WHO estimates for 2001 indicate that death from stroke in low-income and middle-income countries accounted for 85.5% of stroke deaths worldwide, and the disability adjusted life years (DALYs) lost in these countries was almost seven times those lost in high-income countries. Evidence from developed countries suggests that one in 20 adults (aged >14 years) is affected by stroke, including clinically covert strokes, and the incidence of acute cerebrovascular events (stroke and transient ischaemic attack combined) currently exceeds the incidence of acute coronary heart disease. Although rates of stroke mortality and burden vary greatly among countries, low-income countries are the most affected. Current measures of the prevalence of cardiovascular risk factors at the population level poorly predict overall stroke mortality and burden and do not explain the greater burden in low-income countries. This worldwide stroke epidemic and the well recognised medicosocial consequences of stroke (including post-stroke dementia) justify the need for periodic reviews of the best available evidence of worldwide stroke epidemiology. This will advance our understanding of stroke frequency and determinants in various populations, enabling better health-care planning. The most reliable data on stroke incidence and case fatality come from population-based incidence studies. Our last systematic review of population-based stroke incidence and case fatality studies was published in 2003. Several new population-based stroke incidence studies have been published since, which suggests there is a need for more in-depth systematic analysis. In addition, this and other reviews6,7 of population-based stroke incidence studies were limited: they did not include all previously published studies, they did not provide pooled estimates, and they did not systematically analyse stroke morbidity and early mortality in various populations. The aims of this systematic review are to update current knowledge of stroke morbidity and early case fatality with all available population-based stroke incidence studies and to review secular trends in stroke incidence and case fatality.
The prevalence of stroke is difficult to measure in a crosssectional way because more than 30% of patients die in the first year and 20% are left without any disability. Prevalence studies have been done in both rural and urban populations in the region, but most studies have used different definitions and age groups to study neurological disorders (including stroke), making comparisons diffi cult, if not impossible. The crude prevalence rates ranged from 1.7 per 1000 in rural Bolivia to 5.6 per 1000 in urban Colombia, but the numbers of cases were too small to make meaningful comparisons. In people older than 60 years, the range increased from 19.3 to 48.0 per 1000. Prevalence studies generally exclude patients who recover completely because of the difficulty of follow-up or independent verification. Comparisons between studies are difficult because of the failure to publish age-specific rates in mid-decades.
There are trends in stroke incidence among high-income and low to middle income countries over the past four decades, with a 42% decrease in stroke incidence in high-income countries and greater than 100% increase in low to middle income countries. Corresponding trends in stroke incidence are observed in younger (<75 years) and older (≥75 years) age groups, although the differences are far more pronounced in the older group. • In 2000–08, stroke incidence rates in low to middle income countries have, for the first time, exceeded those in high-income countries. • In high-income countries, there was a greater albeit non-signifi cant reduction in the incidence of primary intracerebral haemorrhage than of ischaemic stroke, whereas the incidence of subarachnoid haemorrhage has remained relatively stable over the past four decades. The incidence and proportional frequency of intracerebral haemorrhage and subarachnoid haemorrhage in low to middle income countries are signifi cantly greater than the incidence and frequency in high-income countries. • The pattern of changes in stroke incidence rates in high-income and low to middle income countries corresponds to those reported in studies of international mortality trends, suggesting that changes in stroke mortality rates are most likely to be attributable to the corresponding changes in stroke incidence rates. • In 2000–08, early (21 days to 1 month) case fatality ranged from 17% to 30% (13–23% for ischaemic stroke, 25–35% for primary intracerebral haemorrhage, and 25–35% for subarachnoid haemorrhage) in high-income countries and from 18 to 35% in low to middle income countries (13–19% for ischaemic stroke, 30–48% for primary intracerebral haemorrhage, and 40–48% for subarachnoid haemorrhage). • Early stroke case fatality is decreasing in both high-income and low to middle income countries but, overall, early stroke case fatality in low to middle income countries in the past decade is 25% higher than early stroke case fatality in high-income countries.
Incidence of ischaemic-stroke subtypes The incidence of ischaemic-stroke subtypes according to the Oxfordshire Community Stroke Project classification was reported in both the Iquique, Chile, and Barbados studies. The age and sex-adjusted incidence of first-ever lacunar infarction syndromes were high in both studies, being higher in Barbados (57 per 100 000 per year, 95% CI 50–65) than in Iquique (33 per 100 000 per year, 23–46) and could be attributed to an increased risk of small vessel disease in these populations . The incidence of partial anterior infarction and total anterior infarction were similar (27 and 14, respectively, in Barbados; and 20 and 14 in Iquique). The proportional incidence of ischaemic-stroke subtypes classified according to the Oxfordshire Community Stroke Project in population based studies in the region compared with community studies in the UK showed a high proportion of lacunar infarction in Latin America and the Caribbean . The incidence of ischaemic-stroke subtypes in the community, according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification, in Latin America has only recently been described. The incidence of transient ischaemic attacks in Iquique was lower than in other population-based studies. The frequency of previous transient ischaemic attack in patients with stroke was also low in this population (3%) . The low prevalence of carotid disease or non-presentation for medical attention, as well as under ascertainment factors, might be the cause of this low incidence. Precise estimates of the incidence and prevalence of TIAs are difficult to determine mainly because of the varying criteria used in epidemiological studies to identify TIA. Lack of recognition by both the public and healthcare systems of the transitory focal neurological symptoms associated with TIAs also may lead to gross underestimates. Given these limitations, the incidence of TIA in the United States has been estimated to be 200 000 to 500 000 per year, with a population prevalence of 2.3% that translates into 5 million individuals.
TIA incidence rates have been projected from different study cohorts in the United States and abroad, ranging from 0.37 to 1.1 per 1000 per year. An overall TIA incidence rate of 1.1 per 1000 US population has been estimated on the basis of a review of the National Hospital Ambulatory Medical Care Survey among 2 623 000 TIA cases diagnosed in US emergency departments between 1992 and 2000. From the Greater Cincinnati/Northern Kentucky population between 1993 and 1994, the overall race-, age-, and gender-adjusted incidence rate for TIA was found to be 0.83 per 1000. Between the years 2002 and 2004, the Oxford Vascular Study determined that the overall incidence rate of TIA was 0.66 per 1000 per year. Meanwhile, in rural and urban areas of Portugal, the crude overall annual incidence of TIA per 1000 population was found to be 0.67 and slightly higher in the rural region at 0.96 than in the urban area at 0.61. The Oxford Vascular Study found that, of 2,024 vascular events occurring in a population of 91,206, 45% were cerebrovascular events and 42% were coronary vascular events. 1 The study population comprised those who been admitted to hospital or were begin managed in the community by a general practitioner.
Disease definitions in clinical medicine, including those for ischemic injuries, are most useful when tissue based. Evidence Seeking the pathological basis of disease and directing treatment at underlying biological processes are central tenets of modern medicine. Tissue-based definitions are the rule for ischemic injuries affecting other end organs. For example, angina is distinguished from myocardial infarction not by symptom duration but by evidence of myocardial tissue injury. Time-based definitions unproductively focus diagnostic attention on the temporal course rather than underlying pathophysiology. The key diagnostic issue in patients with cerebral ischemic events is not how long the event lasted but rather the cause of the ischemia and whether cerebral injury occurred. A tissue-based definition of TIA encourages use of neurodiagnostic tests to identify brain injury and its vascular genesis. Conclusion A tissue-based definition of TIA will harmonize cerebrovascular nosology with other ischemic conditions and appropriately direct diagnostic attention to identifying the cause of ischemia and whether brain injury occurred ( Class IIa, Level of Evidence C).
Top: fuzzy DWI lesion in left MCA territory matching an area of diminished time to peak, indicating local hyperperfusion and suggesting spontaneous recanalisation had occurred prior to imaging at 3 h after onset (note the prolonged time to peak at the posterior edge of the DWI lesion, suggesting distal branch occlusion). Middle: the next day, perfusion has essentially normalised as well as the DWI lesion, save for a narrow posterior streak, suggesting the spontaneous recanalisation saved the at-risk tissue from progressing to infarction. Bottom: At day 7, there has been no return of the DWI lesion, indicating the tissue was effectively salvaged, without even minimal damage. DWI has revolutionised the diagnostic sensitivity of imaging ischaemia. DWI can indicate the degree of free diffusion of water molecules—apparent diffusion coefficient. If the cerebral blood flow goes below the penumbra threshold this causes failure of energy dependent processes, resulting in intracellular (cytotoxic) oedema, shrinkage of the extracellular compartment, and consequently reduced apparent diffusion coefficient. The latter translates into a high DWI signal, resulting in even very small ischaemic lesions being conspicuous. Furthermore, DWI is abnormal within minutes of stroke onset. Apparent diffusion coefficient values gradually return to normal in 5–10 days and then increase in chronic lesions. This gradual increase may indicate the development of vasogenic oedema and cellular necrosis. However, the DWI lesion persists for another week or so because it also detects prolonged T2 signal (“T2 shine-through”). Proper interpretation of DWI—eg, to distinguish acute recurrence—must therefore consider the apparent diffusion coefficient map. DWI is more sensitive to acute ischaemia than plain CT or T2-weighted MRI, which show only tissue changes caused by severe and prolonged ischaemia, usually sufficient to cause infarction. Interobserver agreement in stroke more than 6 h after onset is substantially better with DWI than with plain CT. Within 6 h of stroke onset, DWI has reported sensitivity of 95% and specificity of nearly 100% [Lovblad KO, Laubach HJ, Baird AE, et al. Clinical experience with diffusion-weighted MR in patients with acute stroke. Am J Neuroradiol 1998; 19: 1061–66. ]. Pooled data from reports in the literature to date (19 studies) have now confirmed that DWI provides a more precise evaluation of ischemic insult in TIA patients compared with standard CT and MRI studies . These series show convergent results regarding the frequency of DWI positivity among TIA patients; among the 19 studies including 1117 patients, the aggregate rate of DWI positivity is 39%, with frequency by site ranging from 25% to 67%. Few studies have systematically assessed the follow-up imaging characteristics of DWI-positive lesions in the setting of TIA. In 2 series, the proportion of patients demonstrating corresponding T2-weighted signal evidence of permanent injury on follow-up imaging ranged from 76% to 100%. Animal studies have demonstrated that even when early diffusion lesions reverse, the underlying tissue typically demonstrates neuronal dropout. Accordingly, the small group of patients with transient symptoms who evidence acute diffusion abnormalities but not late T2 changes still fall within the broad tissue definition of stroke. In summary, patients with TIA or minor stroke who have DWI lesions, especially when multiple, are at higher risk of recurrent ischemic events. The presence of large-vessel occlusion is also a predictor of new events. MRI can help to triage patients with TIA or minor stroke. In addition, it can help to determine which TIA patients to admit to hospital, and it may help in identifying patients to treat with more aggressive therapies. As shown previously, DWI also can assist with stroke localization and understanding the mechanism of the stroke.
Entre 2416 pacientes con un stroke isquemico, 23% reporto un AIT precedente, siendo la mayoria ocurridos dentro de los dias inmediatos al stroke. Numerous studies also have shown that the short-term risk of stroke is particularly high, with most studies finding risks exceeding 10% in 90 days. Risk is particularly high in the first few days after TIA, with most studies finding that one quarter to one half of the strokes that occur within 3 months occur within the first 2 days. For example, studies in northern California and Oxfordshire found the risk of stroke in the first 24 hours after TIA to be 4% [Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of transient ischemic attack. JAMA. 2000;284:2901–2906. ][Lovett JK, Dennis MS, Sandercock PA, Bamford J, Warlow CP, Rothwell PM. Very early risk of stroke after a first transient ischemic attack. Stroke. 2003;34:e138–e140. ], which is about twice the risk of myocardial infarction or death in patients presenting with acute coronary syndromes (2% at 24 hours). These findings underscore the need for prompt evaluation and treatment of patients with symptoms of ischemia. Ischemic stroke appears to carry a lower short-term risk of subsequent ischemic stroke than TIA, with reported 3-month risks generally ranging from 4% to 8%. The degree of early recovery may be predictive of greater risk, possibly by indicating that tissue is still at risk.
Several prospective population-based cohort studies have also reported high early risks of stroke after TIA. Reanalysis of data from the Oxfordshire Community Stroke Project (OCSP), which was performed in the 1980s, found stroke risks from the date of onset of first-ever TIA of 8.6% at 7 days and 12.0% at 30 days. Interestingly, given a median delay to recruitment of 6 days (interquartile range 2–48 days), the equivalent risks from the date of recruitment were 1.9% (0.1–3.8) and 4.4% (1.6–7.2), respectively, illustrating the importance of study methodology in reliably determining risk. A more recent population-based prospective cohort study in the same population [Oxford Vascular Study (OXVASC)] showed that the early risk of stroke after TIA was still as high during 2002–2004, with recurrent stroke risks at 7 days, 1 and 3 months of 8.0% (23–137), 11.5% (48–182) and 17.3% (93–253) (21). This study also determined the early prognosis after minor ischaemic stroke (NIH scorer 3) and found very similar risks of early recurrent stroke: 11.5% (48–112), 15.0% (75–225) and 18.5% (103–267), respectively.
Cumulative risk of recurrent stroke by aetiological subtype of the presenting stroke in a pooled analysis of data from the Oxford Vascular Study and the Oxfordshire Community Stroke Project. LAA; large-artery atherosclerosis; SVS, Small vessel stroke; CE, cardioembolic; UND, undetermined. It is likely that the early risk of stroke will depend on the underlying causal pathology. A recent meta-analysis of data from population-based studies determined the risk of recurrent stroke according to aetiological subtype using the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. Among 1709 patients with stroke in the pooled analysis, there were 30 recurrent strokes at 7 days, 72 at 30 days and 113 at 3 months. In patients with large artery atherosclerosis, the risks of recurrent stroke were 4.0% (95% CI 0.2–7.8), 12.6% (95% CI 5.9–19.3) and 19.2% (95% CI 11.2–27.2), respectively. The corresponding risks for those with small-vessel stroke were 0%,2%(95% CI 0–4.2) and 3.4% (95% CI 05–63). The risks for those with cardioembolic stroke were 2.5% (95% CI 0.1–4.9), 4.6% (95% CI 1.3–7.9) and 11.9% (95% CI 6.4–17.4). Thus, although large artery atherosclerosis patients comprised only 14% of the 1709 initial strokes, they represented 37% of the recurrences at 7 days and 31% of the recurrences at 3 months. The early risk of recurrence was eight times higher in patients with large-artery atherosclerotic aetiology than small-vessel stroke and three times higher than cardioembolic stroke . It should be stressed, however, that these differences are likely to be less marked in patients presenting with TIA only, where for example some patients with underlying small-vessel disease can have a very high risk of early stroke. However, the high risk of stroke in patients with large artery atherosclerosis is likely to be generalizable. A recent population-based study of prognosis of patients with TIA or stroke and ≥ 50% symptomatic carotid stenosis reported risks of stroke before endarterectomy of 21% (8–34%) at 2 weeks and 32% (17–47%) at 12 weeks; half of the strokes were disabling or fatal.
A recent population-based study of prognosis of patients with TIA or stroke and ≥50% symptomatic carotid stenosis reported risks of stroke before endarterectomy of 21% (8–34%) at 2 weeks and 32% (17–47%) at 12 weeks; half of the strokes were disabling or fatal.
Approximately half of the early risk of stroke after TIA is seen within the first 48 h, necessitating earlier diagnostic workup and earlier treatments to prevent further events. As with stroke, the diagnostic workup should include a clinical history and assessment followed by routine investigations. Brain and carotid imaging should also be undertaken. Risk stratification using the ABCD2 tool is useful to guide management strategies with those with scores of >5 found to have a high risk of stroke (8% 2-day risk) compared with those with scores <4 (1% 2-day risk) . A simpler scoring system using a cut-off of 4 has been suggested to differentiate high and low risk. The use of magnetic resonance imaging (MRI) in addition to the ABCD2 tool increases the prognostic accuracy in patients with TIA and is an emerging area although current access to MRI is limited.
The most widely studied drug was aspirin at doses of 50–150 mg daily, which were at least as effective as higher daily doses. In comparison with placebo, the relative risk reduction for stroke, MI, or vascular death is 13% . Today, doses that are low (<150 mg) are considered as effective as higher doses (160–325 mg). Studies directly comparing the effects of different doses of aspirin failed to show differences in stroke recurrence between low and medium doses or medium and high doses. Aspirin is effective at a daily dose of 50 mg as shown in the aspirin arm of the European Stroke Prevention Study 2 (ESPS-2). The BRAVO trial comparing a GP IIb/ IIIa antagonist with aspirin for the prevention of vascular events in patients with vascular diseases had variable doses of aspirin in the antiplatelet arm. An important result was that aspirin doses higher than 160 mg resulted in a significantly higher rate of major bleeding complications (24% vs. 33%), with a trend for a higher stroke rate with the higher dose of aspirin. Therefore, the recommendation is to use aspirin doses of 50–150 mg for the secondary prevention of stroke.
The CAPRIE study is the largest study to date that has tested clopidogrel in stroke patients. It was a randomized, double-blind study, which compared the effects of 75 mg of clopidogrel with 325 mg of aspirin once daily. The aim was to reduce a composite end-point, which consisted of either ischemic stroke (IS), MI, or vascular death. In all, 19 185 patients with a previous MI or stroke, or established peripheral arterial disease (PAD) were randomized. After a mean followup period of 1.9 years there was a significant absolute risk reduction of 0.5%and a relative risk reduction of 8.7%in favor of clopidogrel (Fig. 1). Thus, clopidogrel is slightly more effective than aspirin in preventing a composite end-point of vascular events. It is the agent of choice in patients with contraindications to, or adverse effects on, aspirin. Taken together the absolute difference between clopidogrel and aspirin was so small that a general use of clopidogrel in stroke patients is not justified. For the subgroup of patients in the CAPRIE trial with IS as the qualifying event, the relative risk reduction was 7.3% and not statistically significant (95% CI 5.7–18.7). However, the CAPRIE study was not designed to address this subgroup of patients specifically. In the post hoc analyses of the CAPRIE trial, the benefit of clopidogrel was demonstrated to be amplified among high-risk subgroups, including patients with a history of previous IS or MI, patients with diabetes, those with prior cardiac surgery, and those receiving lipid-lowering therapy. In patients with a history of previous IS or MI before their qualifying event, clopidogrel produced a relative risk reduction of 14.9% versus aspirin for the primary CAPRIE end-point (P=0.045).
Enrollment time window - FASTER ≤ 24 hours MATCH < 3 months PRoFESS Findings: 20 332 patients (mean age 66 years) were randomised and followed-up for a median of 2·4 years. Recurrent strokes occurred in 916 (9%) patients randomly assigned to ASA with ER-DP and 898 (9%) patients randomly assigned to clopidogrel; 880 (9%) patients randomly assigned to telmisartan and 934 (9%) patients given placebo had recurrent strokes. mRS scores were not statistically different in patients with recurrent stroke who were treated with ASA and ER-DP versus clopidogrel (p=0·38), or with telmisartan versus placebo (p=0·61). There was no signifi cant difference in the proportion of patients with recurrent stroke with a good outcome, as measured with the Barthel index, across all treatment groups. Additionally, there was no significant difference in the median MMSE scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE score of 3 points or more between 1 month and the penultimate visit, and the number of patients with dementia among the treatment groups. There were no significant differences in the proportion of patients with cognitive impairment or dementia among the treatment groups. Interpretation: Disability due to recurrent stroke and cognitive decline in patients with ischaemic stroke were not different between the two antiplatelet regimens and were not aff ected by the preventive use of telmisartan.
The ESPS-2 was a randomized, double-blind, placebo-controlled trial that compared aspirin alone (50 mg daily), modified- release dipyridamole alone (MR-DP, 200 mg twice daily), aspirin plus dipyridamole, and placebo in the secondary prevention of stroke: 6602 patients that had suffered either a TIA or stroke were randomized. Fatal/non-fatal stroke, death from any causes, and stroke and/or death were assessed after a follow-up period of 2 years. The 2-year relative risk reduction of stroke in the aspirin plus dipyridamole group (37.0%) was significantly higher than in either the aspirin group (18.1%) or the dipyridamole group (16.3%) . The 2-year rate of recurrent stroke was 9.5% with aspirin+MR- DP, 12.5% with aspirin, 12.8% with MR-DP alone, and 15.2% with placebo. There was a significance difference for the comparisons of aspirin+MR-DP versus placebo (<0.001), aspirin versus placebo (P=0.013), aspirin+MR-DP versus aspirin monotherapy (P=0.006), and MR-DP versus placebo (0.039). The results of the comparison between aspirin+MRDP and placebo confirm the findings in the First European Stroke prevention Study. The combination treatment doubled the effect of aspirin alone.
The MATCH (Management of ATherothrombosis with Clopidogrel in High-risk patients with recent TIA or IS) trial was a randomized, double-blind, placebo-controlled trial that compared aspirin (75 mg/day) versus placebo in 7599 high-risk patients with recent IS or TIA and at least one additional vascular risk factor in patients receiving 75 mg/day clopidogrel. The duration of treatment and follow-up was 18 months. The primary end-point was a composite of IS, MI, vascular death, or rehospitalization for acute ischemia (including rehospitalization for TIA, angina pectoris, or worsening of peripheral arterial disease). In all, 596 (15.7%) patients reached the primary endpoint in the group receiving aspirin plus clopidogrel compared with 636 (16.7%) patients in the clopidogrel-alone group (relative risk reduction 6.4%, 95% CI - 4.6 to 16.3; absolute risk reduction 1%, 95% CI – 0.6 to 2.7). Life-threatening bleedings were significantly higher in the group receiving aspirin plus clopidogrel [96 (2.6%) vs. clopidogrel alone 49 (1.3%); absolute risk increase 1.3%, 95% CI 0.6–1.9]. Major bleedings were also increased in the group receiving aspirin in addition to clopidogrel, but there was no difference in mortality. Adding aspirin to clopidogrel in highrisk patients with recent IS or TIA is associated with a nonsignificant difference in terms of major vascular events. However, the risk of life-threatening and major bleeding is increased by the addition of aspirin. These results are in contrast with those achieved in cardiology. The main difference is a higher rate of cerebral bleedings in patients with a prior stroke with the combination therapy.
La terapia dual (AAS+clopidogrel) resulto en reduccion absoluta no significativa del riesgo de stroke a los 90 dias(7.1% vs 10.8%). Active clopidogrel was associated with a consistent point-estimate reduction (approximate absolute risk reduction 4%) across all outcomes when compared with placebo. However, active simvastatin was associated with an increase in the primary outcome of stroke when compared with placebo, and this difference narrowed across the other outcomes. Although there was no evidence of a significant interaction between clopidogrel and simvastatin across the three outcomes, the effect of clopidogrel was diluted in the presence of active simvastatin across all three outcomes. The pleiotropic eff ects of statins have raised much interest in their potential role in stroke prevention, withmechanisms such as plaque stabilisation, inhibition of the infl ammatory response, and increased nitric oxide bioavailability improving cerebral blood flow proposed as the means by which statins may improve outcome. However, the results of the FASTER trial do not support the hypothesis that immediate simvastatin use prevents early stroke recurrence. The 95% CIs for the risk ratios of the primary outcome only just included the proposed clinically meaningful relative risk reduction of 20% for a larger clinical trial. The point estimate of excess risk diminishes across the three outcomes, suggesting that it is an effect of the small number of stroke outcomes. This finding is compatible with the cardiac literature.
Summary Background: The risk of recurrent stroke is up to 10% in the week after a transient ischaemic attack (TIA) or minor stroke. Modelling studies suggest that urgent use of existing preventive treatments could reduce the risk by 80–90%, but in the absence of evidence many health-care systems make little provision. Our aim was to determine the eff ect of more rapid treatment after TIA and minor stroke in patients who are not admitted direct to hospital. Methods : We did a prospective before (phase 1: April 1, 2002, to Sept 30, 2004) versus after (phase 2: Oct 1, 2004, to March 31, 2007) study of the eff ect on process of care and outcome of more urgent assessment and immediate treatment in clinic, rather than subsequent initiation in primary care, in all patients with TIA or minor stroke not admitted direct to hospital. The study was nested within a rigorous population-based incidence study of all TIA and stroke (Oxford Vascular Study; OXVASC), such that case ascertainment, investigation, and follow-up were complete and identical in both periods. The primary outcome was the risk of stroke within 90 days of fi rst seeking medical attention, with independent blinded (to study period) audit of all events. Findings: Of the 1278 patients in OXVASC who presented with TIA or stroke (634 in phase 1 and 644 in phase 2), 607 were referred or presented direct to hospital, 620 were referred for outpatient assessment, and 51 were not referred to secondary care. 95% (n=591) of all outpatient referrals were to the study clinic. Baseline characteristics and delays in seeking medical attention were similar in both periods, but median delay to assessment in the study clinic fell from 3 (IQR 2–5) days in phase 1 to less than 1 (0–3) day in phase 2 (p<0·0001), and median delay to fi rst prescription of treatment fell from 20 (8–53) days to 1 (0–3) day (p<0·0001). The 90-day risk of recurrent stroke in the patients referred to the study clinic was 10·3% (32/310 patients) in phase 1 and 2·1% (6/281 patients) in phase 2 (adjusted hazard ratio 0·20, 95% CI 0·08–0·49; p=0·0001); there was no signifi cant change in risk in patients treated elsewhere. The reduction in risk was independent of age and sex, and early treatment did not increase the risk of intracerebral haemorrhage or other bleeding. Interpretation: Early initiation of existing treatments after TIA or minor stroke was associated with an 80% reduction in the risk of early recurrent stroke. Further follow-up is required to determine long-term outcome, but these results have immediate implications for service provision and public education about TIA and minor stroke.
In patients referred to the study clinic, the risk of stroke during the 90 days after presentation was significantly lower in phase 2 than it was in phase 1 (2 ・ 1% vs 10 ・ 3%, p=0 ・ 0001; fi gure 2 and table 3). During the same period, there were three acute myocardial infarctions in phase 1 and one in phase 2, and seven deaths in phase 1 and four in phase 2. The overall risk of non-fatal stroke, myocardial infarction, or death at 90 days was 11 ・ 9% (37/310) in phase 1 and 3 ・ 6% (10/281) in phase 2 (p=0 ・ 0002).
First, the risk of recurrent stroke seen in phase 1 was very similar to that seen between 1981 and 1986 in a population-based study in the same primary-care practices as studied here, the risk of early recurrent stroke without urgent treatment had been stable before the study for at least 20 years. Second, the rate of recurrence changed in October, 2004, immediately after the new clinic was introduced, rather than slowly over the 5 years of the study. Third, there was no evidence of any substantial change in the characteristics of patients presenting with TIA or stroke between the two periods, other than a small increase in the proportion that received premorbid statin treatment, which was due mainly to re-presentation of patients treated in phase 1. There was no significant difference in premorbid statin use if the analysis was confined to first presentations in the study period (data not shown). Moreover, the rate of recurrent stroke was unrelated to premorbid statin use, and a 10% absolute increase in use could account for only a small fraction of the 80% reduction in stroke risk observed.
Process of care in patients referred to the study clinic, assessed at 1-month follow-up, showed that those referred in phase 2 were more likely to be taking a statin, to have been treated with aspirin and clopidogrel, and to be on blood-pressure-lowering medication than those referred to the study clinic in phase 1 (table 5). Mean systolic and diastolic blood pressures at 1 month were lower in phase 2 than in phase 1 (table 5). Similar numbers of patients had carotid endarterectomy for recently symptomatic stenosis during the two periods, but surgery was done earlier in phase 2 than in phase 1 (table 5).
Median follow up 16 months. 3% lost to follow-up • The 90-day stroke rate was 1.24% compared with the predicted stroke rate of 5.96%. (based on ABCD2) • Represents a risk reduction of 80% (HR, 0.2).
The first study of cilostazol — known as the Cilostazol Stroke Prevention Study (CSPS) — conducted by Dr. Shinohara and colleagues in Japan about 10 years ago demonstrated that the drug was more effective compared with placebo, with a low risk of bleeding. This led to the current study, the CSPS-2, which pits the drug against ASA, the current standard of care for secondary stroke prevention. The randomized, multicenter, double-blind, parallel-group study included 2757 noncardioembolic stroke patients from 278 centers. The study took place between December 2003 and December 2008. Patients randomized to receive cilostazol received 100 mg twice daily, whereas subjects in the ASA group received 81 mg once daily. The duration of treatment lasted a minimum of 1 year and a maximum of 5 years. Higher Rate of Nonserious Adverse Effects The study's primary endpoint was occurrence of symptomatic stroke — cerebral infarction, ICH, or subarachnoid hemorrhage during the treatment period. Secondary endpoints included recurrence of symptomatic cerebral infarction, occurrence of ischemic cerebrovascular event, death from any cause, or cluster of stroke, TIA, angina pectoris, MI, heart failure, or hemorrhage requiring hospitalization. Stoke occurred in 82 of the 1337 cilostazol-treated patients, and 2 of these events were fatal during 2965.9 person-years. In the 1335 subjects in the ASA group, there were 119 strokes, including 3 deaths, during 3203.6 person-years. Hemorrhagic stroke or hemorrhage requiring hospitalization occurred in 23 patients in the cilostazol group and 57 in the ASA group — a difference, said Dr. Shinohara, that was highly significant. Although the rate of serious adverse events was lower in the cilostazol group, the drug fared worse compared with ASA with respect to adverse events other than bleeding, with higher rates of headache, diarrhea, palpitations, and dizziness. However, those in the ASA group had greater rates of hypertension and constipation. Cheaper, Not Always Better Dr. Shinohara pointed out that cilostazol is expensive — with a cost that is about 40 times greater than that of ASA. He said his group is currently conducting an economic analysis and subgroup analyses in the hope of characterizing optimal candidates for this treatment. Currently, cilostazol is approved for use in the United States for the treatment of intermittent claudication, a common concern among patients with peripheral artery disease. Asked by Medscape Neurology to comment on the study, Andrei Alexandrov, MD, director, Comprehensive Stroke Center, University of Alabama Hospital in Birmingham, said cilostazol may offer clinicians another potential treatment option. &quot;We need alternatives to aspirin because the main notion is that aspirin protects against stroke and heart attack but is it optimal? The answer is no. Aspirin is cheap, but cheap doesn't mean better. Aspirin protects against stroke, but it carries a risk of bleeding. &quot;We have clopidogrel and we have Aggrenox (a combination of ASA and dipyridamole), but in certain cases you run up against patients who can't take these, and cilostazol would give us another drug in our arsenal against secondary stroke,&quot; said Dr. Alexandrov.
The primary endpoint occurred at a higher yearly rate in the aspirin group than in the cilostazol group, and cilostazol reduced the risk of stroke by 25 ・ 7% compared with aspirin. Because the upper 95% CI limit was lower than the prespecified non inferiority margin of 1 ・ 33, cilostazol seems to be non inferior to aspirin for the prevention of stroke; because the p value for the primary analysis (p=0 ・ 0357) was lower than the adjusted significance level for superiority testing (p=0 ・ 0471), cilostazol also seems to be superior to aspirin. In the analysis of stroke subtypes, cilostazol was associated with a relative risk reduction of 32 ・ 0% for atherothrombotic stroke and 24 ・ 8% for lacunar stroke versus aspirin, although the differences between the drugs were not significant. Although all analyses were done on the full analysis set, intention-to treat analysis of the primary endpoint in 1379 patients on cilostazol and 1378 on aspirin confirmed the findings of our study (HR 0 ・ 749, 95% CI 0 ・ 568–0 ・ 988; p=0 ・ 0404).
Emberson J et al, used estimates of the relative risk reductions from meta-analyses of randomised trials in combination with data from a prospective observational study of CVD (the British Regional Heart Study) to analyse the impact of different risk reduction strategies in primary prevention. The study examined the effects of prevention strategies based on single risk factor assessment or total risk assessment. They concluded that assessment of overall risk leads to more effective intervention than assessment based on single risk factors. Furthermore, multiple interventions have considerably greater benefits than interventions based on targeting single risk factors. Ten percent reductions in long-term mean blood cholesterol and BP could have reduced major CVD by 45%. Jackson R et al, conducted a review of the randomised trials of BP or blood cholesterol lowering treatments and outlined the rationale for targeting BP and blood cholesterol lowering therapy to patients at high absolute CV risk. They concluded that separate management guidelines for raised BP and blood cholesterol need to be replaced by integrated CV risk management guidelines. They also posited that because CV risk factors interact with each other, moderate reductions in several risk factors can be more effective than major reductions in one.
This meta-analysis demonstrates that lowering blood pressure with antihypertensive agents in patients with prior ischemic or hemorrhagic stroke or transient ischemic attack (TIA) reduces the risk of recurrent stroke by 24%. 1 The studies in this meta-analysis comprised Carter 1970, HSCG 1974, Dutch TIA 1993, PATS 1995, TEST 1995, HOPE 2000 and PROGRESS 2001. 1. Rashid P, et al. Stroke 2003;34:2741-2749.
In the secondary end point of fatal and nonfatal stroke, the amlodipine-based regimen was responsible for a significant 23% reduction versus the atenolol-based regimen.
Stroke is a coronary heart disease risk equivalent. 1 Consequently, a low-density lipoprotein (LDL-C) goal of <100 mg/dL (2.6 mmol/L) is recommended in patients with prior stroke. In patients with prior stroke and diabetes, LDL-C may be lowered to <70 mg/dL (1.8 mmol/L). 2 These goals can be achieved by initiating intensive therapeutic lifestyle changes, along with the option of commencing lipid-lowering therapy at the same time. 1
Atorvastatin achieved a 27% reduction in the secondary end point of nonfatal and fatal stroke. The P value of this reduction was less than 0.0236. Because the study protocol specified that all secondary end points had to attain a P value of less than 0.01 to be deemed significant, this reduction in stroke was not significant. Interestingly, this result is congruous with results from other interventional statin studies such as 4S, CARDS, HPS, and GREACE. These studies showed reduction in stroke despite the fact that epidemiological studies have not been able to unambiguously demonstrate an association between lipids and stroke. Take note that this 27% may differ from that found on our core data sheets.
After a median follow-up of 4.9 years, a 16% reduction in risk of recurrent stroke was observed with atorvastatin relative to placebo, after adjusting for geographical region, entry event, time since entry event, gender, and baseline age (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.71-0.99, P =.03). 1
Manejo moderno del Ataque Isquémico Transitorio (AIT) Revisión basada en evidencias
“ AIT es un episodio breve de disfunción neurológica causado por isquemia cerebral focal or retinal ( o espinal ), con síntomas clínicos que típicamente duran menos de una hora, y sin evidencia de infarto agudo”.
“ Pacientes con síntomas focales transitorios de isquemia cerebral – y quienes, en la evaluación diagnostica, presentan evidencias de infarto agudo– no deben ser clasificados como AIT, independiente de la duración de los síntomas clínicos.”
Alberts GW et al. N Engl J Med 2002;347:1713-1716. Easton JD et al. Stroke 2009;40:2276-2293.
Mejor sensibilidad con IRM: Difusión (S:95% , E:100%) FLAIR ADC DWI < 3 hs 1 día 7 días
AIT precede a stroke isquémico 0 5 10 15 20 25 30 35 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Días Porcentaje de pacientes Rothwell PM, et al. Neurology 2005; 64: 817-20 . “ La ventana terapeutica para la prevencion es muy corta”
Riesgo acumulado de stroke luego de AIT o stroke menor en OXVASC Coull AJ, et al. BMJ 2004; 328: 326-528 . 8.0% 11.5% 11.5% 15.0% 17.3% 18.5%
Riesgo de stroke recurrente por sub-tipo etiológico: OXVASC, TOAST Survival free of recurrent stroke Lovett JK et al .Neurology 2004; 62: 569-574. CE : Cardioembolic LAA : Large-artery atherosclerosis UND : Undetermined SVS : Small vessel stroke
Riesgo de stroke luego de AIT o stroke menor en OXVASC Excluyendo oclusiones subsecuentes y stroke previo a atención médica Fairhead JF et al .Neurology 2005; 65: 371-375. Pacientes con ≥ 50% estenosis carotídea sintomática AIT Stroke menor 21% 32% 0 10 20 30 40 0 30 60 90 Días Riesgo de stroke (%)
1707 pacientes con AIT en 16 hospitales en el norte de California Johnston SC, et al JAMA 2000;284:2901-2906 Evento recurrente a los 90 días
Riesgo de Stroke en 90 días después del AIT, se incrementa con el número FR
Flujo de paciente con AIT/Stroke menor ABCD 2 ABCD 2 < 4 Imágenes dentro 7 días ABCD 2 ≥ 4 Imágenes dentro 24 horas Incertidumbre respecto al diagnostico del territorio vascular comprometido Incertidumbre respecto al diagnostico del territorio vascular comprometido Imagen carotídea si el paciente es candidato para intervención carotídea dentro de 1 semana de inicio sintomas Intervencion de carótida dentro 2 semanas IRM /DWI dentro 1 ss SI NO IRM confirma AIT Imagen carotídea si el paciente es candidato para intervención carotídea dentro de 1 semana de inicio sintomas Intervencion de carótida dentro 48 horas IRM /DWI dentro 24 hs IRM confirma AIT SI Estenosis > 95% Estenosis > 95% NO
Flujo de paciente con AIT/Stroke menor ABCD 2 ABCD 2 < 4 Imágenes dentro 7 días ABCD 2 ≥ 4 Imágenes dentro 24 horas Incertidumbre respecto al diagnostico del territorio vascular comprometido Incertidumbre respecto al diagnostico del territorio vascular comprometido Imagen carotídea si el paciente es candidato para intervención carotídea dentro de 1 semana de inicio sintomas Intervencion de carótida dentro 2 semanas IRM /DWI dentro 1 ss SI NO IRM confirma AIT Imagen carotídea si el paciente es candidato para intervención carotídea dentro de 1 semana de inicio sintomas Intervencion de carótida dentro 48 horas IRM /DWI dentro 24 hs IRM confirma AIT SI Tratamiento Medico Estenosis > 95% Estenosis > 95% Oclusión o Estenosis < 50% NO
no evidencia que incremento dosis, mejore eficacia.
no evidencia para rotar a/de warfarina.
Intolerancia AAS :
Manejo de los factores de riesgo CV resulta en dramática reducción en ECV “ Debemos poner especial atención en la evaluación de la PA y en los niveles de colesterol para conocer individualmente el riesgo absoluto CV y sus determinantes” – J. Emberson et al and Jackson et al Emberson J et al. Eur Heart J. 2004;25:484-491. Jackson R et al. Lancet. 2005;365:434-441. 10% Reducción en PA 10% Reducción en CT 45% Reducción en ECV
Tratamiento anti-HTA reduce significativamente el riesgo de recurrencia de stroke Rashid P, et al. Stroke 2003;34:2741-2749. IECA=Inhibidores Enzima Convertidora Angiotensina. * P =.005. † P =.01. ‡ P <.00001. Reduccion Riesgo Relativo (%) Todos Diurético ß-Bloqueador IECA IECA+Diurético -24 * -32 ţ -7 -7 -45 ŧ * † ‡ -50 -40 -30 -20 -10 0
Terapia anti-HTA debe ser iniciado en todos los pacientes con AIT o stroke, a menos exista contraindicación.
Objetivo: PA < 140/90 mmHg. En DM: PA<130/85 mmHg.
Evidencia Grado A, nivel 1 para IECA (± diurético).
Evidencia reciente del beneficio de los Antagonistas de Receptores de Angiotensina.
Rashid P, et al. Stroke 2003;34:2741-2749.
ASCOT-BPLA: Stroke fatal y no fatal (Secondary end point) Dahl ö f B et al. Lancet. 2005;366:895-906.
Manejando niveles de Colesterol después de stroke
Objetivo, sin DM: Colesterol LDL < 100 mg/dl (2.6 mmol/L).
Objetivo, con DM: Colesterol LDL < 70 mg/dl (1.8 mmol/L).
Si el paciente no tiene objetivo C-LDL, iniciar intensivo cambio en estilos de vida.
La terapia para bajar los niveles de colesterol debe ser iniciada al mismo tiempo del cambio de estilo de vida.
Stroke debe ser considerado un equivalente a enfermedad coronaria Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497; Grundy SM et al. Circulation. 2004;110:227-239. The SPARCL Investigators. N Engl J Med 2006;355:549-559.
ASCOT-LLA: Stroke fatal y no fatal (Secondary end point) Sever PS et al. Lancet. 2003;361:1149-1158.
SPARCL Investigators. N Engl J Med 2006;355:549-559. SPARCL: Stroke fatal y no fatal (Primary end point) 16% RR
Prevención secundaria después de stroke/AIT y NNT para prevenir stroke Mac Dougall NJ et al. Expert Rev Cardiovasc Ther 2009;7:1103-1115. Intervención Droga específica Para quien? Efecto en prevencion secundaria (NNT para 1 año) RCT Anti-agregante AAS AAS+Dipir (clopidogrel?) Stroke Isquémico 79: Monoterapia AAS 36: AAS+Dipir (basado en NNT de 18 para 2 años en ESPS-2) PRoFESS ESPS-2 ESPRIT Anti-Hipertensivo IECA (+indapamida) Isquémico y Hemorrágico 100 (25 para 4 años basado en AAR de 4%) PROGRESS Estatinas Simvastatina o Atorvastatina Stroke Isquémico 225: Atorvastatina (45 para 5 años) HPS SPARCL Endarterectomía Carotídea Estenosis>70%, stroke isquémico ipsilateral (>50%, masculino y < 2 ss después evento) 25: realizado dentro de las 2 ss. 65: realizado entre 4 y 12 ss. 70: realizado mayor de 12 ss. EST NASECT
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