in the emergency department or CT scanner area (if CT scanner is not located in the ED). Dosing charts and standardized order sets can also facilitate timely administration and minimize dosing errors

Mix drug and set up the bolus dose and 1-hour infusion pump as soon as a patient is recognized as a possible rtPA candidate, even before brain imaging. Early preparation allows tPA infusion to begin as soon as the medical decision to treat is made. It is the policy of some drug manufacturers to replace, free of charge, medications that are mixed but not used in time-critical emergency situations such as these. Check with your hospital pharmacy for the proper procedures that will allow you to use this strategy to shorten time to treatment without financial risk

When indicated, laboratories such as platelet count and – for patients in whom coagulation parameters should be assessed due to suspicion of coagulopathy – INR(PT)/PTT results should be available as quickly as possible and no later than 45 min after ED arrival. If standard stat laboratory turnaround times cannot meet this target, point-of care testing in the emergency department can provide the data in the needed timeframe

It is essential to initiate a CT scan (or MRI) within 25 min of arrival and complete interpretation of the CT scan within 45 min of arrival to exclude intracranial hemorrhage prior to administration of intravenous tPA

A stroke toolkit containing clinical decision support, stroke-specific order sets, guidelines, hospital-specific algorithms, critical pathways, NIH Stroke Scale, and other stroke tools should be available and used for each patient

A single-call should activate the entire stroke team. A single-call activation system for the stroke team is defined here as a system in which the emergency department calls a central page operator, who then simultaneously pages the entire stroke team, including notification for stroke protocol imaging

Acute triage protocols facilitate the timely recognition of stroke and reduce time to treatment. Acute stroke teams enhance stroke care and should be activated as soon as the stroke patient is identified in the emergency department or after notification from pre-hospital personnel

EMS providers should, if feasible, provide early notification to the receiving hospital when stroke is recognized in the field. Advance notification of patient arrival by EMS can shorten time to CT and improve the timeliness of treatment with thrombolysis

Explanation

Table 2. Stroke key best practice strategies for improving door-to-needle time in acute ischemic stroke

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iv. thrombolysis in AIS

this subgroup of acute stroke patients frequently has poor outcomes [39–41]. Moreover, the observations of a Spanish study indicated that dysarthria-clumsy hand syndrome was the only clinical pattern that was associated with spontaneous in-hospital recovery in ischemic stroke patients [42]. Consequently, in the absence of other contraindications, patients who experience improvement of any degree, but have a persisting neurological deficit that is potentially disabling, should be treated with iv. rt-PA. Furthermore, it was agreed that improvement should only be monitored for the extent of time needed to prepare and administer the iv. rt-PA bolus/infusion. All neurological deficits present at the time of the treatment decision should be considered in the context of individual risk and benefit, as well as the patient’s baseline functional status. The term RISS should be reserved for those who improve to a mild deficit, specifically one which is perceived to be non-disabling [32]. In summary, the intent underlying the concept of RISS within the original NINDS study has clearly been lost. Specifically, the intent of this exclusion criterion was to avoid the unnecessary treatment of TIA. Translation of the understanding of RISS from stroke to non-stroke physicians is a significant barrier to the optimal treatment of patients with AIS. In the absence of contraindications, patients who experience RISS but have residual deficits that are potentially disabling should be treated with iv. rt-PA [32]. iv. thrombolysis in lacunar stroke

Lacunar infarctions account for approximately 20% of all cerebral infarcts and are caused either by an intracranial atheromatous branch disease or an occlusion of a single penetrating artery by microatheromas or lipohyalinosis [43]. Since in these patients there is no proximal artery occlusion, the potential safety and efficacy of iv. thrombolysis in these patients has been questioned. However, the findings of a recent German study have indicated that patients with acute lacunar stroke benefited from iv. thrombolysis without additional complications [44]. Thus, patients with suspected acute lacunar stroke or lacunar syndrome should not be treated differently than other stroke populations with regard to the administration of acute reperfusion therapies. Treatment window in iv. thrombolysis

Nonetheless, there has been a remarkable improvement in organization and management of acute stroke care; it has been estimated that only 8 mm [71]. These findings have recently been reproduced by Yoo and colleagues who have reported in the 2014 International Stroke Conference that occlusion location is the only significant prediction of clot length >8 mm [72]. TABLE 3 summarizes baseline demographic, clinical and neuroimaging variables that affect the benefit-to-risk ratio of thrombolysis for AIS. Comparison of iv. thrombolysis to endovascular reperfusion therapies

Strokes secondary to acute ICA occlusion are associated with extremely poor progCollaterals Good/moderate Poor/absent nosis and the best treatment approach to Location of vessel occlusion M2MCA Terminal ICA acute stroke in this setting is still unknown. A systematic review [73] revealed Clot length (anterior circulation)