Vertebrobasilar insufficiency
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: VBI
Overview
Vertebrobasilar insufficiency (VBI), or vertebral basilar ischemia, refers to a temporary set of symptoms due to decreased blood flow in the posterior circulation of the brain. The posterior circulation supplies blood to the medulla, cerebellum, pons, midbrain, thalamus, and occipital cortex (responsible for vision). Therefore, the symptoms due to VBI vary according to which portions of the brain experience significantly decreased blood flow. In the United States, 25% of strokes (see stroke) and transient ischemic attacks (see transient ischemic attack) occur in the vertebrobasilar distribution. These must be separated from strokes arising from the anterior circulation, which involves the carotid arteries.
Historical Perspective
overview
Vertebrobasilar insufficiency is a pathological hypoperfuse of the posterior circle of brain characterized by an series of symptoms due to insufficient blood flow to the related brain area.The concept “vertebrobasilar insufficiency was first described in 1961 by NIEDERMEYER E.[1]Throughout history many renowned researchers and health care professionals have contributed to the understanding, definition, and recognition of vertebrobasilar insufficiency.
The syndrome of vertebrobasilar insufficiency was first described no later than 1969 by German docters Pfaltz CR, Richter HR.[2]The first surgical treatment was first suggested in 1971 to remedy the vertebrobasilar insufficiency caused by cervical spondylosis[3]And in 1978,the carotid endarterectomy was proved to produced relief of symptoms in 90% of the patients.[4]A 3-steps approach to diagnosis the VBI was put forward in 1979.[5]In the recent 30 years,different kinds of surgery was rapidly developed to treat the VBI,such as microsurgey,fenestration,passby surgery,angioplasty.With the development of interventional techniques,more and more attemps have been made to treat the VBI,but there isn't enough comparative evidence to support the benefit of interventional therapy.
Pathophysiology
The vertebral and basilar arteries supply the brainstem, cerebellum, and in most cases also the inferior temporal lobe, occipital lobe, and the thalamus.Variaties of reasons lead to impress the vertebral artery directly or indirectly can reduce the blood stream of posterior circulation of the brain; stimulation caused by the pathologic changes excite the sympathetic nerve and lead to the spasm of vertebral artery finally.Normally,the reduction of blood supply of unilateral veterbrobasilar artery doesn't arouse the ischemia of brain.However,beacuse of the pre-existing maldevelopment,stenosis,embolism or other reasons leads to the reduction of blood supply of contralateral veterbrobasilar artery, patient will suffer the symptoms of ischemia of conrresponding brain area.Sometimes,the reduction of unilateral vertebralbasilar is too serious that the compensation of blood from the unjuried side isn't enough to maintain the normal function of brain,the patient also suffer the symptoms.The sense organs of the visual, vestibular, and propri- oceptive systems are connected with the cerebellum by way of the vestibular nuclei in the brainstem. Any disease that interrupts the integration of these 3 systems may give rise to symptoms of vertigo and disequilibrium.[6]
Causes
Life Threatening Causes
Common Causes
The most common causes of posterior circulation ischaemia are cardioembolism, large artery athero- sclerosis, and small artery disease.[7]
Causes by Organ System
| Cardiovascular | Intracranial atherosclerosis , vertebral artery dissections ,maldevelopment or absent of unilateral vertebral artery,arterial embolism |
| Chemical / poisoning | No underlying causes |
| Dermatologic | No underlying causes |
| Drug Side Effect | No underlying causes |
| Ear Nose Throat | No underlying causes |
| Endocrine | No underlying causes |
| Environmental | No underlying causes |
| Gastroenterologic | No underlying causes |
| Genetic | No underlying causes |
| Hematologic | No underlying causes |
| Iatrogenic | physiatric cervical manipulation |
| Infectious Disease | No underlying causes |
| Musculoskeletal / Ortho | Cervical spondylosis ,degenerative cervical spine changes ,cervical compressive lesions ,Cervical tuberculosis,Cervical injury,osteoporosis |
| Neurologic | No underlying causes |
| Nutritional / Metabolic | No underlying causes |
| Obstetric/Gynecologic | No underlying causes |
| Oncologic | No underlying causes |
| Opthalmologic | No underlying causes |
| Overdose / Toxicity | No underlying causes |
| Psychiatric | No underlying causes |
| Pulmonary | No underlying causes |
| Renal / Electrolyte | No underlying causes |
| Rheum / Immune / Allergy | No underlying causes |
| Sexual | No underlying causes |
| Trauma | Cervical injury |
| Urologic | No underlying causes |
| Dental | No underlying causes |
| Miscellaneous | Postural changes,like head rotation or extension |
Causes in Alphabetical Order
arterial embolism
cervical compressive lesions
Cervical injury
Cervical spondylosis
Cervical tuberculosis
degenerative cervical spine changes
Intracranial atherosclerosis
maldevelopment or absent of unilateral vertebral artery
osteoporosis
Postural changes
vertebral artery dissections
Differentiating Vertebral Artery Disease from other Diseases
It's wery hard to make differentia diagnosis between the high-risk posterior circulation ischaemic events and carotid artery events before brain imaging.
Epidemiology and Demographics
The incidence of VBI increases with age and typically occurs in the seventh or eighth decade of life. Reflecting atherosclerosis, which is the most common cause of VBI, it affects men twice as often as women and is more prevalent in African Americans. Patients with hypertension, diabetes, smoking, and dyslipidemias also have a higher risk of developing VBI.And intracranial atherosclerosis is more common in individuals with black African[8]or East Asian ethnic origin than in Caucasian populations[9] The stroke caused by VBI account for approximately 20% to 30%21–23 of all strokes[6] a study indicates that prev- alence of >50% vertebral and basilar arterial stenosis, and vertebrobasilar arterial stenosis was more often associated with multiple ischemic episodes and a higher risk of early recurrent stroke.[10]
Risk Factors
The risk factors of VBI is similar to arteriosclerosis: Sudden or excessive neck movement might increase the risk of vertebral artery dissection which might cause the VBI.[11]
Screening
Natural History, Complications and Prognosis
Complications
One of the complications is vertebral artery dissection. It is the development of dissection (a flap-like tear) in the vertebral artery. It is commonly associated with physical trauma but may also develop spontaneously. It is a major cause of stroke in young people.
Diagnosis
The evaluation for VBI starts with a history and physical exam, with great emphasis on the cardiovascular and neurologic exam. It also includes a work-up to exclude benign conditions (such as labyrinthitis, vestibular neuronitis, and benign paroxysmal positional vertigo) that have overlapping signs and symptoms. However, the exact work-up largely depends on the patient’s age and known risk factors. For middle-aged patients, a cardiovascular risk factor evaluation is important. This often includes a cholesterol level, lipid profile (see this [2] to determine what your cholesterol level means), ECG, and echocardiogram. If a person with VBI is under age 45 and has no evidence for atherosclerosis, a work-up for hypercoagulable states (Lupus anticoagulant, anti-cardiolipin antibodies, protein C, protein S, antithrombin III deficiencies) is indicated.
Imaging studies are rarely required to diagnose VBI, but sometimes computed tomography (CT) is performed first. The CT is extremely sensitive in detecting hemorrhage. Duplex ultrasound is widely used to identify carotid stenosis, but is much less sensitive in the detection of vertebral artery stenosis. The vertebral origin can be often, but not always, visualised, but the more distal segments of the vertebral artery cannot be directly seen However, magnetic resonance imaging (MRI) is superior to the CT in detecting ischemic changes in the vertebrobasilar distribution. Magnetic resonance angiography (MRA) also can be used to identify vertebrobasilar occlusions, but it can often overestimate the degree of occlusion.
Symptoms
Vertigo (commonly described as the environment spinning or as if the person is twirling in space) is the most recognizable and quite often the sole symptom of decreased blood flow in the vertebrobasilar distribution. The vertigo due to VBI rarely is brought on by head turning, which could occlude the ipsilateral vertebral artery and result in decreased blood flow to the brain if the contralateral artery is occluded. When the vertigo is accompanied by double vision (diplopia), graying of vision, and blurred vision, patients often go to the ophthalmologist. If the VBI progresses, there may be weakness of the quadriceps and, to the patient, this is felt as a buckling of the knees. The patient may suddenly become weak at the knee and crumple (often referred to as a “drop attack”). Such a fall can lead to significant head and orthopedic injury, especially in the elderly.
Transient ischemic attacks due to VBI will, by definition, have symptoms resolved within 24 hours. More often, however, the symptoms are very brief, lasting a few seconds to half an hour. These symptoms are often provoked by sudden and temporary drops in blood pressure. Postural changes (see orthostatic hypotension), such as getting out of bed too quickly or standing up after sitting for extended periods of time, often provoke these attacks. Exercise of the legs may also bring on the symptoms of VBI. For the sedentary older subject, going up a flight of stairs or walking the dog may be enough to cause pooling of blood in the legs and a drop in blood pressure in the distal arteries of the head. Heat and dehydration may also be contributing causes.
Dysarthria should also raise suspicion for VBI.[12]And there are also some nonspecific symptoms such as unilateral weakness; disturbances of respiration,anomalous hemodynamic change; and disorientation, confusion, and memory loss.The most frequent symptoms were dizziness (47%), unilateral limb weakness (41%), dysarthria (31%), headache (28%), and nausea or vomiting (27%). The most frequent signs were unilateral limb weakness (38%), gait ataxia (31%), unilateral limb ataxia (30%), dysarthria (28%), and nystagmus (24%).[13] Some person with vertebralbasilar insufficency are asymptomatic.In a recent hospital-based study of 3717 patients with clinically manifest atherosclerotic arterial disease, 7·6% of patients (95% CI 6·8–8·5) had an asymptomatic vertebral artery origin stenosis of at least 50% or occlusion on duplex ultrasound. [14]
Physical Examination
Physical examination of VBI isn't enough to diagnosis the disease.Normally,phsician can take several items below:
- Vital signs:In some cases, pulses and blood pressure should be checked in both arms. Most patients with subclavian steal syndrome, which can also cause vertebrobasilar artery insufficiency, have pulse or systolic blood pressure differences between the two arms[6]
- auscultated on neck:The vertebral artery bruitscan be found by auscultated,which suggest atherosclerosis.
- eyes:Positional nystagmus, induced by rapidly changing the position of the head,strongly suggests an organic vestibular disorder caused by central nervous system cause like VBI.internuclear ophthalmoplegia,unreactive pupils, skew deviation, hemianopia, and cortical blindness suggests an vertebrobasilar ischemia.[13]
- Positional testing:If no nystagmus was observed, we can choose the positional testing.In the Hallpike maneuver, patients are moved quickly from an upright seated position to a supine position and the head is turned to one side and extended (to a head-down posture) approximately 30 from the horizontal plane off the end of the stretcher. The eyes should be observed for nystagmus, and patients should be queried for the occurrence of symptoms.This test should be repeated with the head turned to the other side.[6] This test should be performed with caution because of the risk of suddenly dropping of atheromatous plaques.
- other:Some patients are obseved to have right arm weakness and expressive aphasia.
Laboratory Finding
CT
MRI
Treatment
Patients should discuss with their physician possible causes for their VBI symptoms. As discussed above, postural changes, exercise, and dehydration are some of the likely culprits. Treatment usually involves lifestyle modifications. For example, if VBI is attributed mainly to postural changes, patients are advised to slowly rise to standing position after sitting for a long period of time. An appropriate exercise regimen for each patient can also be designed in order to avoid the excessive pooling of blood in the legs. Dehydrated patients are often advised to increase their water intake, especially in hot, dry climates. Finally, when applicable, patients are often advised to stop smoking and to control their hypertension, diabetes, and cholesterol level.
In the event that a patient suffers a “drop attack,” and especially for the elderly population, the most important action is to be evaluated for associated head or other injuries. To prevent drop attacks, patients are advised to “go to the ground” before the knees buckle and shortly after feeling dizzy or experiencing changes in vision. Patients should not be concerned about the social consequences of suddenly sitting on the floor, whether in the mall or sidewalk, as such actions are important in preventing serious injuries.
Sometimes, to prevent further occlusion of blood vessels, patients are started on an antiplatelet agent (aspirin, clopidogrel, or aspirin/dipyridamole) or sometimes an anticoagulant (warfarin) once hemorrhage has been excluded with imaging.
For treatment of vertebrobasilar stenosis due to atherosclerosis, researchers from Stanford University found that intracranial angioplasty can be performed with an annual stroke rate in the territory of treatment of 3.2% and 4.4% for all strokes, including periprocedural events. Randomized control trials need to be performed.
Researchers from Poland found that the Low level laser therapy (LLLT) is a very useful treatment of patient with VBI, The main reason for improvement in global stability, balance, and other VBI symptoms is better blood perfusion.Significant improvement after therapy in headache (p=0.0005), vertigo (p<0.0000), and tinnitus (p=0.0387) and a tendency towards improved stability in all parameterswas was observed[15].
Pharmacotherapy
Aspirin and other antiplatelet drugs have been used to treat vertebrobasilar disease,however,none of the drug used in the treatment of VBI has been evaluated in the ramdomized controlled trials. For patients with acute ischemic syndromes that involve the vertebral artery territory and angiographic evidence of thrombus in the extracranial portion of the vertebral artery, anticoagulation is generally recom- mended for at least 3 months, whether or not thrombo- lytic therapy is used initially[16][17][18][19]The WASID (War- farin versus Aspirin for Symptomatic Intracranial Dis- ease) trial found aspirin and warfarin to be equally efficacious after initial noncardioembolic ischemic stroke[20][21] Ticlopidine was superior to aspirin for secondary prevention of ischemic events in patients with symptomatic posterior circulation disease.[22]
Surgery and Device Based Therapy
Operations are rarely performed to treat vertebral ar- tery occlusive disease, and no randomized trials have addressed operative procedures for posterior cerebral circulation disease, but studies of surgical treatment have demonstrated the feasibility of endarterectomy and vessel reconstruction[23]
Indications for Surgery
In appropriately selected patients,if the patients suffer the atherosclerosis
- If the lesion locates at the origin,we can choose:
- trans-subclavian vertebral endarterectomy.
- transposition of the vertebral artery to the ipsilateral common carotid artery
- reimplantation of the vertebral artery with vein graft extension to the subclavian artery
- If the lesion invades the distal part,we can choose
- trans-subclavian vertebral endarterectomy
- anastomosis of the principal trunk of the external carotid artery to the vertebral artery
2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease (DO NOT EDIT)[24]
Vascular Imaging in Patients with Vertebral Artery Disease (DO NOT EDIT)[24]
| Class I |
| "1. Noninvasive imaging by CTA or MRA for detection of vertebral artery disease should be part of the initial evaluation of patients with neurological symptoms referable to the posterior circulation and those with subclavian steal syndrome. (Level of Evidence: C)" |
| "2. Patients with asymptomatic bilateral carotid occlusions or unilateral carotid artery occlusion and incomplete circle of Willis should undergo noninvasive imaging for detection of vertebral artery obstructive disease. (Level of Evidence: C)" |
| "3. In patients whose symptoms suggest posterior cerebral or cerebellar ischemia, MRA or CTA is recommended rather than ultrasound imaging for evaluation of the vertebral arteries. (Level of Evidence: C)" |
| Class IIa |
| "1. In patients with symptoms of posterior cerebral or cerebellar ischemia, serial noninvasive imaging of the extracranial vertebral arteries is reasonable to assess the progression of atherosclerotic disease and exclude the development of new lesions. (Level of Evidence: C)" |
| "2. In patients with posterior cerebral or cerebellar ischemic symptoms who may be candidates for revascularization, catheter-based contrast angiography can be useful to define vertebral artery pathoanatomy when noninvasive imaging fails to define the location or severity of stenosis. (Level of Evidence: C)" |
| "3. In patients who have undergone vertebral artery revascularization, serial noninvasive imaging of the extracranial vertebral arteries is reasonable at intervals similar to those for carotid revascularization. (Level of Evidence: C)" |
Management of Atherosclerotic Risk Factors in Patients with Vertebral Artery Disease (DO NOT EDIT)[24]
| Class I |
| "1. Medical therapy and lifestyle modification to reduce atherosclerotic risk are recommended in patients with vertebral atherosclerosis according to the standards recommended for those with extracranial carotid atherosclerosis[25][26]. (Level of Evidence: B)" |
| "2. In the absence of contraindications, patients with atherosclerosis involving the vertebral arteries should receiveantiplatelet therapy with aspirin (75 to 325 mg daily) to prevent MI and other ischemic events[27][28]. (Level of Evidence: B)" |
| "3. Antiplatelet drug therapy is recommended as part of the initial management for patients who sustain ischemic stroke or TIA associated with extracranial vertebral atherosclerosis. Aspirin (81 to 325 mg daily), the combination of aspirin plus extended-release dipyridamole (25 and 200 mg twice daily, respectively), and clopidogrel (75 mg daily) are acceptable options. Selection of an antiplatelet regimen should be individualized on the basis of patient risk factor profiles, cost, tolerance, and other clinical characteristics, as well as guidance from regulatory agencies[29][27][30][31][32][33]. (Level of Evidence: B)" |
| Class IIa |
| "1. For patients with atherosclerosis of the extracranial vertebral arteries in whom aspirin is contraindicated by factors other than active bleeding, including those with allergy to aspirin, either clopidogrel (75 mg daily) or ticlopidine (250 mg twice daily) is a reasonable alternative. (Level of Evidence: C)" |
References
- ↑ NIEDERMEYER E (1963) The electroencephalogram and vertebrobasilar artery insufficiency. Neurology 13 ():412-22. PMID: 13938491
- ↑ Pfaltz CR, Richter HR (1969) [Syndrome of vertebrobasilar insufficiency. Etiology and pathogenesis of the cochleovestibular symptoms in cerebral circulation disorders.] Arch Klin Exp Ohren Nasen Kehlkopfheilkd 193 (2):190-200. PMID: 5355581
- ↑ Smith DR, Vanderark GD, Kempe LG (1971) Cervical spondylosis causing vertebrobasilar insufficiency: a surgical treatment. J Neurol Neurosurg Psychiatry 34 (4):388-92. PMID: 5096552
- ↑ Rosenthal D, Cossman D, Ledig CB, Callow AD (1978) Results of carotid endarterectomy for vertebrobasilar insufficiency: an evaluation over ten years. Arch Surg 113 (11):1361-4. PMID: 708258
- ↑ Valvassori G, Dobben GD (1979) Vertebrobasilar insufficiency. Ann Otol Rhinol Laryngol 88 (5 Pt 1):689-92. PMID: 496201
- ↑ 6.0 6.1 6.2 6.3 Schneider JI, Olshaker JS (2012) Vertigo, vertebrobasilar disease, and posterior circulation ischemic stroke. Emerg Med Clin North Am 30 (3):681-93. DOI:10.1016/j.emc.2012.06.004 PMID: 22974644
- ↑ Markus HS, van der Worp HB, Rothwell PM (2013) Posterior circulation ischaemic stroke and transient ischaemic attack: diagnosis, investigation, and secondary prevention. Lancet Neurol 12 (10):989-98. DOI:10.1016/S1474-4422(13)70211-4 PMID: 24050733
- ↑ Markus HS, Khan U, Birns J, Evans A, Kalra L, Rudd AG et al. (2007) Differences in stroke subtypes between black and white patients with stroke: the South London Ethnicity and Stroke Study. Circulation 116 (19):2157-64. DOI:10.1161/CIRCULATIONAHA.107.699785 PMID: 17967776
- ↑ Suri MF, Johnston SC (2009) Epidemiology of intracranial stenosis. J Neuroimaging 19 Suppl 1 ():11S-6S. DOI:10.1111/j.1552-6569.2009.00415.x PMID: 19807851
- ↑ Marquardt L, Kuker W, Chandratheva A, Geraghty O, Rothwell PM (2009) Incidence and prognosis of > or = 50% symptomatic vertebral or basilar artery stenosis: prospective population-based study. Brain 132 (Pt 4):982-8. DOI:10.1093/brain/awp026 PMID: 19293244
- ↑ Kawchuk GN, Jhangri GS, Hurwitz EL, Wynd S, Haldeman S, Hill MD (2008) The relation between the spatial distribution of vertebral artery compromise and exposure to cervical manipulation. J Neurol 255 (3):371-7. DOI:10.1007/s00415-008-0667-3 PMID: 18185906
- ↑ Otto V, Fischer B, Schwarz M, Baumann W, Preibisch-Effenberger R (2008) Treatment of vertebrobasilar insufficiency--associated vertigo with a fixed combination of cinnarizine and dimenhydrinate. Int Tinnitus J 14 (1):57-67. PMID: 18616088
- ↑ 13.0 13.1 Searls DE, Pazdera L, Korbel E, Vysata O, Caplan LR (2012) Symptoms and signs of posterior circulation ischemia in the new England medical center posterior circulation registry. Arch Neurol 69 (3):346-51. DOI:10.1001/archneurol.2011.2083 PMID: 22083796
- ↑ Compter A, van der Worp HB, Algra A, Kappelle LJ, Second Manifestations of ARTerial disease (SMART) Study Group (2011) Prevalence and prognosis of asymptomatic vertebral artery origin stenosis in patients with clinically manifest arterial disease. Stroke 42 (10):2795-800. DOI:10.1161/STROKEAHA.110.612903 PMID: 21852605
- ↑ Lukowicz M, Zalewski P, Bulatowicz I, Buszko K, Klawe JJ (2011) The impact of laser irradiation on global stability in patients with vertebrobasilar insufficiency: a clinical report. Med Sci Monit 17 (9):CR517-22. PMID: 21873949
- ↑ Savitz SI, Caplan LR (2005) Vertebrobasilar disease. N Engl J Med 352 (25):2618-26. DOI:10.1056/NEJMra041544 PMID: 15972868
- ↑ Caplan LR (2003) Atherosclerotic Vertebral Artery Disease in the Neck. Curr Treat Options Cardiovasc Med 5 (3):251-256. PMID: 12777203
- ↑ Canyigit M, Arat A, Cil BE, Sahin G, Turkbey B, Elibol B (2007) Management of vertebral stenosis complicated by presence of acute thrombus. Cardiovasc Intervent Radiol 30 (2):317-20. DOI:10.1007/s00270-006-0016-9 PMID: 16988872
- ↑ Eckert B (2005) Acute vertebrobasilar occlusion: current treatment strategies. Neurol Res 27 Suppl 1 ():S36-41. DOI:10.1179/016164105X25324 PMID: 16197822
- ↑ Kasner SE, Lynn MJ, Chimowitz MI, Frankel MR, Howlett-Smith H, Hertzberg VS et al. (2006) Warfarin vs aspirin for symptomatic intracranial stenosis: subgroup analyses from WASID. Neurology 67 (7):1275-8. DOI:10.1212/01.wnl.0000238506.76873.2f PMID: 17030766
- ↑ Benesch CG, Chimowitz MI (2000) Best treatment for intracranial arterial stenosis? 50 years of uncertainty. The WASID Investigators. Neurology 55 (4):465-6. PMID: 10953174
- ↑ Grotta JC, Norris JW, Kamm B (1992) Prevention of stroke with ticlopidine: who benefits most? TASS Baseline and Angiographic Data Subgroup. Neurology 42 (1):111-5. PMID: 1734290
- ↑ Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL et al. (2011)2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. J Am Coll Cardiol 57 (8):1002-44. DOI:10.1016/j.jacc.2010.11.005 PMID:21288680
- ↑ 24.0 24.1 24.2 Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL; et al. (2011). "2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery". Circulation. 124 (4): 489–532. doi:10.1161/CIR.0b013e31820d8d78. PMID 21282505.
- ↑ "Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report". Circulation. 106 (25): 3143–421. 2002. PMID 12485966. Unknown parameter
|month=ignored (help) - ↑ Ginsberg HN, Kris-Etherton P, Dennis B; et al. (1998). "Effects of reducing dietary saturated fatty acids on plasma lipids and lipoproteins in healthy subjects: the DELTA Study, protocol 1". Arterioscler. Thromb. Vasc. Biol. 18 (3): 441–9. PMID 9514413. Unknown parameter
|month=ignored (help) - ↑ 27.0 27.1 "Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients". BMJ. 324 (7329): 71–86. 2002. PMC 64503. PMID 11786451. Unknown parameter
|month=ignored (help) - ↑ "Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration". BMJ. 308 (6921): 81–106. 1994. PMC 2539220. PMID 8298418. Unknown parameter
|month=ignored (help) - ↑ Adams RJ, Albers G, Alberts MJ; et al. (2008). "Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack". Stroke. 39 (5): 1647–52. doi:10.1161/STROKEAHA.107.189063. PMID 18322260. Unknown parameter
|month=ignored (help) - ↑ "A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee". Lancet. 348 (9038): 1329–39. 1996. PMID 8918275. Unknown parameter
|month=ignored (help) - ↑ Diener HC, Bogousslavsky J, Brass LM; et al. (2004). "Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial". Lancet. 364 (9431): 331–7. doi:10.1016/S0140-6736(04)16721-4. PMID 15276392.
- ↑ Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A (1996). "European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke". J. Neurol. Sci. 143 (1–2): 1–13. PMID 8981292. Unknown parameter
|month=ignored (help) - ↑ Sacco RL, Diener HC, Yusuf S; et al. (2008). "Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke". N. Engl. J. Med. 359 (12): 1238–51. doi:10.1056/NEJMoa0805002. PMC 2714259. PMID 18753638. Unknown parameter
|month=ignored (help)