AIS Treatments

No system can replace the individual initiative, creativity, and insights that lead to great discoveries, but progress is not made by breakthroughs alone. No one’s work is so exalted that it cannot be improved, nor so humble that it has no value. We can all make a difference.

Dr. Vladimir Hachinski

Brain cells die rapidly after stroke and any effective treatment must start as soon as possible [1]. There is a very narrow time window from the first signs of ischemic stroke to the time that people can be successfully treated to reduce the amount of brain damage [2]. In that interval, the likelihood of successful treatment decreases as time elapses [2]. Time is brain [3-6]! The aphorism ‘time is brain’ emphasizes that therapeutic interventions should be emergently pursued [5].

Two major approaches have been developed to treat acute ischemic stroke (AIS): revascularization and neuro­protection (brain protection) [7].

Revascularization includes three separate concepts: recanalization (arterial patency), reperfusion (antegrade microvascular perfusion), and collateralization (microvascular perfusion via pial arteries or other anastomotic arterial channels that bypass the primary site of vessel occlusion) [8,34]. The revascularization strategy uses thrombolytic drugs or mechanical endovascular devices to recanalize occluded vessels. Early recanalization remains the most intuitive and the only approved beneficial therapy to reverse ischemic injury associated with arterial occlusion in AIS [9-11,32,33].

However, the majority of ischemic stroke victims are still left untreated or undertreated due to the fact of factors such as an unknown onset time for the stroke, the narrow therapeutic time window, or the high number of contraindications for currently approved treatments [12,13]. Presently, only 5% – 20% of victims with AIS are treated with revascularization therapies (thrombolysis and/or thrombectomy) [14,15,18,20,35,36]. The majority, around 80% – 95% of all AIS victims, does not fulfill the criteria for revascularization therapies, and also for these patients, there is no effective acute therapy [13-15]. Thus, most of AIS victims receive only supportive care [15,36]. In this regard, the revascularization therapies cannot be regarded as a breakthrough treatment for AIS because only a minority of patients are eligible for this treatment [16-22].

Although pharmacological and mechanical revascularization therapies generally aim at complete recanalization, downstream reperfusion is not always achieved [23,33]. For less than half of the patients who received thrombolysis or thrombectomy obtain permanent benefits from revascularization therapies and up to one-third of the patients continue with long-term substantial disability [24]. Even when the revascularization therapies have been successfully performed, the AIS victims may still suffer the inherent risk of ischemia-reperfusion injury [25].

Furthermore, as current revascularization approaches require specialists found primarily at advanced academic medical centers and are rarely available at smaller community hospitals, making them less than an ideal therapeutic option for most patients [26]. The identification of safe, effective, affordable, and easily applicable AIS treatments is of great importance to public health [27]. There is an urgent need to explore newer therapeutic avenues.

Pharmacological agents selected to interrupt the ischemic injury cascade that can be administered safely to a larger patient population are therefore desirable [26]. However, the development of neuroprotectants for the treatment of AIS has been characterized by success in animal studies and subsequent failure in clinical trials [28]. With the exception of alteplase (r-tPA), which is standard thrombolytic therapy and the only approved drug to treat AIS in Western countries [20,29], no preclinical-tested neuroprotectant, either as a monotherapy or as combination therapy, has been translated into clinical effectiveness [7,36].

Although so far clinical trials have repeatedly failed, brain protection is still a promising option for AIS treatment [30]. The unmet medical needs, the tremendous costs of treatment, and the huge socioeconomic burden of post-stroke care will make even modest advances in brain protection and stroke rehabilitation highly rewarding [31].

References

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