Survivors don't want 'better'. They want 100% recovery! WHEN THE HELL ARE YOU GOING TO DO THE WORK TO GET THERE? Maybe after you are the 1 in 4 per WHO that has a stroke? Perhaps you might want to start researching those solutions now, while you still can.
Intravenous Alteplase in Patients With Minor Acute Ischemic Stroke — Where is the Limit?
Intravenous thrombolysis (IVT) is probably the most effective weapon for stroke physicians in acute ischemic stroke to achieve a better functional outcome. Guidelines and treatment recommendations evolved from a strict NIHSS >3 points regime to a more liberal indication, namely the use in case of disabling symptoms, regardless of NIHSS-scoring. Guidelines do not recommend alteplase thrombolysis for patients with mild non-disabling symptoms (NIHSS 0–5).
At least half of acute ischemic stroke patients present with minor or mild symptoms at admission, but research showed that 29% of patients with minor stroke had a non-excellent outcome (mRS 2-6) after three months.1 Reasons for this are most likely progressive strokes or recurrent strokes. Most major trials excluded patients with mild or minor symptoms; therefore, safety and efficacy of IVT in these patients is not entirely clear. Moreover, the exploration of effects on specific subgroups in previous meta-analyses is not sufficient to draw final conclusions.
Zhang et al. conducted a systematic review and meta-analysis on comparison of IVT with best medical therapy (BMT) in patients with minor stroke to find an answer to the question of IVT or no IVT in these patients.2
The inclusion criteria for this study were patients with minor ischemic stroke (NIHSS score, 0–5) who could receive thrombolysis within 4.5 hours after onset of stroke; IVT with alteplase; comparison: BMT (including dual antiplatelet therapy [DAPT] or single use); and reporting of functional outcomes and any safety outcomes in randomized controlled trials (RCTs) and observational studies. Studies with patients who received mechanical thrombectomy or bridging therapy were excluded. The primary outcome was excellent functional outcome at 90 days (mRS 0-1). Secondary outcomes included favorable functional outcome at 90 days (mRS 0-2), mortality, early neurological deterioration, recurrent stroke, and recurrent ischemic stroke. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and hemorrhagic transformation. Of 5393 publications found until August 2023, 3 RCTs and 17 observational studies were included.
Rates of excellent functional outcome (mRS 0-1) showed no significant difference comparing IVT and BMT (2252/2717, 82.89% versus 3295/4073, 80.90%, p=0.274). The pooled estimated effect on mRS score of 0-1 at 90 days was consistent in each predefined subgroup including age >80 years, disabling symptoms, comparing different antiplatelet regimes, large vessel occlusion, thrombolytic time window of 0 to 3 hours or 0 to 4.5 hours, baseline NIHSS score of 0-3 or 0-5 and premorbid mRS scores of 0 and 0-2. No differences were disclosed between subgroups.
Also, rates of favorable functional outcome (mRS 0-2) showed no significant difference (1790/1960, 91.33% versus 2878/3188, 90.28%, p=0.141). Mortality and recurrent stroke or recurrent ischemic stroke at 90 days also showed no difference comparing IVT and BMT. The study revealed a higher rate of early neurological deterioration, sICH, and hemorrhagic transformation in patients treated with IVT.
This meta-analysis showed no difference between IVT and BMT in patients with minor ischemic stroke (NIHSS score ≤5) regarding excellent or good functional outcome at 90 days. IVT was associated with an increased risk of safety outcomes, such as early neurological deterioration, sICH, and hemorrhagic transformation, while BMT was similar to IVT in preventing recurrent stroke and recurrent ischemic stroke. All in all, functional outcome of patients with nondisabling strokes is not improved by intravenous alteplase, and a small number of patients may actually be harmed by thrombolysis.
These results are subject to use of alteplase as thrombolytic therapy agent. No RCTs on other intravenous thrombolytics such as tenecteplase are available in patients with minor stroke. The TEMPO-2 trial could give more insight, but it is subject to patients with mild deficits and large vessel occlusion. The TRUST trial will assess urokinase in comparison to antiplatelet agents for the management of minor ischemic stroke and is ongoing. Limitations include the lack of a universal recognized definition of disabling symptoms and inconsistencies among the included studies in terms of the time of treatment initiation, baseline NIHSS score, definitions of minor stroke, and dosing paradigms of antiplatelets.
Stroke physicians often see spontaneous neurological improvement in patients with mild symptoms; therefore, these results seem reassuring. The critical question is, what makes a mild/minor stroke a non-disabling stroke? Stroke physicians want to rapidly administer IVT, but in cases like these, we should carefully weigh the risks and benefits and consider the patients’ life circumstances to evaluate if the suspected stroke is causing mild, truly non-disabling symptoms.3 For example, a vocalist with mild dysarthria might consider this a disabling symptom, and a waiter might consider mild paralysis of the non-dominant hand as disabling. It is, therefore, of uttermost importance to consider the whole picture and to carefully assess the risk for sICH like considering age and comorbidities in a setting where time is the enemy.
There are several questions which remain to be answered. First, the arrival of new thrombolytic agents for acute stroke reperfusion therapy, i.e., tenecteplase, might exploit other new RCTs to address the question if IVT with other substances — which are endowed with an increased half-life compared to alteplase — might reduce the risk of progressive stroke and show a beneficial effect on functional outcomes in acute minor ischemic stroke.
Second, most patients who receive IVT in case of mild symptoms in observational studies might be seen as being at a formally higher risk of neurological worsening and, therefore, received IVT despite minor symptoms. These scenarios could include cervical artery dissection, instable plaques, or intracranial stenosis — therefore, one has to raise the question of a selection bias in favor of IVT in these patients.
Third, one has to keep in mind the patients who undergo endovascular treatment and achieve a good outcome. The effect of endovascular treatment on functional outcomes in high-risk patients with minor stroke might narrow the treatment effect of IVT on functional outcomes.
Finally, future research might explore other beneficial effects of IVT and reperfusion in general besides short-term functional outcome, like cognitive function and poststroke dementia.
To conclude, IVT with alteplase seems not to be beneficial in non-disabling stroke to ameliorate functional outcome in the short-term. The arrival of tenecteplase in clinical practice, specific subgroups with potential benefit, and the exploration of other outcomes besides functional outcome after 3 months warrant further investigation of IVT in minor acute ischemic stroke.
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