Thienopyridines or aspirin to prevent stroke and other serious vascular events in patients at high risk of vascular disease? A systematic review of the evidence from randomized trials.

BACKGROUND AND PURPOSE: Aspirin is the most widely studied and prescribed antiplatelet drug for patients at high risk of vascular disease. We aimed to establish how the thienopyridines (ticlopidine and clopidogrel) compare with aspirin in terms of effectiveness and safety. METHODS: We did a systematic review of all unconfounded randomized trials comparing either ticlopidine or clopidogrel with aspirin for patients at high risk of vascular disease. The primary outcome was vascular events (stroke, myocardial infarction, or vascular death). Adverse outcomes were intracranial and extracranial hemorrhage, upper and lower gastrointestinal disturbances, neutropenia, thrombocytopenia, and skin rash. RESULTS: In 4 trials among 22 656 patients (including 9840 presenting with a transient ischemic attack/ischemic stroke), the thienopyridines reduced the odds of a vascular event by 9% (odds ratio 0.91, 95% CI 0.84 to 0. 98; 2P=0.01), preventing 11 (95% CI 2 to 19) events per 1000 patients treated for approximately 2 years. The thienopyridines produced significantly less gastrointestinal hemorrhage and upper gastrointestinal upset (indigestion/nausea/vomiting) than did aspirin. Both thienopyridines increased the odds of skin rash and of diarrhea (ticlopidine by approximately 2-fold and clopidogrel by approximately one third). Only ticlopidine increased the odds of neutropenia. CONCLUSIONS: The thienopyridines appear modestly more effective than aspirin in preventing serious vascular events in high-risk patients. Clopidogrel appears to be safer than ticlopidine and as safe as aspirin, making it an appropriate, but more expensive, alternative antiplatelet drug for patients unable to tolerate aspirin. However, there is insufficient information to determine which particular types of patients would benefit most, and which least, from clopidogrel instead of aspirin.

Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients.

BACKGROUND: The most widely studied and prescribed antiplatelet agent for the prevention of stroke and other serious vascular events among high vascular risk patients is aspirin. Aspirin inhibits platelet activation by inhibiting platelet cyclooxygenase and thromboxane production, and reduces the odds of a serious vascular event by about a quarter. The thienopyridines (ticlopidine and clopidogrel) inhibit platelet activation by a different mechanism to aspirin (blocking the ADP receptor on platelets), and so may be more effective than aspirin. OBJECTIVES: The objective of this review was to determine the effectiveness and safety of thienopyridine derivatives (ticlopidine and clopidogrel) versus aspirin for the prevention of serious vascular events (stroke, myocardial infarction (MI) or vascular death) in patients at high risk of such events, and specifically in patients with a previous TIA or ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (most recent search: March 1999) and the Antithrombotic Trialists' database, and also contacted Sanofi pharmaceutical company. SELECTION CRITERIA: All unconfounded, double blind, randomised trials directly comparing ticlopidine or clopidogrel with aspirin in high vascular risk patients. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Additional data were sought from the principal investigators of the largest trial. MAIN RESULTS: Four trials involving a total of 22,656 high vascular risk patients were included. The trials were of high quality and comparable. Aspirin was compared with ticlopidine in three trials (3471 patients) and with clopidogrel in one trial (19,185 patients). Allocation to a thienopyridine was associated with a modest, yet statistically significant, reduction in the odds of a serious vascular event (12. 0% vs 13.0%; OR: 0.91, 95% CI: 0.84 to 0.98; 2p = 0.01), corresponding to the avoidance of 11 (95% CI: 2 to 19) serious vascular events per 1000 patients treated for about two years. There was also a reduction in stroke (5.7% vs 6.4%; OR: 0.88, 95% CI: 0.79 to 0.98; 7 [95% CI: 1 to 13] strokes avoided per 1000 patients treated for two years). Compared with aspirin, thienopyridines produced a significant reduction in the odds of gastrointestinal haemorrhage and other upper gastrointestinal upset, but a significant increase in the odds of skin rash and of diarrhoea. However, the increased odds of skin rash and diarrhoea were greater for ticlopidine than for clopidogrel. Allocation to ticlopidine, but not clopidogrel, was associated with a significant increase in the odds of neutropenia (2.3% vs 0.8%; OR: 2.7, 95% CI: 1.5 to 4.8). In the subset of patients with TIA/ischaemic stroke, the results were similar to those for all patients combined. However, since these patients are at particularly high risk of stroke, allocation to a thienopyridine was associated with a larger absolute reduction in stroke (10.4% vs 12.0%; OR: 0.86, 95% CI: 0.75 to 0.97; 16 [95% CI: 3 to 28] strokes avoided per 1000 patients treated for two years). REVIEWER'S CONCLUSIONS: The available randomised evidence shows that the thienopyridine derivatives are modestly but significantly more effective than aspirin in preventing serious vascular events in patients at high risk (and specifically in TIA/ischaemic stroke patients), but there is uncertainty about the size of the additional benefit. The thienopyridines are also associated with less gastrointestinal haemorrhage and other upper gastrointestinal upset than aspirin, but an excess of skin rash and diarrhoea. The risk of skin rash and diarrhoea is greater with ticlopidine than with clopidogrel. Ticlopidine, but not clopidogrel, is associated with an excess of neutropenia and of thrombotic thrombocytopenic purpura.

Lead poisoning from Indian herbal medicine (Ayurveda)

OBJECTIVE: To present a case of lead poisoning following ingestion of Indian herbal medicine. CLINICAL FEATURES: A 37-year-old man presented with a history of abdominal pain, anorexia and malaise. He had recently returned from a trip to India where he had been taking two different herbal tonics. Investigation revealed low-grade hepatitis and normocytic anaemia with prominent basophilic stippling. The blood lead concentration was high, and analysis of the herbal tablets revealed a very high lead content. INTERVENTION AND OUTCOME: The patient required narcotic analgesia for abdominal pain and was treated with chelation therapy with calcium ethylenediaminetetra-acetate (calcium EDTA) for five days which resulted in a high urinary excretion of lead and resolution of his symptoms over a period of several days. CONCLUSION: Lead poisoning in Australia is usually the result of chronic industrial exposure, but practitioners should be aware of the possibility of poisoning from other domestic sources such as unglazed pottery, cosmetics and herbal remedies, especially those from Asia and India, in which lead may be present in high concentration. Patients from Asia who present with unexplained anaemia or abdominal symptoms should be asked about exposure to such sources.

Investigation of acute stroke: what is the most effective strategy?

Techniques of investigation of acute stroke syndromes have progressed rapidly in recent years, outpacing developments in effective stroke treatment. The clinician is thus faced with a variety of tests, each with different cost implications and each altering management to a greater or lesser extent. This review will concentrate on the basic tests which should be performed for all strokes (full blood count, ESR, biochemical screen, blood glucose, cholesterol, syphilis serology, chest X-ray and electrocardiogram). Additional tests may be required in selected cases: CT scan to diagnose 'non-stroke' lesions, to exclude cerebral haemorrhage if anti-haemostatic therapy is planned, and to detect strokes which may require emergency intervention (such as cerebellar stroke with hydrocephalus); echocardiography to detect cardiac sources of emboli; and in a few cases lumbar puncture and specialized haematological tests. Other tests, which are currently research tools, may be suitable for widespread use in the future including NMR, SPECT and PET scanning.

Preventing stroke by the modification of risk factors.

Epidemiologic research has revealed the major risk factors in cerebrovascular disease. This review will concentrate on three important risk factors: elevated blood pressure, the most common and important, since it is responsible for up to 70% of all strokes; raised cholesterol; and smoking. These factors are important not only because they increase the risk of stroke, but also because they are amenable to modification by drugs, diet, or other interventions. Strategies to avoid stroke can either 1) try to produce substantial reductions, usually with drugs, in the level of the risk factor in the few individuals in the population with high levels (the "high-risk" approach), or 2) try to produce modest reductions in the level of the risk factor in every individual in the population, usually not with drugs but with lifestyle modification (the "mass" approach). The prevention of stroke could best be achieved through continuing medical efforts to deal with high-risk individuals and through political strategies to encourage a healthier lifestyle in the population as a whole.