C-Reactive protein and outcomes in acute coronary syndromes: a systematic review and meta-analysis

Abstracts

A despeito da associação entre proteína C-reativa de alta sensibilidade (PCR) e eventos recorrentes em síndromes coronarianas agudas sem supradesnível do segmento ST (SCA), a medida rotineira deste marcador não tem sido recomendada. No intuito de avaliar se as evidências científicas atuais justificam a incorporação da PCR para estratificação de risco na admissão hospitalar de pacientes com SCA, realizamos revisão sistemática e metanálise dos trabalhos indexados no MEDLINE, SCIELO ou LILACS, com os seguintes critérios de inclusão: desenho de coorte prospectiva e avaliação do valor prognóstico da PCR, mensurada por método de alta sensibilidade, no momento da admissão hospitalar de pacientes com SCA. Dezenove estudos preencheram os critérios de inclusão. Em relação ao seguimento de longo prazo, houve associação consistente entre PCR e eventos cardiovasculares, com odds ratio (OR) global de 4,6 (95% IC = 2,3-7,6) e OR global multivariado de 2,5 (95% IC = 1,8-3,4). Quanto ao curto prazo, 9 estudos foram positivos e 6 estudos negativos, com OR global de 1,65 (95% IC = 1,2-2,3). O OR global multivariado não foi obtido para o seguimento de curto prazo, pois esta medida foi descrita em apenas três trabalhos heterogêneos. Somente dois trabalhos, de curto prazo, fizeram análise do valor preditor incremental da PCR em relação a modelos multivariados, com resultados contraditórios. Em conclusão, a escassez de avaliação do valor incremental da PCR, aliada a resultados controversos quanto ao valor preditor independente para eventos de curto prazo, não recomenda a utilização rotineira de PCR para estratificação de risco na admissão de SCA.

Proteína C-Reativa; síndrome coronariana aguda; prognóstico; metanálise

A despecho de la asociación entre proteína C-reactiva de alta sensibilidad (PCR) y eventos recurrentes en síndromes coronarios agudos sin supradesnivel del segmento ST (SCA), la medida de rutina de este marcador no ha sido recomendada. Con el propósito de evaluar si las evidencias científicas actuales justifican la incorporación de la PCR para estratificación de riesgo en la admisión hospitalaria de pacientes con SCA, realizamos revisión sistemática y metanálisis de los trabajos indexados en el MEDLINE, SCIELO o LILACS, con los siguientes criterios de inclusión: diseño de cohorte prospectiva y evaluación del valor pronóstico de la PCR, medida por método de alta sensibilidad, en el momento de la admisión hospitalaria de pacientes con SCA. Diecinueve estudios llenaron los criterios de inclusión. En relación al seguimiento a largo plazo, hubo asociación consistente entre PCR y eventos cardiovasculares, con odds ratio (OR) global de 4,6 (95% IC = 2,3 - 7,6) y OR global multivariado de 2,5 (95% IC = 1,8-3,4). En cuanto al corto plazo, 9 estudios fueron positivos y 6 estudios negativos, con OR global de 1,65 (95% IC = 1,2 - 2,3). El OR global multivariado no fue obtenido para el seguimiento de corto plazo, pues esta medida fue descripta en apenas tres trabajos heterogéneos. Solamente dos trabajos, de corto plazo, hicieron análisis del valor predictor incremental de la PCR en relación a modelos multivariados, con resultados contradictorios. En conclusión, la escasez de evaluación del valor incremental de la PCR, aliada a resultados controvertidos en cuanto al valor predictor independiente para eventos de corto plazo, no recomienda la utilización rutinaria de PCR para estratificación de riesgo en la admisión de SCA.

Proteína C-Reactiva; síndrome coronario agudo; pronóstico; metanálisis

C-reactive protein and outcomes in acute coronary syndromes: a systematic review and meta-analysis

Luís C. L. Correia; J Péricles Esteves

Escola Bahiana de Medicina, Universidade Federal da Bahia, Salvador, BA – Brasil

Mailing Address

ABSTRACT

Despite the association between high-sensitivity C-reactive protein (CRP) and recurrent events in non-ST elevation acute coronary syndromes (ACS), routine determination of this marker has not been recommended.

In order to verify whether the current scientific evidence justifies the inclusion of CRP for risk stratification at hospital admission of patients with ACS, we carried out a systematic review and meta-analysis of the studies indexed in MEDLINE, SciELO or LILACS, with the following inclusion criteria: prospective cohort design and assessment of the prognostic value of CPR, as measured using a high-sensitivity method at the moment of hospital admission of patients with ACS. Nineteen studies met the inclusion criteria.

In relation to the long-term follow-up, there was a consistent association between CRP and cardiovascular events, with an overall odds ratio (OR) of 4.6 (95% CI = 2.3 – 7.6) and overall multivariate OR of 2.5 (95% CI = 1.8-3.4). As for the short-term, nine studies were positive and six were negative, with an overall OR of 1.65 (95% CI = 1.2-2.3). The overall multivariate OR was not obtained for the short-term follow-up, because this measurement was described only in three heterogeneous studies. Only two short-term studies analyzed the incremental predictive value of CRP in relation to multivariate models, with contradicting results.

In conclusion, the small number of assessments of the incremental value of CRP, in conjunction with controversial results regarding the independent predictive value of CRP for short-term events does not support the recommendation of the routine use of CRP for risk stratification at admission of patients with ACS.

Key Words: C-Reactive protein; acute coronary syndrome; prognosis; meta-analysis.

Introduction

In patients with acute coronary syndromes (ACS), atherosclerotic plaque instability is accompanied by exacerbation of inflammation¹. The inflammatory phenomenon hinders plaque stabilization, which theoretically makes these patients more vulnerable to recurrent coronary events². This vascular process is widespread, not limited to the site of plaque rupture; it affects the whole coronary bed, and, at the systemic level, may be detected by determining plasma inflammatory markers³. This is the mechanistic rationale for the prognostic value of inflammatory markers in patients with acute coronary syndromes. Among the inflammatory markers, C-reactive protein is the one that has been more frequently studied by means of high sensitivity methods⁴.

Throughout the past 15 years, several publications have indicated that C-reactive protein levels have an independent predictive value for recurrent coronary events in patients with non-ST elevation ACS⁵. However, this approach has not been adopted in clinical practice, nor has the recommendation for the determination of this marker been incorporated to Brazilian⁶, American^5,7 or European⁸ guidelines. Thus, the objective of this systematic review was to evaluate whether the current evidence justifies the inclusion of C-reactive protein for risk stratification at hospital admission of patients with non-ST elevation ACS.

Methods

Literature Research

The MEDLINE (Medical Literature Analysis and Retrieval System) database was the main source used for the systematic review of the articles on the subject studied. To investigate studies not indexed in MEDLINE and carried out in Latin America, the SciELO (Scientific Electronic Library Online) and LILACS (Literatura Latino-Americana e do Caribe em Ciências de Saúde) databases were used by applying the same key words used in MEDLINE. The references of each original article and review articles were checked in order to select studies that had not been identified by the research in the databases.

Initially, the MeSH (Medical Subject Headings) vocabulary was used for the definition of the terms for research in the titles of the studies. The term C-reactive protein was chosen for combination with the terms acute coronary syndromes, myocardial infarction, and unstable angina, resulting in a total of three combinations of two terms connected by the preposition AND. After reading of the titles and summaries retrieved, the studies with the following characteristics were selected: prospective cohort design of patients with non-ST elevation ACS, and assessment of the prognostic value of C-reactive protein, as measured by a high-sensitivity method at the moment of hospital admission.

Studies with evident methodological biases were excluded.

Outcome measures

The following outcome measures were considered: death or composite cardiovascular events. There were different definitions of composite outcome measures in the studies: cardiovascular death and infarction or cardiovascular death, infarction and recurrent angina. These studies were analyzed together, with any of the combinations been considered as cardiovascular events. Outcome measures in the short-term follow-up were defined as occurring during hospitalization or within 30 days at most. Outcome measures in long-term follow-up were defined as those occurring after at least three months of follow-up.

Data analysis

Initially, the characteristics of the different studies were presented in the form of tables. Studies analyzing events in the short-term follow-up (< 30 days) and those analyzing events in the long-term follow-up (> 3 months) were described separately. Some analyzed both outcome measures, and are therefore shown in both tables.

In the univariate analysis, studies reporting the absolute incidence of events according to a cut-off point of C-reactive protein were combined. Studies limited to the assessment of C-reactive protein as a continuous variable were not included in the meta-analysis. Initially, the results of the different studies were compared using the Cochrane Q statistic, with p < 0.05 indicating heterogeneity. When heterogeneity was present, the studies were combined by the random effects model (DerSimonian and Laird method). Otherwise, the fixed effects model was used (Mantel-Haenszel method).

The composite results were expressed as odds ratio (OR) and 95% confidence interval (CI). Also, summary ROC (sROC) curves were obtained with description of the summary C-statistic (area under the curve) and respective 95% CI. The "threshold effect" of the cut-off point of C-reactive protein was evaluated in each study using the Spearman correlation between sensitivity and specificity. For the analysis of sensitivity, the influences of methodological differences on the results of the meta-analysis were tested together using meta-regression analysis.

In order to carry out a joint analysis of data from multivariate analyses, the OR described in each study were combined. Studies describing the multivariate analysis by relative risk or hazard ratio were not combined. The Meta-DiSc software, version 1.4 (Universidad Complutense, Madrid, Spain)⁹ was used for the statistical analysis, except for the combination of odds ratios, when the Comprehensive Meta-Analysis, version 2 (Biostat, Inc, Englewood, NJ, USA)¹⁰ was used.

Results

Study selection

The research on articles published up to May 2009 resulted in 288 studies, of which 259 were excluded by the reading of the title, which indicated that the studies were not related to the assessment of the prognostic value of C-reactive protein in patients with non-ST elevation ACS. Of the remaining 29 studies, 7 were excluded for being review articles and one for being published in a Japanese journal, with full version available only in Japanese¹¹. Other two articles were excluded due to methodological problems: a Japanese study, which evaluated only C-reactive protein combined with serum amyloid A¹²; and a Chilean study which only addressed C-reactive protein as a continuous variable and, in the multivariate model, included only three biomarkers without adjustment for the clinical variables¹³.

Thus, 19 studies were included in this systematic review (Figure 1).

Characteristics of the studies

Nineteen studies were selected; 15 were carried out by North American or European groups^1,14-27, three by Brazilian groups^28-30 and one by an Argentinean group³¹. All these studies were published in journals with an impact factor > 3, except for two Brazilian studies^28,29. The first one dates back to 1994; it was conducted by Liuzzo et al¹⁴ and published in the New England Journal of Medicine. Despite the small sample size of only 32 patients with unstable angina, the impact of this study stems from its original idea of predicting cardiovascular events based on the inflammatory status of patients with ACS. The demonstration that C-reactive protein levels predicted in-hospital events served as the basis for the performance of other 18 studies which started to be published successively as of three years later.

The population samples of these studies consisted predominantly of patients with non-ST elevation ACS and six studies also included ST-elevation myocardial infarction^21,23-26,28. The sample size of the studies increased throughout the years, ranging from 32 to 7,108 patients (mean of 1,123 ± 1,674); seven studies had more than 1,000 patients^20,21,23-27, in a total of 21,339 patients studied. C-reactive protein was measured in all studies by means of a high-sensitivity method; 11 used nephelometry^{14-19,21-24,26,28-30}, three used turbidimetry^1,25,27, one used luminometry²⁰, and two used ELISA (Enzyme Liked Immunosorbent Assay)³¹.

Thus, we can conclude that there is a significant number of studies and patients studied with adequate technique of plasma C-reactive protein determination.

C-reactive protein: long-term prediction of events

Eight studies evaluated the prognostic value of C-reactive protein in relation to recurrent events in a follow-up of at least three months, with mean follow-up of 13 ± 11 months. All showed a significant association between C-reactive protein and cardiovascular events^{1,18,19,22-24,27,31} (Table 1).

As for the meta-analytic grouping of the study results, Bogady et al²³ and Scirica et al²⁴ studies were not included because C-reactive protein was analyzed as a numerical variable, and they did not describe the incidences of events according to the subgroups of CRP investigation. Thus, the long-term results of six studies were combined. In all these studies, there was a positive and statistically significant association between C-reactive protein and outcome measures; however, the analysis of heterogeneity showed a quantitative difference (p = 0.007), i.e., in relation to the magnitude of the association. The combination of studies using the random model resulted in an OR of 4.6 (95% CI = 2.3 – 7.6) (Figure 2). The sROC curve showed a C-statistic of 0.75 (95% CI = 0.65 – 0.85) (Figure 3).

Analysis of sensitivity of the prediction of long-term events

Two characteristics varied significantly among the studies of this meta-analysis. First, the form of determination of the cut-off point for C-reactive protein: three studies identified the cut-off point by using the ROC curve and found 15 mg/L³¹, 10 mg/L¹⁹, and 11 mg/L²², respectively. The other three studies arbitrarily chose the cut-off points of 5 mg/L¹⁸, 10 mg/L¹ and 10 mg/L²⁷, respectively. According to the meta-regression analysis, there was no influence of the form of determination of the cut-off points on the results of the studies (OR = 0.1; 95% CI = 0 – 36; p = 0.23). Also, there was no linear association between sensitivity and specificity (p = 0.40), thus indicating absence of influence of the cut-off point values on the results of the studies (threshold effect).

The second characteristic that differed among the studies was the definition of outcome measures, with two meta-analysis studies analyzing death alone^1,27 and four analyzing composite outcome measures^18,19,22,31. Likewise, the meta-regression analysis did not show any influence of the type of outcome measure on the results (OR = 0.35; 95% CI = 0.02 – 4.5; p = 0.27).

C-reactive protein: short-term prediction of events

Fifteen studies analyzed the prediction of events up to 30 days^{14-17,19-21,25-31}. Unlike for the long-term follow-up, the results of the studies were conflicting: nine studies were positive^{14,17,20,21,25-27,30} and six were negative^{15,16,19,28,29,31} (Table 2). On average, the group of positive studies had larger sample sizes (1,911 ± 2,197 patients), with six of the seven studies with more than 1,000 patients. On the other hand, the group of negative studies had a mean sample size of 225 ± 110 patients, the larger of which with 447 individuals. This suggests that the negative results of these studies may have been due to the reduced statistical power.

Meta-analytic approach was used with the 12 studies which compared the incidence of events between two dichotomous groups according to the level of C-reactive protein^{14-17,19,20,25-27,29-31}. Duarte et al's study²⁸ was not included in this analysis because it assessed C-reactive protein as a continuous variable. One of Oltrona et al's study²¹ and Scirica et al's study²⁴ were not included in the meta-analysis because they expressed their results only as relative risk, and did not provide the absolute incidence of events. The meta-analysis showed significant heterogeneity among the studies (p = 0.002); for this reason, the OR was calculated using the random effects model, which resulted in 1.65 (95% CI = 1.20 – 2.27), thus confirming prediction of in-hospital events (Figure 4). The sROC curve showed a C-statistic of 0.57 (95% CI = 0.54 -0.60) (Figure 5).

Analysis of sensitivity: short-term prediction of events

Three characteristics were significantly different among the studies. First, the form of determination of the cut-off point for C-reactive protein: four studies identified the cut-off point by using the ROC curve^19,26,30,31 and other eight studies chose the cut-off point arbitrarily^{14-17,20,25,27,29}. According to the meta-regression analysis, the form of determination of the cut-off point had no influence on the study results (OR = 1.34; 95% CI = 0.52 – 3.47; p = 0.49). Also, there was no linear association between sensitivity and specificity (p = 0.55), thus indicating absence of influence of cut-off values on the study results.

The second difference among the studies was the definition of outcome measures, with three studies of the meta-analysis evaluating death alone^17,25,27 and the other nine studies evaluating composite outcome measures^{14-16,19,20,26,29-31}. Likewise, the meta-regression analysis did not show influence of the type of outcome measure on the results (OR = 0.35; 95% CI = 0.02 – 4.5; p = 0.27).

Finally, ST-elevation myocardial infarction was included in two studies^25,26, whereas the other 10 analyzed only non-ST elevation ACS. This did not influence the results either (OR = 0.70; 95% CI = 0.36 – 1.35; p = 0.25) (Table 3).

Independent predictive value of C-reactive protein

Most of the studies, except for the three initial ones^14,15,17, adjusted the predictive value of C-reactive protein to the clinical and laboratory variables. In five studies, important covariables were left out of the statistical model^{16,18,25,28,32}, whereas in other 11 studies the multivariate analysis was adequate^{1,19-24,26,27,31}. Foussas et al's²⁶ and Correia et al's³⁰ studies should be particularly pointed out for being the only ones to adjust the level of C-reactive protein to a validated risk score, the TIMI risk score.

Of the eight studies which evaluated the long-term prognostic value of CRP, six confirmed its independent predictive value by using the multivariate analysis^{1,18,19,22,24,27}, and one did not carry out this analysis³¹. On the other hand, the recent Bogaty et al²³ on a cohort of 1,210 patients with ACS found no multivariate association of C-reactive protein with long-term recurrent events; this study was worthy of attention for its negative result²³. Because of the unprecedented finding of the absence of an independent predictive value, this study is worthy of a detailed discussion.

First, the analysis of methodological issues did not show superiority of Bogaty et al²³ in relation to the other studies. Second, it has been demonstrated that the predictive value of C-reactive protein in patients with unstable angina or non-ST elevation myocardial infarction is greater than its predictive ability in ST-elevation myocardial infarction, where the higher degree of necrosis influences C-reactive protein levels²⁵. Thus, the fact that 30.0% of the patients presented with ST-elevation myocardial infarction may have contributed to the negative result of Bogaty et al²³. Third, that study showed significant predictive ability of C-reactive protein in the univariate analysis, but not in the multivariate analysis. Unlike in the other studies, the level of C-reactive protein was included as a continuous variable in the logistic regression, and this reduces its prediction strength because it is evaluated together with other categorical variables. This may have been the main reason for the negative result of Bogaty et al²³.

Five long-term studies reported measures of association from the multivariate analysis. Three of them used OR, thus permitting data combination. These three studies showed homogeneity (p = 0.14), and the fixed effects model resulted in OR = 2.5 (95% CI = 1.8 – 3.4).

In relation to the independent predictive value of C-reactive protein for short-term events, 10 studies carried out a multivariate analysis and only four indicated an independent predictive value, thus showing controversial findings. Only three studies described multivariate OR and, due to the heterogeneous of their results, we chose not to combine them, to avoid a high potential of selection bias in such analysis.

Incremental value of C-reactive protein

Of the 19 articles selected, only two quantified the incremental value of C-reactive protein, both in relation to the short-term predictive value. In the first, Oltrona et al¹⁵ found that the inclusion of C-reactive protein in the logistic regression model did not add to the C-statistic. Oltrona et al¹⁵ has a large sample size (N = 1,773) and the advantage of including a large number of covariables²¹. On the other hand, Oltrona et al¹⁵ study has the disadvantage of also including ST-elevation myocardial infarction, which theoretically reduces the predictive value of C-reactive protein. Although statistically correct, Oltrona et al¹⁵ approach to how much C-reactive protein adds to a predictive model derived from the study sample itself makes it more difficult to find an additional predictive value of a biomarker. This occurs because the multivariate predictive model is optimized since it was derived from the population itself.

In the second study, Correia et al³⁰ specifically selected patients with non-ST elevation ACS and analyzed the incremental value in relation to a validated risk score, the TIMI risk score. Despite its small sample size, after inclusion of the information on C-reactive protein this study showed an increment in TIMI's C-statistic by 0.06³⁰.

Discussion

The objective of the present systematic review was to evaluate whether there are evidences corroborating the use of C-reactive protein as a risk predictor at admission of patients with non-ST elevation ACS. The prognostic value of this marker has been evaluated in the short term (in-hospital or 30 days) and long term (> three months).

We observed that, in the long-term, evidences showing association between C-reactive protein and the incidence of outcome measures are consistent in both univariate and multivariate analyses. On the other hand, the short-term results are qualitatively heterogeneous, i.e., some indicate the absence of association and others suggest an association between C-reactive protein and outcome measures. In the present meta-analysis, the mean effect of short-term studies shows a univariate association between C-reactive protein and cardiovascular risk³². However, the multivariate analyses of these studies are contradictory and the results could not be combined because the minority of them provided the multivariate odds ratio. Thus, the present analysis shows a long-term prognostic value and indicates controversy regarding the short-term prognostic value.

Although the independent risk prediction is a necessary condition in the validation of a new marker, it does not suffice. Interrupting the evaluation of the predictor in this phase, and considering it validated for clinical use is a common mistake. Not all independent predictors add to the prognostic accuracy of the classical prediction models in a clinically relevant fashion³³. This brings up an important question: does the novel risk marker provide an incremental utility to the models applied in clinical practice? The answer should be obtained by comparing the performance of a predictive model including usual variables with that of an alternative model resulting from the incorporation of the novel marker to the classical model. That is, when a new variable is included in a risk score, how much does the performance of this score improve? The most common way of addressing this question is by measuring the increment in C-statistic after incorporation of the novel biomarker³⁴.

In the present review, only two studies addressed this issue with conflicting results, one negative²¹ and the other positive³⁰. Although Correia et al³⁰, whose results were positive, had the methodological advantages reported in the results of the present systematic review, the negative Oltrona et al²¹ has a sample size 20 times larger than that of the former, so that their results should also be valued. Therefore, there are no conclusive evidences regarding the incremental value (clinical utility) of C-reactive protein in relation to the usual risk prediction.

Given the lack of studies on the incremental value of C-reactive protein, we can deduct that it is present based on the strength of association between C-reactive protein and the outcome measures. It has been reported that, in order to add to the C-statistic (> 0.05) in a clinically relevant fashion, a marker usually requires an odds ratio > 3³⁵. In the present analysis, the composite odds ratio of 4.6 for the long term seems a favorable number. However, this is the univariate odds ratio, probably overestimated in relation to the multivariate value. Also, the lower limit of the confidence interval is 2.3, and this raises doubt as to the incremental value. Even more uncertain is the short-term incremental value, because the odds ratio of the meta-analysis was 1.6, thus suggesting absence of an incremental value of C-reactive protein.

We should point out that the reasoning exposed is inferential, and the ultimate answer to this question will come with further analyses on the incremental value, which can be carried out in the very databases of the studies published. The importance of this type of analysis is exemplified by the issue of C-reactive protein as a risk predictor in apparently healthy individuals. In this case, C-reactive protein determination does not add to the C-statistic of the Framingham score, although it has an independent association with cardiovascular events³⁶.

The methodological differences of the studies analyzed represent potential biases in the results of this systematic review. For instance, there is a wide variation among the studies regarding the cut-off points, types of outcome measures used, and target populations. However, the analyses of sensitivity indicated that these characteristics did not influence the results of the meta-analysis. Another limitation is the absence of information concerning the odds ratio of most of the studies, and this prevented them from being correctly combined as regards the analysis of the independent predictive value (multivariate analysis).

The stand of current guidelines on non-ST elevation ACS is not clear in relation to the use of C-reactive protein. The Brazilian guideline does not even mention inflammatory markers, whereas the American and European guidelines describe the studies which show the association between C-reactive protein and outcome, although not conclusively from the point of view of recommendation.

Therefore, the present systematic review fills this gap with the following conclusion: despite the consistent association between the C-reactive protein level at admission and the long-term outcome of patients with ACS, the lack of definitive information regarding its incremental prognostic value does not permit the recommendation of the routine determination of this biomarker in patients with non-ST elevation ACS.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of free teaching of Louis C. L. Correia Federal University of Bahia.

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Publication Dates

• Publication in this collection
  11 Mar 2011
• Date of issue
  July 2011

History

• Reviewed
  14 Apr 2010
• Received
  11 Jan 2010
• Accepted
  17 May 2010