Managing and Preventing Ischemic Stroke: Part II—Risk Assessment and Prevention of Secondary Ischemic Stroke

This continuing medical education activity is sponsored by the Johns Hopkins University School of Medicine, Baltimore, Maryland. The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. These examination questions are based on the article “Managing and Preventing Ischemic Stroke: Part II—Risk Assessment and Prevention of Secondary Ischemic Stroke,” which appears on pages 41-46 in this issue of Clinical Geriatrics.

Accreditation
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation Statement
The Johns Hopkins University School of Medicine designates this education activity for a maximum of 1.0 category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.

Valid
September 1- November 30, 2004.

Estimated time: 1 hour

Educational Objectives
1. To know the benefits and risks of aspirin therapy for secondary prevention of ischemic stroke in the older population
2. To recognize the advantages and disadvantages of ticlopidine compared to aspirin
3. To recognize the advantages and disadvantages of clopidogrel compared to aspirin
4. To recognize the advantages and disadvantages of aspirin/extended-release dipyridamole combination therapy compared to aspirin

Instructions
A certificate of completion will be awarded to physicians completing the posttest and evaluation form. Please complete the following examination answer sheet and mail it with your payment of $10 (write the course number OFP# 55-0615 on your check payable to Johns Hopkins-Office of Funded Programs) to: Johns Hopkins University School of Medicine Office of Funded Programs P.O. Box 64749 Baltimore, MD 21264-4749

You will receive the certificate of completion approximately 6-8 weeks after submitting your materials.  Requests for CME credits must be received within 90 days of the publication date of the issue; void after that date. Please contact the CME office at (410) 614-6152, Fax (410) 614-7315, if you have any questions.
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Treatment of elderly patients with cerebral ischemic events represents a significant health care resource burden. It is important to determine whether secondary prevention strategies are being used effectively to manage patients diagnosed with atherosclerosis, a major potential contributor to ischemic stroke.¹ The risk of secondary stroke in elderly patients following acute myocardial infarction (MI) is lower than the risk following transient ischemic attack (TIA) or stroke. Reduction of cholesterol with simvastatin² or pravastatin³ can reduce the stroke rate by 33% for patients with coronary artery disease. Patients older than 80 years are at high risk for stroke complications after coronary artery bypass graft surgery, and in patients who undergo on-pump surgery, stroke may occur four times as often as in patients of this age group who undergo off-pump surgery.⁴ Cigarette smoking is a significant risk factor for stroke. This risk may be reduced to a level similar to that of nonsmokers after three years of abstinence. With recent increases in life expectancy in the United States, elderly patients should be encouraged to stop smoking to reduce incidence of MI and pulmonary disease as well as stroke. Other considerations in elderly patients include evaluation of polypharmacy, with concern for the potential of drug-drug interactions (a factor in subsequent therapy selection); assessment of nutritional status; and issues of compliance (patient’s cognitive status, caregiver or patient knowledge base of condition and therapy requirements, physical capacity to comply with therapy requirements, social services review for assistance needs). If elderly stroke patients cannot afford their prescriptions, they will not be in compliance with secondary prevention pharmacotherapy.

Pharmacotherapy for Secondary Prevention of Ischemic Stroke

Secondary prevention therapy for ischemic stroke patients who have had either multiple TIAs or a primary ischemic stroke must be tailored to the cause,⁵ not to the current level of damage. For this reason, therapy for the secondary prevention of stroke may differ considerably from therapy for the secondary prevention of acute MI.

Antiaggregant therapy

Platelet antiaggregant therapy has a role for both primary and secondary stroke prevention. Patients with TIA who present with carotid stenosis of less than 70% may be treated with this therapy.⁶ Anticoagulation with warfarin has no advantage over aspirin therapy for patients with stroke that is not due to a cardioembolic source.⁷ Currently, four oral platelet-antiaggregation agents may be used as therapy to prevent secondary ischemic stroke: aspirin, aspirin plus extended-release dipyridamole (ERDP), clopidogrel (CP), and ticlopidine (TP).⁸ Platelet antiaggregant therapy with TP, CP, or aspirin-plus-ERDP capsule has been shown to be effective or slightly more effective (depending on the agent) than standard treatment with aspirin.⁹

Ticlopidine
The Ticlopidine Aspirin Stroke Study (TASS)¹⁰ compared TP and aspirin in more than 3000 patients with TIA or mild ischemic stroke, initiating therapy within 3 months of the event with mean follow-up of 3.4 years. Ticlopidine significantly reduced the risk of stroke (relative risk reduction 21%; P = 0.024) and the risk of stroke plus death (relative risk reduction 12%; P = 0.048) compared to aspirin. The Canadian American Ticlopidine Study (CATS)¹¹ compared TP with placebo in more than 1000 patients with ischemic stroke within the previous 1-16 weeks with mean follow-up for 2 years. Ticlopidine did not show a benefit for reducing the risk of stroke alone, but a significant benefit for preventing stroke, MI, or vascular death (relative risk reduction 30%; P = 0.006). The recently completed Aspirin American Antiplatelet Stroke Study did not show a benefit of ticlopidine over aspirin for the prevention of recurrent stroke in African-American patients.¹² Ticlopidine has serious side effects that limit its use.¹³ Ticlopidine showed severe neutropenia (2%) reversible only by TP cessation and had significantly higher rates of rash and diarrhea than aspirin. There was also a risk of potentially fatal thrombotic thrombocytopenic purpura.¹⁴ Conversely, patients on TP had significantly lower rates of gastritis, ulcer, and gastrointestinal (GI) bleeding than patients on aspirin therapy.¹⁰

Clopidogrel
In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial,¹⁵ more than 6000 patients with recent ischemic stroke formed one of three cohorts. The remaining cohorts were composed of patients with recent MI and symptomatic peripheral arterial disease. The relative risk reduction for the collective endpoint of recurrent stroke, MI, or vascular death produced by CP compared to aspirin in the intention-to-treat analysis of post-stroke patients was 8.7% (P = 0.043). The rate improved slightly to 9.4% in the on-treatment analysis, but was not significant for prevention of stroke alone. Clopidogrel is safer than TP, but has a higher adverse event rate of diarrhea and rashes or skin disorders than aspirin.¹⁵ Caution should be exercised when CP is administered with nonsteroidal anti-inflammatory drugs. The reduction of the endpoint events with CP (nonfatal or fatal stroke, nonfatal or fatal MI, or other vascular death) was only marginally reduced (P = 0.045) compared with aspirin.¹⁵ Combination of aspirin and CP is more effective than CP alone for acute coronary syndromes but increases the risk of bleeding by 50%.¹⁶ Combination therapy is currently being studied in stroke patients.

Aspirin plus extended-release dipyridamole
In the Second European Stroke Prevention Study (ESPS2), patients with stroke or TIA within 3 months prior to entry were randomized to treatment with aspirin alone (50 mg daily), ERDP as monotherapy (400 mg daily), a combined formulation of ERDP (200 mg) and aspirin (25 mg) daily, or placebo. Primary endpoints were stroke, stroke or death, and death. The secondary endpoint was combined as “vascular events,” including TIA, vascular death, nonfatal stroke, nonfatal MI, or other nonfatal vascular events. Vascular death or other nonfatal vascular events included pulmonary embolus, deep vein thrombosis, peripheral artery obstruction, and retinal artery occlusion. A total of 6602 patients, 61% older than 65 years, were followed on treatment for 2 years, 76.3% with stroke and 23.7% with TIA.¹⁷

Diener et al¹⁸ studied efficacy and safety of the three treatment regimens in the ESPS2 randomized trials. Compared to placebo there was an 18.1% risk reduction with aspirin alone (P = 0.013), 16.3% with ERDP alone (P = 0.039), and 37% with aspirin plus ERDP (P < 0.001). The number of patients needed to treat (NNT) to prevent one event was reduced from 31 with aspirin alone to 18 with aspirin plus ERDP. Risk of stroke or death was reduced by 13.2% with aspirin alone (P = 0.016), 15.4% with dipyridamole alone (P = 0.015), and 24.4% with aspirin plus ERDP (P < 0.001). There was a 21.0% relative risk reduction with aspirin plus ERDP versus aspirin (P = 0.005) for the combined secondary endpoint of stroke, MI, and vascular death (n = 1600).¹⁸ In the CAPRIE study, CP showed only an 8% relative risk reduction versus aspirin (P = 0.28) for stroke, and a 7.3% relative risk reduction versus aspirin (P = 0.045) for the combined secondary endpoint of stroke, MI, and vascular death in stroke patients.¹⁵ 

Headache and diarrhea were the primary reasons for early discontinuation of either of the dipyridamole regimens. Bleeding, primarily epistaxis, occurred equivalently in the aspirin monotherapy and the aspirin-plus-ERDP groups. Adverse events were mild and, compared with placebo, the significance of all adverse event categories and early discontinuations was similar (P < 0.001) in all treatment groups.¹⁷ Sivenius et al¹⁹ conducted follow-up checks on the 6602 study patients every 3 months for 2 years. There were no significant differences among the treatment groups in secondary stroke severity. The mean time to reach an endpoint of secondary stroke was longest in patients who used aspirin plus ERDP (P = 0.057), indicating that therapy with aspirin plus ERDP lengthens the time that patients remain free of recurrent stroke. The integrated study groups included a total of 2565 (39%) patients younger than 65 years; 2240 (34%) patients between 65 and 74 years; and 1797 (27%) patients 75 years and older. Compared with placebo, relative risk reductions for the endpoints stroke, stroke and/or death, and vascular events in all age groups were 11.1-27.6% with aspirin, 8-18.7% with ERDP, and 20.3-45.2% with aspirin plus ERDP, demonstrating the superiority of aspirin-plus-ERDP therapy regardless of age.¹⁹ Overall comparisons and considerations for use of platelet antiaggregant therapy in the secondary prevention of ischemic stroke are found in the Table.^17,20-22

Conclusion

Of all stroke patients, 72% are older than 65 years. One of every six strokes is secondary. Patients with a history of stroke or TIA are more likely to have stroke as a secondary event than are patients with a history of acute MI. Secondary prevention therapy for patients with TIAs or ischemic stroke must be tailored to the cause, not to the level of damage. Management of hypertension, diabetes, and hyperlipidemia serves a preventive role, but preventive management also includes advances made in platelet antiaggregant therapy. Currently, four oral platelet-antiaggregation agents are used as therapy to prevent secondary ischemic stroke: aspirin, aspirin plus ERDP, CP, and TP. Ticlopidine reduces the risk of secondary stroke significantly when compared to aspirin, but has a severe side-effect profile. Clopidogrel is safer than TP, but has a higher adverse event rate of diarrhea, rashes, and skin disorders compared to aspirin. Aspirin plus ERDP reduces the risk of secondary stroke at a rate twice that of either aspirin or ERDP alone and lengthens the time that patients remain free from recurrent stroke.

From the Neurovascular Laboratory, Department of Neurology, The Mount Sinai School of Medicine and Division of Neurology, North General Hospital, New York, NY.

Editor’s Note:  For further information on managing and preventing stroke in the older patient, the reader is referred to the first installment of this two-part article, “Managing and Preventing Ischemic Stroke: Part I—Risk Assessment and Treatment of Primary Ischemic Stroke,” which was published in the July issue of Clinical Geriatrics (2004;12[7]:48-54).