No-Go to Tissue Plasminogen Activator for Transient Ischemic Attack
Thrombolysis is not a rational or evidence-based therapeutic option for transient ischemia, irrespective of vascular status. Even with overt middle cerebral artery (MCA) occlusion, complete resolution of symptoms during evaluation does not warrant intravenous tissue plasminogen activator. Symptom resolution may result from head-down positioning with improved hemodynamics, and rapid improvement remains one of the most common reasons cited for withholding thrombolysis.1,2 Multimodal computed tomography and magnetic resonance imaging have since enabled clinicians to rapidly depict proximal arterial occlusion, tissue status, and perfusion through the brain. Identification of an MCA occlusion, however, dangles an elusive carrot that may incite harm with unnecessary thrombolysis.
The prevailing obsession with arterial occlusion has erroneously focused attention on clots rather than ischemia. Hemodynamic insufficiency, and not clots, causes symptoms when collaterals falter.3 The persistence of thrombolysis as the sole treatment for acute ischemic stroke perpetuates the notion that occlusion is a red flag for intervention, yet collaterals may offset or dissipate symptoms, even in proximal arterial occlusion. Asymptomatic occlusion is often noted, with moyamoya serving as the ultimate example of collateral compensation. Robust downstream collateral perfusion may also accompany occlusion with atherosclerotic plaque unamenable to thrombolytics. Imaging of an occlusion without consideration of clinical details or pathophysiologic mechanisms may therefore be misleading.
Thrombolytic decisions should always integrate clinical aspects with vascular imaging features, and clinicians should resist the temptation to treat imaging findings in isolation. Treating vascular lesions alone may be dangerous and based on incorrect assumptions about expected prognoses. The decision on thrombolysis has always been a synthesis of clinical severity, time from onset, and imaging. In transient ischemic attack (TIA) with MCA occlusion, clinical severity is nil, time is reset, and imaging patterns are variable. Others have reported TIAs resulting from thrombolysis, and the presence of minor deficits is radically dissimilar to TIA. Time is intangible, as symptom onset is almost never synonymous with vascular occlusion. The seminal thrombolysis trials also demonstrated that time to presentation increases with diminishing severity, and later “survivors” respond best to tissue plasminogen activator, likely owing to enhanced collateral flow.4,5
Collateral flow may or may not be sufficient to maintain perfusion, yet time will tell, and provocative stimuli may presage subsequent events. Heads-up positioning may challenge collateral perfusion in MCA occlusion, and even when sustained, serial examination of the patient may provide clues to optimal treatment strategies.6 Simply stated, the go/no-go nature of current thrombolytic triage is inappropriate for TIA and unnecessary, as there is time to modernize this outdated paradigm. Close observation, frequent neurologic assessments, and supportive care are essential aspects of care for any patient with cerebral ischemia. Such elements form a cogent argument for admitting TIA patients not to be replaced by the unsubstantiated go/no-go of thrombolysis.
Thrombolysis may not prevent clinical worsening or early recurrence. Only a fraction of cases will recanalize, with even fewer to reperfuse. Opening an artery may be unwarranted, as some patients may never deteriorate. TIA cases may enjoy ischemic preconditioning that prevents later deterioration. The benefit of thrombolysis is purely theoretical, with normal examination at baseline, and subsequent worsening then provides the impetus for rational revascularization.7 Thrombolytic risks and destabilization, however, must also be considered. Partial recanalization may expose more surface area and promote rethrombosis. Distal embolization into multiple branches may also not be tolerated or effectively offset by collaterals, resulting in focal cortical deficits. Finally, any asymptomatic tissue injury associated with TIA may be prone to reperfusion injury or hemorrhage.
Thrombolysis for TIA is an off-label use that eclipses other protocol violations such as acute anticoagulation. Clinical acumen and logic, not absolute rules, should be used to treat such complex cases. Thrombolysis was the nidus to orchestrate acute stroke systems of care, yet resulting systems now have the capacity to extend treatment strategies far beyond the go/no-go of tissue plasminogen activator. Stroke units, clinical expertise, and advanced diagnostic or therapeutic procedures offer more than simple protocol or cookbook approaches to stroke.
Although TIA should not be incorporated, minor deficits and many other aspects should be considered. Imaging should be used to increase and refine thrombolysis decisions around specific risk-benefit profiles, identifying robust collateral perfusion that improves outcome and factors that portend hemorrhage. The mere presence of an MCA occlusion discloses nothing about downstream collateral flow and the corresponding evolution of ischemic injury in a particular case. When time allows, as in TIA with MCA occlusion, hasty and potentially erroneous thrombolysis decisions should be replaced with a modern paradigm that incorporates serial evaluation, imaging, and therapies.
Sources of Funding
This study was supported by National Institutes of Health-National Institute of Neurological Disorders and Stroke awards K23 NS054084 and P50 NS044378.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part 2 in a 3-part series. Parts 1 and 3 appear on pages 3003 and 3007, respectively.
- Received July 16, 2010.
- Accepted July 19, 2010.
Liebeskind DS. Collateral circulation. Stroke. 2003; 34: 2279–2284.
Marler JR, Tilley BC, Lu M, Brott TG, Lyden PC, Grotta JC, Broderick JP, Levine SR, Frankel MP, Horowitz SH, Haley EC Jr, Lewandowski CA, Kwiatkowski TP. Early stroke treatment associated with better outcome: the NINDS rt-PA Stroke Study. Neurology. 2000; 55: 1649–1655.
Bluhmki E, Chamorro A, Davalos A, Machnig T, Sauce C, Wahlgren N, Wardlaw J, Hacke W. Stroke treatment with alteplase given 3.0–4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol. 2009; 8: 1095–1102.
Ali LK, Saver JL, Kim D, Starkman S, Ovbiagele B, Buck BH, Sanossian N, Vespa P, Jahan R, Duckwiler GR, Vinuela F, Liebeskind DS. Heads up! a novel provocative maneuver to guide acute ischemic stroke management. Neurology. 2006; 66.
Liebeskind DS, Kim D, Starkman S, Changizi K, Ohanian AG, Jahan R, Vinuela F. Collateral failure? Late mechanical thrombectomy after failed intravenous thrombolysis. J Neuroimaging. 2008.