Coagulation factors and the increased risk of stroke in nonvalvular atrial fibrillation

We studied whether hemostatic abnormalities contribute to the increased risk of stroke in patients with nonvalvular atrial fibrillation. Hemostatic function was studied in four age-matched groups: 20 patients with nonvalvular atrial fibrillation and a previous ischemic stroke, 20 patients with nonvalvular atrial fibrillation without a previous stroke, 20 stroke patients with sinus rhythm, and 40 healthy controls. Both groups with nonvalvular atrial fibrillation had significantly higher concentrations of von Willebrand factor, factor VIII:C, fibrinogen, D-dimer (a fibrinolytic product), beta-thromboglobulin, and platelet factor 4; a significantly higher fibrinogen/antithrombin ratio; and significantly higher spontaneous amidolytic activity than the healthy controls. Prekallikrein levels were significantly lower in both groups with nonvalvular atrial fibrillation. Stroke patients with sinus rhythm had normal hemostatic function, normal concentrations of platelet-related factors, and a slightly increased concentration of fibrinopeptide A compared with the healthy controls. Both groups with nonvalvular atrial fibrillation differed from the stroke patients with sinus rhythm as they did from the healthy controls. No difference in hemostatic function was seen between the nonvalvular atrial fibrillation patients with and without a previous ischemic stroke. Thus, alterations in hemostatic function may contribute to the increased risk of stroke in patients with nonvalvular atrial fibrillation.     

Antithrombotic and anticoagulation therapy after stroke and transient ischemic attacks

Patients with a transient ischemic attack (TIA) or ischemic stroke are at high risk for a recurrent stroke. Platelet inhibitors can reduce this risk in patients with non-cardioembolic stroke or TIA. Aspirin is used for secondary prevention in patients with a low risk of recurrent stroke while the combination of aspirin and dipyridamole or clopidogrel is recommended in patients with a higher risk. Patients with atrial fibrillation have a five-fold increased risk of stroke. In comparison to placebo oral anticoagulation reduces the risk of stroke by 60-70% in primary and secondary stroke prevention. Aspirin can still reduce the relative stroke risk by 22% in patients with atrial fibrillation who have contraindications against anticoagulation. Given the limitations of oral anticoagulation with vitamin K antagonists a new generation of anticoagulants is currently being investigated which include factor Xa inhibitors and direct thrombin antagonists. Dabigatran has been shown to be as efficacious as warfarin given at a lower dose and significantly more efficacious when administered at a higher dosage. Both cerebral and intracranial hemorrhages were reduced by 60-80% in patients treated with dabigatran when compared to warfarin.     

Antiplatelet agents and randomized trials

Patients who have transient ischemic attack (TIA) or ischemic stroke are at a high risk of having a first or recurrent stroke. The annual risk is between 5% and 15%; the risk is highest in the first 48 hours following a TIA and highest in the first 7 days following an ischemic stroke. Secondary prevention includes antithrombotic therapy, treatment of risk factors, and interventional treatment of carotid stenosis. Antithrombotic options can include antiplatelet drugs such as aspirin, aspirin plus extended-release dipyridamole (ER-DP), clopidogrel, or clopidogrel plus aspirin. Oral anticoagulation is used in patients with a cardiac source of embolism such as atrial fibrillation. Aspirin monotherapy offers a modest risk reduction for recurrent stroke and for the combined endpoint of nonfatal stroke, myocardial infarction (MI), and vascular death. The combination of ER-DP and aspirin was shown to be superior to aspirin monotherapy in several trials. Clopidogrel is superior to aspirin in high-risk patients suffering from stroke, MI, or peripheral arterial disease. The combination of clopidogrel plus aspirin is not superior to aspirin or clopidogrel monotherapy and carries a significantly higher bleeding risk. The combination might offer benefit in short-term secondary prevention after TIA or stroke. Another ongoing trial is currently investigating the possible benefit and side effects of aspirin plus ER-DP versus clopidogrel in secondary stroke prevention.     

EBM of cerebral infarction: message from mega-studies]

A meta-analysis by the Antithrombotic Trialists' Collaboration showed significant reduction of vascular events including stroke. MI, and vascular death by antiplatelet therapy in high risk patients with obstructive vascular disease. Low dose aspirin of 75 to 150 mg was most effective and its very low dose below 75 mg was not proven effective. Cilostazol significantly reduced the risk of recurrence in Japanese patients with ischemic stroke, mostly lacunar stroke. Large randomized controlled trials (RCTs) such as MATCH, ACTIVE, and CHARISMA are ongoing to see an effect of aspirin plus clopidogrel. Among patients with non-valvular atrial fibrillation (NVAF), warfarin is recommended in patients at age over 75 years, and those with history of stroke or TIA, hypertension, congestive heart failure, diabetes or coronary heart disease, while aspirin can be alternative in patients without any of these risk factors of stroke. Target INR of 2.0 to 3.0 is recommended in these NVAF patients, although lower INR of 1.6 to 2.5 is recommended to avoid hemorrhagic stroke in elderly patients with NVAF. SPORTIF was conducted to compare ximelagatran, an oral thrombin inhibitor, with warfarin in NVAF patients with risk factors, and the result showed a comparable efficacy and safety of ximelagatran. WARSS did not show any efficacy of warfarin over aspirin in any subtypes of ischemic stroke patients without NVAF, acute MI, left ventricular thrombi, or prosthetic heart valve. PICSS, a substudy of WARSS, also did not show any efficacy of warfarin over aspirin in stroke patients with patent foramen ovale (PFO), although warfarin might be recommended in PFO patients with deep vein thrombosis.     

Dual Antiplatelet Therapy of Clopidogrel and Aspirin in Secondary Prevention of Ischemic Stroke: Evidence and Indications

Nowadays the dual antiplatelet therapy (DAPT) becomes more widely used in patients with ischemic stroke. Nevertheless, controversies exist for indications of DAPT. In view of evidence‐based medicine analysis, patients with high‐risk transient ischemic attack and minor stroke, severe symptomatic intracranial artery stenosis, symptomatic intracranial and extracranial artery stenosis causing artery‐to‐artery embolism, ischemic stroke attributed to aortic arch plaques, high‐risk atrial fibrillation not suitable for oral anticoagulants, intracranial and extracranial stent implantation, and ischemic stroke with acute coronary syndrome may gain great benefit from DAPT of clopidogrel and aspirin. In clinical practice, individualized antiplatelet therapy strategies should be taken by weighing risks of ischemia and hemorrhage.     

The additive antiplatelet action of clopidogrel in patients with coronary artery disease treated with aspirin

We searched for additional anti-platelet effects of clopidogrel in coronary artery disease (CAD) patients treated with aspirin. Response to clopidogrel was also stratified according to aspirin resistance. Out of 76 screened aspirin-treated CAD male patients, five were aspirin-resistant based on arachidonic acid (AA) and ADP aggregometry. These five patients and 15 aspirin-sensitive patients entered the proper study. Platelet function was assessed at baseline and after one week of additional clopidogrel treatment using aggregometry, flow cytometry (ADP, TRAP-6) and platelet reactivity index (PRI) based on VASP (vasodilatorstimulated phosphoprotein) expression. We evaluated the same markers in 15 healthy men after aspirin treatment. In healthy subjects aspirin did not affect resting or ADP-induced activated GPIIb/IIIa and P-selectin expression. The P-selectin expression on ADP-activated platelets was increased (p < 0.01) in aspirin treated ASA-resistant CAD patients as compared to ASA-sensitive group or aspirin-treated healthy subjects. Clopidogrel significantly decreased ADP and AA-induced platelet aggregation and overcame aspirin resistance in four of five patients. Expression of ADP-induced activation markers was significantly lowered after clopidogrel in all patients. Out of 20 patients, five did not respond to clopidogrel (<10% inhibition of ADP aggregation), and this group showed no change in expression of ADP-induced activation markers after clopidogrel. Clopidogrel treatment significantly reduced PRI only in the clopidogrel-sensitive group. In conclusion, the addition of clopidogrel to aspirin provides greater inhibition of platelets and can overcome aspirin resistance. Flow cytometric analysis of platelets is useful for monitoring of clopidogrel therapy.     

Measurement of platelet fibrinogen binding and p-selectin expression by flow cytometry in patients with cerebral infarction.

We determined the percentages of fibrinogen-bound and P-selectin-expressed platelets in whole blood using flow cytometry in 254 patients with various cerebral infarction subtypes, as well as in 30 age-matched controls. Patients with atherothrombotic stroke showed significant increases in both fibrinogen-bound and P-selectin-expressed platelets. Patients with lacunar stroke also showed significant increases in both of them, but the percentage of P-selectin expression was significantly lower than that in atherothrombotic stroke. Patients with cardioembolic stroke showed a significant increase in P-selectin-expressed platelets without any increase in fibrinogen-bound platelets. Platelet fibrinogen binding and P-selectin expression were significantly lower in patients treated with ticlopidine but not with aspirin than in those not treated with any antiplatelet agent, and were lowest in those treated with both ticlopidine and aspirin. Our findings suggest that expression of adhesion molecules on platelet membrane surface differs among the patients with subtypes of ischemic stroke and differs among the types of antiplatelet regimens.     

Results of the management of atherothrombosis with clopidogrel in high-risk patients trial: implications for the neurologist

The secondary prevention of ischemic stroke is aided by the use of antiplatelet therapy, and the predominant current choices are aspirin, aspirin plus extended-release dipyridamole, and clopidogrel. The potential utility of combining platelet antiaggregants with different mechanisms of action proved successful with aspirin plus extended-release dipyridamole, and this approach has been explored with the combination of clopidogrel and aspirin. In the Management of Atherothrombosis With Clopidogrel in High-Risk Patients trial, this combination was compared with clopidogrel alone for secondary prevention in patients with transient ischemic attack and stroke in a high-risk population with a high prevalence of other vascular risk factors. A nonsignificant trend for a reduction of the combined endpoint of ischemic stroke, myocardial infarction, vascular death, and rehospitalization was observed in the combination therapy group (P = .24). The frequency of serious, life-threatening bleeding adverse effects was almost doubled in the combination arm. Neurologists need to be aware of these results and avoid the use of clopidogrel plus aspirin in patients with stroke or transient ischemic attack until evidence that the combination is safe in this population is provided. Neurologists faced with patients who have had a stroke or transient ischemic attack and are receiving this combination of antiplatelet agents after coronary stenting should inform their cardiology colleagues of the reported bleeding risk, and they should encourage the use of the combination for as short a time period as possible after such coronary intervention.     

Markers of thrombin and platelet activity in patients with atrial fibrillation: correlation with stroke among 1531 participants in the stroke prevention in atrial fibrillation III study

BACKGROUND AND PURPOSE: Markers of thrombin generation and platelet activation are often elevated in patients with nonvalvular atrial fibrillation, but it is unclear whether such markers usefully predict stroke. Therefore, we undertook the present study to assess the relationship between prothrombin fragment F1.2 (F1.2), beta-thromboglobulin (BTG), fibrinogen, and the factor V Leiden mutation with stroke in atrial fibrillation. METHODS: Specimens were obtained from 1531 participants in the Stroke Prevention in Atrial Fibrillation III study. The results were correlated with patient features, antithrombotic therapy, and subsequent thromboembolism (ischemic stroke and systemic embolism) by multivariate analysis. RESULTS: Increased F1.2 levels were associated with age (P<0.001), female sex (P<0.001), systolic blood pressure (P=0.006), and heart failure (P=0.001). F1.2 were not affected by aspirin use and were not associated with thromboembolism after adjustment for age (P=0. 18). BTG levels were higher with advanced age (P=0.006), coronary artery disease (P=0.05), carotid disease (P=0.005), and heart failure (P<0.001), lower in regular alcohol users (P=0.05), and not significantly associated with thromboembolism. Fibrinogen levels were not significantly related to thromboembolism but were associated with elevated BTG levels (P<0.001). The factor V Leiden mutation was not associated with thromboembolism (relative risk 0.5, 95% CI 0.1 to 3.8). CONCLUSIONS: Elevated F1.2 levels were associated with clinical risk factors for stroke in atrial fibrillation, whereas increased BTG levels were linked to manifestations of atherosclerosis. In this large cohort of patients with atrial fibrillation who were receiving aspirin, F1.2, BTG, fibrinogen, and factor V Leiden were not independent, clinically useful predictors of stroke.     

Adding aspirin to clopidogrel after TIA and ischemic stroke: benefits do not match risks

Antiplatelet therapy is effective for reducing the risk of recurrent stroke and other serious vascular events in patients with recent TIA and ischemic stroke. Effective antiplatelet agents include aspirin, ticlopidine, clopidogrel, dipyridamole, and the combination of aspirin and dipyridamole. The combination of aspirin and clopidogrel is more effective than aspirin in patients with acute coronary syndrome but is more hazardous than clopidogrel alone in patients with recent TIA and ischemic stroke. Further trials are needed to determine whether the combination of aspirin and clopidogrel may have a role immediately after TIA and ischemic stroke in patients with symptomatic large artery atherothromboembolism and continued for approximately 3 months before switching to less hazardous antiplatelet regimens.     

How to monitor vascular aging with an ultrasound

Plasma levels of brain natriuretic peptide (BNP) are frequently elevated after an acute stroke and have been shown to be an independent predictor of mortality. However, the relationships between stroke and BNP concentrations have not yet been systematically investigated. Plasma BNP assay and echocardiography were performed in 48 patients with ischemic stroke or TIA with a mean delay of 12.7 h after onset. Median BNP concentration was 88.6 pg/mL (range 5–1270). Older age, chronic heart failure, atrial fibrillation, stroke severity, lower hemoglobin levels, lower left ventricular ejection fraction, and abnormalities of left atrium or appendage (LA/LAA) were univariately associated with increased BNP levels. At multivariable analysis, the presence of at least one LA/LAA abnormality (atrial dilatation, low flow velocity, spontaneous echocontrast or thrombus) had the strongest association with BNP, explaining 38.9% of the variance in the whole sample and 28.5% in patients without atrial fibrillation. In acute ischemic stroke patients, elevated plasma BNP levels have multiple determinants, among which left atrial disease appears to be the stronger, even in patients without atrial fibrillation. These results encourage further investigation of plasma BNP concentration as a potential marker of the presence of left atrial sources of emboli.     

Antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke: a critical review

For patients with ischemic stroke or transient ischemic attack caused by atherothromboembolism, immediate and long-term aspirin reduces the relative risk of recurrent stroke, MI, and death attributable to vascular causes. Oral anticoagulation is not more effective than aspirin. Long-term clopidogrel reduces the relative risk of stroke, MI, or vascular death by about 9% (0.3% to 16.5%) compared with aspirin. Any long-term benefits of clopidogrel combined with aspirin, compared with aspirin or clopidogrel alone, appear to be offset by increased major bleeding. The combination of aspirin and extended-release dipyridamole reduces the relative odds of stroke, MI, or vascular death by about 18% (odds ratio 0.82, 0.74 to 0.91) compared with aspirin alone without causing more bleeding. Cilostazole reduces the risk of stroke, MI, or vascular death by 39% compared to placebo. A large clinical trial comparing clopidogrel with the combination of aspirin and dipyridamole, in >20 000 patients with recent (<120 days) atherothrombotic ischemic stroke, is expected to report in 2008. Emerging antiplatelet therapies presently being evaluated for secondary prevention of atherothromboembolism include other P(2)Y(12) ADP receptor antagonists (prasugrel, cangrelor, AZD 6140), thromboxane receptor antagonists (eg, S18886 - terutroban), and thrombin receptor (PAR-1) antagonists (eg, SCH530348).     

Inhibition of ADP-induced P-selectin expression and platelet-leukocyte conjugate formation by clopidogrel and the P2Y12 receptor antagonist AR-C69931MX but not aspirin

Platelet-leukocyte interactions are recognised to have pro-inflammatory effects, which may be important in the pathophysiology of ischaemic heart disease. Clopidogrel and the novel intravenous antithrombotic agent AR-C69931MX act at the level of the platelet P2Y12 receptor, which is known to amplify platelet activation, aggregation and other responses induced by numerous platelet agonists. We studied the effects of clopidogrel and aspirin on ADP-induced platelet-leukocyte conjugate formation and P-selectin expression in healthy volunteers. The effects of clopidogrel and AR-C69931MX administered to patients with ischaemic heart disease were also assessed. AR-C69931MX and aspirin were also studied in vitro. Clopidogrel and AR-C69931MX suppressed ADP-induced platelet aggregation, P-selectin expression and platelet-leukocyte conjugate formation whereas aspirin had no inhibitory effect. These effects of clopidogrel and AR-C69931MX may confer therapeutic benefits in the management of acute coronary syndromes.     

Prothrombotic responses to exercise are little influenced by clopidogrel treatment

AIMS: Adenosine diphosphate (ADP) is involved in shear-induced platelet activation, which may be important for platelet responses to stress. We therefore tested the hypothesis that ADP receptor antagonism by clopidogrel treatment would attenuate exercise-induced platelet activation. METHODS AND RESULTS: Fifteen healthy volunteers performed exhaustive exercise without and with clopidogrel pretreatment (75 mg/day; 7 days) in a randomised crossover study. Filtragometry readings (reflecting platelet aggregability in vivo) and 11-dehydro-thromboxane B(2) (TxM) in plasma were determined before and after exercise. Platelet and leukocyte activity, platelet-platelet (PPA), and platelet-leukocyte aggregates (PLAs) in vivo and their responsiveness to agonist stimulation in vitro were assessed by flow cytometry. Clopidogrel treatment inhibited ADP-induced platelet P-selectin expression by 72% (54-85%). Exercise increased platelet aggregation (filtragometry and PPAs), elevated plasma TxM, increased single platelet P-selectin expression, elevated circulating PLAs, and enhanced ADP and thrombin-stimulated P-selectin expression. Clopidogrel prolonged filtragometry readings and attenuated agonist stimulated P-selectin expression at rest, but did not influence TxM in plasma or urine or attenuate platelet or leukocyte responses to exercise. Clopidogrel treatment did not influence plasma CD40L (ligand) at rest or after exercise. CONCLUSION: Clopidogrel treatment attenuates platelet activity in vivo at rest, but exercise counteracts the platelet stabilizing effects of clopidogrel. The hypothesis that ADP is involved in stress-induced platelet activation was not supported.     

Reactive leptin resistance and the profile of platelet activation in acute ischaemic stroke patients

Leptin is an adipokine that in vitro enhances agonist-induced platelet aggregation and adipokine expression. Hyperleptinaemia represents a risk factor for cardiovascular disease. We conducted a prospective evaluation of the potential link between blood platelet activation and plasma leptin levels in post-stroke patients. Using five-colour flow cytometry, the platelet surface expression of CD40L, CD62P, the subpopulations of monocyte-platelet aggregates and platelet-derived microparticles (PMPs) as well as the plasma leptin, soluble leptin receptor (sOb-R), leptin/sOb-R ratio, the plasma adiponectin, and leptin/adiponectin ratio were assessed in 98 stroke patients on the first (V?), 10th (V? ) and 90th (V?) day after stroke and once in 78 age-, gender- and vascular risk factor-matched disease controls. We demonstrated that at V0 leptin resistance, defined as leptin/sOb-R ratio, was higher than in the controls [1.1 (0.5-1.8 vs. 0.5 (0.2-1.1); p=0.02]. After adjustment according to the factors which influence platelet activation, we confirmed the relationship between percentage of circulating PMPs and plasma leptin level (B=0.18; p=0.02) or the leptin/sOb-R ratio (B=0.23; p=0.02) in normal-weight subjects in the acute phase of stroke. No correlation could be demonstrated between the adipokine parameters and the percentage of monocyte-platelet aggregates or expression of platelet pro-inflammatory glycoproteins. In conclusion, formation of PMPs on the first day following an ischaemic stroke shows a positive correlation with leptin levels and with resistance to leptin. Leptin level does not seem to affect the expression of platelet surface proinflammatory glycoproteins.     

Prevention of stroke recurrence

Stroke recurrence can be reduced substantially by intervention with the appropriate stroke preventive(s). Control of blood pressure, use of one of the antiplatelet agents aspirin, aspirin plus extended (modified)-release dipyridamole, or clopidogrel, administration of warfarin for patients with atrial fibrillation and high-risk profiles for stroke, and use of carotid endarterectomy in patients with high grades of symptomatic carotid artery stenosis are all proven therapies for prevention of stroke recurrence. Newer therapies to reduce the risk of infection and inflammation promise to further reduce the risk of first and recurrent stroke and are undergoing testing. In this article we review standard and more novel means to prevent stroke recurrence.     

Atrial size, atrial fibrillation, and stroke

M-mode and two-dimensional echocardiographic images were reviewed retrospectively in 20 patients with atrial fibrillation and ischemic stroke with no known valvular disease and in 20 patients with atrial fibrillation without known stroke. Left atrial size was measured and analyzed without knowledge of patient grouping. Two-dimensional echocardiography showed that 90% of the stroke patients had left atrial enlargement compared with only 20% in the nonstroke group. This finding suggests that left atrial enlargement may convey additional stroke risk in patients with atrial fibrillation.     

Ischemic stroke after cardiac pacemaker implantation in sick sinus syndrome

The risk of embolic stroke during sick sinus syndrome before cardiac pacemaker insertion is substantial, but stroke after pacemaker insertion has not been well studied. We observed 10 sick sinus syndrome patients who developed an ischemic stroke 4 days to 112 months after pacemaker insertion. Nine patients represented 6% of the 156 ischemic stroke patients observed during a 30-month period. Eight had a ventricular-demand pacemaker, one had a dual-chamber pacemaker, and one had an atrial-inhibited pacemaker. Six patients were in atrial fibrillation at stroke onset, but none had atrial fibrillation when the pacemaker was inserted. Six patients were taking aspirin, and one was anticoagulated when stroke occurred. Stroke in sick sinus syndrome after pacemaker insertion is not rare, and pacing does not appear to be protective. Sick sinus syndrome patients who convert to atrial fibrillation or who have a ventricular-demand pacemaker might represent high-risk groups for stroke.     

Role of antiplatelet drugs in the prevention of cardiovascular events

Antiplatelet drugs have an established place in the prevention of vascular events in a variety of clinical conditions, such as myocardial infarction, stroke and cardiovascular death. Both European and American guidelines recommend the use of antiplatelet drugs in patients with established coronary heart disease and other atherosclerotic disease. In high-risk patients, such as those with post-acute myocardial infarction (AMI), ischaemic stroke or transient ischaemic attack, and in patients with stable or unstable angina, peripheral arterial occlusive disease or atrial fibrillation, antiplatelet treatment may reduce the risk of a serious cardiovascular event by approximately 25%, including reduction of non-fatal myocardial infarction by 1/6, non-fatal stroke by 1/4 and cardiovascular death by 1/6. Some data indicate that antiplatelet drugs may also have a role in primary prevention. In people who are aged over 65 years, or have hypertension, hypercholesterolaemia, diabetes, obesity or familial history of myocardial infarction at young age, aspirin may reduce both cardiovascular deaths and total cardiovascular events. Aspirin has been studied and used most extensively. It may exert its beneficial effect not only by acting on platelets, but also by other mechanisms, such as preventing thromboxane A₂ (TXA₂)-induced vasoconstriction or reducing inflammation. Indeed, experimental data show that low-dose aspirin may suppress vascular inflammation and thereby increase the stability of atherosclerotic plaque. Moreover, in human studies, aspirin seems to be most effective in those with elevated C-reactive protein levels. Vascular events, however, do occur despite aspirin administration. This may be due to platelet activation by pathways not blocked by aspirin, intake of drugs that interfere with aspirin effect or aspirin resistance. In the CAPRIE (Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events) study, long-term clopidogrel administered to patients with atherosclerotic vascular disease was more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction or vascular death. In the setting of coronary stenting, a double regimen including aspirin and ticlopidine or clopidogrel has proved more effective in the prevention of in-stent thrombosis than aspirin alone. Chronic oral administration of the inhibitors of platelet membrane receptor GP IIb/IIIa has been largely disappointing.