Part 2: Antiplatelet Therapy

Search this website here!

	Web www.londonsurgeon.co.uk

BACK

Introduction to Antiplatelet Therapy:

Antiplatelet agents are used as background therapy in both the medical and surgical arms of carotid endarterectomy trials.

Antiplatelet Agents:

Aspirin:  The cheapest and most commonly used. It inhibits platelet function by acetylating prostaglandin synthesis which impairs platelet aggregation. This effect lasts for the lifetime of the platelet. Low dose aspirin (75-325mg/day) reduces the risk of vascular events in patients with prior stroke or TIA by 13%. There is no dose-effect relationship.

Dipyrimadole:  Its mechanism of action is unclear. Clinical trials have failed to demonstrate significant anti-thrombotic efficacy used alone. Nor does it add to the benefit of aspirin in secondary prevention of stroke1.

Ticlopidine:   Inhibits platelet aggregation by inhibiting ADP-induced aggregation. Its effect starts within 48 hours, peaks in 3-5 days and lasts for the lifespan of the platelet. Three trials including the Ticlopidine Aspirin Stroke Study (TASS)2 reported that ticlopidine results in a 21% reduction in stroke risk and a 12% reduction in risk for stroke and death when compared to aspirin2,3. However, Ticlopidine has more side effects than aspirin including diarrhea, rash, minor bleeding and severe neutropema (1%). It requires bimonthly neutrophil counts for three months. Recommended dose is 250 mg b.d. It does appear to be more effective than aspirin in preventing strokes in patients with TIA's without high grade carotid stenosis and in vertebrobasilar TIA's4 It is recommended for use in aspirin intolerant patients or in break through on aspirin therapy.

Clopidogrel:  A new agent that also inhibits ADP induced platelet aggregation. In the Caprie Study5 it showed a 8.7% relative risk reduction over aspirin for ischaemic stroke, Ml and vascular death. It is safer than ticlopidine in terms of side effects and will probably replace ticlopidine as the main second line antiplatelet drug after aspirin. Dose is 75mg/day.

Platelet GPIIb/IIIa Antagonists: These are a new generation of antiplatelet agents which block the platelet glycoproton 1lb/lIla receptor. They inhibit platelet aggregation but leave platelet adhesion intact. They are thus more platelet specific. Not available for general use at present.

CAROTID STENOSIS
Asymptomatic			Symptomatic
	Mild	Severe	<70%	>70%
Low Medical Surgical Risk	No Antiplatelet therapy	Antiplatelet therapy	Antiplatelet therapy	CEA (NASCET) then Antiplatelet therapy
High Medical Surgical Risk	Antiplatelet therapy for reasons other than stroke prevention	Antiplatelet therapy	Antiplatelet therapy	Antiplatelet therapy  Consider CEA
Abbreviations: CEA - Carotid Endarterectomy2. TASS - Ticlopidine Aspirin Stroke Study8. NASCET - North American Carotid Endarterectomy Study9.

Current Recommendations:

Low risk patients: Meta-analysis of two large trials of aspirin shows no benefit in prevention of stroke or vascular death6. There is no indication for using antiplatelet drugs for primary stroke prevention in low risk patients.

High risk patients: In patients with signs and symptoms of cerebro-vascular disease due to atherosclerosis, risk factor modification and anti-platelet therapy should be initiated for most patients. Aspirin is the drug of choice. Clopidogrel should be for patients who are aspirin intolerant, have a history of gastric ulcer or who continue to have symptoms on aspirin (aspirin failure).

Asymptomatic and symptomatic carotid stenosis: see table.

Secondary Stroke: Secondary prevention with aspirin after prior stroke or TIA reduces vascular events by 13%7. The Canadian-American Ticlopidine Study8 showed a 33.5% risk reduction of secondary stroke over placebo over a 24 month period.

Post Carotid Endarterectomy: Such patients are high risk and should continue on anti-platelet therapy following surgery.

Combination Anti-platelet therapy: No study has shown a significant benefit of combination therapy over aspirin alone6.

Anticoagulation: Eight randomised studies have shown no benefit of anticoagulation over antiplatelet therapy in preventing non cardio-embolic stroke.

References

1. Schafor, AS; Anti platelet Therapy . Am J Med 1996; 101:199-209.

2. Hass WK, Easton 3D, Adams HP, Pryce-Phillips W, Molony BA, Anderson 5, Kamm B, and the Ticlopidine Aspirin Stroke Study Group. A randomised trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med. 1989;321: 50 1-507.

3. Van Gijn J, Alga A. Ticlopidine, Trials and Torture. Stroke. 1994; 26(6):1090-1098.

4. Murray, JC, Kelly MA, Gorelicca PB. Ticlopidine: A New Antiplatelet Agent for Secondary Prevention of Stroke. Clin Neurophannacol.1994; 17(l):23-31.

5. Caprie Steering Committee: A Randomised Blinded Trial of Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (Caprie). Lancet. 1996; 348:1329-1339.

6. Cohen SH. Antiplatelet drugs in Patients with Carotid Bifurcation disease. Sem Vasc Surg 1995; 8(l):2-10.

7. Tijssen JGP. Low Dose and High Dose Salicylic Acid with and without Dipyridamole. Neurology. 1998; 51 (suppl.) 515-516.

8. Gent M, Blakely JA Easton 3D et al. The Canadian American Ticlopidme Study in Thromboembolic Stroke. Lancet. 1989; 1:1215-1220.

9. North American Symptomatic Carotid Endarterectomy Trial Collaborators: Beneficial Effect of Carotid Endarterectomy in Symptomatic Patients with High Grade Stenosis. N. Amer. J Med. 1991; 325:445-453.

CAROTID ATHEROSCLEROSIS
Part III: The Symptomatic Patient

BACK

These trials have defined the beneficial role of carotid endarterectomy for symptomatic carotid stenosis.

1. The European Carotid Surgery Trial (ECST)
   randomised 2518 patients with carotid territory stroke, T.I.A or amaurosis fugax to medical or surgical treatment. The ECST concluded that at a 3 year follow-up, the risk of ipsilateral stroke in the 70-99% carotid stenosis group was 2.8% in the surgical group and 16.8% in the medical treatment group.

2. The Veterans Administration Trial randomised 189
   patients with symptomatic carotid disease into surgical and medical treatment. At 9 months follow-up the neurological event rate for surgical patients was 7.7% compared to 19.4% for the medical group.

3. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) used 50 clinical centres to enroll patients with hemispheric transient ischemic attack monocular blindness or non disabling stroke in the presence of 30-99% carotid stenosis. Carotid endarterectomy was shown to be highly beneficial in patients with carotid stenosis of 70-99% compared to medical treatment. The cumulative risk of ipsilateral stroke at 2 years was 9% of patients randomised to surgery and 26% for medically treated patients.

Severity of Stenosis
The risk of stroke declined with decreasing severity of
stenosis.  Absolute Risk Reduction
   Stenosis     (at 2 Years after surgery.)
   90-99%     26%
   80-89%     18%
   70-79%     12%
This confirmed the importance of the degree of carotid
stenosis in predicting outcome after the initial ischemic event. Fourteen risk factors were evaluated by NASCET:

• >70 years.

• Male sex.

• >160/90mm Hg blood pressure.

• Entry event less than 30 days.

• Minor stroke rather than T.I.A.

• Stenosis greater than 80%.

• Obvious ulceration on angiogram.

• History of smoking.

• Hypertension.

• Myocardial infarction.

• Congestive heart failure.

• Intermittent claudication.

• Diabetes.

• Hyperlipidemia.

The two year stroke risk was significantly higher for patients in the medical group with more than 6 risk factors (17% from 0-5, 23% for 6, and 39% for more than 6 risk factors)2 .The similar stroke rate for the various risk groups following carotid endarterectomy translates into greater surgical benefit for patients at highest risk. A low perioperative myocardial morbidity justifies proceeding with carotid surgery and later addressing stable coronary disease, which is twice more likely than stroke to be the cause of death following uncomplicated endarterectomy.

Plaque Ulceration
NASCET angiographically defined ulceration was shown to have an increased risk of ipsilateral stroke in the medically treated group1. Hazard stroke rates at 24 months escalated from 26.3 to 73.2% as the degree of stenosis increased from 70 to 99%3. Surgically treated patients had only a slight increase of ipsilateral stroke at the highest degree of stenosis. Ulceration in the presence of a lesser stenosis (<70%) may therefore upgrade the risk of a lesion that would otherwise not benefit from endarterectomy.

Hemispheric vs Retinal T.I.A.
The relative risk of ipsilateral stroke in the medical subgroup of patients who experienced a single hemispheric T.I.A. was 3 times the risk for a retinal
T.I.A. Benefit from carotid endarterectomy was however realised in both groups.

Early Surgery Following Minor Stroke
Early endarterectomy after minor nondisabling ischemic stroke is supported by NASCET. The study reported a recurrent ipsilateral stroke rate of 4.9% within 30 days after entry into the trial and similar morbidity for carotid endarterectomy performed before and after 30 days. No relation was identified between an abnormal preoperative CT result and the risk of perioperative stroke in either group4.

Functional Status Following Surgery
Carotid endarterectomy prevented 17 strokes for every 100 patients submitted to surgery5. There is no doubt that carotid endarterectomy dramatically reduced the risk of disabling functional impairments in symptomatic patients with severe stenosis.

References

1. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445-453.

2. Ferguson GG. Current status of the prospective randomized trials of symptomatic carotid bifurcation disease. Seminars in Vasc Surg. 1995;8 (1):46-54.

3. Eliasziw M. Streifler JY, Fox AJ, Hachinski VC, Gerguson GG, Barnett HJ. Significance of plaque ulceration in symptomatic patients with high-grade carotid stenosis. Stroke 1994;22 (2):304-308.

4. Gasecki AP, Ferguson GG, Eliasziw M, Clagett GP, Fox AJ. Hachinski V. Barnett HJ. Early endarterectomy for severe carotid artery stenosis after a nondisabling stroke: Results from the North American Symptomatic Carotid Endarterectomy Trial. J Vasc Surg. 1994;20:228-95.

5. Hughes RB. Taylor DW, Sackett DL, et al: Prevention of functional impairment by endarterectomy for symptomatic high grade stenosis. JAMA. 1994; 271:1256-1259.

CAROTID ATHEROSCLEROSIS
Part IV: Asymptomatic Carotid Stenosis

BACK

Introduction
While the management of symptomatic carotid stenosis is now well defined, the management of asymptomatic carotid stenosis (ACS) remains controversial. Surgery for ACS aims to prevent neurological events. Since the risk of such events in high grade stenosis is low, significant benefit can only be achieved if the risk of operation is very small (less than 3%). The risk of a stroke in ACS may be increased by the severity of stenosis, the type of plaque1,2 (soft friable plaques are more likely to cause strokes or Transient Ischaemic Attacks (TIAs) than firm collagenous ones), the presence of bilateral stenosis or contralateral occlusion and progressively occlusive carotid disease3.

Natural History
Of symptomatic high grade carotid stenosis indicates that the lesions are not entirely benign. The annual stroke rate for critical ACS is 2-5% pa. Carotid artery stenosis is usually identified after TIA but for many people cerebral infarction caused by embolic or carotid occlusion is the initial event. When the carotid artery occludes, a disabling stroke may occur in 20 % of patients and thereafter in 1.5 to 5 % annually4. A serial follow-up study based on duplex scanning strongly suggested that the finding of an 80-99% stenosis of the internal carotid artery identified a group of patients at high risk of TIA, stroke or occlusion. Such patients had a 46% incidence of one of these events within a 36-month period. The risk of stroke alone in this group of patients was 12.5% 5.

Does Carotid Endarterectomy (CEA) change the natural history?
A non-randomised study by Moneta et al.6 suggested that in patients with high grade ACS, those treated medically were
more likely to experience neurological symptoms and carotid occlusion (45%) than the surgically treated group (9%).A number of trials have looked at this question. The Casanova Trial (1991) from Germany and the Veterans Administration Trial (1991) suggested that CEA does offer an advantage over medical treatment in high grade ACS, but felt that large studies were necessary to evaluate this. The largest randomised study to date is the Asymptomatic Carotid Artery Study (ACAS) in the USA which recruited 1662 patients who had 60-99% internal carotid artery stenosis and were randomised to receive medical therapy or surgery. The results of this trial have been interpreted by different groups to back up their own viewpoints. The trial showed that the estimated 5-year risk of ipsilateral stroke or any perioperative stroke or death was 11% for the medical group and 5.1% for the surgical group, i.e. a reduction of 55%. The benefit was mainly in men. This has led many physicians in the USA to feel that CEA has a clear role in haemodynamically significant ACS. Looking at it from another viewpoint, the overall estimated stroke reduction was only from 2% to 1% per year meaning that 100 operations would need to be done to prevent one stroke. Many feel that this is not cost effective. Thus the general feeling in the UK at present is that ACS should be treated medically.

The Future
This lies in identifying high-risk subgroups with ACS who may benefit from prophylactic carotid endarterectomy. The ACAS failed to do but hopefully the current British trial (ACST) will. There may be a suggestion7 that those patients with bilateral critical carotid stenosis or a tight stenosis ipsilaterally and a contralateral occlusion may be the subgroups that may benefit from surgery.

References

1. Bassiouny HS, Davis H, Massana et al. Critical carotid stenosis: Morphological and chemical similarities between symptomatic and asymptomatic plaques. J Vasc Surg 1989; 9:202-2 12.

2. Sterpetli AV, Schult RS, Feldmans RS et al. Ultrasongraphic features of carotid plaques and the risk of subsequent neurological defects. Surgery 1988; 104:652-668.

3. Hafner CD. Totally and nearly occluded extra cranial internal carotid arteries. In Ernst CB, Stanley IC (eds) Current therapy in vascular disease, Philadelphia PA, BC Decker, 1987: pg 46.

4. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid stenosis. JAMA; vol 273 (18): 1421-1428.

5. Roederer GO, Langlois YE, Jager KA et al. The natural history of carotid arterial disease in asymptomatic patients with cervical bruits. Stroke 1984; 15: 605.

6. Moneta GL, Taylor DC, Nicholls SC et al. Operative versus non-operative management of asymptomatic high grade internal carotid artery stenosis. Improved results with carotid endarterectomy. Stroke 1987; 18: 1005-1010,

7. Schneider JR. Which asymptomatic patients should have carotid endarterectomy? J Vasc Surg 1998; Vol 11(1): 12-18.

8. Collins R, Pots R et al. Blood pressure, stroke and coronary artery diseases. Part 2. Short term reduction in blood pressure: overview of randomised trials in their epidemologique context. Lancet 1990; 335: 827-838.

9. Hennerici M, Kleophas W, Gries FA. Regression of carotid plaques during LDL cholesterol elimination. Stroke 1992; 23: 693-696.

10. Kushner M, Nencini P et al, Relation of hypoglycaemia early in ischaemic brain infarcation to cerebral anatomy, metabolism and clinical outcome. Ann Neurology 1990; 28: 129-135.

11. Donahue RP, Abbott RD et al. Alcohol and haemorrhagic stroke. JAMA 1986; 255: 2311-2314.
    

Telephone : 01932 877854
Facsimile: 01932 877846

Home Page

Publications

Carotid disease

Varicose veins

Aneurysm surgery

Femoro - distal bypass

Endoluminal surgery

Thyroid disease

Vascular Surgery

Thyroid disease

Links

Contact us