Response to Letter Regarding Article, “C-Reactive Protein and the Risk of Stent Thrombosis and Cardiovascular Events After Drug-Eluting Stent Implantation”
On the basis of our previous findings,1 we propose a readily available and simple marker, C-reactive protein, for the prediction of stent thrombosis after implantation of drug-eluting stents.2 A priori sample size was determined by use of the assumption of exponential survival curves for the primary end point (definite or probable stent thrombosis). Using Cox regression of the log hazard ratio on a binary covariate (elevated versus nonelevated C-reactive protein) with a ≥30% prevalence, a sample of 2600 observations achieves 80% power at a 0.05 significance level to detect a regression coefficient equal to a hazard ratio of 2.0. The sample size was adjusted for an anticipated stent thrombosis rate of 3.0% at a median follow-up of 4 years.3,4 However, although the sample size was based on data from previous studies, the rate of the primary end point was lower than expected, for reasons that remain unclear. This disparity between the expected and observed event rates might be explained in part by differences in clinical or lesion characteristics, interventional practices, or race or ethnic groups between our population and other observational studies. Although we acknowledge such limitations in our article, we are grateful for the opportunity to clarify our viewpoint on this matter once more. Given that the number of stent thrombosis incidences was small and that this was the novel outcome of interest, it is essential that our findings be validated in other study populations with a large number of patients and with longer-term follow-up.
In previous studies evaluating an additional role of serum biomarkers for the prediction of cardiovascular events,5 the addition of biomarkers to a model with established risk factors resulted in a minor increase in the C statistic without statistical significance. Other findings, however, could also exist in different scenarios.6 Although the discrepancy between the results of our study and those of previous studies could not be clearly explained, it is possible that accurate risk stratification with the individual characteristics of patients, lesions, and procedural factors is considerably limited. The significant increments in the C statistic in the present study indicate that very large independent associations of C-reactive protein values with stent thrombosis exist, and our biomarker approach represents a substantial improvement in the performance of the prediction model, which was also supported by means of statistical measures that evaluate model discrimination, model calibration, and global model fit.
Dr Dominguez-Rodriguez and colleagues express concern regarding the type I error resulting from the small number of events and/or wide confidence intervals, viewing it as the error of excessive credulity. However, the independent, strong association of C-reactive protein values with clinical outcomes was consistent when we used several categories for the biomarkers that have been suggested in the literature or guidelines. Thus, we believe that the type I error does not significantly influence our results.
Park DW, Lee CW, Yun SC, Kim YH, Hong MK, Kim JJ, Park SW, Park SJ. Prognostic impact of preprocedural C reactive protein levels on 6-month angiographic and 1-year clinical outcomes after drug-eluting stent implantation. Heart. 2007; 93: 1087–1092.
Park DW, Yun SC, Lee JY, Kim WJ, Kang SJ, Lee SW, Kim YH, Lee CW, Kim JJ, Park SW, Park SJ. C-reactive protein and the risk of stent thrombosis and cardiovascular events after drug-eluting stent implantation. Circulation. 2009; 120: 1987–1995.
Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005; 293: 2126–2130.
Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Juni P, Sianos G, Hellige G, van Domburg RT, Hess OM, Boersma E, Meier B, Windecker S, Serruys PW. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 2007; 369: 667–678.