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Original research
Safety of full-dose intravenous recombinant tissue plasminogen activator followed by multimodal endovascular therapy for acute ischemic stroke
  1. Raul G Nogueira1,2,
  2. Albert J Yoo3,
  3. Shihab Masrur1,
  4. Leonardo M Batista1,
  5. Reza Hakimelahi3,
  6. Joshua A Hirsch3,
  7. Lee H Schwamm1
  1. 1Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  2. 2Departments of Neurology, Neurosurgery, and Radiology, Emory University School of Medicine, Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Atlanta, GA
  3. 3Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr Raul G Nogueira, Emory Faculty Office Building, 80 Jesse Hill Dr. SE, Room 398, Atlanta, GA 30303, USA; rnoguei{at}emory.edu

Abstract

Background and purpose The optimal management of stroke patients who fail treatment with intravenous recombinant tissue plasminogen activator (rt-PA) remains unknown. A study was undertaken to establish whether treatment with a standard intravenous t-PA dose (0.9 mg/kg) followed by multimodal endovascular therapy would have a similar safety profile to reduced dose (0.6 mg/kg) bridging therapy.

Methods A retrospective analysis was performed of a prospectively collected database. All patients treated with full-dose t-PA and endovascular therapy were included. The primary safety endpoints included ECASS-III symptomatic intracranial hemorrhage (sICH) and ECASS parenchymal hematomas (PH). Secondary safety endpoints included severe systemic bleeding and 90-day mortality. Clinical efficacy endpoints included rates of recanalization (TICI 2–3), ambulation at hospital discharge and 90-day independent outcomes (mRS 0–2).

Results 106 consecutive patients (mean age 69±17 years; mean baseline NIH Stroke Scale 17.8±4.8; 55% women; occlusion sites: MCA-M1 60.4%; MCA-M2 6.6%; ICA-T 19.8%; tandem cervical ICA+MCA-M1 7.5%; basilar artery 5.7%) were identified over a 10-year period. The sICH rate was 8.5% and the PH-1, PH-2 and subarachnoid hemorrhage rates were 2.8%, 8.5% and 2.8%, respectively. There were two (1.9%) severe groin hematomas. The recanalization rate was 66%. At hospital discharge, 41.4% of the patients were ambulatory. The rate of independent functional outcomes at 90 days was 24%; however, this sample is biased since nearly all deaths were captured but detailed 90-day functional outcomes were missing in 27 patients. The 90-day death rate was 32.4%.

Conclusion Combined treatment with full-dose intravenous rt-PA followed by multimodal endovascular therapy seems to be associated with similar rates of sICH to that of bridging therapy with reduced rt-PA dosage.

  • Stroke
  • intravenous thrombolysis
  • rt-PA
  • thrombectomy
  • brain
  • thrombectomy
  • technique
  • complication
  • technology
  • catheter
  • balloon
  • thrombolysis
  • stroke
  • stent
  • stenosis
  • malformation
  • embolic
  • coil
  • atherosclerosis
  • angioplasty
  • angiography
  • aneurysm
  • thrombolysis
  • thrombectomy
  • arteriovenous malformation
  • stroke
  • angiography
  • atherosclerosis
  • artery
  • drug
  • thrombolysis
  • tumor
  • subarachnoid
  • thrombectomy
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The optimal management of patients with acute ischemic stroke (AIS) who fail treatment with intravenous recombinant tissue plasminogen activator (rt-PA) remains unknown. Many investigators have evaluated the feasibility, safety and efficacy of combined intravenous rt-PA with intra-arterial therapy in patients with AIS.1–12 This strategy has the potential of combining the advantages of intravenous thrombolysis (rapid and easy administration) with those of intra-arterial therapy (targeted therapy, titrated dosing, mechanical approaches to recanalization and higher reperfusion rates), resulting in improved speed and rates of reperfusion. We sought to establish whether treatment with a standard intravenous t-PA dose (0.9 mg/kg) followed by multimodal endovascular therapy would have a similar safety profile to reduced dose (0.6 mg/kg) bridging therapy.

Methods

A retrospective analysis of a prospectively collected database of patients with AIS treated with combined endovascular therapy after full-dose intravenous rt-PA treatment was performed. A total of 106 consecutive patients were identified over a 10-year period (February 1999 to April 2009).

Patients

All patients were evaluated on arrival by a stroke neurologist. All potential candidates for reperfusion underwent emergency brain CT, head and neck CT angiography and CT perfusion or brain MRI according to a standard imaging protocol. Patients meeting NINDS rt-PA trial eligibility criteria for intravenous thrombolysis received full-dose (0.9 mg/kg) intravenous rt-PA immediately after a non-contrast head CT scan. Endovascular treatment was offered to all appropriate patients with a significant neurologic deficit (NIH Stroke Scale (NIHSS) score typically ≥8) expected to result in long-term disability that was attributable to occlusion of a large vessel—that is, the basilar artery, vertebral artery, internal carotid artery (ICA) or middle cerebral artery (MCA) M1 or M2 branches. The current study only included patients who had persistent large vessel occlusion after receiving full-dose intravenous rt-PA.

Procedure and techniques

All procedures were performed under general anesthesia in a biplane neuroangiography suite equipped with digital subtraction angiography and road mapping capabilities. Intra-arterial pharmacological thrombolysis was performed in 59.4% of the patients (63/106) with direct microcatheter intra-clot infusion of urokinase (30.2% of patients (32/106); mean dosage 274 000±180 000 units) or rt-PA (29.2% of patients (31/106); mean dosage: 7.3±5.7 mg). The tools for mechanical therapy varied across the 10-year duration of the study and included thrombus disruption with microcatheter and microguidewire, balloon angioplasty and MERCI retriever device (Concentric Medical, Mountain View, California, USA). Occlusions of the cervical ICA were treated with balloon angioplasty and stenting after the occlusive thrombus had been traversed with a microcatheter and microwire.

Clinical variables and measurement of outcome

The primary safety outcome measures included both clinical/CT assessment using the ECASS-III definition for symptomatic intracranial hemorrhage (eg, any apparently extravascular blood in the brain or within the cranium associated with clinical deterioration, as defined by an increase of ≥4 points in the NIHSS score or that leads to death and is identified as the predominant cause of the neurologic deterioration) as well as a pure CT assessment using the previously published ECASS criteria where hemorrhagic infarction type 1 (HI-1) reflects small petechiae, HI-2 confluent petechiae, parenchymal hematoma type 1 (PH-1) where the hematoma is <30% of the infarcted area and PH-2 where the hematoma is >30% of the infarcted area with significant space-occupying effect.

Secondary safety outcome measures included any groin or systemic bleeding requiring intervention or blood transfusion and any mortality. Clinical and angiographic outcome measures included rates of recanalization using the Thrombolysis in Cerebral Infarction scale (successful recanalization defined as TICI 2–3), condition at hospital discharge (ambulatory vs non-ambulatory) and independent functional outcomes (modified Rankin Scale (mRS) 0–2) at 90 days.

Statistical analysis

Means, SDs, medians and ranges were calculated for all continuous data. Descriptive and frequency statistical analyses were performed with the aid of PASW Statistics 18 for Windows V.18.0.0 (SPSS, IBM Corporation).

Results

The baseline characteristics of the patients are summarized in table 1. A total of 106 patients with a mean age of 69±17 years (range 18–103) and a mean baseline NIHSS of 17.8±4.8 were included in the analysis; 58 (55%) were women. Occlusion sites included MCA-M1 (60.4%), MCA-M2 (6.6%), ICA terminus (19.8%), tandem cervical ICA + MCA-M1 (7.5%) and basilar artery (5.7%).

Table 1

Baseline patient characteristics ICA

Table 2 summarizes all the intracranial hemorrhages. With regard to extracranial hemorrhages, there were two (1.9%) significant groin hematomas. One patient required 9 units of blood transfusion and surgical repair of a femoral arteriovenous fistula. Another required 2 units of blood transfusion for a smaller groin hematoma without retroperitoneal extension.

Table 2

Categorization of intracranial hemorrhagic complications

The overall TICI 2–3 recanalization rate was 66% (70/106). At hospital discharge, 41.4% (41/99) of the patients were ambulatory. The rate of independent functional outcomes (mRS 0–2) at 90 days was 24% (19/79 available datasets); however, this sample is biased since nearly all deaths were captured but detailed 90-day functional outcomes were missing in 27 patients. The overall 90-day death rate was 32.4% (34/105).

Discussion

Our study suggests that using 0.9 mg/kg intravenous rt-PA prior to multimodal endovascular therapy is safe, with similar rates of hemorrhagic complications to bridging therapy with a dose of 0.6 mg/kg (table 3). The Interventional Management of Stroke (IMS) investigators have shown that intravenous rt-PA at a dose of 0.6 mg/kg within the first 180 min of an AIS followed by intra-arterial rt-PA is associated with a similar morbidity to that of intravenous rt-PA alone and may increase the rates of recanalization and good outcomes.3 ,5 This approach is therefore being tested in the IMS-III trial.

Table 3

Previous studies of partial (0.6 mg/kg) versus full-dose (0.9 mg/kg) intravenous rt-PA followed by endovascular therapy

However, it is well known that the efficacy of intravenous rt-PA is limited by the large thrombus burden that occurs in the setting of proximal arterial occlusion. Indeed, a recent study demonstrated recanalization rates after full-dose intravenous rt-PA of <5% for intracranial ICA or basilar occlusions and slightly less than one-third for MCA-M1 or MCA-M2 occlusions.13 Similarly, other investigators have reported that intravenous rt-PA has minimal to no potential to recanalize MCA occlusions if thrombus length exceeds 8 mm.14 It is possible that lower dosages of rt-PA would have an even weaker effect in the setting of large clot burden. In fact, a recently published meta-analysis on the comparison of the use of 0.6 mg/kg versus 0.9 mg/kg intravenous rt-PA followed by endovascular treatment for AIS showed that patients in the 0.9 mg/kg group had higher rates of favorable outcome (OR 1.60, 95% CI 1.07 to 2.40, p=0.022) and similar rates of symptomatic intracranial hemorrhage (OR 0.86, 95% CI 0.41 to 1.83, p=0.70) to patients in the 0.6 mg/kg group.15 Another potential disadvantage of the protocols that adhere to a reduced intravenous rt-PA dose is that many of the patients that are currently treated by endovascular techniques are transferred from other institutions after having already received full-dose intravenous rt-PA (‘drip and ship’ approach). As such, the requirement of a reduced dose of intravenous rt-PA will likely have a negative impact on patient enrollment in bridging therapy trials such as the IMS-III trial. More importantly, the current evidence supports the view that patients who can safely receive full-dose intravenous rt-PA do so in as rapid a timeframe as possible, with rescue endovascular therapy for those who do not improve.

A major limitation of the current analysis is related to its retrospective nature. For instance, it is very likely that the overall low rate of independent functional outcomes in our study is related to a selection bias since we were able to capture the data for mortality outcomes in nearly all cases but unable to obtain detailed functional outcome data in all patients through day 90. In fact, over 40% of the patients were ambulatory at hospital discharge. However, the primary endpoint of our study was safety/hemorrhagic complications and all the in-hospital imaging and clinical data were available for complete analysis.

In conclusion, combined treatment with full-dose (0.9 mg/kg) intravenous rt-PA followed by multimodal endovascular therapy seems to be associated with similar rates of symptomatic intracranial hemorrhage to that of bridging therapy with reduced rt-PA dosage (0.6 mg/kg). Adoption of the full-dose intravenous rt-PA approach could potentially facilitate enrollment in future bridging intravenous/intra-arterial thrombolysis trials and may also result in better reperfusion rates and improved clinical outcomes.

References

View Abstract

Footnotes

  • Disclosures Genentech provides drug supply to the Massachusetts General Hospital at no charge for an NINDS funded clinical trial in the SPOTRIAS network.

  • Competing interests RGN: Consultant/Scientific Advisory Board for Concentric Medical, ev3 Neurovascular, CoAxia and Rapid Medical. AJY: Research grant from Penumbra Inc. LHS: Consultant/Scientific Advisory Board for CoAxia and Stroke Systems Consultant to the Massachusetts Department of Public Health. JAH: Equity interest: IntraTech. SM, LMB, RH: none.

  • Ethics approval Ethics approval was provided by Massachusetts General Hospital IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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