We read with interest the report by Chen et al.  regarding the comparable efficacy of a low (0.7 mg kg−1 body weight) and a standard (0.9 mg kg−1 body weight) dose of intravenous (i.v.) tissue plasminogen activator (tPA) in acute ischemic stroke. Their results are highly relevant in the Asian context where acute ischemic stroke accounts for about 3 million deaths annually , often occurring at relatively younger ages when compared with the developed nations . Furthermore, rapid improvements in health-care facilities and public awareness are continually increasing the rates of acute stroke thrombolysis.
Standard-dose tPA was chosen on the basis of a pilot dose-escalation study. The first study tested 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−1 within 90 min of symptom onset and demonstrated a higher proportion of major neurological improvement at 24 h in the 0.85 mg kg−1 tier (55%) compared with the 0.6 mg kg−1 tier (33%), with no symptomatic intracerebral hemorrhage (sICH) when a dose of less than 0.95 mg kg−1 was used . In the second study, tPA was used in patients presenting within 90–180 min after symptom-onset in variable doses of 0.6 (n = 8), 0.85 (n = 6) and 0.95 (n = 6) mg kg−1 and observed sICH in the two higher dose tiers . It is evident that very small numbers of subjects (total 94 in the two studies) were involved in each dose tier to finally decide the optimal dose of tPA. Ironically, a proposed trial to compare 0.6–0.9 mg kg−1 of tPA was not approved for funding by the NINDS . However, the past 17 years have witnessed many large randomized clinical trials for i.v. tPA in acute ischemic stroke in North America and Europe. A meta-analysis of about 3700 patients included in these trials of tPA, administered up to 4.5 h after symptom onset, provides very strong evidence of the overall net benefit of the standard-dose regimen .
Interestingly, there has never been any randomized clinical trial for testing the efficacy of low-dose tPA therapy in acute ischemic stroke. This regimen is largely backed by the Japanese single-arm observational study that showed that the low-dose i.v. tPA regimen (0.6 mg kg−1 body-weight; maximum 60 mg) in Japanese acute ischemic stroke patients provides benefits comparable to the standard-dose used in the American stroke patients in the NINDS trial . Furthermore, patients treated with combined i.v. and intra-arterial tPA and/or mechanical clot retrieval devices do not always receive the full 0.9 mg kg−1 dose, commenced as part of the bridging therapy, because their subsequent cerebral angiography did not demonstrate an intracranial clot. These findings prompted the use of variable dose regimens for acute stroke thrombolysis in Asia, driven also by possible racial differences in blood coagulation–fibrinolysis factors, lower cost, lower risk of hemorrhagic complications and the benefits comparable to the standard-dose. Interestingly, in a systematic review, we demonstrated that in spite of variable doses used in vastly different acute-care settings across Asia, both low- and standard-dose i.v. tPA therapy appears to produce almost similar results .
In the previous study, Chen et al.  evaluated a new dose regimen (0.7 mg kg−1 body weight) for i.v. tPA in acute ischemic stroke in Taiwan. Although no rationale for using this new dose-regimen is provided, their findings are timely and a strong reminder for the need of a large-scale randomized clinical trial to settle the controversy of tPA dose in acute ischemic stroke. However, in order to conduct such a clinical trial and prove non-inferiority of the low-dose against the standard-dose tPA, an estimated sample size of 3300 patients (1650 per group) is required, assuming > 90% power (one-sided α = 0.025). Perhaps the newly launched trial ‘ENhanced Control of Hypertension ANd Thrombolysis in strokE Disease (ENCHANTED)’ would settle the issue of the optimal dose of tPA in acute ischemic stroke (http://clinicaltrials.gov/ct2/show/record/NCT01422616 ). Establishing the non-inferiority (or even superiority) of the low-dose tPA regimen in the ENCHANTED trial might have a major impact in reducing the global stroke burden by providing a cheaper, possibly safer and effective treatment for the developing world.
Finally, in the future, acute stroke management is expected to be largely determined by advanced imaging techniques. Perhaps imaging studies would help in identifying suitable patients for the standard-dose and additional aggressive multimodal therapeutic approaches (i.e. in patients with occlusions of terminal internal carotid artery or proximal middle cerebral artery where tPA alone does not work satisfactorily) whereas the low-dose regimen be reserved for patients with minor strokes as distal arterial occlusions and with small perfusion lesions.