Endovascular Thrombolysis and Thrombectomy: Pharmacologic and Mechanical
Pearls
Neurologic outcome after stroke intervention depends on the volume of the ischemic brain, the time window to recanalization, the ability to have sustained flow restoration, and the morbidity of symptomatic intracranial hemorrhage (SICH) associated with the treatment.
Current treatment options for acute ischemic stroke are aimed at an early and sustained restoration of flow to the penumbra, increasing the time window for treatment and decreasing the rates of SICH.
Endovascular interventions, especially mechanical thrombolysis, are more efficient than intravenous (IV) or intraarterial (IA) pharmacologic thrombolysis in opening up the vessels without the increased risk of SICH associated with the use of pharmacologic thrombolysis.
Although recanalization rates have increased with endovascular therapies, SICH rates also have increased, whereas outcomes have improved only marginally.
Better standards and protocols for physiologic imaging with good reproducibility, improvements in mechanical revascularization strategies, and newer thrombolytics allow the selection of patients who may benefit from endovascular revascularization even up to 24 to 36 hours after stroke symptom onset.
Better patient selection and addition of neuroprotective strategies may improve outcomes in the future.
♦ Epidemiology and Natural History of Acute Large Vessel Occlusions
Stroke remains the third most common cause of death in industrialized nations and the single most common reason for permanent adult disability.1 Each year, approximately 795,000 Americans experience a new or recurrent stroke.2 The direct and indirect costs of stroke for 2009 are estimated at $68.9 billion.2 The incidence of new or recurrent strokes per year is projected to rise to 1.2 million per year by 2025.3 The only U.S. Food and Drug Administration (FDA)-approved medical therapy for acute stroke until recently was intravenous (IV) recombinant tissue-type plasminogen activator (rtPA) administered within 3 hours of symptom onset for patients eligible for thrombolysis.4 , 5 However, <1% of acute ischemic stroke patients in the United States receive rtPA, primarily because of a delay in presentation for treatment.6 Early reocclusion following thrombolysis has been demonstrated by transcranial Doppler imaging to occur in 34% of patients receiving IV rtPA and may result in neurologic worsening in many of these patients.7 – 9
Occlusion of the major intracranial arteries (carotid siphon, middle cerebral artery [MCA], vertebral artery, basilar artery) is an important cause of ischemic stroke.10 The recanalization rates of IV rtPA for proximal, large-vessel arterial occlusions are poor and range from only 10% for internal carotid artery (ICA) occlusion to 30% for MCA occlusion.11 Intravenous thrombolysis (IVT) is not as effective for thromboembolic obstruction of these large, proximal vessels as for more distal smaller vessels.12 Outcomes after large intracranial vessel thromboembolic occlusion currently remain dismal and are associated with high morbidity and mortality.13 – 16
♦ Rationale for Intraarterial Pharmacologic and Mechanical Thrombolysis
The rationale for intraarterial (IA) thrombolytic therapy was based on the observation that most ischemic strokes were the consequence of thrombotic or thromboembolic arterial occlusions.17 Angiographic studies demonstrated the presence of occlusive clots in up to 80% of ischemic strokes.11 In the remaining 20% of stroke events, the putative underlying mechanism was a microthrombus not detected by angiogram or a thrombotic occlusion that spontaneously recanalized.
Recanalization Improves Outcomes and Is Better with Endovascular Therapy
In the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial,18 Multi MERCI trial,19 and the combined analysis of Interventional Management of Stroke (IMS) I and II data,20 the outcome, as measured by the modified Rankin Scale (mRS) score of at ≤2 at 3 months, was significantly better and the 3-month mortality was significantly lower in patients who had Thrombolysis in Myocardial Infarction (TIMI) score 2 or 3 recanalization (partial or complete recanalization, respectively) than in patients in whom vessels failed to recanalize after endovascular therapy. Rha and Saver21 reviewed 53 studies encompassing 2066 patients and found good functional outcomes (mRS score ≤2) at 3 months were more frequent in patients with vessel recanalization than without vessel recanalization (odds ratio [OR], 4.43; 95% confidence interval [CI], 3.32–5.91). The 3-month mortality rate was reduced in patients whose vessels were recanalized (OR, 0.24; 95% CI, 0.16–0.35). Endovascular methods, particularly mechanical therapies, can achieve higher recanalization rates, and hence better outcomes.
Does the Time Window Between Symptom Onset and Treatment Affect Outcomes?
The European Cooperative Acute Stroke Study (ECASS) III trial22 has demonstrated value for extending the time window for IV tissue-type plasminogen activator (tPA) to 4.5 hours. A recent meta-analysis by Lansberg et al23 including data for patients treated in the 3- to 4.5-hour time window in ECASS I (n = 234), ECASS II (n = 265), ECASS III (n = 821), and the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) (n = 302) showed that rtPA treatment was associated at 3 months with an increased chance of favorable outcome on a global outcome measure (a global OR test based on three individual outcome scales at day 90: mRS score 0 to 1, National Institutes of Health Stroke Scale [NIHSS] score 0 to 1, and Barthel Index >95; OR 1.31; 95% CI, 1.10–1.56; p= .002); and the mRS 0 to 1 (OR 1.31, p= .008) and mortality rates (OR 1.04; 95% CI, 0.75–1.43; p = .83) were not significantly different for intravenous thrombolysis (IVT) and placebo-treated patients. The new American Heart Association/American Stroke Association (AHA/ASA) guidelines24 recommend evaluating patients for IV tPA 3 to 4.5 hours after stroke symptom onset using the same eligibility criteria as the 0- to 3-hour time window with application of additional exclusion criteria.
A meta-analysis conducted by Wardlaw et al25 demonstrated higher benefit (compared with the risk of being dead or disabled) up to 6 hours after IVT, thus formally providing level-1 evidence, even in patients selected by “only” noncontrast computed tomographic (NCCT) imaging. The Prolyse in Acute Cerebral Thromboembolism (PROACT) trials26 , 27 established a benefit of IA thrombolysis up to 6 hours after stroke symptom onset, with an increase in recanalization rates. Mechanical revascularization strategies reestablish flow faster than thrombolytics and thus may increase the benefit of treatment even when there is a delay in presentation for treatment. The MERCI trial,18 , 28 Multi MERCI trial,19 and the Penumbra trial29 show effectiveness of mechanical revascularization therapy up to 8 hours after stroke symptom onset. There is increasing evidence that identification of potentially salvageable brain tissue with advanced magnetic resonance imaging (MRI) and computed tomography (CT) may facilitate the selection of patients who can be effectively and safely treated beyond 8 hours post-ictus.22 , 30 – 36 Although the evidence for a longer time window for treatment is increasing, the number needed to treat (NNT) increases with the time window, and the outcome is better if the treatment is initiated earlier.37
The most dreaded complication associated with revascularization therapy is symptomatic intracranial hemorrhage (SICH). The mortality rate after SICH in the National Institute of Neurological Disorders and Stroke (NINDS) trial was 47%.4 The following IVT trials—NINDS, ATLANTIS, and ECASS II— show an increased hemorrhage rate of 6 to 8% with IV thrombolytics, compared with 1% with placebo.38 Theoretically, mechanical revascularization strategies increase the benefit of therapy by increasing the recanalization rate and decrease the risk of SICH by avoiding the use of thrombolytics. This concept becomes increasingly relevant and important as the time window from stroke symptom onset increases.
On the basis of this concept and our experience, the first choice at our center is mechanical revascularization therapy for patients who present after 3 hours of stroke symptom onset and patients with wake-up strokes (in whom the time of stroke symptom onset is not known) after evaluating and confirming large vessel occlusion. IA pharmacologic thrombolysis is used only if the site of occlusion is distal and not reachable for mechanical therapy as an adjunct for distal embolization, if any, after mechanical therapy. Patients who do not meet the eligibility criteria for thrombolytic therapy, fail to improve neurologically after thrombolytic therapy, or who improve and then worsen (patients with reocclusion) are also candidates for mechanical revascularization therapies.
♦ Patient Selection and Complication Avoidance
The principles of patient selection and complication avoidance are the same. As described above, the most dreaded complication leading to poor prognosis is SICH. Better patient selection decreases complications including SICH. The three major criteria for selection of a patient for endovascular thrombolysis are (1) contraindication for IV tPA or neurologic condition did not improve or worsened after improvement with IV tPA (as discussed above); (2) a short time window from stroke symptom onset (as discussed above); and (3) the presence of an ischemic penumbra—the therapeutic target.
The Penumbral Concept
Astrup et al39 established the principle that potentially salvageable cerebral ischemic tissue is present around the ischemic core. The ischemic penumbra is defined as “ischemic tissue that is functionally impaired and is at risk of infarction and has the potential to be salvaged by reperfusion and/or other strategies. If it is not salvaged, this tissue is progressively recruited into the infarct core, which will expand with time into the maximal volume originally at risk.” The criteria established for defining ischemic penumbra are shown in Table 30.1 . Using MRI, up to 44% of stroke patients may have penumbral tissue after 18 hours.40 Using positron emission tomography (PET), Markus et al41 have shown salvageable penumbral tissue in stroke patients even 12 to 48 hours after stroke onset. Therefore, imaging of the penumbra may be relevant in selecting patients for thrombolytic therapy who present beyond the 3-hour time window.
Brain-tissue flow can be described by several parameters, including cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). CBV is defined as the total volume of flowing blood in a given volume in the brain, with units of milliliters of blood per 100 g of brain tissue. CBF is defined as the volume of blood moving through a given volume of brain per unit of time, with units of milliliters of blood per 100 g of brain tissue per minute. MTT is defined as the average transit time of blood through a given brain region, measured in seconds. “Core” is typically operationally defined as the CBV lesion volume, and “penumbra,” as the MTT or CBF lesion volume.
Multimodal Computed Tomography Imaging to Assess the Penumbra
The obvious advantages of CT over other penumbral imaging techniques are its widespread availability, speed of imaging, cost-effectiveness, and accessibility in the emergency department. We use a combined multimodal CT stroke protocol consisting of NCCT, CT perfusion (CTP), and CT angiography (CTA) to select patients for endovascular thrombolysis. Other groups42 – 44 have similarly noted benefits of combined CTA and CTP imaging in rapid assessment of acute stroke.
Noncontrast CT can occasionally identify the penumbra under some circumstances. Isolated focal swelling has been correlated with penumbral tissue and parenchymal hypoattenuation with the infarct core.45 However, on NCCT, acutely hypoperfused regions often appear normal, and CTP is helpful in predicting the fate of ischemic tissue in these cases.46 NCCT also helps in excluding the presence of hemorrhagic stroke or hemorrhage into an ischemic stroke, either of which is a contraindication to thrombolysis.
In patients who do not have an intracranial hemorrhage (ICH), an immediate CT angiogram from aortic arch to vertex, followed immediately by whole-brain CTP on a 320-slice CT scanner, is performed at our center. The newer 320-slice CTP scanner creates whole-brain perfusion maps and CTA within 5 to 10 minutes, has good resolution with fewer artifacts in the posterior fossa, and is comparable with MR perfusion imaging.47 The newer 320-slice scanners provide a delay map that creates CBF and MTT maps without delay artifacts.48 , 49
In our experience, CTA has been found to be significantly better than MR angiography (MRA) with respect to resolution, detail, and avoidance of common MR artifacts secondary to low or turbulent flow phenomenon and vessel calcification. CTA helps in patient selection by evaluating the sites and nature of occlusion, the difficulty in access through the arch and extracranial vessel, and collateral circulation. CTA and CTP require the injection of less than 130 mL of iodinated contrast material, which is generally well tolerated, except for a low risk of nephropathy and in cases of a contrast allergy. Smith et al50 have demonstrated the safety of this approach without previous determination of a serum creatinine level.
The passage of the contrast agent through the brain is recorded, and parametric maps of CBV, CBF, and contrast MTT are generated by CTP. Postprocessing software enables the calculation of absolute CBV and CBF values. Larger regions surrounding the core with decreased CBF and increased MTT (relative to the corresponding contralateral brain tissue >145%) are regarded as tissue at risk.51 , 52 In our experience, patients with a penumbral volume of >50% of the occluded vessel territory benefit from endovascular thrombolysis if feasible. CTA assesses the collateral vessel status surrounding an irreversible infarct.53
Computed tomography perfusion imaging is also helpful in evaluating the ischemic core (very low CBF [>70% reduction], very low CBV [<2 mL/100 g])51 and extremely prolonged transit time.54 – 56 In our experience, patients with large ischemic cores and even small ischemic cores in the basal ganglia region have a high risk of SICH and poor outcome. We try to avoid endovascular thrombolysis in these patients, and if compelled to intervene due to the presence of a large penumbra, we avoid pharmacologic thrombolysis and glycoprotein (GP) IIb/IIIa antagonists. The disadvantages of CTP are its use of radiation, its incomplete validation, and the qualitative differences in postprocessing software.
Symptomatic Intracranial Hemorrhage
As discussed previously, SICH is the most dreaded complication after stroke revascularization. The mortality rate after SICH in the NINDS trial was 47%.4 Pharmacologic thrombolytics have been shown to increase the risk of SICH.38 , 57 Hypertension during the first 24 hours after stroke revascularization and pretherapeutic hyperglycemia contribute to increased risk of SICH.57 In PROACT II,27 there was an increased risk of SICH in patients with a pretherapeutic glycemia value of >200 mg/dL. A glycemia value of >400 mg/dL represents a contraindication to pharmacologic thrombolysis. When dichotomized Alberta Stroke Program Early CT Scores (ASPECTSs) are assessed from NCCT, patients with low stroke burden (ASPECTS ≥7) on CT imaging incur less SICH after IVT and have a greater chance of gaining independence (mRS ≥2).58 The use of CTP images, rather than NCCT, increases the prognostic accuracy of the ASPECT score, with final infarct mirroring CBV or CBF deficits when reperfusion is or is not achieved, respectively.55 As discussed previously, we have found CTP to be very valuable in predicting SICH in our patients, and we try to avoid pharmacologic thrombolysis or any reperfusion therapy in patients at high risk for SICH based on these predictors on a case-by-case basis.
Although IV tPA between 3 and 4.5 hours after stroke symptom onset has been endorsed by the recent AHA/ASA guidelines,24 we still believe that patients should be evaluated for IA therapies if they present with a large vessel occlusion or if they present for treatment after 3 hours of stroke symptom onset. At our center, patients presenting from 3 to 4.5 hours after stroke symptom onset who have no risks of SICH by clinical, radiologic, and physiologic data could be treated with IVT and endovascular thrombolysis. If patients are at higher risk of SICH, irrespective of the time window of presentation, mechanical thrombolysis would be the best therapy, and we defer from using pharmacologic thrombolysis in these patients after 3 hours. At our center, patients will NOT be evaluated for IA therapy if ALL of the following three criteria are present: (1) they present within 3 hours of stroke symptom onset, (2) they do not have a large vessel occlusion, and (3) their neurologic condition improves and does not worsen after IVT therapy.
♦ Revascularization Treatment Strategies
The current protocol for selection of treatment strategies for revascularization of acute ischemic stroke patients at our center is shown in Table 30.2 .
Intraarterial Pharmacologic Thrombolysis
To perform IA thrombolysis (IAT), a microcatheter is placed proximal to or directly into the thrombus. A long 6- or 7-French (F) sheath is placed into the femoral artery, and a 6F or 7F guiding catheter is advanced into the ICA or vertebral artery of the affected side. A microcatheter is then navigated to the occlusion site over a microwire. The theoretical advantages and disadvantages of IAT are presented in Table 30.3 . Results for the important published interventional stroke trials are summarized in Table 30.4 (NINDS4 and ECASS III22 data have been summarized for comparison in the same table).
Intraarterial Thrombolysis Trials
The safety and efficiency of IA administration in the treatment of acute ischemic stroke were evaluated in PROACT I.26 The results of this trial suggested an enhanced recanalization with prourokinase and a positive trend toward better neurologic outcome and survival rate. The PROACT II trial27 was a large-scale, multicenter, randomized (2:1), phase III trial that included 180 patients with angiographically confirmed M1 or M2 occlusion within the first 6 hours after symptom onset. Patients were randomized to receive 9 mg of IA prourkinase plus heparin (n = 121) or heparin only (n = 59). Excellent neurologic outcome (mRS ≤2) was achieved in 40% of the treated patients compared with 25% in the control group (absolute benefit, 15%; relative benefit, 58%; NNT, 7; p= .043). This study was able to demonstrate the beneficial effect of IAT on the recanalization and clinical outcome of patients with M1 and M2 occlusions.
Meta-Analysis of Intraarterial Thrombolysis Trials for Middle Cerebral Artery Occlusion
A meta-analysis of PROACT I and II data showed an OR of better outcome with treatment of 2.49 (p= .022), which was greater than the OR (2.13) in the original PROACT II analysis.59 The Japanese Middle cerebral artery Embolism Local fibrinolytic intervention Trial (MELT)60 studied safety and clinical efficacy of IA infusion of urokinase (UK) in patients with acute stroke treated within 6 hours of symptom onset. As in PROACT I and II, patients displaying angiographic occlusions of the M1 or M2 MCA segments were randomized. The trial was aborted prematurely by the steering committee after the approval of IV rtPA in Japan. A meta-analysis of PROACT I, PROACT II, and MELT, including 204 patients treated with IAT and 130 control patients, showed a lower rate of death or dependency at long-term follow-up within the IAT treatment group, compared with the control group (58.5% versus 69.2%; p= .03; OR, 0.58; 95% CI, 0.36–0.93).61
These studies established superiority of IAT within 6 hours over antithrombotic therapy for MCA M1 and M2 occlusions. There are no level-1 data of the efficacy of IAT for distal ICA or posterior circulation occlusion. The superiority of IAT over IVT has not been demonstrated by randomized clinical studies. The FDA did not approve prourokinase, and it is currently not available for clinical use. Current AHA/ASA guidelines5 , 24 recommend the use of IAT with rtPA within 6 hours from symptom onset for selected patients who have a major stroke due to MCA occlusion and who are not eligible for IVT. Therefore, at present, this approach should not preclude IV administration of rtPA in all other eligible patients.
Special Situations
♦ Wake-Up Strokes
Approximately 16 to 28% of ischemic stroke patients awaken with their deficits.62 , 63 In these wake-up strokes, the onset of symptoms is defined as the “time last seen well.” Because this is the time the patient went to sleep, these patients, unfortunately, are usually placed outside the window for thrombolysis or ineligible for entry into reperfusion clinical trials. Barreto et al64 reported that patients with wake-up stroke have better outcomes when they are treated. Adams et al,65 in their post-hoc analysis of wake-up stroke in the Abciximab in Emergency Stroke Treatment Trial-II (AbESTT-II), reported poorer outcomes after treatment. In our series of 30 patients with stroke onset >8 hours and wake-up stroke (mean presentation NIHSS score 13) who were selected for treatment on the basis of CTP results, a combination of endovascular revascularization strategies resulted in a TIMI score 2 or 3 recanalization in 67% of patients, with a SICH rate of 10%.66 At 3 months, 20% of patients improved to mRS <2, and the mortality was 33.3%.
♦ Posterior Circulation Stroke
Posterior circulation stroke differs in several aspects. The evolution of clinical symptoms is often gradual, making precise assessment of the onset of symptoms and of the time window for treatment difficult. Atherothrombosis (unstable plaque with thrombus) is more common. The risk of reocclusion after recanalization is therefore higher.67 – 70 The natural history shows a poor outcome with a high mortality rate of 70 to 80% unless recanalization is achieved.67 , 71 A meta-analysis of IAT in basilar artery occlusion72 showed a recanalization rate of 64% and a mortality rate of 87% in nonrecanalized patients, with a significant (p <.001) reduction in mortality to 37% in recanalized patients. A meta-analysis of either IVT or IAT for basilar artery occlusion73 showed that the likelihood of a good outcome was 2% without recanalization. Recanalization was achieved more frequently with IAT (65% versus 53%, p= .05), but the outcomes after IAT and IVT were similar. Levy et al74 performed a meta-analysis for predictors of outcome after IAT for vertebrobasilar artery occlusion and found failure to recanalize was associated with a higher mortality rate (relative risk, 2.34; 95% CI, 1.48–3.71). Studies have suggested extending the time window for treatment beyond or up to 24 hours postictus.69 , 75 , 76
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