Stroke is the fifth leading cause of death in America and a leading cause of adult disability, according to the National Stroke Association (1). For patients who experience strokes and the physicians who treat them aggressively, time is brain.
Promising techniques preceded disappointing trials for someone suffering an ischemic stroke for most of the 20th century. Heparin was going to be the savior, and it almost served as a standard, but better studies eventually showed that the treatment was not just worthless, but in reality dangerous, causing more brain hemorrhages than no treatment at all.
In the mid 90’s, NINDS stroke study revealed tissue plasminogen activator (tPA) was as an effective treatment option in the setting of an acute stroke. For the first time, physicians had something to offer patients… About a third of patients who received tPA had better three month outcomes than those that did not. This success rate has been controversial, but patients with severe strokes still did not respond, in most cases.
The typical treatment since NINDS for an acute stroke patient, is IV tPA. It dissolves clots and improves blood flow to the brain. Unfortunately, dissolving the clot can take a few hours. In addition, IV tPA must be started within 3 hours (or 4.5 hours of the onset of the stroke, in certain patient demographics).
Despite IV tPA being indicated for acute stroke < 4.5 hours from onset, IV tPA has long been understood to perform very poorly for patients with large proximal clots. There are poor recanalization rates, terrible outcomes and higher bleeding risks. Multiple alternative therapies to recanalize the vessel have been attempted.
Trials had been focusing on both intra-arterial tPA and thrombectomy. They attempted mechanical retrieval devices improving on the device since its inception. Unfortunately, most trials did not select patients who had a good likelihood of reversal. We now have RAPID Software technology that permits CT perfusion imaging to enable neuro-radiologists to identify patients with a small area of dead brain and larger area of ischemic penumbra. Intuitively, those with an ischemic penumbra are better candidates for intervention.
For patients with more severe strokes, tPA alone is not an effective option. In 2013, three trials of endovascular approaches to stroke were published contemporaneously in the New England Journal of Medicine and all three failed to show any benefit to this approach.
Most recently, two trials published in the New England Journal of Medicine in 2015; The MR CLEAN study from the Netherlands is worth a read and if you have time, would also add EXTEND-IA (9,10). Overall, the new studies on endovascular interventions are exciting and offer hope to patients with large infarcts who otherwise tend to fare poorly.
Rather than applying systemic thrombolysis to every infarct, researchers have advanced the concept of personalized stroke therapy. CT perfusion neuroimaging may be used to determine which patients may benefit from specific interventions.
Most strokes are outside the tPA window or patients may have a contraindication. Fortunately, the treatment window has been extended to 6 hours. More importantly, those receiving anticoagulation could still have the benefit of mechanical thrombectomy. A recent meta-analysis of 1287 patients, demonstrated that thrombectomy still had benefit up to 7.3 hours, in certain cases.(13)
The patients that qualify for this therapy is the subset of stroke patients with anterior cerebral, middle cerebral or distal intracranial artery strokes as demonstrated on neuro-imaging (MCA (M1 &M2), ACA, ICA, Basilar & PCA). These group have been identified by researchers as a group who do not always re-cannulate with thrombolysis and patients in which they feel maximal benefit from mechanical intervention will occur (9,10). Unfortunately, only a few patients will actually qualify for this intervention.
The trials demonstrate that interventional radiology for stroke (in this subset) is effective and safe. However, as with any procedure, risk exist! In the THRACE trial, the two groups had no statistical significant differences in mortality at 3 months, but it was slightly higher in the mechanical thrombectomy group, 11.8% deaths vs 13.1% (12). Symptomatic intracranial hemorrhage at 24 h was also higher in the thrombectomy arm, 2.1% vs 1.5%; p=0.71. Common adverse events related to thrombectomy were vasospasm, 23% patients and embolization in a new territory, 6% of the time.
Ryan Radecki at EMLitofNote has already blogged on this topic and has made some great comments.
Areas of Controversy
A remaining question that I have is what is the optimal anticoagulant strategy for patients undergoing mechanical thrombectomy? Is systemic thrombolysis the best choice for this situation, could it not increase the risk of peri-procedural hemorrhage? Would not such bleeding be difficult to reverse in the event of an intracranial hemorrhage…
It seems counter-intuitive to intentionally treat an arterial occlusion with both systemic thrombolysis and mechanical intervention. For example, thrombolysis is not given to a STEMI patient who is going immediately for percutaneous coronary intervention…
It may be beneficial to use some form of anticoagulation while awaiting neurointervention to prevent extension of the thrombus. A titratable and reversible agent would seem ideal for this purpose, such that it could be discontinued promptly in case of intracranial hemorrhage or perhaps after thrombectomy. Heparin infusions have previously been investigated for this purpose, but this was not beneficial when combined with older interventional techniques (SYNTHESIS 2013 (11))…
Performing catheter-directed thrombectomy following loading with aspirin and systemic thrombolysis could worsen hemorrhagic complications compared to using a less aggressive anticoagulant regimen. Although uncommon, wire perforation of a cranial artery does happen. In the setting of systemic thrombolysis, any intracranial hemorrhage would be exacerbated. A post hoc analysis of 291 patients treated with mechanical thrombectomy, after adjustment for potential confounders found no difference between mechanical thrombectomy with thrombolysis and mechanical thrombectomy alone. (14)
Given this question, I must discuss Anderson et. al’s study of low dose alteplase (6). The study found similar clinical outcomes to standard dose alteplase in a study of mostly Asian patients with acute ischemic stroke. Although this study was a non-inferiority study, the benefit of 0.9 mg/kg is modest improvement in clinical outcomes with a cost of a higher risk of hemorrhagic stroke and early death. Uncontrolled studies have suggested the rate of hemorrhagic stroke is higher among Asian populations. As a result, some organizations have limited the approved dose of alteplase in acute ischemic stroke to 0.6mg/kg from 0.9mg/kg. This study enrolled 3310 patients over a three year period. About 66% of the subjects were Asian and 43% were from China. 53% of patients in the low dose group had a bad clinical outcome compared to 51% in the usual dose group. This difference was slight and not statistically significant. However, this difference did not clear the non-inferiority margin…
Major symptomatic intracerebral hemorrhage occurred in 1% of participants in the low dose group and 2.1% in the standard dose group. This was statistically significant. Fatal events within 7 days occurred in 0.5% in the low dose group and 1.5% in the standard dose group. Despite its statistical failure, this trial clearly demonstrates that reduced dose TPA achieves similar clinical outcomes with decreased death and ICH in this patient population. The usual FDA-approved dose of 0.9mg/kg is likely to remain the standard of care but should be further investigated to ensure the optimal dose, is in fact 0.9 mg/kg. This also, may need to be considered in further thrombectomy trials…
Stroke is a serious disabling condition, resulting in hundreds of thousands of permanent injuries and deaths every year. This decade may witness the greatest advances in the history of stroke treatment. There are still further trials to run, but with these exciting new prospects, comes hope…
Hijinio Carreon DO, FACEP
2. Broderick, JP, Palesch, YY, Demchuk, AM, et al Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903
3. Kidwell, CS, Jahan, R, Gornbein, J, et al A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914-923
4. Ciccone, A, Valvassori, L, Nichelatti, M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013;368:904-913
5. MR-CLEAN & the New Golden Age Ryan Radecki EMLitofNote
6. Anderson, CS et al. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. N Engl J Med. 2016 Jun 16;374(24):2313-23. PMID: 27161018
7. Saver, JL et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015 Jun 11;372(24):2285-95. PMID: 25882376
8. Olvert, BA et al. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke N Engl J Med 2015; 372:11-20 January 1, 2015 DOI: 10.1056/NEJMoa1411587
9. Bruce, CV et al. Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection. for the EXTEND-IA Investigators* N Engl J Med 2015; 372:1009-1018. DOI: 10.1056/NEJMoa1414792
10. Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368:904–913.
11. Maarten GL et al, RAPID Automated Patient Selection for Reperfusion Therapy A Pooled Analysis of the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) and the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) Study Stroke. 2011;42:1608-1614
12. Bracard S, et al. Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomized controlled trial 1138-47. Lancet Neurol. 2016. 1138-47. DOI: 10.1016/S1474-4422(16)30177-6
13. Saver, J et al, Time to treatment with Endovascular Thrombectomy and Outcome From Ischemic Stroke: A Metal-analysis
14. Liebeskind, DS et al, Combined IV Thrombolysis and Thrombectomy vs Thrombectomy Alone for AIS (Pooled Analysis of the SWIFT and STAR Studies) France JAMA Neurol. 2017. doi:10.1001/jamaneurol.2016.5374