The IMS II study was designed to study the safety and potential efficacy of the EKOS Ultrasound Microcatheter in recanalization of acute intracranial arterial occlusions in acute ischemic stroke, following reduced-dose IV rt-PA therapy. Both clinical and technical factors contributed to the actual use of an EKOS Ultrasound Microcatheter in only 33 subjects. Clinical exclusions for AOL location and etiology (atherosclerotic occlusion, dissection) occurred. Technical problems (connector cable problem, difficulty in catheter passage, etc.) further limited ultrasound administration and evaluation in several subjects. Some subjects were excluded from use based on clinical, angiographic, or other operator-defined exclusion factors.
When used, the EKOS Ultrasound Microcatheter tended to achieve faster and more complete AOL recanalization than standard microcatheter use in IMS II, an incomplete 60-minute data set from IMS I, and the complete 120-minute data set from IMS I (Fig. 2), although these differences were not statistically significant. It should be noted that standard microcatheter use in IMS I and II allowed mechanical manipulation of thrombus and guidewire, including microcatheter passage and drug delivery distal to the occlusion initially, as well as 15-minute guidewire/microcatheter advancement. Ultrasound microcatheter use was limited to proximal bolus and drip infusion, with no guide wire manipulation beyond that required for initial and subsequent microcatheter advancement. It is hypothesized that the apparent 15 to 30-minute equivalence of microcatheter use in Fig. 2, with improved early recanalization effect compared to ultrasound, may be due to mechanical microcatheter/guidewire manipulation of favorably-predisposed occlusions that will be achieved with any mechanical manipulation applied within the IV/IA paradigm. Allowing microguidewire/ultrasound microcatheter manipulation in a similar fashion may further enhance recanalization potential.
Identification of 14/81 (17.2%) subjects without AOL qualifying for IA EKOS-Microcatheter ultrasound-assisted thrombolysis confirmed pre-IMS and IMS I study observations: IV rt-PA may recanalize some vessels early, leading to normal arteriograms (n=2), or distal occlusions (n= 10). (Fig. 1).1,10
Comparison of recanalization rates using the combined approach in IMS I and II with studies of IA-only treatment must account for this early post-IV recanalization into the formula.
It is not possible to accurately compare recanalization and reperfusion results achieved with combined IV/IA rtPA therapy paradigm to other reported IA revascularization methods in which treatment was initiated later. The 78% AOL 3 recanalization and 83.3% TICI 2/3 reperfusion of isolated M1 occlusion in IMS II, comparable to 78% for both measures in IMS I, may represent a true recanalization and reperfusion benefit compared to results obtained with r-pro-urokinase treatment in PROACT II (67% TIMI 2/3 for M1 and M2 occlusions), and with the MERCI Retriever in the MERCI and Multi-MERCI Trials (45% and 54% TIMI 2,3, respectively).11,12
However, it still remains uncertain that revascularization end point definitions and application in other revascularization studies are comparable with the IMS studies.
Importantly, TICI reperfusion rates with the IMS IV/IA paradigm again suggest 33/55 (60%) subjects with treatable clot afterIV rt-PA achieve TICI 2–3 distal perfusion with EKOS-Ultrasound-assisted or standard microcatheter IA rt-PA thrombolysis, comparable to IMS I. Differences in baseline AOL in IMS II and IMS I existed, and revascularization results differed for the various AOL treated (). Most notably, there were fewer ICA bifurcation stenoses and occlusions in IMS II than in IMS I. Yet 7/11 (63%) IMS II subjects with ICA occlusion or stenosis achieved mRankin 0–2 outcome. Overall, 35/153 (23%) IMS I and II subjects presented with acute ischemia and severe cervical ICA stenosis (n=21) or occlusion (n=14). Mean baseline NIHSS for all subjects with ICA stenosis/occlusion was 17.7. Distal AOL accompanying ICA occlusion or stenosis (tandem lesions) included 10 (28%) ICA terminus, 20 (57%) M1or M2 occlusions. There were 5 instances of no or distal M3, M4 occlusion. Mean baseline NIHSS for the 30 subjects with major tandem lesions was 17.6, less than for the entire IMS I and II IA-treatment cohort. Functional clinical outcome (MRS ≤ 2 at 90 days) was achieved in 10 (33.3%) of the 30 tandem occlusion subjects, with 20% (6/30) mortality. mRS ≤2 outcomes were achieved in 3/17 (17.6%) of the atherosclerotic ICA stenosis and in 2/8 (25%) of the occlusion groups. Of 8 subjects with atherosclerotic ICA occlusions, four were stented in non-protocol, off-label fashion, with 2 achieving mRS ≤2, and with one death. The two patients with good outcomes had individual baseline NIHSS of 10 and 12, respectively. In the non-stented occlusion group, one achieved mRS ≤2, and there were 2 deaths. There were 5 ICA dissections in the tandem group. One subject with ICA dissection was stented. MRS 0–2 outcome was more favorable for those with ICA dissection compared to atherosclerotic disease (5/5 vs 5/25, p=0.002). A trend toward better outcomes with an IV/IA thrombolysis paradigm in acute ischemia with tandem ICA and distal lesions, compared to IV tPA alone, may be suggested in the IMS studies.13
A relationship between both AOL and TICI revascularization endpoints and mRS 0–2 outcome was demonstrated for ICA-T and M1 occlusion (). TICI 2/3 reperfusion better predicted good outcome than did primary AOL 2/3 recanalization. To further analyze the TICI 2 reperfusion end point in hope of identifying an acceptable or optimal stopping point for revascularization, subjects were also categorized as TICI 2A, or 2B, based on the presence of up to 50% MCA distribution reperfusion, or TICI 2B with less than 50% (,). TICI 2B/3 perfusion best predicted good outcome statistically (p=0.0002), more robustly than TICI 2/3 (p=0.0004). There was a trend for TICI 2B superiority to TICI 2A in predicting good outcome (p=0.08). AOL 2/3 recanalization also predicted good outcome (p=0.027), suggesting recanalization predicts good outcome nearly as well as reperfusion. Safe revascularization appears to be an appropriate surrogate end point for the IV/IA treatment paradigm. It is not as clear that a link between no-revascularization and poor-outcome is due to the no-revascularization effect itself. Procedural factors (e.g., contrast deposition, heparin use, saline deposition, distal emboli, hemorrhage into injured brain) during prolonged, failed revascularization procedures may contribute to the lack of good outcomes observed with this treatment paradigm.
M2 occlusion analysis does not lend itself to the TIMI/TICI method of grading, creating, in effect, a circular reference where the score definition is dependent on perfusion through the involved sentinel M2 distributions. Good outcomes were not dependent on revascularization, with 13/17 IMS (76%) I and II isolated M2 subjects achieving good outcome despite incomplete recanalization and reperfusion. This likely relates to the much smaller volume of ischemic brain with branch occlusions as compared to occlusions of major trunk arteries like the M-1 or ICA.
Of interest, operators scored their revascularization efforts more optimistically than the core lab. Differences between a TIMI score of 2 and 3 are of questionable practical significance, since these 2 scores are commonly viewed together as significant revascularization, correlating with increase in good outcome (). Nevertheless, it raises a legitimate question of accepting unadjudicated prospective data regarding important end points as a determinant of efficacy. In addition, this observation raises questions regarding revascularization end point terminology, definition, convention, and application. “Good” recanalization (AOL 2/3) in 43/71 (60.5%), and “good” reperfusion in 53/71 (74.5%) of ICA-T and M1 occlusions suggests that both measures are legitimate determinants of revascularization, but 15% difference indicates that they they are not equivalent.
Ultrasound microcatheter activity measurably increases catheter-tip temperature. Monitoring this effect as a safety measure provided a unique opportunity to examine the effect of recanalization or catheter retraction on catheter tip temperature. Retrospective correlation of catheter-tip temperature decrease with recanalization suggests that observing tip temperature during a procedure might prospectively allow identification of recanalization between strict prescribed angiogram intervals, and therefore might allow the revascularization procedure to be shortened. Retrospective analysis of temperature changes was not complete for all subjects. However, where available, the correlation between a decrease in temperature and recanalization or catheter retraction from the occlusion was quite strong. Whereas some recanalization was identified in 47.6% of subjects, and temperature decreases were identified in 41% of subjects, treatment time might be reduced accordingly (Fig. 3).
Identification of higher ICH and contrast deposition rates with MCI suggest technical factors may be important in clinical outcomes. Higher ICH rates with ultrasound microcatheter use were confounded by this observation. Demonstration of rupture points of distal lenticulostriate arteries legislated against local ultrasound or local temperature changes as responsible for these ICH cases in several instances. No single etiologic mechanism seems responsible for the observed ICH. Multifactorial contribution of rtPA, heparin, contrast deposition, and microcatheter injection pressure/volume is hypothesized. A correlation between MCI and ICH, as well as PH, has also been found in a thrombolysis registry analysis.14
MRS 0–2 outcomes were achieved in 45% IMS II compared to 42% IMS I subjects, and 27% in the control group, and to 39% in the treated group, of the NINDS study, despite significantly quicker time to IV thrombolytic therapy in the latter. Two IMS II subjects with M2 occlusions, with baseline NIHSS 11 and 21, were lost to follow-up but included in the MRS > 2 group. Six AOLs eligible for an IA therapy did not receive it for a variety of reasons. These occurrences suggest that a target for good outcomes of 50% or greater is not unreasonable with the IV/IA treatment paradigm applied as rapidly as possible, with limited imaging selection. It is reasonable to expect that monitoring catheter tip temperature and other further advances in revascularization with improved thrombus removal devices, balloon angioplasty, and/or stents may play a part in improving interventional outcomes. The IMS III Trial, where 900 subjects will be randomized to either full-dose IV rtPA, or to reduced-dose IV rt-PA plus IA therapy with either Cordis Microcatheter, EKOS Neurowave Catheter, or the Concentric Merci Retriever Device,2
or other devices that may be introduced as their approval status becomes defined, will have the opportunity to test this hypothesis.