Avoid common mistakes on your manuscript.
Despite recent advances in hyperacute therapy to treat the immediate symptoms of stroke, it remains one of the leading causes of disability worldwide. Treatments for stroke rehabilitation are critical for reducing the burden of long-term disability after a stroke. The last 10 years have witnessed a significant increase in stroke recovery therapy options, and a new era of multimodal therapeutic ways to improve post-stroke recovery is set to begin. The term “acute ischemic stroke” describes a condition in which blood supply to the brain is interrupted or stopped, leading to cell death. Stroke poses a substantial medical burden since it is the second most frequent cause of disability and death worldwide [1]. It is anticipated that over this decade, the incidence of stroke would rise even more [2]. With the developments in medicine and the knowledge of the etiology, risk factors, pathophysiology, and prognosis of stroke, this is particularly worrisome. Recanalization and reperfusion are essential elements in the treatment of acute strokes, since they aid in the infarct’s reduction and may even restore neurological abnormalities. Reperfusion measures the amount of blood flow that has been restored to the previously underperfused region of the brain, whereas recanalization measures how much the blocked artery has opened again [3]. Recent years have seen tremendous progress in the treatment of acute ischemic stroke, with two main strategies emerging as frontline therapies: mechanical thrombectomy and thrombolysis. Although the goal of both techniques is to restore blood flow to the damaged brain area, their working principles, levels of effectiveness, and standards for choosing patients are quite different [4,5,6].
Thrombolysis involves the administration of a thrombolytic agent, such as tissue plasminogen activator (tPA), to dissolve the blood clot [6]. Thrombolytic drugs work by activating plasminogen, which is then converted into its active form, plasmin. Plasmin breaks down fibrin, aiding in the dissolution of blood clots and helping to restore blood flow through the affected vessels [7]. This approach has been the standard of care for acute ischemic stroke treatment for over two decades [8]. Thrombolysis is widely available and can be administered in a variety of settings, including community hospitals and emergency departments [9]. The procedure is relatively simple and can be performed by a trained intensivist or Neuro-radiointensivist [6]. Additionally, thrombolysis is a cost-effective treatment option compared to mechanical thrombectomy [10]. Even so, Recent data indicate that around 12% of patients with acute ischemic stroke in the United States receive rtPA treatment [11]. The primary reason for exclusion is that many patients arrive at the emergency department too late to be treated within the critical 4.5-hour window after symptom onset. However, the use of rtPA has increased among patients who do arrive within this timeframe due to several factors: the establishment and certification of designated stroke centers with prioritized EMS triage to their emergency departments, enhanced training and availability of vascular neurologists, education of non-stroke clinicians on rtPA use, and the use of telemedicine to provide rtPA expertise to non-stroke centers.
Alteplase and tenecteplase are the two most often utilized thrombolytic medicines for acute ischemic strokes today. Alteplase was initially developed and authorized in the United States in 1996. Tenecteplase offers significant logistical advantages over alteplase. It has a longer half-life than native tPA, substantially stronger fibrin selectivity, and is more resistant to deactivation by the endogenous inhibitor plasminogen activator inhibitor (PAI-1) [12]. All of these characteristics allow Tenecteplase to be given as a bolus rather than an infusion. This might lead to a faster transition from entering the emergency department to needle time. More significantly, it achieves a therapeutic blood level immediately after the bolus, eliminating the need for the continuous 1-hour infusion required with rtPA [9]. Mechanical thrombectomy, also known as endovascular thrombectomy, involves the use of a device to physically remove the blood clot from the occluded artery [13]. This approach has gained widespread acceptance in the treatment of acute ischemic stroke, particularly in patients with large vessel occlusions [14]. The procedure typically involves the following steps: access, clot retrieval, and reperfusion [15]. A catheter is inserted through the femoral artery in the groin and guided to the occluded artery in the brain, where a thrombectomy device, such as a stent retriever or an aspiration catheter, is used to engage and remove the blood clot [16]. The occluded artery is then reopened, restoring blood flow to the affected brain region [17].
The advantages of mechanical thrombectomy include higher recanalization rates, faster reperfusion, and improved functional outcomes [13]. Studies have demonstrated that mechanical thrombectomy achieves higher recanalization rates compared to thrombolysis, particularly in patients with large vessel occlusions [14]. The HERMES Collaboration, a meta-analysis of five randomized controlled trials, found that mechanical thrombectomy was associated with improved functional outcomes and higher recanalization rates compared to thrombolysis [13]. Additionally, mechanical thrombectomy allows for faster reperfusion of the affected brain region, which is critical in minimizing tissue damage and improving patient outcomes [15].
Thrombolysis, on the other hand, has several limitations, including time-dependent efficacy, limited recanalization rates, and risk of hemorrhagic complications [6]. The efficacy of thrombolysis decreases significantly with time, making it essential to administer the treatment within a narrow time window [8]. Thrombolysis has been shown to achieve lower recanalization rates compared to mechanical thrombectomy, particularly in patients with large vessel occlusions [5]. Furthermore, thrombolysis carries a risk of hemorrhagic complications, including intracerebral hemorrhage and subarachnoid hemorrhage [6]. Hemorrhage is the most serious complication following thrombolysis. The reported incidence of symptomatic intracerebral hemorrhage (sICH) ranges from 1.9 to 6.4%, depending on how it is defined and the study’s design [18]. However, the majority of sICH cases are due to reperfusion injury, which exacerbates already severe strokes that are likely to cause significant disability.
Several studies have compared the efficacy and safety of mechanical thrombectomy and thrombolysis in the treatment of acute ischemic stroke. The results of these studies can be summarized as follows: The HERMES Collaboration, a meta-analysis of five randomized controlled trials, found that mechanical thrombectomy was associated with improved functional outcomes and higher recanalization rates compared to thrombolysis [13]. The MR CLEAN trial, a randomized controlled trial, found that mechanical thrombectomy was associated with improved functional outcomes and higher recanalization rates compared to thrombolysis in patients with acute ischemic stroke [19]. The EXTEND-IA trial, a randomized controlled trial, found that mechanical thrombectomy was associated with improved functional outcomes and higher recanalization rates compared to thrombolysis in patients with acute ischemic stroke [15]. A recent meta-analysis comparing intravenous thrombolysis and mechanical thrombectomy reported no significant differences when compared for distal vessel occlusion, while also highlighting the need for further research to highlight any differences in efficacies amongst the two approaches [20].
In conclusion, mechanical thrombectomy and thrombolysis are two distinct approaches in the treatment of acute ischemic stroke. While both methods have their advantages and limitations, mechanical thrombectomy has emerged as a frontline therapy in patients with large vessel occlusions. Whilst this describes an ideal approach, the availability and feasibility of time should also to be taken into consideration when selecting either of these modalities. The unequal distribution of healthcare facilities also influences the decision at hand. Enhancing triage processes by improving the identification of patients with large intracranial artery occlusions in the field continues to be a priority. Current research directions towards understanding cerebral collateral flow and augmenting it via vasopressors seem promising. A deeper look at the URICO-ICTUS clinical trial found that giving uric acid, an antioxidant, helped prevent early ischemic worsening, but this benefit was only seen in patients who had good collateral blood circulation [21]. In current practice, vasopressors are sometimes used for this purpose. However, the evidence supporting their use is limited to small case series and a single pilot feasibility study [22,23,24,25,26].
What we lack?
New approaches to activity-based therapy and telerehabilitation hold promise in enhancing accessibility and ensuring appropriate dosage. For post-stroke neurorehabilitation, multidisciplinary therapy approaches are essential. To optimize recovery, additional adjuvant therapies including pharmaceutical agents and brain stimulation modalities should be taken into consideration. The most fundamental obstacles in the discipline are the variety of the patients included in the research, the diverse methodology used, and the inconsistent outcomes among small-scale investigations. Both large-scale clinical trials with a well-targeted patient group and biomarker-driven personalized techniques will advance the discipline. Various innovative techniques and technology breakthroughs have shown promise in terms of aiding stroke recovery. These therapies aim to increase brain plasticity and eliminate barriers to rehabilitation access in order to offer a sufficient dosage of rehabilitation while also improving adherence and participation rates. CIMT (Constraint-induced movement therapy) and telerehabilitation show promise in overcoming the issues of accessibility and dose, and the future of recovery is centered on incorporating virtual reality into activity-based therapies. Multidisciplinary treatment approaches are critical for post-stroke neurorehabilitation; additional adjuvant therapies including brain stimulation methods and pharmaceutical medicines should be explored to maximize recovery. Ultimately, there is a critical gap in the diagnosis and treatment of cognitive impairments following a stroke; further methods for screening and diagnosis as well as therapy alternatives are required. The diverse patient populations and methodological variances that make it difficult to draw a broad conclusion are two of the field’s biggest obstacles. The studies’ conflicting findings highlight the significance of selecting the right patient group, making the development of biomarkers essential to directing future therapeutic procedures and research strategies.
Data availability
No datasets were generated or analysed during the current study.
References
GBD 2016 Stroke Collaborators (2019) Global, regional, and national burden of stroke, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol 18(5):439–458. https://doi.org/10.1016/S1474-4422(19)30034-1
Pu L, Wang L, Zhang R, Zhao T, Jiang Y, Han L (2023) Projected global trends in ischemic stroke incidence, deaths and disability-adjusted life years from 2020 to 2030. Stroke 54(5):1330–1339. https://doi.org/10.1161/STROKEAHA.122.040073
Rabinstein AA (2020) Update on treatment of acute ischemic stroke. Contin Minneap Minn 26(2):268–286. https://doi.org/10.1212/CON.0000000000000840
Sardar P, Chatterjee S, Giri J et al (2015) Endovascular therapy for acute ischaemic stroke: a systematic review and meta-analysis of randomized trials. Eur Heart J 36(35):2373–2380. https://doi.org/10.1093/eurheartj/ehv270
Saver JL, Goyal M, van der Lugt A et al (2016) Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis. JAMA 316(12):1279–1288. https://doi.org/10.1001/jama.2016.13647
Hacke W, Kaste M, Bluhmki E et al (2008) Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359(13):1317–1329. https://doi.org/10.1056/NEJMoa0804656
Mican J, Toul M, Bednar D, Damborsky J (2019) Structural biology and protein engineering of thrombolytics. Comput Struct Biotechnol J 17:917–938. https://doi.org/10.1016/j.csbj.2019.06.023
National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333(24):1581–1587. https://doi.org/10.1056/NEJM199512143332401
Grotta JC (2023) Intravenous thrombolysis for acute ischemic stroke. Contin Minneap Minn 29(2):425–442. https://doi.org/10.1212/CON.0000000000001207
Ehlers L, Andersen G, Clausen LB, Bech M, Kjølby M (2007) Cost-effectiveness of intravenous thrombolysis with alteplase within a 3-hour window after acute ischemic stroke. Stroke 38(1):85–89. https://doi.org/10.1161/01.STR.0000251790.19419.a8
Otite FO, Patel S, Sharma R et al (2020) Trends in incidence and epidemiologic characteristics of cerebral venous thrombosis in the United States. Neurology 95(16):e2200–e2213. https://doi.org/10.1212/WNL.0000000000010598
Davydov L, Cheng JW (2001) Tenecteplase: a review. Clin Ther 23(7):982–997 discussion 981. https://doi.org/10.1016/s0149-2918(01)80086-2
Goyal M, Menon BK, van Zwam WH et al (2016) Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet Lond Engl 387(10029):1723–1731. https://doi.org/10.1016/S0140-6736(16)00163-X
Saver JL, Goyal M, Bonafe A et al (2015) Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 372(24):2285–2295. https://doi.org/10.1056/NEJMoa1415061
Campbell BCV, Mitchell PJ, Kleinig TJ et al (2015) Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 372(11):1009–1018. https://doi.org/10.1056/NEJMoa1414792
Nogueira RG, Jadhav AP, Haussen DC et al (2018) Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 378(1):11–21. https://doi.org/10.1056/NEJMoa1706442
Albers GW, Marks MP, Kemp S et al (2018) Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 378(8):708–718. https://doi.org/10.1056/NEJMoa1713973
Seet RCS, Rabinstein AA (2012) Symptomatic intracranial hemorrhage following intravenous thrombolysis for acute ischemic stroke: a critical review of case definitions. Cerebrovasc Dis 34(2):106–114. https://doi.org/10.1159/000339675
Berkhemer OA, Fransen PSS, Beumer D et al (2015) A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 372(1):11–20. https://doi.org/10.1056/NEJMoa1411587
Waqas M, Kuo CC, Dossani RH et al (2021) Mechanical thrombectomy versus intravenous thrombolysis for distal large-vessel occlusion: a systematic review and meta-analysis of observational studies. Neurosurg Focus 51(1):E5. https://doi.org/10.3171/2021.4.FOCUS21139
Amaro S, Laredo C, Renú A et al (2016) Uric acid therapy prevents early ischemic stroke progression: a tertiary analysis of the URICO-ICTUS trial (Efficacy study of combined treatment with uric acid and r-tPA in acute ischemic stroke). Stroke 47(11):2874–2876. https://doi.org/10.1161/STROKEAHA.116.014672
Rordorf G, Koroshetz WJ, Ezzeddine MA, Segal AZ, Buonanno FS (2001) A pilot study of drug-induced hypertension for treatment of acute stroke. Neurology 56(9):1210–1213. https://doi.org/10.1212/WNL.56.9.121
Chavda V, Chaurasia B, Fiorindi A, Umana GE, Lu B, Montemurro N (2022) Ischemic stroke and SARS-CoV-2 infection: the bidirectional pathology and risk morbidities. Neurol Int 14(2):391–405
Chavda V, Madhwani K, Chaurasia B (2021) Stroke and immunotherapy: potential mechanisms and its implications as immune-therapeutics. Eur J Neurosci 54(1):4338–4357
Chavda V, Chaurasia B, Garg K, Deora H, Umana GE, Palmisciano P, Scalia G, Lu B (2022) Molecular mechanisms of oxidative stress in stroke and cancer. Brain Disorders 5:100029
Zaidi DA, Yaqoob E, Chaurasia B, Javed S (2024) Addressing stroke care deficiencies in Pakistan: a call for nationwide reforms and strategic initiatives. Neurosurg Rev 47(1):396
Funding
Not approval.
Author information
Authors and Affiliations
Contributions
All authors (R.S, V.C, B.P, R.B, B.C) have equal contribution.
Corresponding authors
Ethics declarations
Ethical approval
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Savaliya, R., Chavda, V.K., Patel, B. et al. Acute ischemic stroke: research perspective vs. clinical practice. Neurosurg Rev 47, 612 (2024). https://doi.org/10.1007/s10143-024-02853-8
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s10143-024-02853-8