Letter by Dominguez-Rodriguez et al Regarding Article, “C-Reactive Protein and the Risk of Stent Thrombosis and Cardiovascular Events After Drug-Eluting Stent Implantation”
To the Editor:
We read the article by Park et al1 about the relationship between C-reactive protein (CRP) levels and drug-eluting stent (DES) thrombosis. Interestingly, the authors found that when CRP values were incorporated into a model containing the conventional clinical, lesion, and procedural risk factors, the C statistic increased significantly for the prediction of stent thrombosis (C statistic of the multivariable model without CRP is 0.723, which increased to 0.772 with the incorporation of CRP; estimated change=0.049; P<0.05).
The inflammatory response caused by percutaneous coronary intervention in stent implantation has provided a suitable clinical model to assess the value of CRP concentrations to predict later events. Nevertheless, the results in this field have not always been concordant, mainly because of the variety of methodologies and different sample sizes used. The Bern-Rotterdam registry yielded a cumulative incidence of 2.9% at 3 years in 8146 patients,2 and results from the multicenter Spanish registry Estudio Español Sobre Trombosis de stents Farmacoactivos3 indicated a rate of cumulative incidence of 2% at 3 years in 23 500 patients. It is a matter of concern that the study by Park and colleagues1 recruited only 2691 patients, a small population compared with other studies in the same setting,2,3 and that the authors did not perform an a priori sample size calculation. This suggests that the study was not specifically designed to assess the association of CRP levels with DES thrombosis or the contribution of this biomarker to the discrimination ability for the risk of future stent thrombosis. Furthermore, the study by Park et al shows a plain lack of power to evaluate the association of CRP and DES thrombosis. Assuming the data by Park and colleagues, annual risks of DES thrombosis equal to 0.7% in patients with high CRP values (≥3 mg/L) and 0.2% in those with low CRP values (<3 mg/L) show a high/low CRP cohort ratio equal to 1.8 (1721/970). We calculate that the power to detect an association between CRP and DES thrombosis was only 33%. Moreover, the authors reported an absolute contribution of CRP to the area under the curve equal to 4.9% and a wide 95% confidence interval with a lower boundary very close to 0 (0.1 to 10.8). To the best of our knowledge, this finding represents an unexpectedly high contribution of a single determination of CRP levels compared with other studies in different scenarios.4 In these studies, the observed (absolute) contribution of CRP to the area under the curve (containing traditional risk factors) ranged from 0.2% to 1.5%.4 All these data taken together might show the presence of a type I error in the study of Park and colleagues.1 We wonder whether CRP is a powerful predictor of DES thrombosis or whether this study simply represents a beautiful example of a type I error in clinical research with small samples. Of course, we will not know the answer until other studies with more subjects and narrower confidence intervals are performed in the future.
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.
Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Jüni 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.
de la Torre-Hernández JM, Alfonso F, Hernández F, Elizaga J, Sanmartin M, Pinar E, Lozano I, Vazquez JM, Botas J, de Prado AP, Hernández JM, Sanchis J, Nodar JM, Gomez-Jaume A, Larman M, Diarte JA, Rodríguez-Collado J, Rumoroso JR, Lopez-Minguez JR, Mauri J, for the ESTROFA Study Group. Drug-eluting stent thrombosis: results from the multicenter Spanish registry ESTROFA (Estudio ESpañol sobre TROmbosis de stents FArmacoactivos). J Am Coll Cardiol. 2008; 51: 986–990.