Graeme J. Hankey

Homocysteine and vascular disease

For more than 20 years, moderately raised concentrations of total homocysteine have been associated with an increased risk of atherothrombotic vascular events but only recently has evidence mounted to suggest that the association may be causal. The association is independent of other factors, it is fairly consistent across many studies, it is strong and dose-related, and it is biologically plausible. However, the evidence needs to be strengthened by a systematic review of all comparable studies and the demonstration, in randomised trials, that lowering total homocysteine is followed by a significant reduction in atherothrombotic vascular disease. In addition, the measurement of total homocysteine needs to be standardised. If these can be achieved then total homocysteine measurement will become another useful marker of vascular risk, multivitamin therapy will be another therapeutic option for people at risk of atherothrombotic vascular disease, and fortification of food with folic acid will rise high on the political and public health agenda.

Homocyst(e)ine and Cardiovascular Disease: A Critical Review of the Epidemiologic Evidence

Cardiovascular disease remains the major cause of morbidity and death in developed countries and accounts for approximately 40% of all deaths in Canada (1). Smoking cessation and reductions in cholesterol levels and blood pressure have been shown to be effective strategies in the prevention of cardiovascular disease (2). However, these major, classic cardiovascular risk factors and such nonmodifiable risk factors as age, sex, and family history cannot fully explain why some persons develop myocardial infarction, stroke, and other cardiovascular disease but other persons do not (3-5). Other factors may also increase the likelihood of developing cardiovascular disease and contribute to atherogenesis. Pathologic and epidemiologic studies suggest that only about one half to two thirds of the variation in anatomic extent of atherosclerosis and risk for atherosclerotic vascular disease can be explained by classic risk factors (6-9). Therefore, many emerging risk factors have been investigated. Among these, elevated plasma or serum levels of homocyst(e)ine (hyperhomocyst[e]inemia) are of particular interest. Recent epidemiologic studies have shown that moderately elevated plasma homocysteine levels are highly prevalent in the general population and are associated with an increased risk for fatal and nonfatal cardiovascular disease, independent of classic cardiovascular risk factors. This association is usually consistent, strong, dose-related, and biologically plausible. Although simple, inexpensive, nontoxic therapy with folate and vitamins B6 and B12 is highly effective at reducing plasma homocyst(e)ine levels, it remains to be demonstrated that decreasing homocyst(e)ine levels reduces cardiovascular morbidity and mortality. Methods Data Sources We searched the scientific literature for all epidemiologic studies (prospective, casecontrol, cross-sectional, or geographic correlation) on cardiovascular disease (using the terms coronary heart disease, cerebrovascular disease, peripheral vascular disease, and atherosclerosis) and homocysteine or vitamins (using the terms homocysteine, B 12, B 6, and folic acid). We searched the MEDLINE database for articles published from January 1965 to January 1999 and identified additional studies by examining bibliographies of original articles, review articles, and textbooks. Study Selection We used standard definitions to define epidemiologic studies (10) and did not consider case series. The epidemiologic prospective cohort studies varied greatly in terms of patient selection, number of patients and controls, circumstances and techniques of measuring plasma homocyst(e)ine levels, definitions of elevated plasma homocyst(e)ine level, types and definitions of vascular outcome events and surrogate outcome measures, and statistical analyses. A formal meta-analysis of these studies was not performed because the results could have been misleading. We included all prospective epidemiologic studies (up to January 1999) but included only the largest retrospective studies (those that involved at least 150 cases) because prospective studies generally provide a robust estimate of association, whereas small retrospective studies are often subject to various biases. We further restricted the retrospective studies to those published after the meta-analysis by Boushey and colleagues (11) because that article provides a good critical review of the studies done up until 1995. Homocysteine Metabolism Homocysteine is a sulfur-containing amino acid produced during catabolism of the essential amino acid methionine. Homocysteine can be metabolized by two major pathways. When methionine is in excess, homocysteine is directed to the transsulphuration pathway, where it is irreversibly sulfoconjugated to serine by cystathionine -synthase in a process requiring vitamin B6 as a cofactor. However, under conditions of negative methionine balance, homocysteine is primarily metabolized through a methionine-conserving remethylation pathway. In most tissues, homocysteine is remethylated in a process that requires methionine synthase, vitamin B12 as a cofactor, and methyltetrahydrofolate as a cosubstrate. This pathway requires an adequate supply of folic acid and the enzyme methylene tetrahydrofolate reductase (MTHFR) (12). Genetic and acquired abnormalities in the function of these enzymes or deficiencies in folic acid, vitamin B6, or vitamin B12 cofactors can lead to elevated homocysteine levels. In the plasma, approximately 70% of homocysteine circulates in a protein-bound form; approximately 25% combines with itself to form the dimer homocystine; and the remainder (<5%) combines with other thiols, including cysteine, to form disulphide (a homocysteine-cysteine mix) or circulates as the free thiol compound (13). In North America, the term homocyst(e)ine is often used to refer to the total pool of circulating plasma homocysteine, whereas the term tHcy is more common in Europe. Homocyst(e)ine Theory of Atherosclerosis Severe hyperhomocyst(e)inemia associated with homocystinuria can be caused by several rare inherited disorders, including homozygous deficiency of cystathionine -synthase, MTHFR, or methionine synthase or defects in vitamin B12 metabolism (12, 14). These distinct genetic conditions share the following features: extreme elevations of plasma homocyst(e)ine levels and premature atherothrombotic disease with typical histopathologic features of endothelial injury, proliferation of vascular smooth-muscle cells, progressive arterial stenosis, and hemostatic changes suggestive of a prothrombotic state (15). The characteristic clinical and pathologic features of these genetically diverse conditions support the hypothesis that elevated plasma homocyst(e)ine levels are responsible for the vascular damage and led McCully and Wilson (16) to propose the homocyst(e)ine theory of atherosclerosis. Although these genetic errors of metabolism are extremely rare (homozygous cystathionine -synthase deficiency occurs in approximately 1 in 150 000 live births and is associated with plasma homocyst[e]ine levels as high as 400 mol/L), they provide a useful in vivo human model for vascular injury associated with high homocyst(e)ine levels . Laboratory Measurement of Homocyst(e)ine Levels Most assays for measuring homocysteine concentrations are based on chromatographic techniques; high-performance liquid chromatography is still the most widely used (13). However, a simple and relatively inexpensive immunoassay has become commercially available and may soon enable widespread measurement of plasma homocyst(e)ine levels in the clinical laboratory (17). Plasma homocyst(e)ine levels are usually measured in the fasting state and can be measured before or after methionine loading. Methionine loading, a method of stressing the homocyst(e)ine metabolic pathways, may be more sensitive than measurement of fasting homocyst(e)ine levels for detecting mild disturbances in the transsulfuration pathway that may be caused by vitamin B6 deficiency or partial cystathionine -synthase deficiency (18, 19). The procedure involves measuring the baseline fasting plasma homocyst(e)ine level, administering a standard oral dose of methionine, and measuring the plasma homocyst(e)ine level again 4 to 6 hours later. Methionine loading may help to discriminate between defects involving the transsulfuration and remethylation pathways (20); it may also help to identify patients who have impaired homocysteine metabolism despite a normal fasting total plasma homocysteine level and who may, therefore, be at increased risk for vascular disease (19). Reliable measurements of plasma homocyst(e)ine levels require the use of accurate assays as well as optimal procedures for collection and handling of blood samples (13). Patient characteristics (such as fasting state and posture) and recent vascular events may also affect measured total homocysteine levels (20-22). Definition and Prevalence of Hyperhomocyst(e)inemia Hyperhomocyst(e)inemia is usually defined by using arbitrary cut-off pointsfor example, above the 95th percentile or more than two SDs above the mean of values obtained from fasting, healthy controls. This is similar to the way in which high plasma cholesterol levels were originally defined. Normal plasma homocyst(e)ine levels usually range from 5 to 15 mol/L (17). However, the definition of elevated homocyst(e)ine levels is not standardized, and substantial differences exist in the normal reference levels used in the literature. Higher fasting values are arbitrarily classified as mild and moderate hyperhomocyst(e)inemia (16 to 100 mol/L) and severe hyperhomocyst(e)inemia (>100 mol/L). The prevalence of hyperhomocyst(e)inemia depends on the way in which the condition is defined and measured. When the common definition of hyperhomocysteinemialevels of total homocysteine exceeding the 95th percentile of the distribution in a healthy sample of controlsis used, 5% of the normal population will necessarily be defined as having an elevated homocyst(e)ine level (23). Between 13% and 47% of patients with symptomatic atherosclerotic vascular disease have been reported to have hyperhomocystein(e)mia (24). However, little evidence suggests a sudden increase in risk for vascular disease above a certain threshold level of plasma homocyst(e)ine; the relation between plasma homocyst(e)ine levels and risk for cardiovascular disease seems to be graded and linear (25). Causes of Mild and Moderate Hyperhomocyst(e)inemia One or a combination of genetic, physiologic, pathologic, and nutritional factors (Table 1) causes modest elevations in homocyst(e)ine levels without associated homocystinuria. Therefore, MTHFR mutations (for example, thermolabile MTHFR); older age; male sex; postmenopausal status; smoking; sedentary lifestyle; dietary factors, including increased intake of animal proteins (which have a higher methionine content); low intake of folic acid, vitamin B6, and vit

Swallowing Function After Stroke Prognosis and Prognostic Factors at 6 Months

BACKGROUND AND PURPOSE Swallowing dysfunction (dysphagia) is common and disabling after acute stroke, but its impact on long-term prognosis for potential complications and the recovery from swallowing dysfunction remain uncertain. We aimed to prospectively study the prognosis of swallowing function over the first 6 months after acute stroke and to identify the important independent clinical and videofluoroscopic prognostic factors at baseline that are associated with an increased risk of swallowing dysfunction and complications. METHODS We prospectively assembled an inception cohort of 128 hospital-referred patients with acute first stroke. We assessed swallowing function clinically and videofluoroscopically, within a median of 3 and 10 days, respectively, of stroke onset, using standardized methods and diagnostic criteria. All patients were followed up prospectively for 6 months for the occurrence of death, recurrent stroke, chest infection, recovery of swallowing function, and return to normal diet. RESULTS At presentation, a swallowing abnormality was detected clinically in 65 patients (51%; 95% CI, 42% to 60%) and videofluoroscopically in 82 patients (64%; 95% CI, 55% to 72%). During the subsequent 6 months, 26 patients (20%; 95% CI, 14% to 28%) suffered a chest infection. At 6 months after stroke, 97 of the 112 survivors (87%; 95% CI, 79% to 92%) had returned to their prestroke diet. Clinical evidence of a swallowing abnormality was present in 56 patients (50%; 95% CI, 40% to 60%). Videofluoroscopy was performed at 6 months in 67 patients who had a swallowing abnormality at baseline; it showed penetration of the false cords in 34 patients and aspiration in another 17. The single independent baseline predictor of chest infection during the 6-month follow-up period was a delayed or absent swallowing reflex (detected by videofluoroscopy). The single independent predictor of failure to return to normal diet was delayed oral transit (detected by videofluoroscopy). Independent predictors of the combined outcome event of swallowing impairment, chest infection, or aspiration at 6 months were videofluoroscopic evidence of delayed oral transit and penetration of contrast into the laryngeal vestibule, age >70 years, and male sex. CONCLUSIONS Swallowing function should be assessed in all acute stroke patients because swallowing dysfunction is common, it persists in many patients, and complications frequently arise. The assessment of swallowing function should be both clinical and videofluoroscopic. The clinical and videofluoroscopic features at presentation that are important predictors of subsequent swallowing abnormalities and complications are videofluoroscopic evidence of delayed oral transit, a delayed or absent swallow reflex, and penetration. These findings require validation in other studies.

Treatment and secondary prevention of stroke: evidence, costs, and effects on individuals and populations*

This review of the effectiveness of treatment for acute stroke and methods of secondary prevention shows that the highest priority for providers of a stroke service must be to establish a stroke unit and multidisciplinary team that delivers organised stroke care. Acute ischaemic stroke patients should be immediately started on aspirin 300 mg daily, and, if possible, many of them should be entered into further trials of thrombolysis and other promising treatments. After the acute phase, aspirin should be continued in a lower dose, 75 mg daily; smoking should be discouraged; high blood pressure treated initially with a diuretic; and fibrillating ischaemic stroke/transient ischaemic attack survivors anticoagulated long-term with warfarin or given aspirin if anticoagulation is not sensible. Statins are probably indicated in patients who already have symptomatic coronary heart disease. Adding dipyridamole to aspirin, substituting clopidogrel for aspirin, and carotid endarterectomy are all expensive interventions to prevent stroke, but if ways could be found to focus them on those patients at especially high risk, they would become more affordable.

Five-Year Survival After First-Ever Stroke and Related Prognostic Factors in the Perth Community Stroke Study

Background and Purpose Few community-based studies have examined the long-term survival and prognostic factors for death within 5 years after an acute first-ever stroke. This study aimed to determine the absolute and relative survival and the independent baseline prognostic factors for death over the next 5 years among all individuals and among 30-day survivors after a first-ever stroke in a population of Perth, Western Australia. Methods Between February 1989 and August 1990, all individuals with a suspected acute stroke or transient ischemic attack of the brain who were resident in a geographically defined region of Perth, Western Australia, with a population of 138 708 people, were registered prospectively and assessed according to standardized diagnostic criteria. Patients were followed up prospectively at 4 months, 12 months, and 5 years after the index event. Results Three hundred seventy patients with first-ever stroke were registered, and 362 (98%) were followed up at 5 years, by which time 210 (58%) had died. In the first year after stroke the risk of death was 36.5% (95% CI, 31.5% to 41.4%), which was 10-fold (95% CI, 8.3% to 11.7%) higher than that expected among the general population of the same age and sex. The most common cause of death was the index stroke (64%). Between 1 and 5 years after stroke, the annual risk of death was approximately 10% per year, which was approximately 2-fold greater than expected, and the most common cause of death was cardiovascular disease (41%). The independent baseline factors among 30-day survivors that predicted death over 5 years were intermittent claudication (hazard ratio [HR], 1.9; 95% CI, 1.2 to 2.9), urinary incontinence (HR, 2.0; 95% CI, 1.3 to 3.0), previous transient ischemic attack (HR, 2.4; 95% CI, 1.4 to 4.1), and prestroke Barthel Index <20/20 (HR, 2.0; 95% CI, 1.2 to 3.2). Conclusions One-year survivors of first-ever stroke continue to die over the next 4 years at a rate of approximately 10% per year, which is twice the rate expected among the general population of the same age and sex. The most common cause of death is cardiovascular disease. Long-term survival after stroke may be improved by early, active, and sustained implementation of effective strategies for preventing subsequent cardiovascular events.

Pravastatin Therapy and the Risk of Stroke

Background Several epidemiologic studies have concluded that there is no relation between total cholesterol levels and the risk of stroke. In some studies that classified strokes according to cause, there was an association between increasing cholesterol levels and the risk of ischemic stroke and a possible association between low cholesterol levels and the risk of hemorrhagic stroke. Recent reviews of trials of 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors have suggested that these agents may reduce the risk of stroke. Methods In a double-blind trial (the Long-Term Intervention with Pravastatin in Ischaemic Disease study), we compared the effects of pravastatin on mortality due to coronary heart disease (the primary end point) with the effects of placebo among 9014 patients with a history of myocardial infarction or unstable angina and a total cholesterol level of 155 to 271 mg per deciliter (4.0 to 7.0 mmol per liter). Our goal in the present study was to assess effects on stroke from any c...

Long-Term Disability After First-Ever Stroke and Related Prognostic Factors in the Perth Community Stroke Study, 1989–1990

Background and Purpose— Few reliable estimates of the long-term functional outcome after stroke are available. This population-based study aimed to describe disability, dependency, and related independent prognostic factors at 5 years after a first-ever stroke in patients in Perth, Western Australia. Methods— All individuals with a suspected acute stroke who were resident in a geographically defined region (population, 138 708) of Perth, Western Australia, were registered prospectively and assessed according to standardized diagnostic criteria over a period of 18 months in 1989 to 1990. Patients were followed up prospectively at 4 and 12 months and 5 years after the index event. Results— There were 370 cases of first-ever stroke, and 277 patients survived to 30 days. Of these early survivors, 152 (55%) were alive at 5 years, and among those who were neither institutionalized (n=146) nor disabled (n=129) at the time of their stroke, 21 (14%) were institutionalized in a nursing home, and 47 (36%) were disabled. The most important predictors of death or disability at 5 years were increasing age, baseline disability defined by a Barthel Index score of <20/20 (odds ratio [OR], 6.3; 95% confidence interval [CI], 2.7 to 14), moderate hemiparesis (OR, 2.7; 95% CI, 1.1 to 6.2), severe hemiparesis (OR, 4.5; 95% CI, 1.1 to 19), and recurrent stroke (OR, 9.4; 95% CI, 3.0 to 30). A low level of activity before the stroke was a significant predictor of institutionalization, and subsequent recurrent stroke was a consistent, independent predictor of institutionalization, disability, and death or institutionalization, increasing the odds of each of these 3 adverse outcomes by 5- to 15-fold. Conclusions— Among 30-day survivors of first-ever stroke, about half survive 5 years; of survivors, one third remain disabled, and 1 in 7 are in permanent institutional care. The major modifiable predictors of poor long-term outcome are a low level of activity before the stroke and subsequent recurrent stroke. Efforts to increase physical activity among the elderly and to prevent recurrent stroke in survivors of a first stroke are likely to reduce the long-term burden of cerebrovascular disease.

Long-Term Risk of First Recurrent Stroke in the Perth Community Stroke Study

BACKGROUND AND PURPOSE Few community-based studies have examined the long-term risk of recurrent stroke after an acute first-ever stroke. This study aimed to determine the absolute and relative risks of a first recurrent stroke over the first 5 years after a first-ever stroke and the predictors of such recurrence in a population-based series of people with first-ever stroke in Perth, Western Australia. METHODS Between February 1989 and August 1990, all people with a suspected acute stroke or transient ischemic attack of the brain who were resident in a geographically defined region of Perth, Western Australia, with a population of 138 708 people, were registered prospectively and assessed according to standardized diagnostic criteria. Patients were followed up prospectively at 4 months, 12 months, and 5 years after the index event. RESULTS Three hundred seventy patients with a first-ever stroke were registered, of whom 351 survived >2 days. Data were available for 98% of the cohort at 5 years, by which time 199 patients (58%) had died and 52 (15%) had experienced a recurrent stroke, 12 (23%) of which were fatal within 28 days. The 5-year cumulative risk of first recurrent stroke was 22.5% (95% confidence limits [CL], 16.8%, 28.1%). The risk of recurrent stroke was greatest in the first 6 months after stroke, at 8.8% (95% CL, 5.4%, 12.1%). After adjustment for age and sex, the prognostic factors for recurrent stroke were advanced, but not extreme, age (75 to 84 years) (hazard ratio [HR], 2.6; 95% CL, 1.1, 6.2), hemorrhagic index stroke (HR, 2.1; 95% CL, 0.98, 4.4), and diabetes mellitus (HR, 2.1; 95% CL, 0.95, 4.4). CONCLUSIONS Approximately 1 in 6 survivors (15%) of a first-ever stroke experience a recurrent stroke over the next 5 years, of which 25% are fatal within 28 days. The pathological subtype of the recurrent stroke is the same as that of the index stroke in 88% of cases. The predictors of first recurrent stroke in this study were advanced age, hemorrhagic index stroke, and diabetes mellitus, but numbers of recurrent events were modest. Because the risk of recurrent stroke is highest (8.8%) in the first 6 months after stroke, strategies for secondary prevention should be initiated as soon as possible after the index event.

Ten-Year Risk of First Recurrent Stroke and Disability After First-Ever Stroke in the Perth Community Stroke Study

Background and Purpose— Limited information exists on the long-term prognosis after first-ever stroke. We aimed to determine the absolute frequency of first recurrent stroke and disability and the relative frequency of recurrent stroke over 10 years after first-ever stroke in Perth, Western Australia. Methods— For a 12-month period beginning February 1989, all individuals with suspected acute stroke or transient ischemic attack who lived in a geographically defined and representative region of Perth were registered prospectively. Patients with a definite first-ever stroke were followed up 10 years after the index event. Results— Over 10 years of follow-up, the cumulative risk of a first recurrent stroke was 43% (95% confidence interval [CI], 34 to 51). After the first year after first-ever stroke, the average annual risk of recurrent stroke was ≈4%. Case fatality at 30 days after first recurrent stroke was 41%, which was significantly greater than the case fatality at 30 days after first-ever stroke (22%) (P =0.003). For 30-day survivors of first-ever stroke, the 10-year cumulative risk of death or new institutionalization was 79% (95% CI, 73 to 85) and of death or new disability was 87% (95% CI, 81 to 92). Conclusions— Over 10 years of follow-up, the risk of first recurrent stroke is 6 times greater than the risk of first-ever stroke in the general population of the same age and sex, almost one half of survivors remain disabled, and one seventh require institutional care. Effective strategies for prevention of stroke need to be implemented early, monitored frequently, and maintained long term after first-ever stroke.

Swallowing Disorders following Acute Stroke: Prevalence and Diagnostic Accuracy

We prospectively examined 128 patients with acute first-ever stroke to determine the prevalence of swallowing disorders, the diagnostic accuracy of our clinical assessment of swallowing function compared with videofluoroscopy, and interobserver agreement for the clinical and videofluoroscopic diagnosis of swallowing disorders and aspiration. We found clinical and videofluoroscopic evidence of a swallowing disorder in 51% [95% confidence interval (CI) 42–60%] and 64% (95% CI 55–72%) of patients, respectively, and aspiration in 49% (95% CI 40–58%) and 22% (95% CI 15–29%) of patients, respectively. The optimal clinical criteria for detecting videofluoroscopic evidence of a swallowing disorder and aspiration were any clinical evidence of a swallowing disorder (sensitivity 73%, 95% CI 62–82%; specificity 89%, 95% CI 76–96%), and any clinical evidence of aspiration (sensitivity 93%, 95% CI 76–99%; specificity 63%, 95% CI 53–72%). The interobserver agreement between two speech pathologists for the clinical diagnosis of a swallowing disorder (κ: 0.82 ± 0.09) and aspiration (κ: 0.75 ± 0.09) was good, and between a speech pathologist and radiologist for the videofluoroscopic diagnosis of a swallowing disorder (κ: 0.75 ± 0.09) and aspiration (κ: 0.41 ± 0.09), it was good and fair, respectively. Although clinical bedside examination underestimates the frequency of swallowing abnormalities and overestimates the frequency of aspiration compared with videofluoroscopy, it may still offer valuable information for the diagnosis of swallowing impairment. Long-term follow-up studies are required to determine the independent functional significance of the findings of the bedside and videofluoroscopic examinations in predicting the occurrence of important outcome events such as aspiration pneumonia.