Further Randomized Controlled Trials of Tissue Plasminogen Activator Within 3 Hours Are Required
Although early (within 3 hours of onset) tissue plasminogen activator (tPA) has been approved as a treatment for stroke in several countries and endorsed by experts, it remains underused. Clinicians are still uncertain about whom to treat.
Why Are Stroke Physicians Uncertain of the Benefits of Early tPA?
An independent national survey1 of 1716 stroke physicians in the United Kingdom reported that 74% were uncertain of the benefits of thrombolytic therapies. A recent United States survey2 reported that less than half of the responding neurologists had administered tPA and only 30% believed the efficacy of intravenous tPA was “very convincing.”
The Available Evidence
The randomized controlled trials (RCTs) of thrombolysis for acute ischemic stroke have been systematically reviewed with data from just over 5000 patients in 17 trials.3 The majority of the data derives from the 8 tPA trials (2955 patients). In the review it was noted that few older patients (aged ≥80 years) had been included. Unfortunately, there were too few data to perform many subgroup analyses, but overall 3 important conclusions were drawn: (1) there was a definite substantial risk of fatal intracranial hemorrhage; (2) there was a nonsignificant excess of deaths; and (3) these risks appeared to be balanced by an increase in independent survival, which appeared most beneficial for tPA given early (<3 hours after onset).
However, there were too few data to help determine the risk for individual patients. We do not have data on the effects of tPA subdivided by initial CT brain scan appearances, stroke severity, stroke subtype, patient age, or whether the benefits of tPA persist much beyond 6 months.
It is important to note that the NINDS4 trial was unusually positive and in general, has, been overemphasized. We cannot avoid the uncomfortable fact that no studies have been as positive. Was there something unique about the NINDS trial? Were they simply lucky? The use of block randomization ensured that 302 of the 624 patients in the NINDS trials were treated within 90 minutes. Patients had to recognize their symptoms, get to an appropriate hospital quickly, be assessed, be scanned, and provide consent, all within 90 minutes of the onset of symptoms—an astonishing achievement. Perhaps clinicians contemplating a tPA service feel unable to replicate this?
Ischemic stroke is such a heterogeneous entity that, given all the factors that could shift the risk/benefit equation (ie, age, time from stroke onset, severity, subtype, CT scan appearances, and comorbidity), it is far too simplistic to rely on just one of these to determine treatment eligibility (ie, time from onset). Does the fast-tracking change the case mix of those who present early (usually patients with severe stroke5)? If so, this could change the risk-benefit equation of tPA used within 3 hours of stroke onset.
More Trials Are Needed
There is no doubt that tPA can be effective. However, clinicians now need more data to implement treatment. For whom is treatment most beneficial or risky? Case series and audit have not, and will not, be able to reliably answer these questions.6 We need more data from RCTs, including a wider range of patients. Uncertainty must still remain for many categories of patients with stroke seen within 3 hours; otherwise, why are these patients not currently being treated? Ethically, which is better: To continue as we are, with few patients worldwide being treated, thus possibly failing to deliver an effective treatment, or randomizing hundreds more patients under 3 hours to provide convincing evidence?
What Makes Clinicians Change Their Practice?
By the mid-1980s, 33 thrombolytic therapy RCTs had been completed in acute myocardial infarction (MI), and a systematic review demonstrated a statistically significant benefit in survival.7 However, opinion did not change until convincing data emerged from the 17 187 patients randomized in the ISIS-2 trial.8 Eventually, some 60 000 patients were included in RCTs of thrombolysis for MI, and these robust results demonstrated that most major subgroups of patients could benefit from treatment.9 Really reliable and convincing data led to thrombolysis becoming a routine treatment for acute MI.
Some 16 years later we seem to be in a similar situation. We have positive results from one major study4 and a promising systematic review.3 However, unlike those with MI, many stroke patients do not have access to organized inpatient care, fast-tracking of stroke patients is limited to tertiary referral centers, the specialty of stroke medicine is only just emerging, and funding for stroke research is scandalously low.10 Our challenge is to ensure that stroke unit care is available at every emergency hospital, improve stroke funding, work collaboratively across national boundaries, and randomize many more thousands of patients into appropriate intervention trials. The most promising treatment to start with is tPA, but if we continue to argue among ourselves, nothing will happen.
Dr Richard Lindley is supported by the Scottish National Health Service.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.
Dr Lindley has accepted sponsorship from Boehringer Ingelheim UK Ltd to attend the European Stroke Conferences in his role of editor of Stroke Matters, an industry-sponsored national newsletter for stroke multidisciplinary teams. Boehringer Ingelheim hold the license for alteplase (tPA) in the United Kingdom.
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