Drip, Ship, and Retrieve
Cooperative Recanalization Therapy in Acute Basilar Artery Occlusion
Background and Purpose— In acute basilar artery occlusion, intra-arterial thrombolysis or endovascular mechanical recanalization may result in higher recanalization rates than intravenous thrombolysis. However, many patients are admitted to community hospitals, where endovascular therapy is usually not readily available. We initiated a “drip, ship, and retrieve” cooperative treatment protocol in 2006, in which thrombolysis was initiated in the community hospital with simultaneous referral to our stroke center and the use of endovascular mechanical recanalization as required.
Methods— The outcome of all consecutive patients treated by this protocol between 2006 and June 2009 was compared with that of a similar population of referred patients who had received primary intra-arterial therapy with or without tirofiban bridging at our center between 2003 and 2005.
Results— In both groups, 26 patients were identified. The rate of symptomatic intracranial hemorrhage was 12% in previous patients and 8% in those treated under the new protocol. Recanalization rates were similar: 92% in previous patients and 85% with the new protocol; 38% of these had recanalization after intravenous thrombolysis alone. Functional outcome was better among those treated with the new protocol, with more patients achieving a modified Rankin scale score ≤2 (38% versus 12%; P=0.03) and ≤3 (50% versus 23%; P=0.04).
Conclusions— “Drip, ship, and retrieve” seems to be feasible and safe in acute basilar artery occlusion. Patients appear to benefit from initiation of intravenous thrombolysis in the community hospital before transfer. Randomized controlled trials will have to confirm the expected benefit of subsequent on-demand mechanical recanalization on clinical outcome.
Prognosis in untreated acute basilar artery occlusion (BAO) is poor.1,2 Early recanalization seems to reduce mortality and improve outcome.1–3 Recanalization may be achieved by intravenous thrombolysis (IVT), intra-arterial thrombolysis (IAT),4–6 endovascular mechanical recanalization (EMR),7–9 or a combination of these therapies.10,11 Preliminary data suggest that recanalization rates may be higher with intra-arterial therapy (IA therapy).4 However, recently published data from the large multicenter registry BASICS (Basilar Artery International Cooperation Study) did not demonstrate superiority of IA therapy on clinical outcome.12 Because of the absence of prespecified treatment protocols, the findings of this registry have to be interpreted with caution. Specifically, they cannot prove nonsuperiority of IA therapy. Moreover, <10% of the patients included in this registry were treated with a combination of IVT and IA therapy, an approach that may allow for early treatment initiation and high recanalization rates.10 This combination therapy may be particularly valuable in patients primarily admitted to a community hospital.13 IVT could be initiated there and followed by on-demand IA therapy after immediate transfer to a specialized stroke center. The initiation of IVT in a community hospital with subsequent transfer to a specialized stroke center is referred to as the “drip and ship” approach. Several reports have demonstrated the safety and feasibility of this strategy in acute stroke patients.14,15 In 2006, we implemented a treatment protocol for acute BAO patients, by which cooperating community hospitals were encouraged to initiate IVT (“drip”) on site and immediately transfer the patients to our center (“ship”). In persisting BAO despite IVT, immediate EMR (“retrieve”) was attempted on arrival at our center. This treatment concept was now evaluated by comparing the outcome of patients treated in this way with that of a similar in-house population of referred acute BAO patients treated by primary IA therapy with or without tirofiban bridging in 2003 through 2005.
Patients and Methods
As a tertiary interdisciplinary stroke center in Germany, we closely cooperate with nearby community hospitals. Acute stroke patients are discussed via telephone or a telemedical network by which patients can be examined in a video conference while neuroimaging is electronically transferred. Whenever endovascular treatment seems to be an option, patients are transferred to our center. This way, ≈10 patients with confirmed acute BAO are transferred to our center per year.
Two different patient groups were derived from our in-house prospective database on BAO patients. Patient allocation was based on the fundamental change in our treatment concept for referred patients with acute BAO in 2006. Until then, primary IA therapy was considered the in-house treatment of choice. IVT played no therapeutic role at that time. Accordingly, all consecutive patients treated at our center between 2003 and 2005 were included in this group (group I) if the following inclusion criteria were fulfilled: (1) primary admission at cooperating community hospitals, (2) acute BAO confirmed by CT angiography (CTA) or conventional angiography, (3) referral and admission to our stroke center within 8 hours after estimated time of BAO, and (4) primary IA treatment with or without bridging with the glycoprotein IIb/IIIa inhibitor tirofiban.
The new treatment concept of “drip, ship, and retrieve” was implemented in January 2006. Patients treated thereafter were included in group II if the following inclusion criteria were fulfilled: (1) primary admission at cooperating community hospitals, (2) acute BAO confirmed by CTA, (3) full-dose IVT (0.9 mg recombinant tissue-type plasminogen activator per kg body weight over 1 hour, maximum 90 mg, 10% as a bolus) initiated at the community hospital within 6 hours after estimated time of BAO, (4) referral and admission to our stroke center within 8 hours after estimated time of BAO, and (5) on-demand EMR. To check the status of the basilar artery after IVT, all patients received a second CTA immediately on arrival at our center.
As in the BASICS registry, we used the estimated time of BAO to specify intervals to treatment.12 The beginning of IA therapy was defined as the time when the microcatheter was placed at the thrombus. Recanalization after IA therapy was defined as Thrombolysis in Myocardial Infarction II (perfusion with incomplete or slow distal branch filling) or Thrombolysis in Myocardial Infarction III (full perfusion with filling of all distal branches).16 Comorbidity was quantified by the Charlson Index, a validated measure of preexisting morbidity.17
To quantify infarct extension after BAO, an MRI-based 10-point score was used.18 This score reflects the extent of diffusion-weighted imaging lesions in the different vertebrobasilar territories (medulla, pons, mesencephalon, thalamus, cerebellum, and temporo-occipital lobe). It has been shown to correlate with clinical outcome.18
In patients who had survived the acute hospital phase at our center, 3-month outcome was assessed by telephone. The patients’ clinical status was documented using a structured interview and the modified Rankin Scale (mRS), an ordinal scale rating daily life functioning from 0 (no symptoms at all) to 6 (death). The telephone interview used to determine mRS scores had been validated previously and shown to give reliable results.19 All procedures were in accordance with our institutional guidelines. Patients contacted by telephone gave informed consent for anonymous data analysis and publication.
The statistical software package SPSS 17.0 was used. Values are given as mean±SD. Groups were compared by univariate analysis using the independent t test for comparison of continuous variables and the Fisher exact test for comparison of proportions. Because of the low number of patients and outcomes, we did not perform a logistic regression analysis.
During the study period (January 2003 to June 2009), a total of 70 patients with radiologically confirmed BAO were treated at our stroke center after referral from cooperating community hospitals. Thirty-three of them were treated between 2003 and 2005 (group I) and the remaining 37 after implementation of our “drip, ship, and retrieve” protocol in 2006 (group II). In a few patients (n=4 in group I and n=3 in group II), recanalization was not attempted because of already documented extensive brain stem infarction. Of the remaining patients, 26 in each group fulfilled the inclusion criteria (Figure 1). Reasons for exclusion were delayed presentation (n=3 in group I and n=4 in group II), contraindications for IV thrombolysis (n=2 in group II), and temporary nonavailability of CTA in the community hospital (n=2 in group II). About half of the eligible patients (24 of 52) were transported by helicopter and the others by ambulance. Complications associated with transportation did not occur. In all patients of group II, full-dose IVT was initiated before transport. Because of immediate transfer, IVT was running at the beginning of transportation in all of these patients. In a minority of patients (8 of 26), IVT was still running at the time of arrival at our stroke center. Some of the data from 13 patients have been reported previously.10,12
Patient Characteristics and Therapy
Patient characteristics, including age, risk factors, comorbidity, clinical presentation, extension of BAO, stroke etiology, time to admission at our stroke center, and time to IA therapy, were comparable in the 2 groups (Table 1). The only obvious difference was the treatment concept: primary IA therapy after referral to our stroke center in group I and primary IVT initiated at the community hospital followed by on-demand EMR at our stroke center in group II (Table 1). Nine patients in group I (35%) received tirofiban as a bridging therapy during transfer (Table 1). EMR was performed with a similar frequency in both groups (Table 1); however, more patients in group I received IAT (Table 1). The doses of intra-arterial recombinant tissue-type plasminogen activator in the 3 group II patients who received IAT after IVT and in combination with EMR ranged from 20 to 30 mg. Devices used for EMR were (partly in combination) the Merci Retriever,20 the AngioJet (Possis Medical Inc.),7 and the Penumbra Stroke System (Penumbra Inc21; Table 1). Because of unavailability before 2006, the Penumbra Stroke System was used only in patients of group II (Table 1).
Overall, recanalization rates were high and comparable in the 2 groups (Table 2). Differences in devices used had no significant influence on recanalization. Looking at group II separately, IVT alone led to prompt recanalization in 10 of 26 patients (38%), as demonstrated by CTA within 2 hours after treatment. Immediate EMR (combined with low-dose IAT in 3 patients) led to recanalization in 12 of the remaining 16 patients of this group (75%).
Symptomatic intracerebral hemorrhage was an infrequent complication in both groups (12% in group I and 8% in group II; Table 2) but led to death in all affected patients. Repeated application of contrast agent during CTA or EMR was well tolerated in all patients. No patients developed renal insufficiency.
Seventeen patients in group I (65%) and 20 patients in group II (77%) received a control MRI including diffusion-weighted imaging within 2 weeks after BAO. MRI demonstrated reduced infarct extension in group II compared with group I (Table 2).
Mortality and Functional Outcome
In 6 of 52 patients (12%), recanalization was not achieved (2 patients in group I and 4 patients in group II). All these patients died within 7 days after BAO because of extensive vertebrobasilar infarction.
At follow-up (3 months after BAO), patients in group II had a lower mean mRS than patients in group I (Table 2). Moreover, mRS scores of ≤2 and ≤3 were more frequently achieved in group II, whereas differences in mortality were not significant (Table 2; Figure 2). Outcome within group I was similar in patients who had received tirofiban as a bridging therapy compared with those who had not (mRS ≤2, 11% versus 12%; mRS ≤3, 22% versus 24%). Outcome within group II was similar in patients in whom recanalization was achieved by IVT compared with those who depended on subsequent EMR (mRS ≤2, 40% versus 42%; mRS ≤3, 50% versus 50%). Use of different devices had no influence on clinical outcome.
The key to successful treatment in acute BAO is early recanalization. Our findings demonstrate that in the case of primary admission to a community hospital, on-site initiation of IVT, subsequent transfer to a stroke center, and on-demand EMR provide both early treatment initiation and high recanalization rates. In our patients, this “drip, ship, and retrieve” approach was safe and feasible. Specifically, repeated application of contrast agent was well tolerated, no complications occurred during transportation, and symptomatic intracerebral hemorrhage was an infrequent event. We compared the outcome of these patients with a nearly identical in-house population of referred acute BAO patients treated by primary IA therapy with or without tirofiban bridging in the 3 years before 2006.
We are well aware that this analysis cannot compete with a randomized controlled trial. Moreover, the sample size (26 patients per group) was too small for multivariate analysis. Therefore, possible confounders may have been overlooked. Conversely, baseline patient data were very similar in both groups. This argues against a relevant bias. With better evidence still lacking, our data suggest that on-site initiation of IVT improves outcome in patients subsequently transferred to a stroke center for EMR.
Some authors suggested to use glycoprotein IIb/IIIa inhibitors as a bridging therapy in BAO.22,23 Nine of our patients in group I received tirofiban before IA therapy. Therefore, one may argue that group I was too inhomogeneous to serve as a control group for “drip, ship, and retrieve.” However, outcome in group I was similar in patients with and without tirofiban bridging, which should justify merging of the patients to one group. It may be possible that patients in group II benefited from the availability of new devices (Penumbra Stroke System) or the increasing experience of the performing interventionalists. However, recanalization rates were very similar in both groups, and the use of different devices had no significant influence on recanalization rates or clinical outcome. Therefore, we do not believe that possible advances in EMR can explain the observed differences in clinical outcome between the 2 groups.
All patients of group II were treated by IVT initiated at the community hospital. They received a control CTA immediately on arrival at our center. Thereby, early recanalization (within 2 hours after IVT) was demonstrated in 38% of our patients. Previous reports on BAO patients have suggested even higher IVT recanalization rates of 53% and 67%.4,12 However, in these patients, vessel patency was evaluated hours to days after IVT. Therefore, we believe that our findings may more reliably reflect the immediate recanalization rate after IVT in BAO. Because our findings suggest that the majority of patients do not immediately recanalize after IVT alone, simultaneous referral to a specialized stroke center for on-demand escalation therapy seems very reasonable. In this context, the findings of the BASICS registry12 should not be misinterpreted as evidence that IVT alone is sufficient in the treatment of BAO. Our findings suggest that subsequent on-demand EMR is of substantial benefit for patients with persistent BAO after IVT. As expected, EMR was associated with high recanalization rates. But more important, 5 of the 12 patients who recanalized on EMR after ineffective IVT had a good clinical outcome with functional independence after 3 months (mRS ≤2).
It remains an interesting question for future analyses whether the preceding IVT may have stabilized critical tissue perfusion in the patients who depended on EMR. In other words, one may speculate that the effects of IVT in BAO may be 2-fold: (1) recanalization in some patients, and (2) tissue protection and bridging for immediate EMR in the remaining patients.
In our personal opinion, full-dose rather than reduced-dose IVT should be the initial treatment. Full-dose IVT is a proven therapy in acute ischemic stroke and certainly not restricted to the anterior circulation. In our series, it led to recanalization in more than one third of patients. Moreover, with EMR being increasingly performed, interventionalists may depend less and less on IAT to achieve recanalization. This should justify full-dose IVT without the need to “save” recombinant tissue-type plasminogen activator for consecutive IAT.
Existing data as well as our presented findings still do not provide unequivocal evidence on the best treatment strategy in BAO. Recently published data from the BASICS registry confirm this uncertainty.12 However, this registry impressively demonstrated the broad interest of the stroke community to work on this challenging project. IVT is the standard treatment for acute ischemic stroke.24 Therefore, a future randomized controlled trial should compare IVT alone with IVT plus IA therapy. With intravenous recombinant tissue-type plasminogen activator already applied, IA therapy may predominantly consist of EMR. Therefore, endovascular interventionalists will have the chance to prove the expected clinical impact of mechanical recanalization in BAO as a model for large artery ischemic stroke.
In conclusion, “drip, ship, and retrieve” is a feasible and safe treatment concept for patients with acute BAO. Patients seem to benefit from initiation of IVT in the community hospital before transfer. Randomized controlled trials will have to confirm the expected impact of subsequent IA therapy on clinical outcome.
In 14 of the 52 reported patients, the contact between the community hospital and our stroke center was mediated by the Telemedical Pilot Project for Integrative Stroke Care in Bavaria/Germany (TEMPiS). We thank Dr J. Schenkel and coworkers from TEMPiS for this very valuable cooperation. We also thank K. Ogston for language editing of the manuscript.
T.E.M. received financial research support from Penumbra Inc. for including patients in a clinical study investigating the Penumbra Stroke System.
- Received September 7, 2009.
- Revision received November 11, 2009.
- Accepted November 26, 2009.
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