Acute ischemic stroke: comparison of low-dose and standard-dose regimes of tissue plasminogen activator

Review

Intravenously administered tissue plasminogen activator (IV-TPA) remains the only approved therapeutic agent for acute ischemic stroke (AIS). IV-TPA in AIS was licensed on the basis of the NINDS trial [1], which demonstrated that an intravenous dose of 0.9 mg/kg body-weight (10% as bolus, 90% as 1-h infusion; maximum dose 90 mg) within 3 h of the symp-tom onset improved outcomes. On the basis of a meta-analysis of the initial clinical trials of IV-TPA [2] and positive third ECASS III [3], the time criteria for IV-TPA was recently extended to 4.5 h. The evidence among 4000 patients randomized to different forms of thrombolysis is strong for an overall net benefit despite an increased risk of symptomatic intracerebral hem-orrhage (SICH) [4]. Despite this risk, patients who receive IV-TPA early after the onset of AIS have an overall ≥30% relative increased chance of having little or no residual disability [5]. The treatment effect translates into 1 fewer patient dead or physically dependent for every 10 patients treated, 1 fewer dying per 100 treated and 1 fewer SICH per 14 treated [5]. The treat-ment benefits with IV-TPA are substantial, with a relative risk reduction of 9.8%, an absolute risk

reduction of 5.5%, corresponding to a number needed to treat of 18 [6].

How was standard dose of IV-TPA determined?The currently employed standard-dose IV-TPA (0.9 mg/kg bodyweight; maximum 90 mg) was chosen on the basis of pilot dose-escalation stud-ies. The first study used doses of 0.35 (n = 6), 0.60 (n = 12), 0.85 (n = 30), 0.95 (n = 25) and 1.08 (n = 1) mg/kg bodyweight tested within 90 min of AIS [7]. It showed that the proportion of patients with major neurological improvement at 24 h was higher in the 0.85 mg/kg tier (55%) compared with the 0.6 mg/kg tier (33%), and there were no SICH in doses <0.95 mg/kg.7 The second study used 0.6 (n = 8), 0.85 (n = 6) and 0.95 (n = 6) mg/kg in patients 90–180 min after stroke and observed one SICH occurring in each of two highest dose-tiers [8]. However, the numbers of patients included were too small to reach any firm conclusion regarding the opti-mum dose. Ironically, a proposed clinical trial to compare 0.6 versus 0.9 mg/kg of TPA was not approved for funding by the NINDS in the mid-1990s [9].

Vijay K Sharma*1,2, Ghulam Kawnayn1 and Nabin Sarkar1

1Division of Neurology, Department of Medicine, National University Hospital, 5 Lower Kent Ridge Road, 119074 Singapore2Yong Loo Lin School of Medicine, National University of Singapore, Singapore*Author for correspondence: Tel.: +65 677 241 26 Fax: +65 687 235 66 [email protected]

Intravenous tissue plasminogen activator (IV-TPA), administered within 4.5 h of symptom onset, is the only therapeutic agent approved for achieving arterial recanalization in acute ischemic stroke. Current major guidelines recommend the use of a standard dose (0.9 mg/kg bodyweight; maximum 90 mg) of IV-TPA. However, comparable efficacy of IV-TPA was demonstrated in the observational studies from Japan when a lower dose (0.6 mg/kg bodyweight; maximum 60 mg) was used and later approved by the regulatory authorities. Although limited in numbers, considerable variations in the dose of IV-TPA are noted in recent publications from Asia, with variable results and optimal dose of TPA in Asia remains controversial. The authors present a systemic review of the existing literature and compare the efficacy and safety of standard-versus the low-dose IV-TPA therapy in acute ischemic stroke.

Keywords: acute ischemic stroke • Asian • developing countries • thrombolysis • tissue plasminogen activator

Acute ischemic stroke: comparison of low-dose and standard-dose regimes of tissue plasminogen activatorExpert Rev. Neurother. 13(8), 895–902 (2013)

Expert Review of Neurotherapeutics

© 2013 Informa UK Ltd

10.1586/14737175.2013.827412

1473-7175

1744-8360

Review

THEMED ARTICLE ❙ Stroke

10.1586/14737175.2013.827412 895ISSN 1473-7175© 2013 Informa UK Ltdwww.expert-reviews.com

mailto:[email protected]

Review

How was low dose of IV-TPA determined?Low-dose IV-TPA was first evaluated in three small double-blind randomized controlled trials of duteplase (similar to TPA) within 6-h of AIS in Japan [10, 11]. It was observed that 20 mega-interna-tional units (MIU) of duteplase (equal to 0.33 MIU/kg or 0.6 mg/kg of TPA) was superior to placebo and comparable with 30 MIU on both angiographic recanalization and clinical improvement. Importantly, massive ICH was more frequent in patients who received 30 MIU of duteplase. Interestingly, careful in vitro stud-ies indicated no further increase in the degree of clot lysis with TPA doses above 0.6 mg/kg [12]. Furthermore, a lower dose of TPA (0.5–0.75 mg/kg) for acute myocardial infarction in Japan resulted in rates of coronary artery patency comparable with the standard dose (1–1.25 mg/kg) in other countries [13]. Finally, the Japanese Alteplase Clinical Trial (J-ACT) [14], undertaken with 0.6 mg/kg (60 mg maximum) TPA in an open non-randomized evaluation of patients within 3 h of AIS, showed equivalent clini-cal outcomes but a reduced risk of SICH compared with the standard dose. J-ACT and comparable data from subsequent reg-istries in Japan [15,16] led to approval of the 0.6 mg/kg dose as the treatment regimen for AIS patients in Japan.

Findings from Japan caused considerable confusion in other parts of Asia, where there is continued uncertainty regarding the balance of benefits and risks of low- versus standard-dose TPA. Thus, 0.6 mg/kg dose of TPA (which requires use of a single 50 mg vial of Actylise®, Boehringer Ingelheim) became an attractive ‘low-cost’ and possibly ‘safer’ option for patients who cannot afford the full dose. The high cost of TPA (~US$2000 per 2 × 50 mg vials for 0.9 mg/kg dose) is a major out-of-pocket expense for many people in fee-for-service healthcare systems of low-middle income countries [17].

Major randomized clinical trials & observational studies with standard-dose IV-TPAIV-TPA is the current standard of care in AIS and, initiated within the first 3 h, offers substantial benefits in preventing disabling deficits and even in the 3- to 4.5-h window, the benefits are mod-est [1,2]. The NINDS trials included patients treated within 3 h of their symptom onset [1]. Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trial included patients up to 6 h of stroke onset in part A and in the 3- to 5-h time window in part B [18]. European Cooperative Acute Stroke Study (ECASS) I and II recruited patients up to 6 h [19,20]. The pooled analysis of these six clinical trials revealed improved outcomes, if treatment was initiated within 90 min (odds ratio [OR]: 2.8; 95% CI: 1.8–4.5) [2]. However, the poten-tial benefit existed even beyond 3 h (OR: 1.4; 95% CI: 1.05–1.85 for 180–270 min) [2]. This led to the initiation of the ECASS III, which was a double-blind randomized placebo-controlled trial [3]. It was designed to evaluate acute IS treated with IV-TPA within 3–4.5 h and recruited 821 patients from 19 European countries. Treated at a median time of 3 h 59 min, patients receiving IV-TPA had favorable outcomes compared with placebo (52.4 vs 45.2%; OR: 1.34; 95% CI: 1.02–1.76; p = 0.04). Although the inci-dence of SICH was higher with TPA (2.4 vs 0.2%; p = 0.008),

mortality did not differ significantly between the two groups (7.7 vs 8.4%; p = 0.68) [3]. The controversy about the efficacy of TPA in AIS patients older than 80 years of age was evaluated by the International Stroke Trial III (IST-III) [21] in 3035 patients and concluded that in patients older than 80 years of age, IV-TPA was as efficacious as in patients less than 80 years of age.

Major observational studies with standard-dose IV-TPADespite consistent and convincing data from the randomized clinical trials with IV-TPA, concerns were raised over the appli-cability of the results to individuals in daily clinical practice, especially considering the short time within which treatment must be given and the potential risks of SICH are applied. In the European Union, a license for using IV-TPA was granted in 2002 on two conditions: the setting in place of an observational safety study, the SITS-MOST [22] to assess the safety profile of IV-TPA in routine clinical practice within 3 h of the symptom onset, and the initiation of ECASS III study [3], with a therapeutic window extended beyond 3 h. The main aim of SITS-MOST was to investigate whether treatment with IV-TPA within 3 h of ischemic stroke symptoms is as safe as is reported in rand-omized controlled trials, when incorporated into clinical practice across a wide range of centers. SITS-MOST registry [22], a pro-spective, open, monitored, observational study, included 6483 patients from 285 centers in 14 countries between 2002 and 2006. Baseline characteristics of patients in SITS-MOST were much the same as those in the pooled randomized controlled trials. At 24 h, the proportion of patients with SICH was 1.7% (107 out of 6444; 95% CI: 1.4–2.0). The mortality rate at 3 months in SITS-MOST was 11.3% (701 out of 6218; 95% CI: 10.5–12.1) compared with 17.3% (83 out of 479; 95% CI: 14.1–21.1) in the pooled randomized controlled trials. Similar observations have been reported from various countries that evaluated their data submitted to the SITS-ISTR registry [23–25]. These data confirmed the safety and efficacy of IV-TPA in routine clinical use when used within 3 h of stroke onset, even by centers with little previous experience of thrombolytic therapy for acute stroke.

Major observational studies with low-dose IV-TPAThere has been no randomized clinical trial for testing the low-dose regimen for IV-TPA against placebo or the standard dose. The optimal dosage of IV-TPA for AIS has not been properly explored. The pilot dose-escalation studies for the NINDS TPA trial [7,8] were not conclusive. The initial rationale for choosing IV-TPA in a dose of 0.6 mg/kg instead of 0.9 mg/kg in J-ACT trial [14] on Japanese AIS patients was based on dose-rate findings of duteplase trials [10,11,26]. Furthermore, some racial differences in blood coagulation/fibrinolysis factors influenced the use of low-dose TPA in Japan [13].

The J-ACT trial was a prospective open-label cohort study with-out controls that recruited 103 patients. Primary end points were the proportion of patients with modified Rankin Scale (mRS) score of 0–1 at 3 months and the incidence of SICH within 36 h. Thresholds for these end points were determined by calculating 90% CIs of weighted averages derived from historical NINDS

Expert Rev. Neurother. 13(8), (2013)896

Sharma, Kawnayn & Sarkar

Review

Table 1. Various studies of intravenous thrombolysis for acute ischemic stroke with standard- and low-dose tissue plasminogen activator, and their comparison with the NINDS and SITS-MOST studies.

Study (year) Country Cases (n)

Type of study

IV-TPA dose (n)† Good functional outcome at 3 months (%; 95% CI)‡

SICH (%; 95% CI)§ Ref.

NINDS (1995; part 1 and 2)

USA 312 Randomized controlled trial

Standard: 312 42.6 (37.2–48.2) 6.4 (4.1–9.6)¶ [1]

SITS-MOST group (2007)

European Union members in 2002

6483 Prospective Standard: 6483 38.8 (37.7–40.1) 4.6 (4.1–5.1) [22]

Yamaguchi et al. (2006)

Japan 103 Prospective Low: 103 36.9 (28.0–46.5) 5.8 (2.4–11.7) [14]

Suwanwela et al. (2006)

Thailand 34 Retrospective Low: 2 0 (0–77.6) 0 (0–77.6) [33]

Standard: 32 46.8 (30.2–64.1) 5.9 (1.1–19.2)

Yoneda et al. (2007) Japan 20 Retrospective Low: 20 25 (9.8–47.0) 5 (0.2–22.2) [26]

Padma et al. (2007) India 54 Retrospective Standard: 54 68.5(55.3–79.8)#,†† 0 (0–5.4) [29]

Salam et al. (2009) India 56 Retrospective Low dose ≤50 mg: 56

mRS ≤2: 50.9 (38.0–63.6)

1.7 (0.1–8.3) [30]

Sharma and Sharma (2008)

India 32 Retrospective Standard: 32 mRS 1.2: 87.5% (72.6–95.9)#,††

6.3 (1.1–19.2) [31]

Hsu et al. (2009) Taiwan 43 Retrospective Standard: 43 33 (19.9–47.5) 4.7 (0.8–14.5) [38]

Wasay et al. (2010) Pakistan 21 Retrospective Standard: 21 Not available Fatal ICH: 14 Non-fatal ICH: 10 Total ICH: 5 (23.8; 9.3–45.2)††

[44]

Sharma et al. (2010) Singapore 130 Retrospective Low: 48 35.4 (22.9–49.6) 14.5 (6.6–26.7)†† [41]

Standard: 82 59 (47.7–68.8)†† 1.2 (0.1–5.9)

Toyoda et al. (2009) Japan 600 Prospective Low: 600 33.2 (29.5–37.0)#,†† 3.8(2.5–5.6) [15]

Mori et al. (2010) Japan 58 Retrospective Low: 58 46.6 (34.0–59.4) 0 (0–5.0) [28]

Nguyen et al. (2010) Vietnam 121 Retrospective Low: 48 56.3 (42.1–69.7)†† 2.1 (0.1–9.8) [42]

Standard: 73 34.2 (24.1–45.7) 5.5 (1.8–12.7)

Chao et al. (2010) Taiwan 241 Prospective Low: 116 41.4 (32.7–50.5) 2.6 (0.7–6.9) [39]

Standard: 125 37.7 (29.4–46.3) 8.0 (4.1–13.8)

Lau et al. (2010) Hong Kong 17 Retrospective Standard: 17 52.9 (29.7–75.2) 5.9 (0.3–25.8) [43]

Boddu et al. (2010) India 72 Retrospective Standard: 72 47.2 (35.9–58.8) 5.5 (1.8–12.9) [32]

Zhou et al. (2010) China 105 Retrospective Low: 54 37 (25.0–50.4) 3.9 (0.6–11.7) [36]

Standard: 51 51 (37.4–64.5) 3.9 (0.7–12.4)

Dharmasaroja et al. (2011)

Thailand 209 Retrospective Standard 209 47 (39.8–53.2) 4.3 (1.9–9.3) [35]

†Standard dose: 0.9 mg/kg bodyweight (maximum 90 mg); low dose: 0.6 mg/kg bodyweight (maximum 60 mg).‡Good functional outcome defined by mRS score 0–1, unless otherwise specified.§SICH defined as intracranial hemorrhage within 36 h resulting in neurological deterioration (increase in NIHSS score by ≥4 points) unless otherwise specified.¶Defined as blood seen on CT scan, and any decline in neurological status.#Statistically significant difference as compared with NINDS.††Statistically significant difference as compared with SITS-MOST.ICH: Intracerebral hemorrhage; IV-TPA: Intravenous tissue plasminogen activator; mRS: Modified Rankin scale; SD: Standard deviation; SICH: Symptomatic intracranial hemorrhage.

897www.expert-reviews.com

Low- versus standard-dose thrombolysis in stroke

Review

TPA study. The protocol was defined according to the NINDS TPA stroke study. In this study, mRS of ≤1 at 3 months achieved in 38 (36.9%) patients exceeded the pre-determined threshold of 33.9%. Furthermore, SICH seen in 6 (5.8%) patients was lower than the threshold of 9.6%. The trial concluded that TPA, when administered at 0.6 mg/kg to Japanese AIS patients, might offer a clinical efficacy and safety that are compatible with data reported in North America for a 0.9 mg/kg dose [14].

After the approval of low-dose IV-TPA in Japan in 2005, SAMURAI registry [15], a retrospective, multicenter, observa-tional study evaluated the clinical outcomes when this dose was applied in general practice at 10 Japanese stroke centers. A registry of 600 AIS patients showed that 40.6% (95% CI 35.9–45.5%) achieved mRS of 1 or less at 3 months, similar to those from the post-marketing surveys using the standard-dose therapy. Similar observations were reported in the recently published J-MARS registry from Japan that included 7492 patients from 942 cent-ers [16]. This registry reported favorable outcomes in 33.1% (95% CI: 31.8–34.4%) patients.

Observational studies with low-dose IV-TPA in AsiaLonger distance to the hospital, poor healthcare facilities, poor public awareness, high cost of TPA and anticipated risk of the dreaded SICH are some of the major contributors to the poor rates of thrombolysis for AIS in Asia. The approval of low-dose IV-TPA regimen in Japan led to an interesting controversy across Asia. Furthermore, restricting the total usage of TPA to one vial (50 mg), irrespective of the bodyweight of the patient provided an attractive cost-saving option to the clinicians in the developing nations in Asia.

In this systemic review, we evaluated the available literature related to the variable dose regimes for IV-TPA in AIS. This is an update of our previous publication in 2012 [27].

MethodsWe searched the available literature from various online databases (PubMed, EMBASE and Google Scholar) from January 1990 through December 2012. The following keywords were used: ‘stroke’, ‘acute ischemic stroke’, ‘thrombolysis’, ‘thrombolysis AND stroke’, ‘tissue plasminogen activator’, ‘stroke AND Asia’, ‘throm-bolysis AND Asia’, ‘tissue plaminogen activator AND dose’ or their combinations in the title/text. Further information was retrieved through a manual search of references from recent reviews and other relevant published studies. We included a published study if it was an original article in English, included at least 10 patients and reported functional outcomes and rates of SICH rates.

Data collection & outcome measuresData for various studies were independently extracted by two investigators (NS and GK) and the discrepancies were resolved by discussion with a third investigator (VKS). For each study, the recorded information included total number of participants, country, age of patients, baseline National Institute of Health Stroke Scale (NIHSS) score, time between symptom onset and IV-TPA administration, IV-TPA dose, good functional out-come at 3 months (defined by mRS score 0–1) and incidence of SICH (defined as intracranial hemorrhage within 36 h and resulting in a neurological deterioration [increase in NIHSS score by ≥4 points]). We contacted the corresponding authors of the published papers if any additional information was required.

Table 1. Various studies of intravenous thrombolysis for acute ischemic stroke with standard- and low-dose tissue plasminogen activator, and their comparison with the NINDS and SITS-MOST studies (cont.).

Study (year) Country Cases (n)

Type of study

IV-TPA dose (n)† Good functional outcome at 3 months (%; 95% CI)‡

SICH (%; 95% CI)§ Ref.

Muengtaweepongsa et al. (2012)

Thailand 100 Retrospective Standard: 100 42 (32.6–51.8) 2 (0.3–6.5) [34]

Pan et al. (2013) China 83 Retrospective Standard: 19 57 (48.1–61.4)†,‡ 3 (2.1–4.7) [37]

0.75–0.90 mg/kg: 33

61.2 (57.4–66.8)†,‡ 9.7 (4.9–11.1)

<0.75 mg/kg: 31 (maximum TPA dose 50 mg)

51.5 (44.3–55.2)‡ 10.5 (5.3–13.2)

Chen et al. (2012) Taiwan 261 Retrospective Low (0.7 g/kg): 105 41 (32.4–44.1) 3.8 (1.1–9.8) [40]

Standard: 156 38.4 (29.8–43.8) 1.3 (0.7–3.9)†Standard dose: 0.9 mg/kg bodyweight (maximum 90 mg); low dose: 0.6 mg/kg bodyweight (maximum 60 mg).‡Good functional outcome defined by mRS score 0–1, unless otherwise specified.§SICH defined as intracranial hemorrhage within 36 h resulting in neurological deterioration (increase in NIHSS score by ≥4 points) unless otherwise specified.¶Defined as blood seen on CT scan, and any decline in neurological status.#Statistically significant difference as compared with NINDS.††Statistically significant difference as compared with SITS-MOST.ICH: Intracerebral hemorrhage; IV-TPA: Intravenous tissue plasminogen activator; mRS: Modified Rankin scale; SD: Standard deviation; SICH: Symptomatic intracranial hemorrhage.



Review

Statistical analysisWe compared the results of each study included in this review against NINDS trial [1] and SITS-MOST registry [22], since these were also used as reference standards by the Japanese studies that employed low-dose IV-TPA. The OpenEpi v2.3 software was used to calculate proportions of subjects in each study with good functional outcome and SICH with their 95% CIs [101].

ResultsVarious observational studies from Asia have been summarized in Table 1. Out of 44 countries in Asia, only 9 (21%) have reported their results (Japan [14,15,26,28], India [29–32], Thailand [33–35], China [36,37], Taiwan [38–40], Singapore [41], Vietnam [42], Hong Kong [43] and Pakistan [44]). Most of the studies employed standard param-eters like demographic characteristics, NIHSS score at presenta-tion, systolic blood pressure (BP) before IV-TPA initiation, mRS at 3 months as well as SICH according to the specified definitions. Therefore, it is possible to draw some conclusions.

Onset to treatment time in the Asian studies ranged from a mean of 130 to 173 min is acceptable, considering the dis-tances and other logistic issues [27]. One noticeable difference in the Asian studies was the higher proportion of cardioembolic stroke subtype [27]. Compared with NINDS trial [1] and the SITS-MOST registry [22], cardioembolic strokes constituted considerably higher proportions in most of the Asian studies [27]. Distinctly, in the two case–control observational studies in Japan [14,15], cardio embolic strokes comprised 77 and 63%, respectively. Lacunar strokes constituted about a quarter of the stroke subtypes in the Asian studies, while the contribution by large artery atherosclerosis was comparable with the Western TPA studies [27].

Functional outcome at 3 months were reported in almost all Asian studies using mRS score, 0–1 considered as good functional outcome. The functional outcome from various studies were com-pared individually against NINDS trial and the SITS-MOST reg-istry. As shown in Table 1, the results with standard-dose IV-TPA in most of the Asian studies were comparable with the NINDS trial and SITS-MOST registry, with significantly better results from Singapore [41] and India [29,31]. Interestingly, the functional outcomes with low-dose IV-TPA were also comparable with the NINDS trial [1] and SITS-MOST registry [22]. Only the studies from Vietnam 42] and China 44] demonstrated better results with low-dose IV-TPA.

Both dose regimes of IV-TPA thrombolysis were associated with rates of SICH comparable with that seen in NINDS [1] and SITS-MOST [22] studies. Only one study with standard dose [44] and one with low dose [41] reported unacceptably high rates of hemorrhagic complication after thrombolysis.

In our previous review, we performed meta-analysis of the studies that included patients with low as well as the stand-ard dose of IV-TPA [27]. Although, only four studies could be included in the meta-analysis, there was considerable hetero-geneity (Chi2 = 15.07; degrees of freedom = 4 (p = 0.005): I2 = 73%), there were no conclusive differences in the functional outcome or SICH risk related to either TPA dose regimes.

Similar findings have been reported in a recent meta-analysis by Chen et al. [40]. However, there is no reliable randomized evidence to support the low-dose IV-TPA. Additionally, the evidence for low-dose regimen is available only from Asian AIS patients. Accordingly, the Cochrane review emphasized that even when no clear differences in outcome or SICH risk are seen by the indirect comparisons of different IV-TPA dosages, an uncertainty exists about the benefits and risks of low- versus standard-dose TPA [4].

ConclusionThe practice of using a low-dose IV-TPA is widely prevalent. Although, there is no head-to-head comparison or randomized controlled studies regarding the low- and standard-dose regimes of IV-TPA, the currently available data appear to suggest a possible place for the low-dose IV-TPA regimen. The recently launched ENCHANTED clinical trial [102] is currently eval-uating the low-dose IV-TPA (0.6 mg/kg bodyweight; 60 mg maximum; 15% as IV bolus and remaining 85% as continu-ous infusion over 1 h) against the standard-dose regimen. The trial employs a non-inferiority margin based on the Cochrane review [4], where the overall risk ratio of standard-dose TPA versus control with respect to death or disability was 0.76 (95% CI: 0.66–0.87). The trial adopts a non-inferiority margin of 1.14 that would provide assurance that low-dose TPA retains at least half of the effects of standard-dose TPA. Since the trial has a parallel arm of intensive BP control versus the guideline-based management, there is potential for a negative interaction between intensive BP lowering and low-dose TPA. This leads to a sample size of 3300 (1650 per group) with >90% power (one-sided α = 0.025) to achieve the non-inferiority setting (assum-ing a 5% dropout) with the ability to assess the superiority of low- versus standard-dose TPA.

Expert commentaryThe optimum dose of IV-TPA remains controversial. The ini-tial studies for determining the optimal dose of IV-TPA in AIS included small number of patients and appear suboptimal. Japanese observational studies suggested the clinical efficacy and safety of low-dose IV-TPA comparable with standard dose. Reduced treatment cost, anticipated lower rates of SICH and comparable efficacy appear attractive options. We have discussed the evidence behind selecting the standard dose of IV-TPA in the western studies as well as the low dose by Japanese neurolo-gists followed by the clinical observational studies across Asia. The results are compelling for conducting a large-scale controlled clinical trial to settle the controversy about the TPA dose. The ENCHANTED clinical trial is a big and bold step toward solving this long-standing controversy.

Five-year viewAlthough IV-TPA is the only proven therapy for stroke, it is used in only a minority of cases due to various logistic issues and the high cost. As most strokes occur in the developing countries, only low-cost treatments that are widely applicable will have significant



Review

public health impact. Since low-dose TPA fulfils these require-ments, ENCHANTED could have a major impact in reducing the burden of stroke by providing evidence for cheaper, safer and effective treatments for AIS. Given the applicability to millions of people with AIS worldwide each year, the positive results of ENCHANTED trial will have an immediate impact on the current clinical practices.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Intravenous tissue plasminogen activator (IV-TPA) remains the only approved drug therapy for achieving arterial recanalization in acute ischemic stroke.

• The recommended standard dose of IV-TPA is 0.9 mg/kg bodyweight (10% as bolus and remaining as infusion over 60 min; max 90 mg).

• Japanese Alteplase Clinical Trial study concluded that the low-dose IV-TPA (0.6 mg/kg bodyweight, 10% bolus and remaining as infusion over 60 min; max 60 mg) has comparable efficacy with the standard-dose regime used in Caucasian population.

• The studies of variable dose regimes for IV-TPA appear to produce comparable results and safety. Use of variable doses of IV-TPA is widely prevalent without any solid evidence.

• Current data appear compelling to conduct a randomized clinical trial to settle the prevailing controversy about the TPA dose regime.

• The ENCHANTED trial, a newly launched multinational clinical trial is expected to settle the controversy about IV-TPA dose in acute ischemic stroke.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

1 No authors listed. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N. Engl. J. Med. 333(24), 1581–1587 (1995).

• Thispivotalclinicaltrialledtotheapprovalofintravenouslyadministeredtissueplasminogenactivator(IV-TPA)inacutestrokeinadoseof0.9mg/kgbodyweight(max90mg),labeledasthestandarddose.

2 Hacke W, Donnan G, Fieschi C et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS and NINDS rt-PA stroke trials. Lancet 363(9411), 768–774 (2004).

• ThisstudyreportedtheresultsofpooledanalysisofallthesixclinicaltrialswithIV-TPAinNorthAmericaandEurope.ThestudyshowedthatoutcomesafterthrombolysiswithTPAaredependentonthetime-to-treatmentandpotentialbenefitsofIV-TPAmayexistupto270minafterstrokeonset.

3 Hacke W, Kaste M, Bluhmki E et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Engl. J. Med. 359(13), 1317–1329 (2008).

4 Wardlaw JM, Murray V, Berge E, Del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst. Rev. 4, CD000213 (2009).

5 Saver JL. Number needed to treat estimates incorporating effects over the entire range of clinical outcomes: novel derivation method and application to thrombolytic therapy for acute stroke. Arch. Neurol. 61(7), 1066–1070 (2004).

6 Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lancet 371(9624), 1612–1623 (2008).

7 Brott TG, Haley EC, Levy DE et al. Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 23(5), 632–640 (1992).

8 Haley EC, Levy DE, Brott TG et al. Urgent therapy for stroke. Part II. Pilot study of tissue plasminogen activator administered 91–180 minutes from onset. Stroke 23(5), 641–645 (1992).

9 Khatri P, Broderick JP, Pancioli AM. Risk of thrombolysis-associated intracerebral hemorrhage: the need to compare apples with apples. Stroke 36(6), 1109–1110 (2005).

10 Mori E, Yoneda Y, Tabuchi M et al. Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Neurology 42(5), 976–982 (1992).

11 Yamaguchi T, Kikuchi H, Hayakawa H et al. Clinical efficacy and safety of intravenous tissue plasminogen activator in acute embolic stroke: a randomized, double-blind, dose-comparison study of duteplase. In: Thrombolytic Therapy in Acute Ischemic Stroke III. Yamaguchi T, Mori E, Minematsu K, del Zoppo GJ (Eds). Springer-Verlag, Tokyo, Japan, 223–229 (1995).

12 Shaw GJ, Meunier JM, Lindsell CJ, Pancioli AM, Holland CK. Making the right choice: optimizing rt-PA and eptifibatide lysis, an in vitro study. Thromb. Res. 126(4), 305–311 (2010).

13 Ueshima S, Matsuo O. The differences in thrombolytic effects of administrated recombinant t-PA between Japanese and Caucasians. Thromb. Haemost. 87(3), 544–546 (2002).

14 Yamaguchi T, Mori E, Minematsu K et al.; Japan Alteplase Clinical Trial (J-ACT) Group. Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT). Stroke 37(7), 1810–1815 (2006).

• Thiscase–controlobservationalstudyonJapanesestrokepatientsshowedthatIV-TPAinadoseof0.6mg/kgbodyweight(max.60mg)producedtheoutcomesthatarecomparablewiththeNINDS-TPAstudy.Thishasbeenreferredtoaslow-doseIV-TPAregimen.

15 Toyoda K, Koga M, Naganuma M et al. Routine use of intravenous low-dose recombinant tissue plasminogen activator in Japanese patients; general outcomes and prognostic factors from the SAMURAI register. Stroke 40(11), 3591–3595 (2009).

16 Nakagawara J, Minematsu K, Okada Y et al. Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic stroke in routine clinical practice. The Japan post-Marketing Alteplase Registra-tion Study (J-MARS). Stroke 41(9), 1984–1989 (2010).



Review

17 Pandian JD, Srikanth V, Read SJ, Thrift AG. Poverty and stroke in India: a time to act. Stroke 38(11), 3063–3069 (2007).

18 Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset: the ATLANTIS study – a randomized controlled trial. JAMA 282(21), 2019–2026 (1999).

19 Hacke W, Kaste M, Fieschi C et al. Intravenous thrombolysis with recombi-nant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA 274(13), 1017–1025 (1995).

20 Hacke W, Kaste M, Fieschi C et al. Randomised double-blind placebo-con-trolled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 352(9136), 1245–1251 (1998).

21 The IST-3 collaborative group; Sandercock P, Wardlaw JM, Lindley RI et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST 3]): a randomised controlled trial. Lancet 379(9834), 2352–2362 (2012).

22 Wahlgren N, Ahmed N, Da’valos A et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementa-tion of Thrombolysis in Stroke Monitoring Study (SITS-MOST): an observational study. Lancet 369(9558), 275–282 (2007).

• ThislargemultinationalregistrydemonstratedtheresultsobtainedwhenIV-TPAwasusedacrosstheEuropeanUnioninreal-lifesituations.

23 Topakian R, Brainin M, Eckhardt R et al.; SITS-Austria group. Thrombolytic therapy for acute stroke in Austria: data from the Safe Implementation of Thrombolysis in Stroke (SITS) register. Eur. J. Neurol. 18(2), 306–311 (2011).

24 Kobayashi A, Czlonkowska A, Ahmed N et al.; SITS Poland Collaborative Group. Intravenous recombinant tissue plasminogen activator for acute stroke in Poland: an analysis based on the Safe Implementation of Thrombolysis in Stroke (SITS) Registry. Acta Neurol. Scand. 122(4), 229–236 (2010).

25 Simpson MA, Dewey HM, Churilov L et al. Thrombolysis for acute stroke in Australia: outcomes from the Safe Implementation of Thrombolysis in Stroke

registry (2002–2008). Med. J. Aust. 193(8), 439–443 (2010).

26 Yoneda Y, Yamamoto S, Hara Y et al. Post-licensed 1-year experience of systemic thrombolysis with tissue plasminogen activator for ischemic stroke in a Japanese neuro-unit. Clin. Neurol. Neurosurg. 109(7), 567–570 (2007).

27 Sharma VK, Ng KW, Venketasubramanian N, Teoh HL, Chan BP. Intravenous thrombolysis for acute ischemic stroke in Asia. Expert Rev. Neurother. 12(2), 209–217 (2012).

• Thissystemicreviewevaluatedthesafetyandefficacyoflow-versusthestandard-doseIV-TPAinacuteischemicstrokeamongtheAsianstudiesandcomparedtheresultswiththepivotalNINDStrialandtheSITS-MOSTregistry.ThestudyconcludedthatbothTPAdosesappeartoproducecomparableresults.

28 Mori E, Minematsu K, Nakagawara J et al. Effects of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in middle cerebral artery occlusion. Japan Alteplase Clinical Trial II (J-ACT II). Stroke 41(3), 461–465 (2010).

29 Padma MV, Singh MB, Bhatia R et al. Hyperacute thrombolysis with IV rtPA of acute ischemic stroke: efficacy and safety profile of 54 patients at a tertiary referral center in a developing country. Neurol. India 55(1), 46–49 (2007).

30 Salam KA, Ummer K, Pradeep Kumar VG, Noone ML, Laila A, Ragini J. Intravenous thrombolysis for acute ischemic stroke: The Malabar experience 2003 to 2008. J. Clin. Neurosci. 16(10), 1276–1278 (2009).

31 Sharma SR, Sharma N. Hyperacute thrombolysis with recombinant tissue plasminogen activator of acute ischemic stroke: feasibility and effectivity from an Indian perspective. Ann. Indian Acad. Neurol. 11(4), 221–224 (2008).

32 Boddu DB, Prasad RG, Bandaru VCSS et al. Predictors of major neurologic improvement after Intravenous thromboly-sis in acute ischemic stroke: a hospital based study from Hyderabad, India. Ann. Indian Acad. Neurol. 58(3), 403–406 (2010).

33 Suwanwela NC, Phanthumchinda K, Likitjaroen Y. Thrombolytic therapy in acute ischemic stroke in Asia: the first prospective evaluation. Clin. Neurol. Neurosurg. 108(6), 549–552 (2006).

34 Muengtaweepongsa S, Dharmasaroja P, Kummark U. Outcomes of intravenous thrombolytic therapy for acute ischemic stroke with an integrated acute stroke

referral network: initial experience of a community-based hospital in a developing country. J. Stroke Cerebrovasc. Dis. 21(1), 42–46 (2012).

35 Dharmasaroja PA, Dharmasaroja P, Muengtaweepongsa S. Outcomes of Thai patients with acute ischemic stroke after intravenous thrombolysis. J. Neurol. Sci. 300(1–2), 74–77 (2011).

36 Zhou XY, Wanga SS, Collins ML, Davis SM, Yan B. Efficacy and safety of different doses of intravenous tissue plasminogen activator in Chinese patients with ischemic stroke. J. Clin. Neurosci. 17(8), 988–992 (2010).

37 Pan SM, Liu JF, Liu M et al. Efficacy and safety of a modified intravenous recombi-nant tissue plasminogen activator regimen in Chinese patients with acute ischemic stroke. J. Stroke Cerebrovasc. Dis. 22, 690–693 (2013).

38 Hsu YC, Sung SF, Ong CT, Wu CS, Su YH. Intravenous thrombolytic therapy for acute ischemic stroke: the experience of a community hospital. Acta Neurol. Taiwan. 18(1), 14–20 (2009).

39 Chao AC, Hsu HY, Chung CP et al. Outcomes of Thrombolytic Therapy for Acute Ischemic Stroke in Chinese Patients. The Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) Study. Stroke 41(5), 885–890 (2010).

40 Chen CH, Hsieh CY, Lai TB, Chuang MT, Chen WL, Sun MC. Optimal dose for stroke thrombolysis in Asians: low dose may have similar safety and efficacy as standard dose. J. Thromb. Haemost. 10(7), 1270–1275 (2012).

41 Sharma VK, Tsivgoulis G, Tan JH, Ong BKC, Chan BPL, Teoh HL. Feasibility and safety of intravenous thrombolysis in multiethnic Asian stroke patients in Singapore. J. Stroke Cerebrovasc. Dis. 19(6), 424–430 (2010).

• ThisstudyinamultiethnicpopulationinSingaporedemonstratedthatthestandard-doseIV-TPAresultedingoodfunctionalrecoveryinabout59%patients.BeingamultiethniccountrywithagoodmixtureofChinese,MalayandIndians,thestudypopulationcouldbeconsideredasarepresentativesampleofAsianpopulation.

42 Nguyen TH, Truong ATL, Ngo MB et al. Patients with thrombolysed stroke in Vietnam have an excellent outcome: results from the Vietnam thrombolysis registry. Eur. J. Neurol. 17(9), 1188–1192 (2010).

• ThisVietnamesestudyrevealedthatlow-doseIV-TPAregimenforacutestroke



Review

patientsissignificantlysuperiorandsafertothestandard-doseregimen.

43 Lau AY, Soo YO, Graham CA et al. An expedited stroke triage pathway is the key to shortening the door-to-needle time in delivery of thrombolysis treatment. Hong Kong Med. J. 16(6), 455–462 (2010).

44 Wasay M, Barohi H, Malik A, Yousuf A, Awan S, Kamal AK. Utilization and outcome of thrombolytic therapy for acute stroke in Pakistan. Neurol. Sci. 31(2), 223–225 (2010).

45 Adams HP, Bendixen BH, Kappelle LJ et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24(1), 35–41 (1993).

Websites

101 Dean AG, Sullivan KM, Soe MM. OpenEpi: Open Source Epidemiologic Statistics for Public Health, Version 2.3. www.openepi.com

102 Enhanced Control of Hypertension and Thrombolysis Stroke Study. www.enchanted.org.au (Accessed on 18 May 2013)

• Thisnewlylaunchedrandomizedlarge-scalemultinationalclinicaltrialattemptstoperformahead-to-headcomparisonofthelowversusthestandarddosewithaquasifactorialdesign.Theotherarmofthistrialwouldcomparetheearlyintensivecontrolagainsttheguideline-basedcontrolofbloodpressureinacuteischemicstrokeafterthrombolysis.



Documents

Acute ischemic stroke: comparison of low-dose and standard-dose regimes of tissue plasminogen activator