Primary prevention and health services delivery.

Stroke remains the third leading cause of death in the US and other Western countries,1 and at least 1 populationbased study found that the incidence of stroke was greater than that of acute coronary syndromes.2 Although there have been substantial falls in stroke incidence in some countries over the last 2 decades,3 a large US study found that the advances in stroke prevention during the 1990s were not associated with decreases in the rate of stroke hospitalizations or in case-fatality rates between 1993 and 1999.4 Moreover, based solely on demographic changes in the population of selected countries within the European Union, the World Health Organization predicts a 27% increase in stroke events between the years 2000 and 2025.5 The proportion of deaths attributed to stroke is even higher in Asian countries.6 Although much of stroke risk may be related to socioeconomic factors, more effective prevention strategies are critical. Several studies have contributed to the body of knowledge related to primary stroke prevention over the last year. Numerous studies support an association between elevated homocysteine levels and atherosclerotic disease.7 The B vitamins (folic acid, B12, and B6) reduce homocysteine serum levels raising the hope that treatment would be associated with reduced risk. That hope was diminished with publication of results of the Vitamin Intervention for Stroke Prevention (VISP) trial in 2004.8 Although a secondary rather than a primary stroke prevention trial, VISP had compared highand low-dose B-vitamin supplementation and found no treatment effect on the risk of recurrent stroke (risk ratio [RR] 1.0; 95% CI, 0.8 to 1.3), or in the combined risk of any stroke, coronary heart event, or death (RR, 1.0; 95% CI, 0.8 to 1.1). The difference in homocysteine levels between treatment groups, however, was small (2 mol/L). The results of 2 additional randomized trials of homocysteine-lowering are now available. The Norwegian Vitamin (NORVIT) trial evaluated the efficacy of B-vitamin supplementation on the prevention of recurrent myocardial infarction, stroke and sudden death (primary end point) in patients who had an acute myocardial infarction.9 Despite a 27% reduction in homocysteine levels among patients given folic acid plus vitamin B12, there was no reduction in these combined risks (RR, 1.08; 95% CI, 0.93 to 1.25) and no reduction in stroke (10.2/1000 observation-years with treatment versus 9.7 with placebo; RR, 1.02; 95% CI, 0.68 to 1.51). Based on the primary end point, there was a suggestion of a harmful effect in those given the combination of folic acid, vitamin B12, and vitamin B6 (RR, 1.22; 95% CI, 1.00 to 1.50), and no effect on stroke (RR, 0.83; 95% CI, 0.47 to 1.47). The study, however, was not powered to detect an effect on stroke outcomes (only 98 of 3749 subjects had strokes). The Heart Outcomes Prevention Evaluation (HOPE) 2 trial randomly assigned 5522 patients with vascular disorders or diabetes to a combination of folic acid, vitamin B12, and vitamin B6 or placebo.10 There was no effect of treatment on the combined risk of myocardial infarction, stroke or cardiovascular death (RR, 0.95; 95% CI, 0.84 to 1.07). Significantly fewer patients assigned to active treatment had a stroke (4.0% versus 5.5%; RR, 0.75; 95% CI, 0.59 to 0.97), despite there being a small number of stroke events (n 258). As pointed out by the study’s authors, this finding is not adjusted for multiple comparisons and may have occurred as a result of chance. Another large secondary prevention trial is ongoing,11 and additional studies will be required to determine whether treatment of elevated homocysteine is independently associated with a reduction of stroke in high-risk primary prevention populations. Case-control studies have generally found an association between the presence of a patent foramen ovale (PFO) and cryptogenic stroke.12 Two new reports, however, suggest that PFO may not be a risk factor for stroke in the general population.13,14 In 1 study, transesophageal echocardiography (TEE) was used to identify PFO among 595 randomly sampled community subjects over age 45.14 Over 5.1 years, 41 subjects had a stroke or transient ischemic attack (TIA). After adjustment for age and comorbidity, PFO was not an independent risk factor for these events (hazard ratio, 1.46; 95% CI, 0.74 to 2.88). Only 1.9% had an atrial septal aneurysm, and larger studies will be required to determine whether its presence is independently associated with stroke risk. The second study used a case-control design.13 Using the presence of a large PFO in randomly selected controls as a reference, after adjustment for comorbidity, the odds of having a large PFO among those with a cryptogenic stroke was 1.10 (95% CI, 0.63 to 1.90). It was suggested that the importance of PFO in cryptogenic stroke reported in previous studies might have been overestimated because of a combination of referral bias and underascertainment in controls.13 The rates of recurrent cryptogenic stroke are similar in those