TIA

Dual Antiplatelet Therapy in Acute Transient Ischemic Attack and Minor Stroke.

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Some patients with stroke and transient ischemic attack (TIA) of the brain are at high risk for early recurrent stroke, usually due to arterial thromboembolism.1,2 Aspirin reduces the risk of early recurrent stroke by only 12% (95% confidence interval [CI], 3 to 20).3 Adding clopidogrel to aspirin in patients with acute coronary syndromes reduces the risk of recurrent vascular events by 20% (95% CI, 10 to 28) but increases the risk of major bleeding by 38% (95% CI, 13 to 67).4 For patients with acute ischemic stroke, who are prone to early spontaneous hemorrhagic transformation of infarcted brain, adding clopidogrel to aspirin may cause more major bleeding than may otherwise occur in acute coronary syndromes. Among 731 patients with acute ischemic stroke or TIA (onset within the previous 3 days) enrolled in five small trials, the addition of clopidogrel to aspirin was associated with nonsignificant trends toward a reduction in recurrent stroke (4.5% with clopidogrel and aspirin, as compared with 6.6% with aspirin alone) and an increase in major bleeding (1.1% and 0%, respectively).5

Wang and colleagues now report in the Journal the impressive results of the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial.6 Among 5170 Chinese patients with acute minor ischemic stroke or TIA (onset within the previous 24 hours) at high risk for recurrence, the addition of clopidogrel to aspirin reduced the relative risk of recurrent stroke at 90 days by 32% (8.2% vs. 11.7%; hazard ratio, 0.68; 95% CI, 0.57 to 0.81; absolute risk reduction, 3.5 percentage points). The effect was consistent among 11 predefined subgroups. There was no difference between the group that received both clopidogrel and aspirin and the group that received aspirin alone in the incidence of moderate or severe hemorrhage (0.3% in each group; P=0.73) or hemorrhagic stroke (0.3% in each group; P=0.98).

The CHANCE investigators completed a large, scientifically rigorous trial that proves the concept that dual antiplatelet therapy can be more effective than single antiplatelet therapy in preventing early recurrent stroke in patients with acute symptomatic atherothrombosis (predominantly intracranial) of the brain. Moreover, the absolute benefits of dual antiplatelet therapy can be substantial in patients at high risk for recurrent stroke1; treating 29 patients for 90 days with clopidogrel plus aspirin for the first 21 days, followed by clopidogrel alone from day 22 to day 90, prevented one stroke, as compared with aspirin alone. Indeed, most of the absolute benefit of clopidogrel plus aspirin is realized within the first few days after TIA and ischemic stroke, when the underlying atherosclerotic plaque is most unstable and the risk of recurrence is highest.

The safety results show that dual antiplatelet therapy can be given without excess harm in patients with acute focal brain ischemia, provided that patients have a low risk of hemorrhagic transformation — no fresh brain infarction (i.e., TIA) or a very small volume of fresh brain infarction (i.e., minor ischemic stroke). The CHANCE investigators had to screen 41,561 patients with stroke or TIA to find 5170 appropriate patients (12.4%). Hence, the results cannot be generalized to most patients; the study excluded patients with major ischemic stroke, who are at risk for hemorrhagic transformation, and patients with TIA due to isolated sensory, visual, or vertiginous syndromes, who are at low risk for recurrence.1 The results may also not apply to non-Chinese patients with different forms of underlying arterial disease (e.g., a higher prevalence of extracranial large-artery atherosclerosis) and different prevalences of genetic polymorphisms of liver cytochrome P-450 (CYP) isozymes, which metabolize clopidogrel to its active metabolites. The absolute benefits of clopidogrel plus aspirin observed in this trial may also not be realized in persons and populations at lower absolute risk for recurrent stroke, such as those with a low prevalence of risk factors for recurrent stroke and those with access to effective secondary stroke prevention. Finally, the results of this trial cannot be generalized beyond 90 days after ischemic stroke, when the cumulative risks of bleeding with clopidogrel plus aspirin, as compared with aspirin or clopidogrel alone, offset the benefits.7-9

The implication of this trial is that Chinese patients with acute TIA or minor ischemic stroke (onset within the previous 24 hours) who are at high risk for recurrence should be regarded as a medical emergency. They should be treated immediately with clopidogrel plus aspirin for 21 days, followed by clopidogrel alone, for a total of 90 days, before continuing long-term treatment with clopidogrel, aspirin, or the combination of aspirin and extended-release dipyridamole. A bolus loading dose of at least 162 mg of aspirin and 300 mg of clopidogrel is required on day 1 to rapidly inhibit platelet aggregation, given that starting with daily doses of 75 mg of aspirin and clopidogrel takes several days to produce maximal inhibition of platelet aggregation. The benefits of dual antiplatelet therapy are greatest in the first days after TIA and ischemic stroke.

I think that clinicians should continue to enroll non-Chinese patients with acute TIA and minor ischemic stroke into ongoing large clinical trials of the safety and efficacy of dual and triple antiplatelet therapy.10,11 Moreover, I hope that researchers will evaluate new antiplatelet agents (e.g., ticagrelor and prasugrel) and new anticoagulant agents (e.g., rivaroxaban) that are effective in atherothrombotic acute coronary syndrome in patients with acute TIA and minor ischemic stroke due to arterial thromboembolism.

Source: NEJM

 

Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack.

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Transient ischemic attack (TIA) and acute minor ischemic stroke are common and often lead to disabling events. In China, there are approximately 3 million new strokes every year, and approximately 30% of them are minor ischemic strokes.1,2 The incidence of TIA in China has not been determined, but on the basis of the incidence in other countries, there are probably more than 2 million TIAs annually in China.3-5 The risk of another stroke occurring after a TIA or minor stroke is high, with approximately 10 to 20% of patients having a stroke within 3 months after the index event; most of these strokes occur within the first 2 days.5-8

The role of antiplatelet therapy for secondary stroke prevention has been well established. However, aspirin is the only antiplatelet agent that has been studied in the acute phase of stroke, during which its benefit is modest.9,10 Aspirin and clopidogrel synergistically inhibit platelet aggregation,11,12 and such dual therapy reduces the risk of recurrent ischemic events in patients with the acute coronary syndrome.13,14 Large-scale trials of secondary prevention of ischemic events after stroke have not shown a benefit of the combination of clopidogrel and aspirin.15-17 However, these trials did not study the early, high-risk period after stroke, they included some patients with strokes of moderate severity, and they included few if any patients with TIA. Three small pilot trials have shown trends toward a benefit of the combination therapy and minimal safety concerns in patients with minor stroke or TIA.18-20

We conducted the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial to test the hypothesis that 3 months of treatment with a combination of clopidogrel and aspirin would reduce the risk of recurrent stroke, as compared with aspirin alone, among patients with acute high-risk TIA or minor ischemic stroke.

DISCUSSION

In this large-scale trial involving patients with high-risk TIA or minor ischemic stroke, we found that the addition of clopidogrel to aspirin within 24 hours after symptom onset reduced the risk of subsequent stroke by 32.0%, as compared with aspirin alone. Event rates during this early period were very high, and clopidogrel was associated with an absolute risk reduction of 3.5 percentage points, equivalent to a number needed to treat of 29 patients to prevent one stroke over a period of 90 days. Combination therapy with clopidogrel and aspirin, as compared with aspirin alone, was not associated with an increased incidence of hemorrhage, although there was a worrisome trend in overall bleeding toward more events with the combination therapy.

The results of our trial differ from those of other trials of combination therapy with clopidogrel and aspirin after cerebral ischemic events.7,8,17 One possible explanation is that, unlike previous trials, our trial targeted a population at particularly high risk for recurrent ischemia and at low risk for hemorrhage. Previous trials included patients with more severe strokes than our trial did, and they did not enroll patients in the first hours after an index minor stroke or TIA, during which the risk of recurrent ischemia is particularly high. This may explain why other trials did not show a reduction in the risk of ischemic events but did show an increased risk of hemorrhage.

In our study, the curves for survival free of stroke were particularly steep in the first few days, during which the curves representing the treatment groups diverged dramatically. Subsequently, the rates of stroke were similar. This suggests that the requirement for randomization within 24 hours after the onset of symptoms, with nearly half the patients enrolled within 12 hours (and treated shortly thereafter), was important. Although we did not see a relative difference in the efficacy outcome between patients randomly assigned to a study group within 12 hours and those assigned after a longer interval, absolute event rates were higher among those who were enrolled within 12 hours. In clinical practice, treatment with clopidogrel and aspirin as soon as possible after symptom onset is likely to produce the greatest absolute benefit, since ischemic event rates are highest in the initial hours after symptoms appear.

Our trial was conducted entirely in China, a country with approximately 150 to 250 deaths from stroke per 100,000 persons per year, which is five times as high as the rate in the United States.23Although diagnostic tools and therapies commonly used in the United States and Europe are available in most hospitals in China, some patients cannot afford this level of care.24,25 Secondary prevention practices are also less rigorous in China, where rates of treatment of hypertension, diabetes, and hyperlipidemia are low, as shown in our study population (Table S3 in theSupplementary Appendix). Furthermore, the distribution of stroke subtypes in China differs from that in more developed countries; China has a higher incidence of large-artery intracranial atherosclerosis25 and a higher prevalence of genetic polymorphisms that affect the metabolism of clopidogrel.26 The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial (ClinicalTrials.gov number, NCT00991029), sponsored by the National Institutes of Health, which is similar to our trial, is now enrolling patients at sites primarily in the United States.27 The POINT trial is assessing a higher loading dose of clopidogrel (600 mg) and a narrower time window (treatment within 12 hours after symptom onset) than were used in our study.

Several common clinical conditions mimic TIA, including seizures, migraine, peripheral vertigo, syncope, and anxiety.28 To minimize the risk of enrolling patients with TIA mimics, we excluded all patients with isolated sensory symptoms, isolated visual changes, or isolated dizziness or vertigo without evidence of acute infarction on baseline CT or MRI of the head. In addition, enrollment of patients with TIA was limited to those with a high ABCD2 score (≥4) to increase the likelihood that spells were due to true TIAs and to ensure that we were enrolling patients who were at high risk for subsequent ischemic events.29 The risk of subsequent stroke in the trial was high for this patient population, suggesting that our strategy was successful. Our findings may not apply to other populations of patients with ischemic events.

In conclusion, our study shows that among patients with high-risk TIA or minor ischemic stroke who are initially seen within 24 hours after symptom onset, treatment with clopidogrel plus aspirin for 21 days, followed by clopidogrel alone for a total of 90 days, is superior to aspirin alone in reducing the risk of subsequent stroke events. The combination of clopidogrel with aspirin did not cause more hemorrhagic events in this patient population than aspirin alone.

Source: NEJM

Even Minor Strokes Can Cause Long-Term Disability.

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In a prospective study, 15% of patients had not recovered full functioning 3 months after transient ischemic attack or minor ischemic stroke.

Most randomized trials of thrombolytic therapy for acute ischemic stroke have excluded patients with minor neurological deficits. A substantial proportion of these patients leave the hospital with some form of disability, but whether that disability persists in the long term remains uncertain. To address this uncertainty, researchers conducted a prospective observational study to ascertain 3-month functional outcomes in patients with transient ischemic attack (TIA) or minor stroke.

The CATCH study enrolled 510 patients with high-risk TIA (focal weakness or speech dysfunction lasting 5 minutes) or minor ischemic stroke (NIH Stroke Scale [NIHSS] score 3). Patients who received thrombolysis or had preexisting disability were excluded. All patients underwent baseline computed tomographic (CT) angiography.

Among 499 patients with complete follow-up, 15% had disability (modified Rankin Scale [mRS] score 2) at 3 months. Twenty-six percent of these patients had a recurrent ischemic event; in the remaining 74%, long-term disability presumably resulted from the original event. Disability rates ranged from 7% among patients with a baseline NIHSS score of zero, to 22% among those with a score of 3. In patients without recurrent events, disability was predicted by ongoing symptoms at the time of evaluation (odds ratio, 2.4) and large-vessel occlusion or acute infarction on CT angiography (OR, 2.4). These predictive associations were also significant when patients with recurrent events were included.

Comment: The authors justifiably call for more research into why patients without recurrent events end up with disability, particularly when there are no apparent deficits at baseline. In the meantime, this study should motivate us to ensure adequate follow-up and rehabilitation for patients with seemingly minor ischemic events. Additionally, these results support the use of thrombolytic therapy for minor ischemic stroke, and they help make a case for acute-treatment trials in this population.

Source:Journal Watch Neurology

 

B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial

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Epidemiological studies suggest that raised plasma concentrations of total homocysteine might be a risk factor for major vascular events. Whether lowering total homocysteine with B vitamins prevents major vascular events in patients with previous stroke or transient ischaemic attack is unknown. We aimed to assess whether the addition of once-daily supplements of B vitamins to usual medical care would lower total homocysteine and reduce the combined incidence of non-fatal stroke, non-fatal myocardial infarction, and death attributable to vascular causes in patients with recent stroke or transient ischaemic attack of the brain or eye.

Methods

In this randomised, double-blind, parallel, placebo-controlled trial, we assigned patients with recent stroke or transient ischaemic attack (within the past 7 months) from 123 medical centres in 20 countries to receive one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B6, and 0·5 mg vitamin B12). Patients were randomly allocated by means of a central 24-h telephone service or an interactive website, and allocation was by use of random permuted blocks stratified by hospital. Participants, clinicians, carers, and investigators who assessed outcomes were masked to the assigned intervention. The primary endpoint was the composite of stroke, myocardial infarction, or vascular death. All patients randomly allocated to a group were included in the analysis of the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT00097669, and Current Controlled Trials, ISRCTN74743444.

Findings

Between Nov 19, 1998, and Dec 31, 2008, 8164 patients were randomly assigned to receive B vitamins (n=4089) or placebo (n=4075). Patients were followed up for a median duration of 3·4 years (IQR 2·0—5·5). 616 (15%) patients assigned to B vitamins and 678 (17%) assigned to placebo reached the primary endpoint (risk ratio [RR] 0·91, 95% CI 0·82 to 1·00, p=0·05; absolute risk reduction 1·56%, −0·01 to 3·16). There were no unexpected serious adverse reactions and no significant differences in common adverse effects between the treatment groups.

Interpretation

Daily administration of folic acid, vitamin B6, and vitamin B12 to patients with recent stroke or transient ischaemic attack was safe but did not seem to be more effective than placebo in reducing the incidence of major vascular events. These results do not support the use of B vitamins to prevent recurrent stroke. The results of ongoing trials and an individual patient data meta-analysis will add statistical power and precision to present estimates of the effect of B vitamins.
source:lancet