Editors: Norris, John W.; Hachinski, Vladimir
Title: Stroke Prevention, 1st Edition
Copyright 2001 Oxford University Press
> Table of Contents > II - Secondary Prevention > 9 - Cardiac Anomalies
The aims in treating stroke are three-fold: (1) to reopen an occluded cerebral artery (thrombolysis), (2) to provide protection against the metabolic cascade caused by ischemic injury leading to neuronal death (neuroprotection), and (3) to prevent recurrent stroke (secondary prevention). Secondary prevention of stroke is the most important of these three since neither thrombolysis nor neuroprotection are currently practical in the majority of patients. In studies performed before the 1980s, stroke recurrence rate varied from 2% 13% in the first month, irrespective of treatment, and from 2% 22% in untreated patients. 1
No difference has been found in the early recurrence rate among patients with vascular causes compared to those with presumed cardioembolic stroke (CES).2,3 In strokes with cardiac causes, 13% 21% will experience a recurrence within two weeks, which worsens the prognosis.4,5,6,7 The Cerebral Embolism Study8 found the risk of recurrence was slightly higher during the first 6 days, and Yasaka et al.7 noted that recurrence was especially frequent 2 14 days after the initial stroke.
Little information exists about the recurrence rates of stroke for the various types of cardioembolic sources, except for rheumatic heart disease, in which recurrence rates differ among subgroups of patients with the same cardioembolic source, e.g. atrial fibrillation. Therapeutic strategies include anticoagulants, antiplatelet agents, and surgical procedures (e.g., closure of patent foramen ovale).
Atrial Fibrillation (AF)
Approximately 16% (11% 29%) of all ischemic strokes are associated with nonvalvular AF,10 and among patients over 70 years old with ischemic stroke, more than one-third suffer AF.11,12 AF increases the relative risk of ischemic stroke about five-fold, roughly 1% 5% per year for elderly people. 10 Wolf et al.12,13 reported a five-fold increase in stroke incidence patients with nonrheumatic atrial fibrillation compared with a normal age matched population. The stroke risk associated with AF was 0.2 per 1,000 in the 30 39 year age group, and 39 per 1,000 in the 80 89 year age group. The risk of very early stroke recurrence among patients with AF (the most common cause of cardiogenic embolism) is estimated at 0.1% 1.3% per day during the first two weeks. 2,3,14,15,16,17,18,19,20,21,22,23,24 Moreover, AF patients with prior ischemic stroke or transient ischemic attack (TIA) have a high risk for recurrence of 12% per year for the subsequent two to three years.25,26 Those with more remote stroke or TIA have a similar high risk.27 These variations of recurrence rates are due to the retrospective design of most studies and also to the inclusion of AF patients irrespective a coexistent cardiac disorder.
Nine recent randomised clinical trials AFASAK, SPAF I, BAATAF, CAFA, SPINAF, SPAF II, EAFT, ESPS SPAF III have convincingly demonstrated the efficacy of anticoagulants and aspirin in stroke prevention nonvalvular AF,28,29 but only two EAFT 25 and ESPS II 26 dealt specifically with secondary prevention.
Five trials of primary prevention AFASAK, SPAF I, BAATAF, CAFA, SPINAF comparing warfarin vs. placebo found a relative risk reduction of 33% 86% per year for ischemic stroke and 2.5% 4.7% absolute rate reduction.10,30 The Atrial Fibrillation investigators, analyzing pooled data from the first five primary prevention trials, found an annual stroke rate of 4.5% in controls vs. 1.4% in the warfarin group (risk reduction = 68%). The death ra and combined outcome rate (stroke, death, systemic embolism) were also significantly reduced in the treatment group.
The efficacy of aspirin for stroke prevention in AF patients has been studied in only two of the original five primary prevention trials (AFASAK and SPAF I) and in one secondary prevention trial (EAFT), yielding a pooled risk reduction of 20%, a modest reduction compared to placebo.10 In the SPAF II trial of primary prevention, warfarin [international normalized ration (INR 2.0 4.5)] produced a 50% risk reduction compared to aspirin at 325 mg/day.31 Evaluation of
The stroke prevention benefit of warfarin carried no serious risk major bleeding in most of these trials: 1.0% for placebo, 1.0% aspirin, and 1.3% warfarin.10,30 Also, the incremental increase in severe haemorrhage among elderly, anticoagulated AF patients in these trials was only 0.3% 2.0% per year with INR 1.5 4.0,10 although trial patients have a lower bleeding risk than those in clinical settings. The risk of major hemorrhage in AF patients receiving warfarin was related to the intensity of anticoagulation, patient age, and fluctuation in INRs.10 High-risk AF patients, defined as those with prior TIA or stroke, a history of hypertension, or a substantially impaired left ventricular systolic function, had a higher risk of stroke (>7% per year) that was significantly reduced by warfarin.10
In the SPAF III study,29 892 patients with AF who were at low risk of stroke and taking 325 mg aspirin per day were followed for a mean of 2.0 years. The rate of primary events (ischemic stroke and systemic embolism) was 2.2% per year, while for all ischemic stroke it was 2.0% per year and for disabling ischemic stroke it was 0.8% per year. Those with hypertension had a significantly higher rate of primary events (3.6% per year vs. 1.1% year), while the rate of disabling stroke was low. This study illustrates that AF patients with a low risk of ischemic stroke benefited less with anticoagulation than with aspirin.
Risk Stratification for Patients with AF Based on Primary Prevention Studies
The risk of stroke from AF depends on various factors, including age,13 duration of fibrillation, 32 coexisting heart failure and hypertension.33 One evaluation of pooled data from five randomized primary stroke prevention trials found that the major risk factors were prior stroke or TIA, diabetes, hypertension, and age, while angina, previous myocardial infarction, and congestive heart failure were also significant.34 Mitral stenosis and thyrotoxicosis were also associated with increased stroke risk in retrospective series.34
The annual rate of ischemic stroke in AF is about 5%, varying between 0.5% and 12% depending upon the subgroup at risk.28 Patients with paroxysmal AF tend to be younger and have less cardiovascular disease, so that their risk of stroke is less.28
In the SPAF III study,29 patients were divided into high-risk and low-risk groups depending upon four prespecified risk factors: (1) left ventricular function associated with congestive heart failure or reduced extraction fraction on echocardiography; (2) systolic blood pressure >160 mm Hg; (3) prior ischemic stroke, TIA, or systemic embolism; and (4) female older than 75 years. The results of this trial indicated 3 levels of risk: (1) low (about 1.0% per year) for those
Based on these findings, Hart et al.9,10 recommended aspirin at 325 mg/day for low-risk patients, aspirin or warfarin for moderate risk patients, and warfarin, INR 2.0 3.0, for patients <75 years, and 1.6 2.5 >75 years for high-risk patients.28
Echocardiography helps gauge the risk stratification, but it is unclear at present if left ventricular dysfunction, atrial size, and mitral annular calcification diagnosed by transthoracic echocardiography (TTE) represent consistent additional stroke risk factors in AF patients. A pooled analysis of three studies, BAATAF, SPINAF, and SPAF I, showed that moderate to severe left ventricular dysfunction diagnosed by TTE was an independent predictor of stroke, but not left atrial size.35,36 Similarly, Shively et al.37 noted increased stroke risk associated with decreased left atrial flow velocity (<15 cm/sec), ventricular dilatation, and decreased left atrial ejection fraction in patients with AF and atrial enlargement. In another study, spontaneous echo contrast was significantly associated with AF-related stroke, possibly by changing blood coagulability consecutive to atrial stasis.38
Transesophageal echocardiography (TEE) in the SPAF III study39 showed that the presence of complex aortic plaques ( 4 mm or mobile) carried an annual stroke risk of 16%, compared with 4% in high-risk patients without such plaques. Unlike TEE, TTE is very insensitive for atrial thrombi detection.40
The decision to use anticoagulant or aspirin therapy depends upon risk stratification of patients with AF. Aspirin carries a lower bleeding risk and requires less medical monitoring than do anticoagulants, and at 325 mg/day reduces the stroke risk in these patients from 6.3% per year in the placebo group to 3.6% year in the aspirin group, a risk reduction of 42%.36 This therapeutic effect was higher in noncardiac sources of stroke than those from arterial causes. In AF patients with a low stroke risk (1% per year) on aspirin, only small reductions in ischemic stroke could be expected from anticoagulation, but this causes a higher risk of intracranial bleeding. In those with a high risk of stroke (6% 12% per year) on aspirin, a much greater reduction can be expected with warfarin.
Secondary Prevention Strategies
The only large placebo-controlled trial of secondary prevention stroke in AF, the European Atrial Fibrillation Trial (EAFT),25,41 enrolled AF patients with prior TIAs or minor ischemic strokes and was divided into three groups: warfarin alone, aspirin 300 mg/day alone, and warfarin vs. aspirin. The rate of recurrent stroke, 12% per year in the placebo group, was reduced by 17% in the aspirin group (n.s.) and 66% in the warfarin group (p = 0.001).
In this trial, the INRs varied between 2.5 and 4.0, but values of 2.0 to 2.9 reduced the stroke risk (including hemorrhagic events) by 80%, compared to INRs of less than 2.0. INRs between 3.0 and 3.9 reduced the rate by 40 %. Only INRs higher than 3.9 increased the complication rate, principally because of hemorrhagic complications.
In the ESPS II trial,26 in which dipyridamole with aspirin reduced recurrent stroke, this therapeutic effect was not seen in the subgroup of patients with AF.26,42 In a similar secondary prevention study, Studio Italiano Fibrillazione Atriale,43 using indobufen (100 mg-200 mg twice a day) or warfarin (INR, 2.0 3.5) no superiority of one treatment over the other was detected, and bleeding complications were low. Hence, indobufen is an acceptable alternative therapy to anticoagulation in AF patients.
Some questions remain unanswered, such as the efficacy of ticlopidine and anti-glycoprotein Ilb/IIIa inhibitors in preventing recurrent stroke AF patients, especially in elderly or hypertensive patients whom anticoagulation is more risky, as well the efficacy of thrombolytic agents. Finally, there is no convincing evidence that restoring sinus rhythm by cardioversion reduces cerebral embolic potential (Table 9.1).
Atrial Flutter and Atrial Fibrillation-Flutter
Data concerning this uncommon cardiac disorder are scant, and the exact risk of stroke associated with atrial flutter is unknown. Nevertheless, in a recent small retrospective study in patients without history of brain ischemia, the annual risk of stroke was only 1.6%.44 Available data suggest that the risk of embolism from atrial flutter is less than AF following cardioversion. Atrial fibrillation-flutter carries the same risk of stroke as AF and so requires the management
Sick Sinus Syndrome (SSS)
In a recent prospective study of sick sinus syndrome, previous cerebral ischemic events, an age >65 years, left atrial spontaneous echocardiographic contrast and depressed atrial ejection force were independent risk factors for stroke.45 Those with AF showed a thromboembolic rate of 5% per year, compared to 3.5% per year in those without AF,10 though a more recent study reported stroke rate of 10% per year.45 Dual-chamber cardiac pacemakers reduced both the occurrence of AF as well as thromboembolism in comparison to ventricular pacing.
For secondary prevention in patients with well established SSS, anticoagulation should be considered, irrespective of the presence or absence AF.10 The value of antiplatelets, the optimal intensity anticoagulation, and the safety chronic anticoagulation in elderly patients remains uncertain.
TABLE 9.1. Prevention of Stroke in Atrial Fibrillation Patients: Recommendations
Patent Foramen Ovale
During the last decade, there has been an increasing emphasis on the role of patent foramen ovale (PFO) in the genesis of ischemic stroke, particularly young. Several case control studies46,47,48,49,50,51,52,53,54 have shown that PFO was significantly associated with stroke in patients younger than 60 years of age. Cerebral paradoxical embolism is usually a presumed diagnosis, because direct evidence, such as a thrombus lodged in the PFO shown on transesophageal echocardiography or the discovery of a deep venous thrombosis, is commonly lacking.46,49,50,51,52,53,54,55,56 Despite these ongoing controversies, it is reasonable to incriminate a cerebral paradoxical embolism in young patients with no other identified cause of stroke than PFO.
The optimal treatment of these patients remains a matter debate, mainly because of a lack controlled clinical trials. There are four therapeutic options: antiplatelets drugs, anticoagulants, closure of PFO by transcatheterization or closure of PTO by surgery. The only two studies57,58 secondary prevention of stroke in patients with PFO show that the risk recurrent stroke is relatively low, about 1% per year, in patients treated with aspirin or shortterm anticoagulation. 10 In the Lausanne Study57 and the French Study Group,58 the annual rate of TIA was 3.8% and 3.4%, of stroke alone, 1.9% 1.2%, respectively.
At present, there is little information on the risk of stroke recurrence in those with PFO associated with an atrial septal aneurysm (ASA) compared to PFO alone, and some have suggested that PFO with an ASA, or large PFOs with rightto-left shunting, have more stroke risk.59,60,61,62 On these grounds, Nendaz et al.63 created a decision analysis model for the clinician. This model indicates that a stroke risk recurrence of 0.8% to 7% per year, there was more benefit from surgical closure of the PFO than from any other treatment. When the risk exceeds 0.8% 1.4% per year, anticoagulants and antiaggregants are better than placebo, while when it is <0.8% per year, neither medical nor surgical treatment is indicated. Further studies are planned to determine the stroke risk in subgroups of PFO patients using transcranial Doppler ultrasound with the microbubble technique, which may be more accurate than TEE.64 At present, treatment is limited to the application of empirical clinical criteria.
Surgical closure of PFO without recurrence stroke has been reported,65,66,67 but others have not been so fortunate.68 An alternate procedure consists of transcatheter closure of the PFO, which was effective in 82% of cases, but recurrence occurred in 4 of 34 patients on follow-up.69 Considerably more information is needed concerning the efficiency, safety, and long-term complications of the transcatheter technique before it can replace surgery.
The use of anticoagulants is risky in young patients with a long life expectancy because of the major bleeding risk, estimated at 1.5% 11% per year.67 The authors recommend anticoagulants when a deep venous thrombosis (DVT) is
Prosthetic Heart Valves (PHV)
Thromboembolic events occur at a rate of 1 5% per year in patients with prosthetic heart valves, despite oral anticoagulation, and 85% of these are cerebral.68 Stroke may occur from either inadequate anticoagulation or because thrombogenic factors are inadequately suppressed despite adequate anticoagulation therapy. The precise pathophysiology of thromboembolism in patients with PHV remains uncertain. Increased shear rates at the valve surfaces may activate platelets, generating platelet-derived microparticles, which could have potent procoagulant activity.71 Also, the presence of microemboli, frequently encountered in these patients, may result from harmless gaseous bubbles (cavitation) rather than from actual paniculate elements.70,71 High-intensity transient signals (HITS) detected by the Doppler technique are seen overwhelmingly with mechanical heart valves compared to biological prostheses, and these may produce a cognitive alteration.72 Even with the combination of anticoagulation and antiplatelets, the annual incidence rate of thromboembolism in patients with PHV remained at 2% to 3%.70
As yet, no prospective randomized studies have been done in patients with mechanical valves to assess the efficacy of antithrombotic therapy. In a meta-analysis comprising more than 53,000 patient-years, the major embolism rate without antithrombotic therapy was 4.0% per year, reduced to 2.2% year with antiplatelets and to 1.0% per year with anticoagulants.73 The embolic rate with a combination of anticoagulants and antiplatelets was higher, at 1.7% per year, than for anticoagulants alone, and much higher with dipyridamole, at 5.4% per year than with aspirin alone, at 1.4% per year. Major embolism is more frequent mitral valves, with mitral plus aortic valves, and with caged ball prostheses.
The exact level of anticoagulation needed to prevent thromboembolism in patients with mechanical valves remains uncertain. In the past, high-intensity anticoagulation was used, and a recent meta-analysis based on 12 studies found an INR of 2.5 3.6 was best, resulting in an American College Chest Physicians
TABLE 9.2. Secondary Prevention in Patients with Patent Foramen Ovale-Associated Stroke: Recommendations (Risk of stroke on aspirin: 1%/year [0 4% / year])
Acute Myocardial Infarction (AMI)
About 1% to 5% of patients with AMI have an ischemic stroke, most of them cardioembolic, occurring within two to four weeks. Stroke occurred especially in those with anterior AMI, in whom the risk of ischemic stroke was 12%,10 and in patients with large anterior infarcts.79,80 In the first month after AMI, incidence rates were 1% 3.2%, and AF and ST segment elevation were significant risk factors.81
Left ventricular thrombi (LVT), in older patients with large infarcts, especially those with congestive heart failure, have an increased risk of stroke. TTE is needed to diagnose ventricular thrombi, but it should be performed at least 24 hours after AMI, because since these develop 1 10 days after AMI. Approximately 15% of AMI patients with recognised LVT will suffer stroke, while /3-adrenergic blocking drugs may favor the development of LVT.10
No randomised trials have been carried out comparing aspirin to anticoagulants to prevent stroke following AMI, though anticoagulants alone were shown effective in preventing recurrent AMI (INR 2.8 4.8) and stroke the Anticoagulants in Secondary Prevention of Events Coronary Thrombosis (ASPECT) trial. No comparison with aspirin was made.82 Early randomised trials showed that heparin followed by low-intensity oral anticoagulation (INR 1.6 2.5) reduced stroke by about 70% in the weeks following AMI (mean rate 2.9% 1.2%).10 Because the stroke rate three months after AMI is so low, long-term anticoagulation beyond three months is not justified unless other major cardiac embolic risk factors, such as mural thrombosis, are present.
A risk stratification approach may be useful. Early treatment with low-dose heparin and aspirin for those with uncomplicated AMI is recommended, but full dose anticoagulation is needed for patients with LVT detected by echocardiography.
Timing Of Anticoagulant Treatment
Prevention of recurrent stroke by anticoagulantion in patients with cardioembolic stroke remains controversial, and the stroke risk must be balanced against the risk of hemorrhagic transformation the cerebral infarct. The timing anticoagulation is uncertain. In the International Stroke Trial83 and other studies, neither heparin nor heparinoid were efficacious because the benefit of reducing recurrent ischemic strokes was offset by an increase in hemorrhagic strokes. Until adequate data are available from randomized trials, the therapeutic decisions for these patients will remain arbitrary.
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