Antiplatelet drugs in cardiovascular prevention: stroke prevention in patients with thrombogenic heart disease

(1) In patients with atrial fibrillation and a moderate embolic risk, aspirin reduces the risk of stroke and has a comparable risk-benefit ratio to oral anticoagulants. (2) Oral anticoagulants are superior to aspirin in patients with atrial fibrillation and a history of stroke. (3) In patients with a mechanical valve prosthesis and a high embolic risk, the oral anticoagulant + aspirin combination has a better risk-benefit ratio than oral anticoagulant alone.     

Antiplatelet drugs in cardiovascular prevention: coronary events: acute phase and secondary prevention

(1) Aspirin reduces acute-phase mortality after myocardial infarction, and also reduces the risk of myocardial infarction and death in patients with unstable angina. Aspirin reduces the risk of myocardial infarction in patients with stable angina and after unstable angina, and the risk of relapse after myocardial infarction. It reduces the risk of complications during coronary angioplasty, and the risk of venous coronary bypass graft occlusion after coronary surgery. (2) The best risk-benefit ratio with aspirin is achieved at a daily dose of 75-350 mg; 160 mg/day is the best-validated dose in the acute phase of myocardial infarction. (3) Aspirin must be combined with a thrombolytic agent in patients with myocardial infarction, and with heparin in patients with unstable angina. During coronary stenting the aspirin + clopidogrel combination may have a better risk-benefit ratio than the aspirin + ticlopidine combination. (4) Clopidogrel can be used when aspirin is contraindicated or poorly tolerated. (5) Oral anticoagulants seem a better option than aspirin after complicated myocardial infarction.     

Ischaemic stroke: acute-phase drug therapy. Mostly aspirin and heparin

(1) In the acute phase of ischaemic stroke, antiplatelet or anticoagulant treatments reduce the risk of recurrence and pulmonary embolism, but carry a risk of haemorrhagic transformation. (2) Aspirin has been tested in several placebo-controlled trials and has a positive risk-benefit balance, preventing about 5 deaths per 1000 patients with ischaemic stroke. Aspirin must be given as soon as computed tomography has ruled out intracerebral haemorrhage, unless thrombolytic treatment is planned. (3) Heparin has as many potential benefits as risks: it tends to be beneficial at low doses but harmful at high doses. Low-dose heparin therapy appears to be justified, especially for patients with emboligenic heart disease, tight carotid stenosis, or at risk of pulmonary embolism. Higher-dose heparin is only warranted for the rare patient with a high thrombotic risk. (4) Some thrombolytic drugs can reduce the frequency and severity of complications, but their use carries a high immediate risk of aggravation or death by haemorrhagic transformation. Alteplase has a somewhat positive risk-benefit balance in certain highly specific situations: for example, in some patients with persistent ischaemic stroke who are treated within three hours of onset, and without signs of severe stroke or risk factors for bleeding (high blood pressure, aspirin use). (5) Clinical trials have shown that routine use of "neuroprotective" treatments (calcium channel blockers, haemodilution, parenteral magnesium, oxygen therapy) does not reduce the risk of death or disability. (6) Arterial hypertension frequently occurs in the immediate aftermath of stroke, and then generally subsides. Few clinical trials have evaluated the use of antihypertensive drugs in this setting and there is little evidence of benefit. One trial showed that a sudden drop in blood pressure led to neurological aggravation. Antihypertensive drugs should only be used in stroke patients with severe hypertension or cardiac complications. (7) Cerebral oedema is an important cause of death after stroke: treatments (especially mannitol, mechanical ventilation and neurosurgery) have been poorly evaluated. (8) Other treatments recommended only for patients with persistent complications include oxygen therapy, antibiotics, paracetamol, insulin, and anticonvulsants. (9) A controversial meta-analysis suggested that management by a specialised multidisciplinary team reduced the mid-term risk of death and disability in comparison with management in a non specialised unit.     

Aspirin or heparin in acute stroke

Acute stroke treatment using aspirin and/or heparin was studied in the International Stroke Trial (IST) and Chinese Acute Stroke Trial (CAST) which randomised over 40,000 patients altogether. Combining the results demonstrated that aspirin (150-300 mg) given within 48 h of the onset of stroke produced a small but significant improvement in outcome (death or dependency) 4 weeks to 6 months after stroke of about 1 patient per 100 treated. There was a significant reduction in recurrent ischaemic stroke of similar degree, which was not associated with significant increase in cerebral haemorrhage. Therefore, aspirin should be used as early secondary prevention against recurrent stroke, after excluding cerebral haemorrhage by scanning the patient. Heparin does not improve clinical outcome after stroke even in patients in atrial fibrillation. It decreased recurrent ischaemic stroke significantly in IST, but at the cost of a significant increase in cerebral haemorrhage. Low molecular weight heparins and heparinoids have not proved any more beneficial. Therefore, heparin does not appear to be a useful routine therapy in acute stroke. The use of heparin should, therefore, be limited to patients at high risk of deep vein thrombosis or early recurrence.     

Risk-benefit assessment of anticoagulant therapy

Thromboembolic disease is a common medical condition which, if untreated, carries a significant risk of morbidity and mortality. Treatment with anticoagulant therapy, while clearly beneficial, may expose patients to potentially serious side effects. A thoughtful risk-benefit assessment is therefore crucial before initiating therapy. Thromboembolic disease involves syndromes of both the venous and arterial circulation, and its pathogenesis is best understood by considering the elements of Virchow's Triad. This model defines the risk factors for venous thromboembolism and allows us to classify surgical and medical patients into low, moderate and high risk groups. Similar analysis allows risk assessment for patients prone to cardiogenic embolism resulting from nonvalvular atrial fibrillation, ischaemic heart disease, rheumatic heart disease and valvular prostheses. All anticoagulant therapy is prophylactic. Primary prophylaxis involves instituting anticoagulant therapy in patients at risk, before thromboembolism occurs, while secondary prophylaxis involves treating patients with established disease. The 2 major anticoagulants, heparin and warfarin, differ in their mechanism of action, mode of administration and methods of monitoring. Either may be used as primary or secondary prophylaxis. Heparin, because it acts immediately, is the drug of choice for the short term treatment of thromboembolic disease. Warfarin is the drug of choice for long term oral maintenance therapy. The principal complication of heparin therapy is haemorrhage, although thrombocytopenia and osteoporosis may also occur; the complications of warfarin include haemorrhage and skin necrosis. The risks of complications vary with the underlying thromboembolic disease. After the benefits of treatment are weighed against the risks of complications, recommendations for therapy can be established. The use of anticoagulants in pregnancy is especially complex. Here heparin is probably the preferred agent since, unlike warfarin, it does not cross the placenta and is nonteratogenic.     

Optimising stroke prevention in non-valvular atrial fibrillation

Atrial fibrillation is associated with substantial morbidity and mortality. Pooled data from trials comparing antithrombotic treatment with placebo have shown that warfarin reduces the risk of stroke by 62%, and that aspirin alone reduces the risk by 22%. Overall, in high-risk patients, warfarin is superior to aspirin in preventing strokes, with a relative risk reduction of 36%. Ximelagatran, an oral direct thrombin inhibitor, was found to be as efficient as vitamin K antagonist drugs in the prevention of embolic events, but has been recently withdrawn because of abnormal liver function tests. The ACTIVE-W (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) study has demonstrated that warfarin is superior to platelet therapy (clopidogrel plus aspirin) in the prevention af embolic events. Idraparinux, a Factor Xa inhibitor, is being evaluated in patients with atrial fibrillation. Angiotensin-converting enzyme inhibitors and angiotensin II receptor-blocking drugs hold promise in atrial fibrillation through cardiac remodelling. Preliminary studies suggest that statins could interfere with the risk of recurrence after electrical cardioversion. Finally, percutaneous methods for the exclusion of left atrial appendage are under investigation in high-risk patients.     

Aspirin and primary cardiovascular prevention. Uncertain balance between benefits and risks

Most individuals with no pre-existing cardiovascular disease have a low risk of experiencing arterial thrombosis. Using the standard Prescrire methodology, we reviewed the literature on the risk-benefit balance of aspirin in the primary prevention of cardiovascular events. In the general population, a meta-analysis in 95 456 persons suggests that aspirin has no effect on either total or cardiovascular mortality. Aspirin may slightly reduce the risk of stroke in women and myocardial infarction in men, but it increases the risk of bleeding. It is unclear whether the benefits outweigh the risks. Aspirin does not reduce mortality in the elderly. in one trial, aspirin reduced the risk of ischaemic stroke and myocardial infarction in women aged 65 and over. However, the risk of cerebral haemorrhage associated with aspirin increases with age. Therefore, the risk-benefit balance of aspirin in primary cardiovascular prevention in the elderly is uncertain. Aspirin is more beneficial in patients with cardiovascular risk factors, but the bleeding risk is sometimes higher too. In clinical trials, aspirin did not reduce either total or cardiovascular mortality in hypertensive or diabetic patients. In contrast, it reduced the risk of myocardial infarction in hypertensive patients and diabetic men. Aspirin did not prevent cardiovascular events in smokers, and has not been assessed in patients with hypercholesterolaemia. In practice, the risks outweigh the benefits when aspirin is used to prevent a first thrombotic event in people at low risk. When the cardiovascular risk is higher than in the general population, for example in patients with risk factors, the weak preventive effects of aspirin on myocardial infarction and ischaemic stroke may outweigh the small extra risk of bleeding. The possible value of aspirin for cardiovascular prevention should be discussed with each individual patient. In general, it is preferable to recommend measures with a proven impact on mortality, such as dietary changes, smoking cessation, or drug therapy for patients with risk factors.     

Clopidogrel: a review of its use in the prevention of atherothrombosis

Clopidogrel is an ADP receptor antagonist that is indicated for the reduction of atherosclerotic events including myocardial infarction, ischaemic stroke and vascular death in patients with atherosclerosis manifested by recent stroke, myocardial infarction or established peripheral vascular disease. In the 19 185 patients enrolled in the multicentre, randomised double-blind CAPRIE study, the annual risk of the combined end-point of ischaemic stroke, myocardial infarction and death from vascular disease (vascular death) was significantly lower during treatment with clopidogrel 75 mg/day than aspirin 325 mg/day [5.3 vs 5.8%/year, respectively; relative risk reduction (RRR) 8.7%, p = 0.043] after a mean follow-up of 1.9 years. Clopidogrel provided even greater reductions in the risk of recurrent ischaemic events than aspirin in patients with a history of coronary artery bypass surgery, diabetes mellitus and in those receiving concomitant lipid-lowering therapy. Moreover there was a significant reduction in the incidence of hospitalisation in patients treated with clopidogrel. In a patient population (Saskatchewan, Canada) with a greater risk of ischaemic events than the CAPRIE study population, the number of patients needed to be treated with clopidogrel to prevent 1 ischaemic event was estimated to be 70 (vs 200 in the CAPRIE study). In randomised trials and registry surveys, clopidogrel 75 mg/day plus aspirin had similar efficacy (as measured by adverse cardiac outcomes) to ticlopidine 250mg twice daily plus aspirin during the 30 days after placement of intracoronary stents. Tolerability of clopidogrel was significantly better than ticlopidine in the randomised, double-blind CLASSICS study. Among patients treated with clopidogrel or aspirin in the CAPRIE study, the overall gastrointestinal tolerability of clopidogrel was generally better than that of aspirin; the frequency of gastrointestinal haemorrhage was significantly lower among patients treated with clopidogrel than aspirin. Diarrhoea, rash and pruritis were significantly more common with clopidogrel than aspirin. CONCLUSION: Clopidogrel was significantly more effective than aspirin in the prevention of vascular events (ischaemic stroke, myocardial infarction or vascular death) [corrected] in patients with atherothrombotic disease manifested by recent myocardial infarction, recent ischaemic stroke or symptomatic peripheral arterial occlusive disease [corrected] in the CAPRIE study. The overall tolerability profile of the drug was similar to that of aspirin, although gastrointestinal haemorrhage occurred significantly less often in clopidogrel recipients. The drug is widely used in combination with aspirin for the prevention of atherothrombosis after placement of intravascular stents, and available data suggest that this combination is as effective as ticlopidine plus aspirin for this indication.     

Safety of clopidogrel and aspirin for stroke prevention: implications of the CHARISMA trial.

Antiplatelet therapy is universally recommended for the prevention of recurrent events in patients with noncardioembolic ischaemic stroke or transient ischaemic attack (TIA), acute and chronic coronary artery disease, or peripheral arterial disease. However, choosing which antiplatelet agents to use in these situations remains controversial. The use of aspirin, aspirin plus extended-release dipyridamole, or clopidogrel is recommended as initial therapy in patients with noncardioembolic ischaemic stroke or TIA to reduce the risk of recurrent stroke and other cardiovascular events. Based on the results of the MATCH trial, combination therapy with aspirin plus clopidogrel is not recommended for patients with ischaemic stroke or TIA due to the increased risk of haemorrhage.The results of the CHARISMA trial support this recommendation; despite previous data demonstrating a favourable benefit-risk profile of aspirin plus clopidogrel in patients with acute coronary syndrome, this combination should not be used in patients at high risk for atherothrombosis and those with previous stroke or TIA. In these patients, the CHARISMA trial demonstrated a lack of significant clinical efficacy and an increased risk of bleeding with clopidogrel plus aspirin compared with aspirin alone.Further research is needed to assess the benefit-risk ratio of clopidogrel plus aspirin in specific subpopulations of patients at high risk for atherothrombotic events, and to determine the role of clopidogrel plus aspirin in preventing cardioembolic stroke or early recurrent stroke after symptomatic large-vessel atherostenosis. Recent and ongoing studies are seeking to better define the roles of different antiplatelet regimens in preventing recurrent stroke.     

Use of oral anticoagulants in older patients

Recently published American and British guidelines have comprehensively reviewed the indications for long term anticoagulation. The best evidence currently available supports the use of long term oral anticoagulants in patients with nonvalvular atrial fibrillation (NVAF), venous thromboembolic disease, ischaemic heart disease, mural thrombi, and mechanical heart valves. Selected patients with valvular heart disease, cerebral vascular disease, and peripheral arterial disease may also benefit from the use of these drugs. When no specific contraindications are present, elderly patients with either paroxysmal or persistent NVAF should be considered candidates for treatment with anticoagulants. Pooled analyses of the results from 9 randomised trials demonstrate that warfarin significantly reduces the risk of ischaemic stroke in patients with NVAF, particularly those in a 'high risk' category defined by the presence of additional clinical or echocardiographic risk factors. Long term anticoagulation does not appear to be justified in patients with NVAF considered to be at 'low risk' for stroke. Because the prevalence of NVAF and most other cardiovascular conditions increases with advancing age, many elderly patients will be candidates for thromboprophylaxis. The potential benefit of long term anticoagulation must be carefully weighed against the risk of serious haemorrhage in such patients. Bleeding complications with anticoagulant drugs appear to occur more frequently in older patients than in younger individuals. Advanced age (>75 years), intensity of anticoagulation [International Normalised Ratio (INR) >4.0], history of cerebral vascular disease (recent or remote), and concomitant use of drugs that interfere with haemostasis [aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory drugs] are among the most important variables in determining an individual's risk for major bleeding with anticoagulants. Older patients often display increased sensitivity to the effects of warfarin, both in the early induction phase and during the long term maintenance phase of therapy. Conditions such as congestive heart failure, malignancy, malnutrition, diarrhoea and unsuspected vitamin K deficiency, enhance the prothrombin time response. The decision to interrupt anticoagulant therapy before elective surgery in elderly patients should evaluate the thrombotic risk of such a manoeuvre versus the risk of bleeding if anticoagulants are continued. In non-surgical patients, excessively elevated INRs without associated haemorrhage can usually be managed by simply witholding one or several doses of warfarin. If more rapid reversal is needed, small doses of phytomenadione (vitamin K1) can be administered safely without overcorrection or the development of vitamin K-induced warfarin resistance.     

Predictors of Warfarin Use in Atrial Fibrillation Patients in the Inpatient Setting

Background

There is substantial published evidence that warfarin reduces the risk of stroke in patients with atrial fibrillation (AF). However, the current literature suggests that not all patients who could benefit from warfarin receive the drug.

Objective

To evaluate patient-related demographic and clinical factors that could influence warfarin use or other anticoagulant use in hospitalized patients with AF.

Study Design

Retrospective observational study using claims data from the Wolters Kluwer Pharma Solutions Hospital Patient Level Database, evaluating characteristics of patients hospitalized in the US between 1 November 2003 and 31 October 2004.

Setting

Hospital care.

Patients

The study included 44 193 patients aged ≥40 years who were hospitalized between 1 November 2003 and 31 October 2004 and had a diagnosis of AF during hospitalization (AF did not need to be the cause of hospitalization).

Interventions

Use of warfarin or other anticoagulants (unfractionated heparin [UFH] or low-molecular-weight heparin [LMWH]) was evaluated.

Main Outcome Measures

A logistic regression model was used to identify factors associated with warfarin use, international normalized ratio (INR) monitoring, or the use of anticoagulants (UFH or LMWH).

Results

In this analysis of hospitalized patients with AF in the real-world setting, about 56% of patients received anticoagulation therapy with warfarin. Elderly patients aged ≥75 years were less likely to be treated with warfarin than younger patients, but patients between the ages of 60 and 74 years were more likely to use warfarin than their younger counterparts. Except for patients with congestive heart failure or vascular malformation, patients with other bleeding risk factors (hepatic disease, renal disease, aspirin use, and fractures) were significantly less likely to receive warfarin than those without these risk factors. CHADS₂ scores for stroke risk of 2 and 3 were associated with a significantly higher likelihood of warfarin treatment than scores of 0 or 1. Patients admitted through a routine admission (an outpatient department) were significantly more likely to be prescribed warfarin than patients admitted through an emergency room. Patients aged ≥75 years and aspirin users were more likely to have their INR monitored during hospitalization. With respect to other anticoagulant use, females and older patients (≥65 years) were less likely to use UFH or LMWH, and patients with renal disease or vascular malformation and those receiving aspirin were more likely to use UFH or LMWH than patients without these conditions/not receiving aspirin. Patients admitted through the emergency room were more likely to receive an anticoagulant than patients admitted through an outpatient department, an inpatient transfer, or any other source.

Conclusions

Older age, female sex, and certain risk factors for bleeding, including hepatic disease, renal disease, aspirin use, and fractures, were associated with a lower likelihood of warfarin treatment, while a higher stroke risk (as indicated by CHADS₂ scores) was associated with a higher likelihood of warfarin treatment, in hospitalized patients with a diagnosis of AF. The likelihood of INR being monitored increased for patients aged ≥75 years and for aspirin users. Older patients and female patients were less likely to be prescribed other anticoagulants (UFH or LMWH) also.     

Atrial fibrillation: rate control often better than rhythm control

(1) The treatment aims in atrial fibrillation are to reduce patients' symptoms and to prevent both embolism and deterioration of any underlying heart disease. Therapy consists of anticoagulant or antiplatelet drugs, treatment of any underlying heart disease, and heart rate control. (2) Digoxin, betablockers, diltiazem and verapamil slow the heart rate but rarely restore sinus rhythm. Amiodarone, disopyramide, flecainide, quinidine and sotalol can be used to prevent relapse of atrial fibrillation after electrical cardioversion, but they all have potentially serious adverse effects. New trials of antiarrhythmic treatments have been published since our last review of this subject. (3) In one trial in 403 patients, amiodarone was more effective than sotalol and propafenone in restoring and maintaining sinus rhythm. After 15 months of follow-up, there were fewer strokes among patients treated with amiodarone, but there was no difference between the three drugs in the overall incidence of cardiovascular events. (4) A clinical trial with 4060 patients compared rhythm control (mainly with amiodarone, sotalol or propafenone; sometimes combined with electrical cardioversion) and rate control (with digoxin, betablocker, diltiazem or verapamil; systematically combined with anticoagulant therapy). The antiarrhythmic treatment restored sinus rhythm in more than half the patients in the long term. But rhythm control did not reduce the risk of death or serious cardiovascular events during a mean follow-up period of 3.5 years. Rhythm control caused more adverse events than rate control; subgroup analyses (weak evidence) suggest that rhythm control may also have caused more deaths among patients over 65 and among patients with coronary heart disease. (5) In another trial, electrical cardioversion followed by antiarrhythmic therapy (mainly sotalol) sustainably restored sinus rhythm in more than one-third of 522 patients. But, compared with rate control treatment plus anticoagulant therapy, rhythm control did not reduce the risk of cardiovascular events, and was associated with a larger number of serious adverse cardiac effects. (6) Other recent trials confirm the risk of serious adverse effects, including severe arrhythmia with sotalol (especially at the start of treatment), and adverse thyroid and pulmonary effects with amiodarone. (7) Combined radiofrequency ablation and cardiac stimulation improved symptoms in some patients with incapacitating atrial fibrillation who had not responded to other treatments. However, this approach carries a risk of serious adverse effects, and its impact on the risk of cardiovascular events and death is not known. (8) In practice, an attempt should be made to restore sinus rhythm with amiodarone and/or electrical cardioversion, in symptomatic, recent or paroxysmal atrial fibrillation in patients under 65 who have no signs or symptoms of coronary heart disease. In other situations, rate control is the first-line option, using digoxin, betablockers (other than sotalol) or calcium channel blockers (diltiazem or verapamil). Whatever the option, treatment must be combined with anticoagulant or antiplatelet therapy, and with treatment of any underlying heart disease.     

Secondary prevention of stroke in patients with nonvalvular atrial fibrillation: optimal intensity of anticoagulation

Nonvalvular atrial fibrillation (NVAF) is frequently seen in elderly people and has become a main cause of cardioembolic stroke. The efficacy of anticoagulation for primary prevention of stroke or transient ischaemic attacks (TIAs) in patients with NVAF has been established by prospective, randomised and controlled trials. Warfarin decreased the frequency of all strokes by 68% and the rate of the combined outcome of stroke, systemic embolism or death by 48%. Anticoagulation with warfarin using international normalised ratios (INRs) ranging from 2.0 to 3.0 is recommended for patients with NVAF, who have any of the risk factors identified by the Atrial Fibrillation Investigators (AFI) [previous stroke or TIA, history of hypertension, diabetes mellitus, advanced age (> or = 65 years old), congestive heart failure and coronary artery disease], the American College of Chest Physicians (ACCP) [increased age (> 75 years old), prior stroke, hypertension and heart failure], or the Stroke Prevention in Atrial Fibrillation (SPAF) investigators [women > 75 years old, prior stroke, systolic blood pressure > 160mm Hg, recent heart failure, and fractional shortening < 25% on echocardiography]. For the secondary prevention of stroke, the efficacy of adjusted-dose warfarin therapy has been demonstrated by 2 major randomised trials. SPAF III (INR 2.0 to 3.0) demonstrated a lower incidence of ischaemic stroke or systemic embolism (3.4 %/year) compared with low fixed-dose warfarin plus aspirin (acetylsalicylic acid) [11.9%]. The European Atrial Fibrillation Trial [EAFT] (INR 2.5 to 4.0) showed a lower incidence of all stroke (4.0 %/year) with adjusted-dose warfarin compared with placebo (12.0 %/year). The incidence of major bleeding in the adjusted-dose warfarin group in SPAF III and EAFT was 2.4 and 2.8 %/year, respectively. EAFT incidence rates for the occurrence of a first ischaemic or haemorrhagic complication analysed by INR range indicated that the rate was lowest at INRs of 2.0 to 2.9, and higher with INRs of 3.0 to 3.9. Therefore, the optimal intensity of anticoagulation for prevention of recurrent stroke seems to be an INR of between 2.0 and 3.0, as for primary prevention. Retrospective and prospective studies from Japan reported that in the elderly, haemorrhagic complications occur frequently with INRs above 2.6 and major ischaemic events cannot be prevented at INRs below 1.6. Therefore, an INR target between 1.6 and 2.6 may be an alternative for secondary prevention of stroke in elderly patients with NVAF who have a potential risk of bleeding, to avoid both major ischaemic and haemorrhagic events. Antiplatelets may be administered in patients who are unable to manage taking warfarin properly or who have a high risk of falling and subsequently sustaining a head injury, although the efficacy of antiplatelets for secondary prevention of stroke in NVAF has not yet been established.     

Antiplatelet therapy for the prevention of recurrent stroke and other serious vascular events: a review of the clinical trial data and guidelines

ABSTRACT

Background: One strategy of reducing the burden of stroke is the prevention of recurrent stroke, following an initial ischaemic stroke or transient ischaemic attack (TIA) of arterial origin, by means of antiplatelet therapy.

Scope: This review article surveys and discusses the current clinical trial data and guidelines for the use of antiplatelet therapy in the prevention of recurrent stroke/TIA of arterial origin (not stroke due to atrial fibrillation). Based on the latest available evidence, a new antiplatelet treatment algorithm for the long-term treatment of patients following atherothromboembolic ischaemic stroke or TIA is proposed.

Findings: Meta-analyses of randomised clinical trials in patients with TIA and ischaemic stroke of arterial origin indicate that, compared with control, the relative risk reduction (RRR) for recurrent stroke and other serious vascular events is 13% (95% confidence interval [CI] 6% to 19%) with aspirin, 13% (4% to 21%; p = 0.046) with dipyridamole and 34% (24% to 43%) with the combination of aspirin and dipyridamole. Compared with aspirin, the relative risk of recurrent stroke and other serious vascular events is reduced by 7.3% (95% CI –5.7% to 18.7%) with clopidogrel and 18% (9% to 26%; p = 0.0003) with the combination of aspirin and dipyridamole. The combination of aspirin and clopidogrel is not significantly more effective in preventing serious vascular events than clopidogrel alone (RRR 6.4%; –4.6% to 16.3%) in the long-term treatment of patients with previous ischaemic stroke and TIA, mainly because of a cumulative excess of bleeding complications. The relative risks and benefits of long-term treatment with clopidogrel and the combination of aspirin and dipyridamole are being compared in an ongoing large clinical trial (PRoFESS). Current Australian therapeutic guidelines for antiplatelet therapy among patients with TIA and ischaemic stroke of arterial origin have incorporated important new findings from recently published clinical trials and recommend aspirin or the combination of dipyridamole plus aspirin as the preferred long-term antiplatelet therapy.

Conclusion: Whilst awaiting the results of the PRoFESS trial, the combination of dipyridamole plus aspirin is the preferred antiplatelet regimen to reduce the risk of recurrent vascular events among patients with TIA and ischaemic stroke of arterial origin.     

Ximelagatran

Despite the significant advances over the last 50 years with regard to anticoagulant therapy, warfarin remains the definitive standard for the long-term prevention of thromboembolic events in at-risk patients, except those with acute coronary syndromes, in which antiplatelets are preferred. Ximelagatran, a prodrug of melagatran, is an orally administered direct thrombin inhibitor whose therapeutic potential has been investigated in venous thromboembolism, acute coronary syndromes and prevention of stroke in atrial fibrillation. Clinical studies have demonstrated ximelagatran to be comparable in efficacy to the oral vitamin K antagonist warfarin and low molecular weight heparin for prophylaxis of venous thromboembolism, comparable to warfarin for stroke prevention in the setting of atrial fibrillation, and, when combined with aspirin, more effective than aspirin alone at preventing major adverse cardiovascular events in patients with a recent myocardial infarction. Double-blind trials have also revealed the efficacy of ximelagatran in the secondary prevention of venous thromboembolism and shown the agent to be as effective as enoxaparin/warfarin in treating patients with acute deep vein thrombosis. Adverse effects with ximelagatran include elevations in alanine transaminase (ALT), which may require monitoring, and bleeding complications. Bleeding complications appear to be less than or at least comparable to those occurring with standard anticoagulant treatments like warfarin or low molecular weight heparin. In addition to its favorable efficacy and safety profile in comparison with standard anticoagulant therapy, the convenience of its oral, fixed-dose administration without the need for anticoagulation monitoring might help encourage a wider use of appropriate anticoagulation using ximelagatran across the population at risk, reducing the incidence of thromboembolic events.     

Ticlopidine. An updated review of its pharmacology and therapeutic use in platelet-dependent disorders

Ticlopidine inhibits platelet aggregation induced by adenosine diphosphate (ADP) and most other platelet agonists in ex vivo studies of human platelets. The drug also improves other abnormalities of platelet function seen in patients with cerebrovascular disease, peripheral arterial disease, ischaemic heart disease or other conditions involving platelet hyperaggregation. Abnormal platelet activity has been implicated in a variety of clinical conditions in which patients are at high risk of thromboembolic events, and thus the effectiveness of ticlopidine has been investigated in such patients. Since the initial review of the drug appeared in the Journal, data from several large multicentre studies have shown that ticlopidine has a substantial benefit to offer patients who have experienced transient ischaemic attacks or stroke, and in those with peripheral arterial disease or ischaemic heart disease. Ticlopidine reduces the incidence of further stroke, myocardial infarction or vascular death, and is superior to placebo and aspirin in this regard in studies of patients with recent stroke or transient ischaemic attacks, or intermittent claudication. Ticlopidine is equally effective in both men and women and also improves symptoms of claudication in patients with peripheral arterial disease, and appears to reduce anginal pain. Patients with subarachnoid haemorrhage and sickle cell disease have shown some improvement with ticlopidine administration. The drug reduces thromboembolic events and re-stenosis in patients undergoing haemodialysis and cardiac surgery, and appears to prevent the progression of nonproliferative diabetic retinopathy. Ticlopidine in large clinical trials is associated with a higher incidence of adverse effects than placebo and an overall incidence similar to aspirin. Most adverse effects do not require withdrawal of treatment. Gastrointestinal symptoms (particularly diarrhoea) are most common, occurring almost twice as frequently with ticlopidine as with aspirin. Other adverse effects associated with ticlopidine include skin rash, haemorrhagic disorders, and haematological effects; these latter effects require careful monitoring of patients during the initial weeks of therapy. In conclusion, ticlopidine is a valuable addition to the prophylactic treatments available for the management of patients with cerebrovascular disease, peripheral arterial disease or ischaemic heart disease, who present a high risk of thromboembolic events. Although tolerability may be a problem for some patients, the overall benefit conferred by the drug would appear to outweigh this potential disadvantage. Because of its antiplatelet activity, ticlopidine has a promising role in other disorders mediated by platelet dysfunction. However, the precise role of the drug in these additional therapeutic indications awaits clarification with wider clinical experience.     

Thrombolytic therapy for stroke: a review with particular reference to elderly patients

Clinical trials in the 1990s of intravenous thrombolysis for ischaemic stroke have involved over 3000 patients. Alteplase given within 3 hours of onset significantly reduces the combined end-point of death and disability. Although alteplase appears safe when given up to 6 hours after onset, individual trials have failed to confirm efficacy beyond 3 hours. Meta-analysis indicates that intravenous alteplase given up to 6 hours after stroke onset significantly reduces death or dependence 3 months after stroke. Two trials of intra-arterial pro-urokinase confirm benefits of treatment up to 6 hours in highly selected patients with angiographically confirmed proximal middle cerebral occlusion. Streptokinase increased the risk of early death significantly in 3 trials, with no overall reduction in eventual death and disability. Patients over 80 years have been excluded from most trials of alteplase, and experience in this age group is minimal. Increased incidence and poorer functional outcome in the elderly mean that thrombolysis may have greater absolute benefit in this group than in the young, but there is also a higher prevalence of absolute or relative potential contraindications to treatment (ranging from increased use of anticoagulant drugs to higher prevalence of atrial fibrillation). Further trials are necessary to address age restrictions and other important issues in the use of alteplase. Thrombolysis is likely to remain feasible for a minority of stroke patients of all ages, and there is a need for other acute treatment options.     

新型口服抗凝药在伴有慢性肾脏疾病的非瓣膜性房颤患者中抗凝的研究进展

心房颤动是常见的心律失常疾病,持续48 h即可形成血栓,血栓脱落可导致动脉栓塞,其中90%是缺血性脑卒中,而慢性肾脏疾病可进一步增加房颤患者的卒中和出血风险。因此,在伴有慢性肾脏疾病的非瓣膜性房颤患者中的抗凝尤为重要。华法林用于肾功能不全的房颤患者虽可减少血栓栓塞的发生率,但是随着肾功能的恶化,华法林可增加出血的风险,且维持国际标准化比值（INR）在目标范围的时间非常困难。与华法林相比,新型口服抗凝药物能显著地降低卒中、颅内出血和死亡风险。然而新型口服抗凝药物在轻度、中度、重度,甚至血液透析房颤患者的应用仍存在争议。     

Risk of haemorrhage associated with long term anticoagulant therapy

This literature review was conducted to determine: (a) the rate of bleeding (major, minor and fatal) during long term oral anticoagulant therapy (greater than 4 weeks) in various disorders (ischaemic cerebrovascular disease, prosthetic cardiac valves, chronic atrial fibrillation, ischaemic heart disease and venous thrombosis); and (b) the clinical and laboratory risk factors which predispose such patients to bleeding. Using strictly defined methodological criteria, 167 studies were evaluated and classified into 1 of 5 categories based on the strength of the study design, with level I (randomised trials) representing studies which provided the most reliable information and level V (cases series) the least reliable. The risk of bleeding was substantial, and was most marked in patients with ischaemic cerebrovascular disease (29%), ischaemic heart disease (19%) and venous thromboembolism (23%). Major bleeding in venous thrombosis and cerebrovascular disease was frequently associated with an underlying risk factor. In venous thromboembolism these coexisting conditions (cancer, recent surgery and paraplegia) were also predisposing factors for thrombosis. In cerebrovascular disease major bleeding was almost always intracerebral, possibly because of associated hypertension or the cerebrovascular disease per se. We were unable to determine whether bleeding events were concentrated soon after commencing anticoagulant therapy. Haemorrhagic episodes frequently occurred when the prothrombin time (or thrombotest) was within the targeted therapeutic range, but the relationship between bleeding and the level of anticoagulant therapy was properly evaluated in only 1 study (in venous thrombosis) which demonstrated that the risk of bleeding was reduced by using a less intense anticoagulant regimen. In conclusion, the risk of bleeding during oral anticoagulant therapy is substantial. Our analysis was limited by the lack of concise reporting of clinical and laboratory information and we would suggest that future clinical studies report these in greater detail.     

Adverse effects and drug interactions of antithrombotic agents used in prevention of ischaemic stroke

Stroke is the third most common cause of death in the US. Primary prevention of stroke can be achieved by control of risk factors including hypertension, diabetes mellitus, elevated cholesterol levels and smoking. Approximately one-third of all ischaemic strokes occur in patients with a history of stroke or transient ischaemic attack (TIA). The mainstay of secondary prevention of ischaemic stroke is the addition of medical therapy with antithrombotic agents to control the risk factors for stroke. Antithrombotic therapy is associated with significant medical complications, particularly bleeding.Low-dose aspirin (acetylsalicylic acid) has been shown to be as effective as high-dose aspirin in the prevention of stroke, with fewer adverse bleeding events. Aspirin has been shown to be as effective as warfarin in the prevention of noncardioembolic ischaemic stroke, with significantly fewer bleeding complications. Ticlopidine may be more effective in preventing stroke than aspirin, but is associated with unacceptable haematological complications. Clopidogrel may have some benefit over aspirin in preventing myocardial infarction, but has not been shown to be superior to aspirin in the prevention of stroke. The combination of clopidogrel and aspirin may be more effective than aspirin alone in acute coronary syndromes, but the incidence of adverse bleeding is significantly higher. Furthermore, the combination of aspirin with clopidogrel has not been shown to be more effective for prevention of recurrent stroke than clopidogrel alone, while the rate of bleeding complications was significantly higher with combination therapy. The combination of aspirin and extended-release dipyridamole has been demonstrated to be more effective than aspirin alone, with the same rate of adverse bleeding complications as low-dose aspirin. When selecting the appropriate antithrombotic agent for secondary prevention of stroke, the adverse event profile of the drug must be taken into account when assessing the overall efficacy of the treatment plan.