The PRoFESS trial: future impact on secondary stroke prevention

Patients with transient ischemic attack and ischemic stroke have a high risk of recurrent stroke and death. While aspirin is accepted as standard therapy in these patients, recent trials demonstrate that a combination of aspirin and extended-release dipyridamole or clopidogrel is superior to aspirin monotherapy. Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers may also reduce recurrent stroke. The ongoing Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial is designed to evaluate whether extended-release dipyridamole plus aspirin compared with clopidogrel, and whether telmisartan in addition to usual care, in individuals after a stroke, will reduce the risk of further strokes. PRoFESS is a multicenter, randomized, double-blind trial involving 695 sites from 35 countries or regions. The primary outcome for the trial is recurrent stroke, using a time-to-event analysis. Safety is evaluated by assessing the risk of major hemorrhagic and other serious adverse events. With over 20,000 patients randomized, and utilizing a 2 x 2 factorial design, PRoFESS is the largest stroke trial to investigate the prevention of recurrent stroke.     

Management of atherothrombosis with clopidogrel in high-risk patients with recent transient ischaemic attack or ischaemic stroke (MATCH): study design and baseline data

BACKGROUND: The CAPRIE study showed the superiority of clopidogrel over acetylsalicylic acid (ASA) for reducing the combined risk of major atherothrombotic events in patients with recent myocardial infarction (MI), recent ischaemic stroke (IS) or established peripheral arterial disease. The benefit of clopidogrel over ASA is amplified in high-risk patients. Proof of concept for the benefit of clopidogrel in addition to ASA in patients with coronary manifestations of atherothrombosis was provided by the CURE trial. METHODS: MATCH is a randomized, double-blind, placebo-controlled trial that compares clopidogrel and ASA versus clopidogrel alone in high-risk patients with recently symptomatic cerebrovascular disease. Eligible patients have experienced a transient ischaemic attack (TIA) or IS within the last 3 months and have evidence of at least 1 additional risk factor within the last 3 years (prior IS, MI, stable or unstable angina pectoris, diabetes or symptomatic peripheral arterial disease). Patients were randomized to receive ASA 75 mg once daily or placebo, with both groups receiving clopidogrel 75 mg once daily as part of standard therapy. The primary end point is the composite of IS, MI, vascular death and rehospitalization for an acute ischaemic event. The duration of treatment and follow-up is 18 months for each patient. RESULTS: Enrollment was completed in April 2002, with 7,599 patients randomized to receive the study medication. The mean age at randomization was 66 years, and the qualifying event was IS in 78.9% of patients and TIA in 21.1%. The baseline features of the study cohort indicate a population that is at a high risk for atherothrombotic recurrence. CONCLUSION: MATCH is a major ongoing trial that will provide important data on the benefit of clopidogrel and ASA compared with clopidogrel alone for reduction of vascular ischaemic events in patients with recent TIA or IS who are at high risk of atherothrombotic event recurrence.     

Second European Stroke Prevention Study: antiplatelet therapy is effective regardless of age

Background - The Second European Stroke Prevention Study (ESPS2) was a randomized, placebo-controlled trial that investigated the efficacy of low-dose acetylsalicylic acid (ASA) and modified-release dipyridamole (DP), alone or in combination, in the secondary prevention of ischemic stroke. The trial demonstrated that the combination was significantly more effective than either agent used alone. The aim of the present study was to evaluate the influence of age on the efficacy of ASA and DP, alone or in combination, in the secondary prevention of stroke in the ESPS2 population. Methods and results - A total of 6602 patients were recruited to the ESPS2 and there were 4 treatment groups: ASA (25 mg twice daily), DP (200 mg twice daily), ASA and DP in a combined formulation, or placebo. Primary endpoints were stroke, death, and stroke or death together. The endpoints evaluated in the present study were stroke, stroke and/or death, and vascular events. Stroke was the qualifying event in 76% of the patients, while 24% had a transient ischaemic attack. Patients were reviewed at 3-month intervals for 2 years. The study population consisted of 2565 (39%) patients aged less than 65 years, 2240 (34%) patients aged between 65 and 74 years, and 1797 (27%) patients aged 75 years and over. Advancing age was associated with an increased incidence of endpoints in all 4 treatment groups. The combination of ASA and DP significantly reduced the incidence of all endpoints, compared with placebo, in each age group. There was no influence of age on the efficacy of antiplatelet therapy for any of the evaluated endpoints. Relative risk reductions of treatment compared with placebo were 11.1–27.6% in the ASA group, 8.0–18.7% in the DP group, and 20.3–45.2% in patients receiving combination therapy. Conclusion - This study clearly demonstrates that combination therapy with DP and ASA is superior to either agent used alone in the secondary prevention of ischemic stroke, irrespective of the age of the patient.     

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).     

Ongoing and planned trials of antiplatelet therapy in the acute and long-term management of patients with ischaemic brain syndromes: setting a new standard of care

Among high vascular risk patients, acetylsalicylic acid (ASA) reduces the relative risk of serious vascular events by about one fifth. However, because ASA fails to prevent four fifths of serious vascular events, more effective, yet equally safe and affordable, antiplatelet regimens are desired. Compared with ASA, clopidogrel alone reduces the odds of serious vascular events by about 10%, and the combination of dipyridamole and ASA reduces the odds of serious vascular events by about 6%. Combining ASA with an orally administered platelet glycoprotein (GP) IIb/IIIa blocker is not effective, and indeed more hazardous than ASA alone. Among patients with non-ST-segment acute coronary syndromes (ACS), the addition of an intravenously administered GP IIb/IIIa receptor antagonist to ASA reduces the risk of vascular events by about 10% compared with ASA, and the addition of clopidogrel to ASA reduces the risk of vascular events by 20% compared with ASA alone. Among patients undergoing percutaneous coronary intervention (PCI), both the addition of an intravenously administered GP IIb/IIIa receptor antagonist to ASA, and the addition of clopidogrel to ASA reduce the risk of vascular events by 30% compared with ASA alone. The greater efficacy of the combinations of ASA with clopidogrel, and ASA with an intravenously administered GP IIb/IIIa receptor antagonist, in patients with ACS and those undergoing PCI has fostered several ongoing and planned trials of these regimens in the acute and long-term management of patients with ischaemic brain syndromes. The combination of ASA and clopidogrel is being compared with ASA alone within 12 h of onset of symptoms of TIA in two trials (FASTER, ATARI), and the use of an intravenously administered GP IIb/IIIa receptor antagonist is being compared with placebo within 6 h of onset of acute ischaemic stroke in two trials (AbESST, AbESST-2). Six trials are assessing the combination of clopidogrel and ASA in the long-term management of patients with ischaemic brain syndromes due to atherothrombosis (MATCH, CHARISMA, ARCH, CARESS, SPS3) or atrial fibrillation (ACTIVE). The MATCH trial of clopidogrel and ASA versus clopidogrel alone in patients with recent TIA or ischaemic stroke is the first which is likely to report its results - in mid 2004. The combination of dipyridamole and ASA is being compared with ASA in the ESPRIT trial and with the combination of clopidogrel and ASA in the planned PRoFESS trial. These ongoing and planned clinical trials of antiplatelet therapy promise to further define the role of combination antiplatelet therapy in the acute and long-term management of patients with ischaemic brain syndromes.     

Evidence with antiplatelet therapy and ADP-receptor antagonists

Antiplatelet drugs have been shown to prevent a range of atherothrombotic events, including transient ischaemic attack (TIA) and ischaemic stroke. Clopidogrel and ticlopidine are adenosine diphosphate (ADP)-receptor antagonists that inhibit ADP-induced fibrinogen binding to platelets, a necessary step in the platelet aggregation process. The Antithrombotic Trialists' Collaboration recently published a major meta-analysis that assessed the effect of antiplatelet therapy in patients with various manifestations of atherosclerosis. In total, this analysis included 135,000 patients in comparisons of antiplatelet agents versus control and 77,000 patients in comparisons of different antiplatelet regimens. This meta-analysis found that overall, antiplatelet therapy reduces the combined odds of stroke, myocardial infarction (MI) or vascular death by 22%, and that antiplatelet agents reduce the odds of a non-fatal stroke by 25% over a wide range of patients with or without a history of cerebrovascular disease. In the CAPRIE trial of clopidogrel versus acetylsalicylic acid (ASA), there was a 10% odds reduction for stroke, MI or vascular death in favour of clopidogrel (p = 0.03). In a meta-analysis performed by the Cochrane Stroke Group, ADP-receptor antagonist therapy significantly reduced the odds of a serious vascular event (stroke, MI or vascular death) by 9% (2p = 0.01) and of any stroke by 12%. The safety/tolerability profile of clopidogrel was superior to that of ticlopidine, and at least as good as that of ASA. In CURE, a long-term benefit was observed with the use of clopidogrel on top of standard therapy (including ASA in all patients), with a 20% relative risk reduction for the primary endpoint of cardiovascular death, MI or stroke (p < 0.001) in patients with unstable angina and non-Q-wave MI. A consistent benefit was seen across all patient subgroups, including patients with a previous history of stroke. More recently, CREDO has demonstrated the incremental benefit of prolonged use of clopidogrel on top of ASA in patients undergoing elective PCI, with a 27% reduction in the combined risk of death, MI or stroke after 12 months of therapy (p = 0.02) and a 25% reduction in stroke over the same time period. The MATCH trial is currently being conducted to test the hypothesis that long-term administration of clopidogrel on top of ASA is superior to clopidogrel alone for the reduction of major ischaemic events in patients with recent TIA or ischaemic stroke who are at high risk of atherothrombotic recurrence. Further trials of clopidogrel on top of standard therapy (including ASA) are planned in neurology; these include SPS3, in patients with small subcortical strokes, and ATARI, in patients who have recently recovered from a TIA.     

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.     

Current Status of Antiplatelet Agents to Prevent Stroke

Stroke is one of the leading causes of disability; most are due to atherothrombotic mechanisms. About one third of ischemic strokes are preceded by other stroke or transient ischemic attacks. Stroke survivors are at high risk for vascular events (i.e., cerebrovascular and cardiovascular). Prevention of recurrent stroke and other major vascular events can be accomplished by control of risk factors. Nonetheless, the use of antiplatelet agents remains the fundamental component of secondary stroke prevention strategy in patients with noncardioembolic disease. Currently, the uses of aspirin, clopidogrel, or aspirin plus extended-release dipyridamole are valid alternatives for stroke or transient ischemic attack patients. To maximize the beneficial effects of these agents, the treatment should be initiated as early as possible and continue on a lifelong basis.     

ESPRIT: is aspirin plus dipyridamole superior to aspirin alone in TIA or minor stroke patients?

Transient ischemic attack (TIA) or a (minor) ischemic stroke increases the risk of a recurrent stroke or death. Antiplatelet therapy with aspirin or clopidogrel is, in the absence of a potential cardiac embolic source, common practice to lower this risk. Until recently, adjuvant dipyridamole or low intensity oral anticoagulation were not generally prescribed in secondary prevention. In this article, we will summarize and discuss the published results of the European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT). In this trial, treatments with anticoagulants, aspirin alone and the combination of aspirin plus dipyridamole were compared, in a multicenter, three-armed, randomized, open-label study in patients with TIA or minor stroke.     

Secondary Stroke Prophylaxis with Clopidogrel Produces Sufficient Antiplatelet Response

Background

Antiplatelet therapy is a cornerstone prevention strategy for secondary ischemic stroke (IS) and transient ischemic attack (TIA). Yet, a proportion of patients who receive antiplatelet therapy experience recurrent ischemic cerebrovascular events. A recent meta-analysis found an increased risk of recurrent stroke in clopidogrel- or aspirin-treated patients with ischemic stroke who had high on-treatment platelet reactivity (HTPR). Few studies have focused specifically on clopidogrel HTPR. Therefore, the aim of this study was to examine the relationship between clopidogrel HTPR and recurrent ischemic events in a population of Danish patients with IS.

Incidence, case-fatality rate, and prognosis of ischaemic stroke subtypes in a predominantly Hispanic-Mestizo population in Iquique, Chile (PISCIS project): a community-based incidence study

BACKGROUND: Incidence of ischaemic stroke subtypes, classified by cause, seems to vary between communities. We aimed to prospectively ascertain the incidence of first-ever ischaemic stroke in a predominantly Hispanic-Mestizo population in the northern desertic region of Chile. METHODS: Between July, 2000, and June, 2002, all patients with possible stroke or transient ischaemic attacks were identified from multiple overlapping sources and were rapidly assessed by two field neurologists. All identified patients were diagnosed by at least two stroke neurologists according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) definitions and were followed up at 6 months. Annual incidence rates were age adjusted to WHO, European, and US populations by the direct method to allow comparisons. FINDINGS: A total of 239 ischaemic strokes were identified, of which 185 (77%) were first-ever cases. 151 (82%) patients were hospitalised, of whom only 70 (38%) were assessed within 6 h of symptom onset. The mean age of patients was 66.4 years (SD 14.9) and 56% were men. The crude annual incidence rates (per 100 000) according to stroke subtype were: cardioembolic, 9.3; large-artery disease, 2.0; small-vessel disease, 15.8; other determined cause, 0.2; and undetermined cause, 17.4. Hypertension was the most common cardiovascular risk factor in all subtypes and atrial fibrillation was the most common cause of cardioembolic stroke. Case fatality at 30 days was highest in cardioembolic strokes (28%) and lowest in small-vessel disease (0%). Dependency or death at 6 months was also highest in cardioembolic strokes (62%) and lowest in small-vessel disease (21%). INTERPRETATION: Incidence and prognosis of small vessel and cardioembolic infarction was similar to that in other populations and incidence of large-artery atherothrombotic infarction was lower than in most previous reports. Hypertension and atrial fibrillation were the most common risk factor and cause, respectively, of ischemic stroke in this population. These findings should help the national stroke programme in the prevention of cardioembolic stroke, increase access to specialists and acute brain imaging and vascular studies, and improve stroke care.     

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.     

复发性缺血性脑卒中患者二级预防措施执行情况调查

目的分析复发性缺血性脑卒中患者二级预防措施依从性,总结二级预防失败患者药物治疗不当的原因和教训。方法登记2008年5月至2011年6月因再发脑梗死入院患者,按改良TOAST分型进行基线资料以及二级预防执行情况分析,从抗血小板药物使用、血压控制、他汀药物使用情况、糖尿病、吸烟等5个方面调查二级预防措施长期执行情况。结果急性缺血性脑卒中638例,其中复发性缺血性脑卒中106例,动脉粥样硬化血栓形成是最主要的病因类型(78.3%),其两次卒中事件时间间隔小于小血管病变(P<0.05)。二级预防措施执行情况分析显示69.4%患者未规律服用抗血小板药物,54.5%高血压患者血压控制不达标,87.7%高脂血症患者未达到血脂控制目标,76.5%糖尿病患者血糖不达标,86.7%吸烟患者未戒除吸烟。结论二级预防各项措施与指南之间均存在较大差距,迫切需要在基层医务人员和患者中强化二级预防的教育。     

Antiplatelet Agents for Stroke Prevention

Stroke is one of the leading causes of disability and death. Ischemic stroke is a syndrome with heterogeneous mechanisms and multiple etiologies, rather than a singularly defined disease. Approximately one third of ischemic strokes are preceded by another cerebrovascular ischemic event. Stroke survivors are at high risk of vascular events (i.e., cerebrovascular and cardiovascular events), particularly during the first several months after the ischemic event. The use of antiplatelet agents remains the fundamental component of secondary stroke prevention. Based on the available data, antiplatelet agents should be used for patients with noncardioembolic stroke. The use of combination therapy (aspirin plus clopidogrel) has not been proven to be effective or safe to use for prevention of early stroke recurrence or in long-term treatment. There is no convincing evidence that any of the available antiplatelet agents are superior for a given stroke subtype. Currently, the uses of aspirin, clopidogrel, or aspirin combined with extended release dipyridamole are all valid alternatives after an ischemic stroke or transient ischemic attack. However, to maximize the effects of these agents, the treatment should be initiated as early as possible and be continued on a lifelong basis.     

Recent clinical trial results with antiplatelet therapy: implications in stroke prevention

Dual antiplatelet therapy that inhibits more than one pathway of platelet activation is appealing and biologically rational. The CURE study evaluated the efficacy and safety of clopidogrel on top of acetylsalicylic acid (ASA) versus standard therapy (including ASA) in over 12,000 patients with unstable angina or non-ST-segment elevation myocardial infarction (MI). Clopidogrel in combination with ASA reduced the relative risk of the combined atherothrombotic endpoint of cardiovascular death, MI or stroke by 20% (95% CI 0.72-0.90; p < 0.001) and the absolute risk of this composite endpoint by 2.1%. While the study was not powered or designed to demonstrate a reduction in stroke, there was a 14% reduction in stroke risk (p > 0.05). Dual antiplatelet therapy was associated with an acceptable 1% increase in the incidence of major bleeding events (p = 0.001). PCI-CURE, a prespecified substudy of patients who underwent percutaneous coronary intervention (PCI) during CURE, confirmed the early and sustained benefits of clopidogrel therapy seen in the overall CURE study. CREDO was a randomized, double-blind, placebo-controlled trial in more than 2,100 patients that evaluated the continuation of clopidogrel on top of standard therapy including ASA for 12 months after PCI, and the benefit of a preprocedural clopidogrel loading dose. The long-term results at 1 year showed that there was a 27% reduction in the risk of stroke, MI or death with long-term clopidogrel therapy (p = 0.02). There was a consistent benefit of extended clopidogrel therapy for each component of the composite endpoint, with a 25.1% relative risk reduction for all-cause stroke. In patients who received clopidogrel > or =6 h before PCI, there was a 39% reduction in the risk of death, MI or urgent target-vessel revascularization at 28 days (p = 0.051). These data suggest important implications in the future for the use of an early loading dose of clopidogrel in patients undergoing carotid stenting and, if proven in current or future trials, the use of a loading dose followed by long-term continuation of clopidogrel in other high-risk atherothrombotic patients such as those with transient ischaemic attack or ischaemic stroke.     

Piracetam versus acetylsalicylic acid in secondary stroke prophylaxis. A double-blind, randomized, parallel group, 2 year follow-up study

Piracetam has been shown to inhibit platelet aggregation. Therefore, we performed a double-blind, randomized, parallel group study to compare the efficacy of daily 1600 mg piracetam t.i.d. vs. 200 mg acetylsalicylic acid (ASA) t.i.d. in secondary stroke prophylaxis. 563 patients after stroke as confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) were enrolled and received either piracetam or ASA during a 2 year follow-up period. The primary endpoint was the rate of stroke, transient ischaemic attack (TIA), or death from vascular cause. The secondary endpoint was the rate of adverse events leading to a premature discontinuation of the study medication. Patients were visited at home every 3 months and were examined in hospital after 1 and 2 years. At every visit, the platelet function was evaluated. No significant difference and no significant equivalence could be shown for the primary endpoint between the piracetam and the ASA group both in the intention-to-treat and in the per-protocol analysis. However, there was a not significant trend in favor of ASA (11.7 vs. 15.2%). After excluding those patients who did not respond to antiplatelet medication in vitro, however, piracetam and ASA were equivalent in secondary stroke prophylaxis (stroke, TIA, or vascular death 10.1% in the piracetam group vs. 9.7% in the ASA group). Piracetam was significantly superior to ASA in the secondary endpoint (P=0.0039). The data suggest that the overall efficacy of piracetam in secondary stroke prophylaxis is not as good as that of ASA but that piracetam is better tolerated. However, our data furthermore show that nonresponders to pharmacological inhibition of platelet function are more frequent under piracetam therapy and that they may influence the results of large studies on secondary prophylaxis in vascular diseases.     

Recurrent stroke/TIA in cryptogenic stroke patients with patent foramen ovale

BACKGROUND: Patent foramen ovale (PFO) is present in 40% of patients with cryptogenic stroke and may be associated with paradoxical emboli to the brain. Therapeutic options include antiplatelet agents, anticoagulation, percutaneous device and surgical closure. We assessed the hypothesis that there are differences in rates of recurrent TIA or stroke between patients in the four treatment groups. METHODS: Patients presenting from January 1997 with cryptogenic stroke or TIA and PFO were followed prospectively until June 2003. Treatment choice was made on an individual case basis. The primary outcome was recurrent stroke. The secondary outcome was a composite of stroke, TIA, and vascular death. RESULTS: Baseline. Our cohort consisted of 121 patients; 64 (53%) were men. Median age was 43 years. Sixty-nine percent presented with stroke and 31% with TIA. One or more vascular risk factor was present in 40%. Atrial septal aneurysm (ASA) was present in 24%. Treatment consisted of antiplatelet agents (34%), anticoagulation (17%), device (39%) and surgical closure (11%). Follow-up. Recurrent events occurred in 16 patients (9 antiplatelet, 3 anticoagulation, 4 device closure); 7 were strokes, 9 were TIA. Comparing individual treatments there was a trend toward more strokes in the antiplatelet arm (p = 0.072); a significant difference was seen for the composite endpoint (p = 0.012). Comparing closure versus combined medical therapy groups, a significant difference was seen for primary (p = 0.014) and secondary (p = 0.008) outcomes, favoring closure. Age and pre-study event predicted outcome. CONCLUSION: Patent foramen ovale closure was associated with fewer recurrent events. Complications of surgical and device closure were self-limited.     

Recurrent cerebrovascular ischaemic events in patients with interatrial septal abnormalities: a follow-up study

Abstract The aim of this study was to evaluate the risk of recurrent ischaemic cerebrovascular events (stroke or transient ischaemic attack (TIA)) in patients with patent foramen ovale (PFO) or atrial septal aneurysm (ASA) treated with different therapeutic regimens. We enrolled 86 patients aged 18–60 years with an unexplained ischaemic stroke or TIA referred to our inpatient department in the period May 1994–December 1999. Follow-up lasted until April 2003. Patients were excluded if the stroke or TIA was related to large-artery atherosclerosis, small artery occlusion, major cardiac sources of embolism or other uncommon causes. During a follow-up (mean±SD) of 64.1±28.8 months (range 8.1–105.6) a recurrent ischaemic cerebrovascular event occurred in 11/86 patients (12.8%) (5 TIA and 6 strokes). Eight events (4 TIA, 4 strokes) occurred in the 59 patients with PFO alone, three (1 TIA, 2 strokes) in the 21 with PFO plus ASA and none in the 6 patients with ASA alone. In the overall population the cumulative risk of recurrent stroke/TIA was 1.2% at 2 years, 5.5% at 4 years, 7.6% at 6 years and 23.6% at 8 years, and was similar in patients with PFO alone vs. patients with PFO plus ASA (9.0% vs. 6.1% at 6 years, 26.0% vs. 23.1% at 8 years; p>0.05). Nine cerebral ischaemic events (4 TIA, 5 strokes) occurred in the 48 patients treated with antiplatelet drugs (7 in patients with PFO, 2 in patients with PFO plus ASA), and two (1 TIA, 1 stroke) in the 17 patients treated with oral anticoagulants (1 with PFO, 1 with PFO plus ASA). No events occurred in patients submitted to transcatheteral closure.     

Burden of Premature Atrial Complexes and Risk of Recurrent Stroke and Death in Patients with Mild to Moderate Ischemic Stroke

BackgroundPremature atrial complexes (PACs) meet increased attention as a potential intermediary between sinus rhythm and atrial fibrillation (AF). Patients with even high numbers of PACs do not fulfill current guidelines for oral anticoagulation treatment though an associated stroke risk is suspected. Objective: We aimed to determine whether a high number of PACs or runs of AF less than 30 seconds in 2-day continuous electrocardiogram (ECG) recording was associated with risk of recurrent ischemic stroke/transient ischemic attack (TIA) or death in a large cohort of patients with acute ischemic stroke or TIA and no prior AF.MethodsWe performed 48 hours continuous ECG recording within 1 week after ischemic stroke/TIA. PACs were reported as mean number of PACs per hour. Patients were followed in Danish Stroke Registry, Danish Civil Registration System, and Danish National Patient Registry. Cox Regression analysis was used to calculate hazard ratios.ResultsWe included 1507 patients with TIA (40%) or ischemic stroke (60%), of which 98.7% had mild to moderate strokes. Mean age was 72.9 (7.8) years, 43.4% were females. Follow-up was 2.3 (1.3) years. Hazard ratio for recurrent stroke/TIA or death did not differ between quartiles of PAC burden, nor did any of the 2 components of this composite endpoint. Nonsustained AF less than 30 seconds was not associated with higher risk of recurrent stroke/TIA or death.ConclusionsIn a large cohort of patients with recent ischemic stroke or TIA, burden of PACs or nonsustained AF less than 30 seconds were not associated to higher risk of recurrent stroke/TIA or death.     

Stroke recurrence and its prevention in patients with patent foramen ovale

BACKGROUND: It is unclear whether medical or invasive (surgical or catheter interventional) treatment is preferable to prevent recurrence of cerebral ischemia in patients with patent foramen ovale (PFO) as the suspected cause of stroke and what the role of concomitant risk factors is in stroke recurrence. METHODS: Over a period of ten years, 124 patients (mean age 51 +/- 15 years) with cryptogenic cerebral ischemia and PFO were included into the study and prospectively followed over a mean of 52 +/- 32 months. Of these, 83 were treated medically, 34 underwent transcatheter closure, and seven had surgical closure of the foramen. Of the medically treated patients, 11 stopped medication during follow-up. Recurrent ischemic events and risk factors for recurrence were analyzed. RESULTS: Annual stroke recurrence rates were generally low and comparable in catheter and medically treated patients, and in patients who had stopped medication (2.9%/2.1%2.2%/year). Patients suffering from recurrence after transcatheter closure (n = 2) both had residual shunts. No stroke recurrence was observed in the few surgically treated patients. An atrial septal aneurysm was not a predictor of recurrent or multiple strokes (p > 0.05, OR = 0.31, and OR = 0.74). Large shunts and a history of previous ischemic events were considerably more frequent in patients with recurrent strokes (p < 0.05, OR = 5.0, and OR = 4.4). Pulmonary embolism and case fatality rates were significantly higher in patients with stroke recurrence (p < 0.001, and p < 0.01). CONCLUSIONS: The absolute risk of recurrent cerebrovascular events in patients with PFO receiving medical or catheter interventional therapy is low. The small group of untreated patients had a comparably low rate of stroke recurrences. Previous ischemic events and shunt size were risk factors in this observational study. Given conflicting findings across multiple studies, enrollment into a randomized controlled trial would be the optimal choice.