Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese

Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese

gression analysis of the log RR weighted by the inverse of variance was performed to assess the possible dose-response relation. Results: The number o...

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gression analysis of the log RR weighted by the inverse of variance was performed to assess the possible dose-response relation. Results: The number of participants ranged from 553 (Netherlands, 1985) to 84,688 (USA, 2002) and ages ranged from 30 to 84 years. Compared with those who never consumed fish or ate fish less than once per month, individuals with a higher intake of fish had lower CHD mortality. The pooled multivariate RRs for CHD mortality were 0.89 (95% CI, 0.79 –1.01) for fish intake 1 to 3 times per month; 0.85 (95% CI, 0.76 – 0.96) for once per week; 0.77 (95% CI, 0.66 – 0.89) for 2 to 4 times per week; and 0.62 (95% CI, 0.46 – 0.82) for 5 or more times per week. Each 20 g/d increase in fish intake was related to a 7% lower risk of CHD mortality (p for trend⫽0.03). Conclusions: These results indicate that fish consumption is inversely associated with fatal CHD. Mortality from CHD may be reduced by eating fish once a week or more. Perspective: Eating fish once a week might reduce deaths from CHD by as much as 15%. The benefit of fish was more apparent in studies with a follow-up of at least 12 years. Fish intake increases consumption of long-chain omega-3 polyunsaturated fatty acids, which when given as supplements reduce mortality in men and women following a myocardial infarction. The plausible explanations include decrease in platelet aggregation, antiarrhythmic effects, and anti-inflammatory effects. MR

for stroke in 370T homozygotes vs. 370A homozygotes were 3.6 (95% confidence interval [CI], 1.5– 8.8) and 3.6 (95% CI, 1.3–9.8) in prospective and cross-sectional studies, respectively. Furthermore, average age at onset of stroke in 370T homozygotes tended to be lower than in heterozygotes and 370A homozygotes combined (59 vs. 66 years; p⫽0.08). In contrast, neither levels of cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, nor risk of ischemic heart disease was associated with genotype. Conclusions: The data suggest an association between a polymorphism in the LDL receptor and stroke. Perspective: This prospective study suggests that a common single nucleotide polymorphism in the LDLR gene might be associated with a threefold increased risk of stroke, independent of lipid levels, and perhaps with an earlier onset of disease in a white population. The results may point toward a hitherto unknown function of this receptor in the brain. DM

Serum Total Homocysteine Concentrations and Risk of Stroke and Its Subtypes in Japanese Iso H, Moriyama Y, Sato S, et al. Circulation 2004; 109:2766 – 72. Study Question: Is serum homocysteine (Hcy) a risk factor for stroke in the Japanese? Methods: A prospective, nested, case-control study of Japanese subjects 40 to 85 years of age was conducted by using frozen serum samples from 11,846 participants in cardiovascular risk surveys collected from 1984 to 1995 for one community and 1989 to 1995 for two other communities. By the end of 2000, 150 incident strokes occurred, the subtypes of which were confirmed by imaging studies. Three control subjects per case were selected by matching for gender, age, community, year of serum storage, and fasting status. Results: Mean age was 65 years and 53% were men; 51% of cases had hypertension versus 36% of controls (p⬍0.001). There was no difference in BMI, alcohol use, smoking, lipids or C-reactive protein (CRP). Compared with control subjects, total (n⫽150), hemorrhagic (n⫽52), and ischemic (n⫽98) strokes had higher values of Hcy and higher proportions of Hcy ⱖ11.0 ␮mol/L. The 50th to 75th percentile range of Hcy was 8.7 to 11 ␮mol/L. The multivariate odds ratios (95% CI) for highest (ⱖ11.0 ␮mol/L) versus lowest quartiles (⬍7.0 ␮mol/L) of Hcy after adjustment for BMI, smoking, alcohol, and other cardiovascular risk factors were 2.99 (1.51–5.93) for total stroke, 3.89 (1.60 –9.46) for ischemic stroke, 3.36 (1.27– 8.90) for lacunar infarction, and 1.63 (0.44 – 6.00) for hemorrhagic stroke. The respective multivariate odds ratios associated with a 5 ␮mol/L increase in Hcy were 1.40 (1.09 –1.80), 1.52 (1.07–2.14), 1.48 (1.01–2.18), and 1.10 (0.76 –1.59). The excess risk of total and ischemic strokes did not vary significantly according to gender, age, smoking status, or hypertensive status.

Single Nucleotide Polymorphism in the Low-Density Lipoprotein Receptor Is Associated With a Threefold Risk of Stroke: A Case-Control and Prospective Study Frikke-Schmidt R, Nordestgaard BG, Schnohr P, Tybjærg-Hansen A. Eur Heart J 2004;25:943–51. Study Question: More than 600 different, but rare, mutations in the low-density lipoprotein (LDL) receptor have been identified as the cause of familial hypercholesterolemia. In contrast, only a single common amino acid– changing polymorphism (A370T) has been reported in this gene. The study goal was to ascertain the possible association between the common A370T polymorphism in the LDLR gene and variations in lipid and lipoprotein levels, as well as risk of stroke and ischemic heart disease. Methods: The investigators obtained genotypes for 9238 individuals from The Copenhagen City Heart Study, of which 465 had stroke and 1019 had ischemic heart disease. Results: In this cohort from the Danish general population, 90.2% (n⫽8332), 9.5% (n⫽875), and 0.3% (n⫽31) subjects were 370A homozygotes, A370T heterozygotes, and 370T homozygotes, respectively. The incidences of stroke in 370A homozygotes, A370T heterozygotes, and 370T homozygotes were 28, 26, and 100 per 10,000 personyears, respectively (370T homozygotes vs. 370A homozygotes: log-rank, p⫽0.002). The relative risk and odds ratio



Fondaparinux or Enoxaparin for the Initial Treatment of Symptomatic Deep Venous Thrombosis

Conclusions: High total Hcy concentrations were associated with an increased risk of total stroke, more specifically ischemic stroke and lacunar infarction, among Japanese men and women. Perspective: Because acute strokes are associated with an increased Hcy level, prospective studies from stored serum samples are necessary to determine the significance of increased levels. The finding in this Japanese cohort is similar to several studies among whites. Though nested case-controlled studies have a high degree of reliability, a clinical trial is necessary to determine whether Hcy is causally related to strokes and whether therapy with supplemental folic acid and B-vitamins is beneficial. MR

Buller HR, Davidson BL, Decousus H, Gallus A, et al. Ann Intern Med 2004;140:867–73. Study Question: Does subcutaneous fondaparinux, a synthetic and selective inhibitor of factor Xa, have the efficacy and safety similar to those of enoxaparin in patients with deep vein thrombosis (DVT)? Methods: A total of 2205 patients with acute symptomatic DVT were randomized in a double-blind fashion to fondaparinux, 7.5 mg (5.0 mg in patients weighing ⬍50 kg and 10.0 mg in patients weighing ⬎100 kg) subcutaneously once daily, or enoxaparin, 1 mg/kg of body weight, subcutaneously twice daily for at least 5 days and until vitamin K antagonists induced an international normalized ratio greater than 2.0. Patients with a pulmonary embolism (PE) were excluded. Follow-up was for 3 months with primary end points of symptomatic recurrent DVT, PE, or bleeding. Results: There was no baseline difference between groups with the following: age 61 years; 55% men, creatinine, 54% femoral or iliac DVT, previous DVT 25%, cancer 11%, estrogens 11.5%, or other prothrombic states. Forty-three (3.9%) of 1098 patients randomly assigned to fondaparinux had recurrent thromboembolic events compared with 45 (4.1%) of 1107 patients randomly assigned to enoxaparin (absolute difference, ⫺0.15 percentage point [95% CI, ⫺1.8 to 1.5%]). Major bleeding occurred in 1.1% of patients receiving fondaparinux and 1.2% of patients receiving enoxaparin, and none had antiplatelet antibodies. Mortality rates were 3.8% and 3.0%, respectively. Conclusions: Once-daily subcutaneous fondaparinux was similarly effective (not inferior) and safe as twice-daily, body weight–adjusted enoxaparin in the initial treatment of patients with symptomatic DVT. Perspective: Results would have been stronger had an objective end point such as routine follow-up venous studies been performed in addition to the clinical end points. This study adds to the evidence that factor Xa inhibitors (including oral ximelagatran) will have an important role in the prevention and treatment of venous thromboembolism. The particular advantage of fondaparinux is the absence of thrombocytopenia. It can be self-administered in a weightadjusted dosing schedule. Cost of both agents studied in this trial remains an issue. MR/KE

The Risk of Recurrent Venous Thromboembolism in Men and Women Kyrle P, Minar E, Biolonczyk C, et al. N Engl J Med 2004;350: 2558 – 63. Study Question: Is there a gender difference in risk of recurrent venous thromboembolism (VTE)? Methods: A total of 826 patients with a first episode of spontaneous VTE whose anticoagulation was discontinued were followed for the primary end point of development of symptomatic VTE. The following were exclusion criteria at baseline or detected during follow-up: pregnancy; deficiency of antithrombin, protein C, or protein S; lupus anticoagulant; cancer; atrial fibrillation; or a requirement for long-term antithrombotic treatment. Results: Mean ages of men and women were 51 and 45 years, respectively; p⬍0.001. Mean follow-up was 23 months (interquartile range, 10 – 49 months) for men and 28 months (interquartile range, 12–57 months) in women; p⫽0.02. Venous thromboembolism recurred in 74 of the 373 men, as compared with 28 of the 453 women (20% vs. 6%); a (RR) of 3.6 (95%CI, 2.3–5.5); p⬍0.001. The risk remained unchanged after adjustment for age, the duration of anticoagulation, and the presence or absence of a first symptomatic pulmonary embolism, factor V Leiden, prothrombin G20210A, or an elevated level of factor VIII or IX. At 5 years, the likelihood of recurrence was 30.7% among men, as compared with 8.5% among women (p⬍0.001). The RR of recurrence was similar among women who had had their first thrombosis during oral-contraceptive use or HRT and those women in the same age group in whom the first event was idiopathic. Conclusions: The risk of recurrent VTE is higher among men than among women. Perspective: There is no currently understood explanation for the threefold gender difference in VTE. Recent clinical trials have concluded that long-term anticoagulation with warfarin is warranted in “idiopathic VTE” with or without prothrombotic markers in both men and women. MR

Comparison of Surgery and Compression With Compression Alone in Chronic Venous Ulceration (ESCHAR study): Randomized Controlled Trial Barwell JR, Davies CE, Dcacon J, et al. Lancet 2004;363:1854 – 9. Study Question: Chronic venous leg ulceration can be managed by compression treatment, elevation of the leg, and