Re: Anticardiolipin Antibodies Are Not an Independent Risk Factor for Stroke
To the Editor:
The role of anticardiolipin antibodies (aCL) as risk factors for stroke was examined in an incident case-referent study nested within the MONICA and Västerbotten Cohort Project.1 The authors conclude that while aCL were associated with future stroke, they did not constitute an independent risk factor. Their data do not support a causative role for IgA-aCL and IgG-aCL but neither do the data justify dismissing IgM-aCL as an independent risk factor.
On multivariate adjustment for hypertension, diabetes mellitus, current cigarette smoking, and smokeless tobacco, the odds ratio for future stroke associated with IgM-aCL decreased from 1.34 to 1.24 and was no longer statistically significant. However, the 95% confidence interval was fairly narrow (0.98 to 1.56). It is highly likely that a type II error could explain this loss of statistical significance. The authors gave no indication of the power of the study to detect the independence of aCL as risk factors for stroke. The effective sample size would also have decreased because of missing values. Data from Table 1 of the article suggests that several patients and controls had no data on the covariates included in multivariate logistic regression model on which the authors based their conclusion. For example, 11 patients and 15 controls had no data on hypertensive status.
Smoking was not an independent risk factor in this study, either. However, it would be imprudent to suggest on the basis of this study that smoking is not a risk factor for stroke.2 3 As the authors indicate, this is the only prospective study to report an association between aCL and stroke. Furthermore, few studies have examined the role of IgM-aCL. In light of this, the consequences of a misleading conclusion are important.
Some of the risk associated with IgM-aCL was explained by the other classic risk factors included in the regression model, and the antibodies could be the result of endothelial cell damage induced by these factors.4 On the other hand, they may have a causal role, and this needs to be further investigated. IgM-aCL increased the risk of stroke by only 24% in this study. If this is a true indication of the strength of the association, then future studies will need larger sample sizes to be able to assess the independence of IgM-aCl as a stroke risk factor.
- Copyright © 2001 by American Heart Association
Ahmed E, Stegmayr B, Trifunovick J, Weinehall L, Hallmans G, Lefvert AK. Anticardiolipin antibodies are not an independent risk factor for stroke: an incident case-referent study nested within the MONICA and Västerbotten Cohort Project. Stroke. 2000;31:1289–1293.
Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking and stroke. BMJ. 1989;298:789–794.
Cheng HW. Pathogenicity of antiphospholipid antibodies. In: Immunophysiology of Antiphospholipid Antibodies. Austin, Tex: RG Landes Co; 1994:67–89.
We examined antibodies against cardiolipin as predictive factor for future stroke in an incident case-referent study within the MONICA and Västerbotten cohort project.R1 According to our results, IgM ACL were associated with future stroke but not independent from the other risk factors hypertension, diabetes mellitus, serum cholesterol, and smoking.
Sargeant and coworkers have questioned this conclusion. We do agree that the title of the paper is a little provocative, and also that the power of the study should preferably have been stronger. In our study, we analyzed samples drawn an average of 34.1 months before the incident. The relative risks we report may thus have underestimated the long-term risk for stroke in healthy individuals having ACL. Nevertheless, this is the first truly prospective study that has analyzed all 3 isotypes of ACL. A possible association to IgM ACL would have been missed by the only previous study on IgG antibodies in healthy individuals and future stroke.R2
It is of interest to note our previous study on antibodies against oxidatively modified LDL in the same patient population as in the present study: there was no association of these antibodies to future stroke.R3 Our earlier study on antibodies against cardiolipin and oxidatively modified LDL as predictors for myocardial infarction showed that raised levels of these antibodies at 50 years of age correlated positively with the incidence and mortality related to myocardial infarction 10 to 20 years later.R4 In contrast to our study of stroke, only IgG and IgA antibodies against cardiolipin were associated with myocardial infarction. The predictive power of IgA and IgG antibodies was strong and largely independent of that of other strong risk factors.
It should finally be noted that the population we studied comes from the northern part of Sweden, an area that differs in many respects from that of the rest of the Swedish Caucasian population. There are genetic differences and also marked environmental and lifestyle differences that might affect the results of our study.
We thus agree with Sargeant et al that larger epidemiological studies are warranted to clarify the issue on the predictive value of antibodies against cardiolipin for stroke. In addition, since these antibodies are clearly heterogeneous,R5 functional studies of ACL of different isotypes and specificities are necessary to understand their effect on the vessel wall.
Ahmed E, Stegmayr B, Trifunovic J, Weinehall L, Hallmans G, Lefvert AK. Anticardiolipin antibodies are not independent risk factors for stroke: an incident case referrent study within the MONICA and Västerbotten cohort project. Stroke. 2000;31:1289–1293.
Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Hennekens CH, Stampfer MJ. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med. 1992;117:997–1002.
Ahmed E, Trifunovic J, Stegmayr B, Hallmans G, Lefvert AK. Antibodies against modified LDL do not constitute a risk factor for stroke: a nested case-control study. Stroke. 1999;30:2541–2546.
Wu R, Nityanand S, Berglund L, Lithell H, Holm G, Lefvert AK. Antibodies against cardiolipin and oxidatively modified LDL in 50-year-old men predict myocardial infarction. Arterioscler Thromb Vasc Biol. 1997;17:3159–3163.
Lefvert A. Heterogeneity of autoantibodies against cardiolipin and oxidatively modified LDLs revealed by human monoclonal antibodies. J Intern Med. 2000;3:385–390.