Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Review: Anticoagulants and platelet antiaggregants prevent strokes in high-risk patients

ACP J Club. 1994 Nov-Dec;121:60. doi:10.7326/ACPJC-1994-121-3-060


Source Citations

Matchar DB, McCrory DC, Barnett HJ, Feussner JR. Medical treatment for stroke prevention. Ann Intern Med. 1994 Jul 1;121:41-53.

American College of Physicians. Guidelines for medical treatment of stroke. Ann Intern Med. 1994 Jul 1;121:54-5.


Abstract

Objective

To review the effectiveness of anticoagulant and platelet antiaggregant agents for preventing stroke in patients at increased risk for stroke. Data were used to prepare clinical guidelines.

Data sources

Studies were identified using MEDLINE from 1977 to 1993 and Current Contents using search terms for the therapeutic use and adverse effects of aspirin, all anticoagulants, sulfinpyrazone, or dipyridamole in conjunction with all cerebrovascular disorders. Review articles, textbooks, and guidelines were examined for additional articles.

Study selection

Studies were selected if they were randomized controlled trials of anticoagulant or platelet antiaggregant agents that reported outcomes of subsequent stroke, death from causes other than stroke, or nonfatal major complications in patients with asymptomatic carotid stenosis or bruit, transient ischemic attack (TIA), previous stroke, nonvalvular atrial fibrillation (NVAF), or other vascular diseases. 900 studies were identified and 33 selected for inclusion.

Data extraction

Patient risk factors, treatment regimen including dose or therapeutic target, person-years of follow-up, and outcomes (absolute numbers and rates). Attributable risk (AR) (number of events avoided annually by treating 1000 patients) was calculated for the combined data.

Main results

Patients with NVAF had fewer strokes and fewer deaths from causes other than stroke when taking warfarin compared with placebo, and had fewer strokes and fewer deaths from causes other than stroke when taking warfarin compared with aspirin (Table). Patients with previous TIA or minor stroke had fewer strokes , fewer deaths from causes other than stroke , but more nonfatal major complications when taking aspirin compared with placebo, and fewer strokes and nonfatal major complications when taking ticlopidine compared with aspirin (Table). Patients with previous stroke who were taking ticlopidine had fewer subsequent strokes compared with those taking placebo (Table). Patients with previous myocardial infarction had fewer strokes when taking warfarin compared with placebo and when taking aspirin compared with placebo (Table).

Conclusion

Patients who are at increased risk for stroke have fewer strokes and lower mortality when treated with the appropriate anticoagulant or platelet antiaggregant agent.

Source of funding: Not stated.

For article reprint: Dr. D.B. Matchar, Center for Health Policy Research and Education, Duke University, P.O. Box 90253, Durham, NC 27708, USA. FAX 919-286-5601.


Table. Treatment regimens for preventing additional events in high-risk patients

Risk factor Treatment comparisons Strokes Deaths from causes other than stroke Major nonfatal complications
Attributable risk reduction* (95% CI)
NVAF Warfarin vs placebo 28 (17 to 38) 19 (8 to 30)
Warfarin vs aspirin 24 (3 to 45) 19 (3 to 36)
Attributable risk reduction (CI) Attributable risk increase (CI)
TIA or minor stroke Aspirin vs placebo 6 (1 to 11) 5 (0 to 9) 3 (2 to 5)
Attributable risk reduction (CI)
Ticlopidine vs aspirin 7 (0 to 15) 3 (1 to 5)
Stroke (major and minor) Ticlopidine vs placebo 31 (9 to 53)
Previous MI Warfarin vs placebo 11 (3 to 19)
Aspirin vs placebo 2 (0 to 4)

* Attributable risk = additional events avoided (reduction) or induced (increase) per 1000 patient-years; NVAF = nonvalvular atrial fibrillation; TIA = transient ischemic attack; MI = myocardial infarction.


Commentary

In the past five years, the International Stroke Trial (IST), Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial, and European Stroke Prevention Study 2 (ESPS-2) have shown that large collaborative randomised trials can be conducted in stroke medicine and can provide statistically and clinically significant results. They, and other current studies (e.g., Chinese Acute Stroke Trial [CAST], Trial of Org 10172 in Acute Stroke Treatment [TOAST]), have highlighted the potential hazards of early anticoagulation and the effectiveness and safety of early (and continuous) antiplatelet therapy in limiting early stroke recurrence and its consequences. In addition, they have shown that antiplatelet agents with differing mechanisms of action can have different effects and, perhaps, additive effects when combined.

Current concepts in antithrombotic strategies of secondary stroke prevention are that:

† Secondary stroke prevention strategies, using antithrombotic agents, should begin immediately after stroke (time is brain) (1, 2).

† Aspirin, given immediately after stroke, prevents one quarter of early recurrent ischemic strokes (1, 2).

† Heparins and heparinoids have little role in preventing early recurrent stroke (1, 3, 4).

† Aspirin is effective, safe, and inexpensive in limiting stroke recurrence but is not effective enough, preventing only a small minority of major vascular events (5).

† Stroke prevention strategies should be targeted at the underlying cause, and antithrombotic treatments should be tailored to the type of cardiovascular disease.

† Antiplatelet agents with a different mechanism of action to that of aspirin (e.g., adenosine diphosphate antagonists such as clopidogrel) may be more effective in limiting stroke recurrence [6]).

† The combination of antiplatelet agents with different mechanisms of action (e.g., aspirin plus dipyridamole) may have additive effects in preventing stroke recurrence (7).

† Oral anticoagulation is more effective than aspirin in preventing stroke among high-risk fibrillating patients, such as those with recent TIA or stroke, or a history of hypertension or diabetes (8, 9).

† Oral anticoagulation (International Normalized Ratio [INR] 3.0 to 4.5) is hazardous in patients with cerebral ischemia resulting from arterial disease, particularly in the elderly with leukoariosis (10).

† Oral anticoagulation (INR 2.0 to 3.0) may be safe and effective in selected patients with cerebral ischemia from arterial disease and is presently being studied (11, 12).

It is hoped that future trials will determine the role in secondary stroke prevention of inhibitors of the platelet glycoprotein IIb/IIIa complex (the final common pathway of platelet aggregation), the combination of antiplatelet agents with different mechanisms of action (e.g., aspirin and clopidogrel, aspirin and IIb/IIIa inhibitors), the combination of antiplatelet agents and oral anticoagulants (which may simultaneously modify platelet function and fibrin production), and the combination of antithrombotic and cholesterol-lowering (statin) medication (13).

Graeme J Hankey, MBBS, MD
Royal Perth Hospital and University of Western AustraliaPerth, Western Australia, Australia


References

1. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet. 1997;349:1569-81.

2. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet. 1997;349:1641-9.

3. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA 1998;279:1265-72.

4. Sandercock PA, Gubitz G, Counsell C, Signorini D. Immediate anticoagulant therapy for acute ischaemic stroke. Part 1: A systematic review of 21 randomised trials of anticoagulant vs control, including 23,374 patients [Abstract]. Stroke. 1999;30:248.

5. Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J Neurol Neurosurg Psychiatry. 1996;60:197-9.

6. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329-39.

7. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1-13.

8. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993;342:1255-62.

9. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154:1449-57.

10. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol. 1997;42:857-65.

11. WARSS Study Group. The feasibility of a collaborative double-blind study using an anticoagulant. Cerebrovasc Dis. 1997;7:100-12.

12. ESPRIT (European and Australian Stroke Prevention in Reversible Ischemia) Trial. Anticoagulants versus aspirin and the combination of aspirin and dipyridamole versus aspirin only in patients with transient ischaemic attacks or nondisabling ischaemic stroke. Stroke. 1999;30:487-91.

13. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. (The Database of Abstracts of Reviews of Effectiveness.). In: The Cochrane Library. Oxford: Update Software.