Should Interventional Cardiologists Treat Ischemic Strokes? A Global Perspective

Anteroposterior (top) and lateral (bottom) digital subtraction angiographic image demonstrating occlusion of the right middle cerebral artery at the M1 segment.
Anteroposterior view demonstrating persistent occlusion following infusion of 2 units of reteplase.
Fluoroscopic anteroposterior view demonstrating balloon angioplasty of the middle cerebral artery (MCA) (arrow) distal to a stent placed in the proximal MCA.
Anteroposterior (left) and lateral (right) digital subtraction angiographic images demonstrating recanalization of the right middle cerebral artery and robust filling of the middle cerebral artery distribution.
CT scan approximately 1 week after thrombolysis demonstrating a small area of hypodensity in the anterior portion of the right temporal lobe, lateral to the sylvan fissure.

Elad I. Levy, MD, *Michael J. Rinaldi, MD, Jay U. Howington, MD,
Bernard R. Bendok, MD, Stanley H. Kim, MD, Mark R. Harrigan, MD, Adnan I. Qureshi, MD, Lee R. Guterman, PhD, MD, L. Nelson Hopkins, MD

Need for stroke interventionists. More than 750,000 strokes occur annually in the United States.1,2 Currently, stroke is the third leading cause of death (60.2 deaths per 100,000 population) and the leading cause of severe neurological disability in our nation. As the elderly segment of the population continues to grow, the stroke death rate has the potential to reach epidemic proportions. Historically, ischemic stroke has been a disease entity approached in terms of prevention and palliation. The phrase “brain attack” is being used more frequently as recent advances have reshaped the focus to an active role in terms of acute intervention. As with the coronary circulation, the duration of ischemia and degree of collateral circulation have the greatest influence on morbidity and mortality in stroke. Early intervention can potentially limit the devastation caused by a stroke, but is it possible for the several hundred neurointerventionists currently in practice to expeditiously evaluate, treat and care for this volume of patients? Clearly, it is impossible. Thus, the interventional treatment of stroke continues to suffer from, among other problems, the lack of sufficiently trained physicians to supply the necessary expeditious care that these patients require.

The logical source. Ideally, dedicated neurointerventionists with extensive experience in all minimally invasive intracranial techniques would perform invasive therapies for acute stroke. Currently, there are at most several hundred trained neurointerventionists nationwide. To provide 24-hour coverage for all major medical centers, several thousand more physicians would need to be trained. The relatively small number of elective neurointerventional procedures performed annually could not support the number of specialists required to provide invasive therapy for and manage the care of patients with acute stroke. Thus, the mass training of neurointerventional specialists to provide the majority of invasive acute stroke interventions is not feasible. Fortunately, an infrastructure for the provision of emergent endovascular care already exists. By contrast to the relatively uncommon elective neurointerventional procedure, more than 1 million coronary angioplasty procedures are performed annually in the United States, supporting over 2,000 procedure rooms and nearly 8,000 interventional cardiologists.3 The incorporation of a “brain attack” program into an existing primary angioplasty program for myocardial infarction (MI) would require no additional personnel other than a stroke neurologist. Most contemporary cardiac catheterization laboratories are equipped with the digital subtraction and road-mapping capabilities necessary to perform intracranial work. Techniques employed in the intervention of acute stroke, such as clot removal and angioplasty with stent placement, are similar to those already familiar to the interventional cardiologist, thus minimizing the time required to learn a new skill set. For example, more than 60% of cardiac catheterization laboratories have physicians who perform angioplasty, and most of these laboratories provide emergent angioplasty for acute MI.3 Additionally, interventional cardiologists have gained much insight into the utility and practicality of thrombolytic and anticoagulant therapies. As recent studies have confirmed the safe and effective implementation of primary angioplasty in centers without surgical backup, the proportion of interventional cardiologists will continue to rise.4,5
In addition to the aforementioned reasons supporting the training of cardiologists for acute stroke intervention, it should be remembered that a majority of strokes are the result of cardiac or aortic disease. Cardiologists are often involved in the treatment of patients at risk for stroke and are in an ideal position to provide this care.6,7 Coronary artery disease is a leading cause of death in patients who experience transient ischemic attacks (TIA) or stroke. Fifty consecutive patients with TIA or stroke were studied to determine the prevalence of coronary artery disease, and 29 of these patients had significant coronary artery disease.8 These patients typically are followed by cardiologists for their predisposing heart disease. In one study of 300 consecutive patients with acute focal brain ischemia who underwent a clinical examination by a cardiologist in conjunction with routine electrocardiography, Holter-electrocardiography, and echocardiography, a total of 188 patients had a potential cardiac source of embolism.9
In addition to the coexistent medical conditions that increase the risk for stroke, there is an inherent risk in performing coronary angiography. The stroke rate associated with the performance of 20,924 cardiac catheterizations for interventional procedures was 0.12%.10 The rate of acute neurological complications resulting from cardiac catheterization procedures (n = 3,648) in children was 0.38%.11 This rate is likely attributable to congenital anomalies of the heart and great vessels, with which pediatric interventional cardiologists are intimately familiar. In our opinion, optimal care is to institute interventional stroke treatment as soon as possible, necessitating that cardiologists begin treatment.

Evidence for intraarterial therapy. Favorable results of the National Institute of Neurological Disorders and Stroke (NINDS) study12 demonstrating the benefits of intravenous recombinant tissue plasminogen activator (t-PA, alteplase) in patients who present within 3 hours of the onset of acute ischemic stroke led to approval of this agent by the Food and Drug Administration (FDA) in 1996. However, the results of the European Cooperative Acute Stroke Studies (ECASS)13,14 and the Standard Treatment with Alteplase to Reverse Stroke (STARS) trial15 indicated that intravenous therapy was not recommended for use in an unselected population of acute ischemic stroke patients in that both reported rates of major morbidity and death higher than 50% after intravenous therapy (Table 1).
The unsatisfactory results of current intravenous therapy have spawned several studies examining the effectiveness of intraarterial therapy.16,17 In the Prolyse in Acute Cerebral Thromboembolism (PROACT) I trial,16 patients with acute ischemic stroke resulting from MCA occlusion and onset of symptoms within 6 hours were treated with intraarterial infusions of recombinant pro-urokinase (r-pro UK). Recanalization rates (TIMI grade 2 or 3) were 58% in the r-pro UK group, which were, remarkably, more than four times those in the placebo group. PROACT I determined the safety of intraarterial pro-urokinase and led to the conduct of PROACT II17 to determine the effectiveness of this therapy. In the second trial, the recanalization rates (TIMI grade 2 or 3) were 66% in the r-pro UK group and 18% in the placebo group. A 15% absolute increase in favorable outcome, as defined by modified Rankin score, was greater in the treatment arm than in the placebo arm.
The advantages of the intraarterial approach for thrombolysis are clear. First, angiography localizes the vascular territory of the lesion and determines whether there is persistent occlusion or autogenous recanalization (Figure 1). Second, direct transcatheter delivery of the thrombolytic agent (i.e., t-PA or reteplase) to the occlusion is accomplished without systemic administration (a lesser amount of the drug can actually be used) (Figure 2). Visual appreciation of clot dissolution or recalcitrance provides clinicians with the information necessary to determine if adjuvant mechanical means are necessary to recanalize the vessel (Figures 3–5). Currently, significant disadvantages to the intraarterial approach are the paucity of physicians capable of performing the procedure and the increased risk of direct vascular injury and/or intracranial hemorrhage. Recognition of the symptoms as indicative of a stroke and rapid triage of the patient to a center where he or she can receive treatment continue to be of primary concern.
In addition to the intraarterial studies conducted, several studies have examined the effectiveness of a combination of intravenous and intraarterial thrombolysis in patients with acute ischemic stroke.18–22 The results are summarized in Table 2. The notion that large vessel occlusions (e.g., those of the intracranial ICA or the M1 segment of the middle cerebral artery) respond poorly to intravenous therapy, coupled with the knowledge that intravenous therapy can be initiated faster than intraarterial therapy, helped lay the foundation for the combination intraarterial-intravenous approach. On the basis of promising results derived from several small pilot studies, the NINDS funded a Phase II pilot study, the Interventional Management of Stroke (IMS) trial.23 The safety and efficacy of initiating a combination of intravenous and intraarterial t-PA therapies within 3 hours of symptom onset in 80 ischemic stroke patients with an NIHSS score > 10 was examined. Dosing regimens involved 0.6 mg/kg of intravenously administered t-PA over 30 minutes (15% as a bolus) followed by intraarterially administered t-PA at a dose of up to 22 mg over the course of 2 hours if thrombus was identified by a cerebral angiogram. Recanalization rates of 40% were observed with a 16% rate of mortality.
Mechanical disruption of clot in combination with intraarterial thrombolysis has great potential benefit for the treatment of acute ischemic stroke, just as it has for the treatment of acute MI. In a study by Qureshi et al. in which combination therapy was used for the treatment of 19 patients with acute ischemic stroke, complete or near-complete recanalization was seen in 16 patients (84%), twelve had neurological improvement and 3 had intracranial hemorrhages.24

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