Why Is the Treatment with Intravenous rtPA Ineffective in the Majority of Acute Ischemic Stroke Patients?

This question may surprise, after the 3rd European Cooperative Acute Stroke Study (ECASS 3) has shown that the therapeutic time window is open up to 4.5 h and more patients will benefit from intravenous recombinant tissue-type plasminogen activator (i.v. rtPA) than before [1]. What is the real gain, however, for our patients, and why could we not achieve more? These are questions stimulated by the pioneer of causal stroke treatment and a great teacher, Hermann Zeumer.

Under the ideal circumstances of treatment within 90 min of stroke onset, 13% of patients will benefit from i.v. rtPA, but 87% will not [2]. According to the pooled analysis of randomized controlled trials (RCTs), the beneficial effect disappears within 6 h [3]. Why is the effect size of i.v. thrombolytics small? Why does it disappear? And more importantly: how can we reduce the proportion of nonresponders?

Theoretically, ischemic stroke patients do not benefit from thrombolysis because of three main reasons:

1. Recanalization and reperfusion of ischemic brain tissue are achieved, but too late to enable the recovery of brain functions.
2. Thrombolysis is not required because of spontaneous recanalization with subsequent recovery.
3. The treatment with i.v. rtPA does not recanalize the obstructed artery or recanalization does not result in reperfusion.

It is clear that a better understanding of the reasons for not responding to i.v. rtPA requires the assessment of arterial obstruction and recanalization. To the regret and against the advice of Hermann Zeumer, RCTs testing thrombolysis have used a black-box design taking as outcome event clinical symptoms disregarding the vascular pathology being treated. It remains unknown whether study patients had arterial occlusions at all. It remains unknown what types of obstructions were present, e.g., thromboembolic, atherosclerotic, inflammatory, infectious, dissections, single or multiple. The kind and site of vascular disease and the volume and constitution of clots were not assessed. Moreover, it was not studied whether i.v. thrombolytics could effectively recanalize the artery. Diagnostics at baseline were minimal and included a baseline CT to exclude patients with primary hemorrhage (all trials) and with major ischemic brain damage (ECASS). The diagnostics were kept short in order not to lose time and, thus, treatment effectiveness. With view to the maximal 13% gain in beneficial outcome by early treatment, one may wonder whether the concept “time is brain” is the only and most effective one to increase effectiveness of acute stroke treatment.

In the NINDS rt-PA stroke study, the beneficial effect of rtPA disappeared within 3 h [4]. Putting patients into the model being treated up to 6 h, the effect is present, however, up to 6 h [3]. No study has tested the effect of rtPA after 6 h of stroke onset so far. Another thrombolytic, desmoteplase, showed a beneficial effect on clinical outcome and reperfusion in a time window of 3–9 h [5] that has not yet been confirmed by a larger phase III trial. It is not quite clear, why the beneficial effect of rtPA disappeared over time, and whether these observations really prove that rtPA is ineffective after 6 h. It could be that recanalization is harder to achieve the later the drug is given, because of thrombus growth and organization. Another possibility is that recanalization and reperfusion are becoming ineffective because of a disappearance of viable ischemic brain tissue. This popular hypothesis is supported by observations on the growth of infarct core [6], not seen, however, in all patients [7]. It seems as if an ischemic penumbra exists up to 24 h in about 50% of stroke patients [8]. Moreover, a valid definition of penumbra on CT or MRI does not exist.

What are other factors diminishing the effect size of i.v. rtPA? First of all, we have many acute stroke patients who do not need thrombolysis. In RCTs, 26–45% placebo-treated patients had a good clinical outcome with a modified Rankin Score (mRS) of 0 or 1 [1, 2, 9–11]. It can be presumed that the majority of these patients had no or no longer arterial occlusion when they were treated. Kassem-Moussa & Graffagino described nonocclusion or early spontaneous recanalization within 6 h of stroke onset in 221 of 775 patients (29%, 95% confidence interval: 25–32%), which is just in the range of spontaneous stroke recovery [12]. The exclusion of patients without arterial occlusions – presumably 45% in ECASS 3 – would have doubled the effect size from 7% to 14% for patients being treated within 3–4.5 h. The assessment of arterial occlusion is, therefore, crucial to identify patients who need thrombolysis and who do not. This is quickly feasible with CT or MR angiography. Moreover, the effect of thrombolytics on arterial obstruction and recanalization can only be studied and, hopefully, improved with this information.

Can we do more? Many studies have shown that the treatment effect is directly linked to successful recanalization. Complete recanalization of the middle cerebral artery (MCA, stem and branches) occurred in 32% of 99 alteplase-treated patients at 6 h after stroke onset and partial recanalization in 21% [13]. Full recanalization was associated with disability and death (mRS: 3–6) in 14% (3–51%) of patients only, partial recanalization in 64% (39–84%), and no recanalization in 90% (74– 97%), meaning that absolute risk reduction due to full recanalization was 76% and 26% due to partial recanalization. A meta-analysis of the impact of recanalization on ischemic stroke outcome revealed good outcome (mRS: 0–2) in 51% of patients being recanalized within 6 h of stroke onset versus 11% of nonrecanalized patients (effect size: 40%) [14]. Mattle et al. compared the two University Hospitals of Zurich and Bern, Switzerland, one using i.v. thrombolysis with rtPA only, the other intraarterial (i.a.) thrombolysis with urokinase combined with mechanical clot disruption in patients with stroke and hyperdense MCA sign. Intraarterial treatment achieved partial and complete recanalization in 71% of patients. Favorable clinical outcome was more frequent after i.a. thrombolysis (53%) than after i.v. thrombolysis (23%) [15]. It is thus obvious that the effect size of acute stroke treatment is predominantly affected by the presence of arterial obstruction and the achievement of recanalization and to a lesser extent depending on the time interval between stroke onset and treatment initiation. The question is then justified whether we gain more for our stroke patients if we take the time to prepare and perform direct arterial intervention. Arterial recanalization is the main factor with the best impact on clinical outcome in acute stroke treatment. We need to study which types of arterial occlusions can be treated with i.v. thrombolytics and which require direct interventions or a combination of both. That means that pretreatment diagnostics should include angiography; and the effect of treatment should be monitored with angiography or transcranial Doppler ultrasound. We should be prepared for our stroke patients. Excuse us, Hermann Zeumer, you have taught this for decades. We are learning slowly – to the disadvantage of our patients.

Rüdiger von Kummer,
Dresden, Germany

References

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