Atherosclerotic Peripheral Vascular Disease Symposium II

Abstract

HomeCirculationVol. 118, No. 25Atherosclerotic Peripheral Vascular Disease Symposium II Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBAtherosclerotic Peripheral Vascular Disease Symposium IIExecutive Summary Mark A. Creager, MD, FAHA, Conference Chair, Christopher J. White, MD, FAHA, Conference Cochair, William R. Hiatt, MD, Michael H. Criqui, MD, FAHA, Shellie C. Josephs, MD, Mark J. Alberts, MD, FAHA, William H. Pearce, MD, Bruce H. Gray, DO and Krishna J. Rocha-Singh, MD Mark A. CreagerMark A. Creager Search for more papers by this author , Christopher J. WhiteChristopher J. White Search for more papers by this author , William R. HiattWilliam R. Hiatt Search for more papers by this author , Michael H. CriquiMichael H. Criqui Search for more papers by this author , Shellie C. JosephsShellie C. Josephs Search for more papers by this author , Mark J. AlbertsMark J. Alberts Search for more papers by this author , William H. PearceWilliam H. Pearce Search for more papers by this author , Bruce H. GrayBruce H. Gray Search for more papers by this author and Krishna J. Rocha-SinghKrishna J. Rocha-Singh Search for more papers by this author Originally published16 Dec 2008https://doi.org/10.1161/CIRCULATIONAHA.108.191170Circulation. 2008;118:2811–2825The Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group was commissioned by the American Heart Association (AHA) to provide a forum to address important and emerging issues in this multidisciplinary area of clinical science. The working group was a primary outgrowth of the AHA Atherosclerotic Vascular Disease Conference held in Boston, Mass, in July 2002. It was created in recognition of the fact that atherosclerosis is a systemic disease with important sequelae in many regional circulations in addition to the heart, including the brain, kidneys, mesentery, and limbs. Its mission is to provide a forum for the multiple disciplines engaged in research, evaluation, and management of patients with noncoronary atherosclerosis. The goals of the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group are to develop a strategy to increase awareness of atherosclerotic vascular disease, identify important gap areas in knowledge that require further clinical investigation, and develop programs that will facilitate prevention and treatment of peripheral atherosclerotic diseases.Developments in research and technology that are relevant to atherosclerotic vascular disease are emerging rapidly. As a result, greater opportunities to translate science to clinical practice are available. The American College of Cardiology/AHA practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic) provide many evidenced-based recommendations for diagnosing and treating patients with atherosclerotic vascular diseases.1 Nevertheless, in some areas, the evidence has not matured sufficiently for definitive guidelines. Some of these areas have engendered considerable controversy among practitioners. Among these are the efficacy and outcome of screening programs for vascular disease and the appropriate and timely use of endovascular interventions. Accordingly, the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group convened the second AHA conference on Atherosclerotic Vascular Disease, which took place in Boston, Mass, in July 2006. The conference was also sponsored by the AHA Councils on Arteriosclerosis, Thrombosis, and Vascular Biology; Epidemiology and Prevention; Cardiovascular Radiology and Intervention; Cardiovascular Surgery and Anesthesia; Cardiovascular Nursing; Clinical Cardiology; Council for High Blood Pressure Research; Council on the Kidney in Cardiovascular Disease; and Stroke Council. It was cosponsored by the Society of Cardiovascular Angiography and Interventions, the Society of Interventional Radiology, and the Society for Vascular Medicine and Biology. The overall objectives of this conference were as follows: (1) to develop a consensus about the feasibility, importance, and efficacy of screening for atherosclerotic vascular diseases; (2) to provide a state-of-the-art review of contemporary imaging modalities, specifically computed tomographic angiography (CTA) and magnetic resonance angiography (MRA); (3) to address recent developments and controversies with regard to the appropriate and timely use of interventions in patients with various manifestations of atherosclerotic vascular disease; and (4) to recommend nomenclature for atherosclerotic vascular diseases that could be adapted by clinicians and scientists to facilitate communication.The conference was divided into the following 8 themes that were addressed by individual writing groups: (1) Nomenclature for Atherosclerotic Vascular Diseases; (2) Screening for Atherosclerotic Vascular Diseases: Should Nationwide Programs Be Instituted?; (3) Vascular Magnetic Resonance and Computed Tomographic Imaging; (4) Stroke Intervention: State of the Art; (5) Controversies in Carotid Artery Revascularization; (6) Controversies in Abdominal Aortic Aneurysm Repair; (7) Lower-Extremity Revascularization: State of the Art; and (8) Intervention for Renal Artery Disease.Writing Group 1: Nomenclature for Vascular DiseasesPeripheral vascular diseases are important components of cardiovascular medicine. The high prevalence of these disorders in the clinical setting mandates effective communication among healthcare providers. The public health significance of these conditions requires clear and consistent terminology for community audiences. Therefore, the goal of Writing Group 1 was to suggest definitions, usage, and nomenclature of specific terms commonly used to describe vascular diseases by cardiovascular specialists and primary care communities. The major structural components of the vascular system consist of veins, lymphatic vessels, and arteries. Venous and lymphatic diseases were outside the scope of this conference. Diseases of arteries are classified further into atherosclerotic occlusive disorders, nonatherosclerotic occlusive disorders, and aneurysms.Specific terminology for vascular diseases is provided in Table 1. The term “vascular diseases” should refer to all diseases of arteries, veins, and lymphatic vessels. Coronary artery disease was not included in Table 1 because it was outside the scope of this conference. “Atherosclerotic vascular disease” refers to diseases of arteries caused by atherosclerosis. The term “peripheral artery disease” (PAD) is recommended to describe disease that affects the lower- or upper-extremity arteries. PAD should replace “peripheral vascular disease,” which was often used in the past to describe leg artery disease but is too nonspecific, because it can encompasses venous, lymphatic, and vasospastic diseases in addition to arterial disorders. Table 1 provides additional definitions for atherosclerotic vascular diseases as they apply to the noncoronary circulations. Definitions are provided for peripheral (lower- and upper-extremity), mesenteric (celiac, superior mesenteric, and inferior mesenteric arteries), renal, and cerebral artery (intracranial and extracranial) disease. These are further subdivided into the major manifestations of each disease. Universal use of the term “disease” is preferred rather than the selective use of the term “stenosis,” for example, “renal artery disease” rather than “renal artery stenosis.” This was done because an artery can have an occlusion or a stenosis with similar clinical manifestations, and the term “disease” was meant to cover both conditions. Some causes of these arterial diseases are listed in Table 1. Table 2 provides terminology for aneurysms of the aorta and its visceral and limb branches. Although the definitions vary, an artery can be considered aneurysmal when its diameter is increased by 50% compared with the normal dimension. Table 1. Major Vascular TermsRecommendedPrevious TermsPathophysiologyAnatomyDuration and SeverityCommentsVascular diseasesDiseases of arteries, veins, and lymphatics; includes atherosclerosis and nonatherosclerotic diseasesAll vessels without anatomic designationAcute to chronic; asymptomatic to severeBroadest term to describe all vascular diseases: coronary, cerebral, peripheral, renal, and mesenteric artery occlusive disease, aneurysms, venous and lymphatic diseasesPeripheral artery diseasePeripheral vascular disease, peripheral arterial disease, peripheral arterial occlusive disease, arteriosclerosis obliteransAtherosclerosis, thrombosis, noncardiac emboli, inflammatory, etcStenosis or occlusion of upper- or lower-extremity arteriesAcute to chronic. May be asymptomatic. Symptoms and signs range from asymptomatic with functional limitations to intermittent claudication, rest pain, ulcers, and gangreneLimited to artery disease; excludes renal, coronary cerebral, mesenteric, and aneurysmsMesenteric artery diseaseVisceral or mesenteric ischemia or angina, intestinal ischemia/anginaAtherosclerosis, thrombosis, emboli, extrinsic compression, vasculitisCeliac trunk, superior mesenteric artery, inferior mesenteric arteryAcute to chronic. Most patients are asymptomatic. Symptoms include postprandial pain and weight lossRenal artery diseaseRenal artery stenosis, renovascular diseaseAtherosclerosis, thrombosis, emboli, arterial dysplasiaMain renal arteries and extrarenal branchesAcute to chronic, mild to severeAssociated with hypertension and/or renal insufficiencyCerebral artery diseaseCerebral vascular disease (confused with cardiovascular disease); extracranial arterial occlusive diseaseAtherosclerosis and nonatherosclerotic causes such as dissection, arterial dysplasiaAortic arch to intracranial vesselsAcute and chronic. Symptoms and signs of stroke and transient ischemic attack depend on affected territoryMay be asymptomatic Extracranial cerebral artery diseaseCervical carotid disease, vertebral-basilar insufficiencyAtherosclerosis and nonatherosclerotic causes as aboveAortic arch, carotid, vertebral, and extracranial vesselsAs aboveExcludes intracranial artery diseases Intracranial cerebral artery diseaseAtherosclerosis and nonatherosclerotic causesIntracerebral vesselsAs aboveExcludes extracranial artery diseases (although may coexist)Table 2. Aneurysm TerminologyRecommendedPathophysiologyAnatomySeverityAneurysmAffects all 3 layers of the affected artery; atherosclerosis, connective tissue, congenital, infection (mycotic), traumatic, dissection, inflammationAffects all major peripheral arteriesAsymptomatic, symptomatic (depending on contiguous structures); ruptured, leaking (contained rupture)Aorta Thoracic aortic aneurysmAs aboveAscending, transverse, arch, descending (DeBakey I or II or Stanford A or B)As above Thoracoabdominal aortic aneurysmAs aboveCrawford class I–IVAs above Abdominal aortic aneurysmAs aboveCrawford class IV, suprarenal, pararenal, juxtarenal, infrarenalAs aboveAortic branch Visceral (celiac, superior mesenteric, inferior mesenteric, hepatic, splenic, renal) artery aneurysmAs aboveAll visceral branches of the aortaAs abovePeripheral Iliac, femoral, poplitealAs aboveAs aboveIn addition, several terms are recommended for the clinical manifestations, assessment, and treatment of PAD. Patients with PAD who do not have symptoms are designated “asymptomatic.” Effort-induced (usually walking) discomfort of the calf, thigh, and/or buttock, variably described as cramping, aching, tightness, pain, or fatigue, is termed “intermittent claudication.” “Atypical claudication” is a term that refers to exertional leg pain that does not fulfill all the characteristics of classic claudication. “Critical limb ischemia” refers to pain in the feet or toes at rest, with or without ischemic ulcers or gangrene.Terms are suggested for the hemodynamic and functional assessment of patients with PAD, including “ankle–brachial index,” “peak walking time,” and “claudication onset time.” In addition, suggested nomenclature includes terms for interventions. “Endovascular revascularization” is the recommended term for catheter-based treatment of a peripheral artery stenosis, occlusion, or aneurysm. “Open revascularization” is the term recommended for open surgical treatment of an artery stenosis, occlusion, or aneurysm. The nomenclature process should be continually dynamic to reflect scientific and clinical advances in the diagnosis and management of vascular disorders.Writing Group 2: Screening for Atherosclerotic Vascular Diseases: Should Nationwide Programs Be Instituted?Controversy exists about the appropriateness and efficacy of screening programs to detect atherosclerotic vascular diseases. Writing Group 2 considered the noninvasive detection of 4 specific types of noncoronary atherosclerotic vascular disease: the ankle–brachial index for assessment of PAD; carotid duplex ultrasound for assessment of intimal–medial wall thickness, plaque, and stenosis; abdominal ultrasound for detection of an abdominal aortic aneurysm (AAA); and duplex ultrasound for the detection of renal artery disease.First, screening criteria were reviewed with regard to the 4 measures. Specific criteria included the public health importance of the problem, a detectable latent phase, reasonable prevalence (at least in a targeted population), safety, precision, feasibility, ethical appropriateness, acceptability to potential screenees, cutoff levels validated by test characteristics, and cost-effectiveness.In discussing each test, it was recognized that the “gold standard” would be a randomized clinical trial of each assessment in a targeted population with rigorous outcome criteria. However, such data are quite limited in this area. Thus, alternative forms of evaluation based on observational data are necessary, such as cost-effectiveness modeling, although rigorous studies of this nature are few.Peripheral Artery DiseaseThe ankle–brachial index has many attractive features for use in targeted screening programs. It is inexpensive, can be performed quickly, and has high validity and good reproducibility. In addition, it can be used to assess 2 separate problems. First, it can help detect early PAD and, with appropriate intervention, help prevent progression to critical leg ischemia and amputation. Second, it robustly predicts future ischemic cardiac and cerebral events and thus can be used to detect persons who would benefit from aggressive medical therapy. This risk prediction has recently been demonstrated to be independent of and to add incrementally to the Framingham risk score.2 Finally, screening can be targeted to high-risk groups, which facilitates yield and cost-effectiveness. No randomized trial data on screening are available, nor to the best of our knowledge are there currently plans to obtain such data. Nevertheless, the above characteristics suggest that a cost-effectiveness analysis would be supportive of screening for PAD in targeted populations.Carotid Artery DiseaseCarotid ultrasound screening potentially provides information on 2 distinct but related issues: First, it can determine the presence of a stenosis significant enough to indicate the need for intervention to prevent a future stroke. Second, it can provide evidence of overall future atherosclerotic event risk. Measurements include the presence of plaque, the degree of any stenosis, and the intimal–medial thickness of the carotid arteries at selected sites. Ultrasound screening for carotid artery stenosis cannot be recommended at this time, because no randomized clinical trials are available to support routine screening, even in “at-risk” patients, but such studies, along with cost-effectiveness analyses, would be helpful. Also, measurement of carotid wall thickness appears to allow discrimination of risk even in young adults, but methods are technically challenging and need further evaluation and refinement before they can be considered for population-based screening programs.Abdominal Aortic AneurysmUltrasound screening for AAA can be performed safely, quickly, inexpensively, and accurately. A large, prospective study in men 65 to 74 years of age has demonstrated the utility and cost-effectiveness of ultrasound screening in reducing aneurysm-related deaths.3 The frequency of routine re-imaging to assess aneurysm growth rates can be correlated reliably to the size of the aneurysm at the index screening. Current American College of Cardiology/AHA guidelines recommend ultrasound screening of AAAs for men ≥60 years of age who are siblings or offspring of patients with AAAs (Class 1) and men 65 to 75 years of age who have ever smoked (Class 2a).1Renal Artery DiseaseAlthough duplex ultrasound of the renal arteries can be performed safely and with a high degree of accuracy, routine screening for the presence of renal artery disease cannot be recommended at this time. There are several reasons for this: (1) No evidence indicates that identifying renal artery disease in patients without clinical manifestations will be of any benefit to the patient. Treatment is only advised for specific clinical manifestations (hypertension, renal failure, and pulmonary edema), not for “asymptomatic” renal artery stenosis. (2) Noninvasive screening of renal artery disease by duplex ultrasound is not readily available. Far fewer laboratories are capable of performing high-quality renal artery duplex ultrasound than ultrasound in other vascular territories; therefore, it would be difficult to initiate a widespread screening program. (3) No cost–benefit data are available on the use of duplex ultrasound to screen for renal artery disease. (4) Other imaging tests, such as MRA or CTA, clearly would not be cost-effective. The ongoing Cardiovascular Outcomes in Renal Atherosclerotic Lesions Trial (CORAL), a randomized treatment trial of patients with renal artery stenosis, should provide additional insight.4RecommendationsRecommendations refer to the use of the 4 tests discussed above for screening in appropriately targeted populations. The low cost, high yield, and strong prognostic significance of the ankle–brachial index suggest it would be appropriate as a screening tool. No randomized trial data for this exist, nor is such an evaluation planned. A careful cost-effectiveness analysis is a high priority. Carotid duplex ultrasound is more expensive and more technically challenging than the ankle–brachial index. Randomized screening trial data for carotid duplex ultrasound are unavailable, and no studies of this nature are currently planned. A cost-effectiveness analysis would be useful. No recommendation for ultrasound screening for carotid artery disease can be made at this time. Ultrasound for AAA detection has strong clinical trial support in appropriate populations, and its use is likely to become more widespread. Finally, duplex ultrasound for renal artery disease has the weakest evidence base among the screening tests discussed herein and thus is problematic for use in screening; however, an ongoing treatment trial of patients with renal artery stenosis should provide additional insight.Writing Group 3: Vascular Magnetic Resonance and Computed Tomographic ImagingOver the past 10 years, there has been rapid adoption of new technology that has enabled imaging of the vascular system in a noninvasive manner with CTA and MRA for carotid, renal, and peripheral vascular diagnostic examinations. The goal of Writing Group 3 was to review the evidence-based approach to selection of these imaging modalities.Multidetector-row computed tomographic (CT) scanners provide excellent images of the vascular tree from the head to the distal segments of the extremities. CTA allows acquisition of high-resolution volumetric data sets that can be viewed in multiple planes and with a variety of visualization techniques. Compared with catheter-based angiography and MRA, CTA is faster and more comfortable for patients, although it has been suggested that the interpretation time may be longer than for the other imaging modalities. Physicians should be able to review images in more than the standard transverse plane, because multiplanar reformations, curved planar reformations perpendicular to the median arterial centerline, volume rendering, and maximum-intensity projections all have different advantages and disadvantages. Rapid advances in MRA technology in the past several years have led to improved resolution, anatomic coverage, and speed of image acquisition. The lack of radiation exposure and noninvasive nature of MRA offer advantages over CT in many settings. Traditional MRA techniques include both multislice (2-dimensional) and volumetric (3-dimensionsal) time-of-flight techniques. These have shown excellent utility in carotid and intracranial applications. However, most carotid, body, and peripheral MRA currently is performed with gadolinium-enhanced sequences to improve examination speed, anatomic coverage, and small-vessel resolution. Intravenous injection of gadolinium shortens the T1 relaxation time of blood, which leads to a transiently higher intravascular signal that can be captured with proper MRA sequence timing.CT and Magnetic Resonance Contrast AgentsIodinated contrast agents used in CT increase the risk for contrast-induced nephropathy. Patients who are considered at highest risk are those with renal insufficiency, especially those with diabetes mellitus. Other risk factors for contrast-induced nephropathy include multiple myeloma, proteinuria, concomitant nephrotoxic drug use, hypertension, congestive heart failure, hyperuricemia, and dehydration. High-osmolar contrast is associated with twice the risk of contrast-induced nephropathy as low-osmolar contrast in patients with preexisting renal impairment. Conflicting observations exist about whether iodixanol, an isosmolar nonionic dimer, is less nephrotoxic than other low-osmolar contrast material. Overall, patients with preexisting renal insufficiency are at increased risk for contrast-induced nephropathy, no matter what type of contrast is used. Physicians and facilities using contrast material should have screening programs to identify patients at high risk for contrast-induced nephropathy so that procedures can be instituted for patient safety.Gadolinium-based contrast agents used in MRA have long been touted as non-nephrotoxic. Recently, however, the safety of gadolinium in patients with severe renal insufficiency has come into question.5 The use of gadolinium in patients with renal impairment has been linked to the development of nephrogenic systemic fibrosis. Nephrogenic systemic fibrosis is still considered to be rare, with only 90 cases reported at the time of a US Food and Drug Administration advisory warning; however, it can be severely debilitating and has been linked to patient death due to respiratory compromise from diaphragmatic and cardiac involvement. In addition, acute renal failure has been reported in patients receiving high doses of gadolinium chelates (>0.3 mmol/kg), which is a fairly typical dose for lower-extremity MRA examinations.6 The patients most at risk are those with diabetic nephropathy and a low glomerular filtration rate. The greatest benefit of MRA compared with CTA in the recent past has been the use of non-nephrotoxic agents in imaging patients at high risk for iodinated contrast-induced nephropathy. That presumed benefit may no longer hold true. Physicians should be aware that there are potential nephrotoxic and systemic risks with the use of high-dose gadolinium chelates and should exercise caution in high-risk patients. Screening procedures are recommended before gadolinium use is considered in patients with any degree of renal insufficiency.Clinical ApplicationsCerebrovascular DiseaseDuplex ultrasound is a well-validated screening tool for the presence of carotid artery stenosis; however, it can be operator and patient dependent, so results are often confirmed by additional testing before treatment. Additional testing with gadolinium-enhanced MRA and occasionally CTA is used. MRA or a combination of MRA and duplex ultrasound has a sensitivity and specificity of approximately 95% and 90%, respectively, compared with digital subtraction angiography.7 CTA has a sensitivity approaching 100% for detecting >70% stenosis and a high negative predictive value.8 CT and magnetic resonance imaging now go beyond brain structural analysis to allow a comprehensive physiological assessment of stroke and its causes. CT and magnetic resonance imaging can rapidly define both the “core” of the infarcted tissue and the “penumbra,” which is the surrounding tissue at risk. The penumbra is a target for acute stroke intervention. Both the core and penumbra can be defined operationally with noninvasive CT and magnetic resonance studies that include perfusion imaging. Postprocessing algorithms create maps of the key blood-delivery perfusion parameters, including mean transit time, cerebral blood volume, and cerebral blood flow. With magnetic resonance imaging, diffusion-weighted imaging is able to detect ischemic changes within minutes of stroke onset much better than noncontrast CT. Perfusion imaging can determine whether there is tissue at risk beyond the early infarct core, that is, an ischemic penumbra that is rationally targeted for treatment.Renal Artery DiseaseDuplex ultrasound is a good technique for evaluation of renal artery stenosis; however; it is limited by operator experience, patient cooperation, and body habitus. Renal CTA and MRA are useful noninvasive imaging modalities when renal artery stenosis is suspected.CTA has a sensitivity of 94% to 100% and a specificity of 92% to 99% for significant renal artery stenosis.9 Contrast-enhanced MRA has a sensitivity of 88% to 100% and a specificity of 75% to 100%.9 Studies comparing multidetector CTA and MRA have shown them to be equally sensitive and specific for the detection of renal artery stenosis; however, patient acceptance of CTA is higher than for MRA. CTA is better than MRA for assessment of renal arteries after stent placement.Peripheral Artery DiseaseCTA or MRA is used frequently to determine the vascular anatomy and to plan treatment of patients with PAD who have lifestyle-altering claudication or critical limb ischemia. The choice of study should be based on regional availability and expertise. Multidetector CTA may visualize segments of arteries distal to occlusions that are not visible on routine digital subtraction angiography imaging. The sensitivity and specificity of multidetector CTA for PAD are 89% to 99% and 83% to 100%, respectively.10,11Gadolinium-enhanced 3-dimensional MRA examinations can be performed with a bolus chase (moving table) sequence, which allows improved visualization of the peripheral arteries. The abdominal aorta and superficial femoral segments are imaged reliably with this technique, but problems can arise with imaging of the infrapopliteal arterial segments in some patients because of venous contamination. Other techniques are being developed to help eliminate this problem, including integrated parallel acquisitions and hybrid studies with dedicated stations at the calf and foot. Hybrid MRA of the calf and foot may be able to detect target vessels for revascularization that are not visible on standard digital subtraction angiography. Sensitivity encoding or parallel acquisition, either alone or in combination with dedicated peripheral phased-array coils, has increased the speed of image acquisition of MRA so that the timing of imaging at the calf or the resolution of the imaging can be improved.RecommendationsThe writing group has identified the following important topics as areas for future research: (1) intravascular device safety at high-field-strength magnetic resonance imaging (3 Tesla and greater); (2) functional imaging for significant stenoses and clinical response to treatment; (3) lowering CT radiation exposure without sacrificing satisfactory image quality; (4) plaque characterization, especially in the carotid arteries; (5) prevention of contrast-induced nephropathy, including strategies to reduce the volume of contrast needed; (6) means of identifying patients at risk for developing nephrogenic systemic fibrosis; and (7) rapid techniques for visualizing blood vessels on magnetic resonance imaging that do not require the use of gadolinium-based contrast agents.Writing Group 4: Stroke Intervention: State of the ArtStroke remains a leading global cause of death and disability. Approaches to acute therapy for ischemic stroke include acute reperfusion, neuroprotection, and restorative and rehabilitative therapies. Writing Group 4 focused on novel and investigational therapies to reduce death and disability caused by an acute ischemic stroke.Reperfusion StrategiesIntravenous recombinant tissue plasminogen activator administered within 3 hours of stroke onset is the most widely used acute therapy, with an estimated treatment rate of 2% to 4%.12 The narrow time window, concerns about a 5% to 6% rate of intracranial hemorrhage, and lack of medical infrastructure limit its wider use. Mechanical clot removal and other endovascular approaches, although technically feasible and successful, may not work in some cases, and clinical efficacy remains somewhat limited. The use of new technologies such as telemedicine and air ambulances has the potential to extend and expand the use of acute therapies, such as intravenous recombinant tissue plasminogen activator, to a wider rural population that may be somewhat remote from large acute-care hospitals.Neuroprotection