Author + information
- Received March 14, 2014
- Revision received June 3, 2014
- Accepted June 18, 2014
- Published online December 1, 2014.
- Anna Toso, MD∗∗ (, )
- Mario Leoncini, MD∗,
- Mauro Maioli, MD∗,
- Francesco Tropeano, MD∗,
- Emilio Di Vincenzo, MD∗,
- Simona Villani, PhD† and
- Francesco Bellandi, MD∗
- ∗Cardiology Division, Prato Hospital, Prato, Italy
- †Section of Biostatistics and Clinical Epidemiology, Department of Public Health, Neurosciences, Experimental, and Forensic Medicine, Pavia University, Pavia, Italy
- ↵∗Reprint requests and correspondence:
Dr. Anna Toso, Division of Cardiology, Misericordia e Dolce Hospital, Via Cavour, 2 Prato 59100, Italy.
Objectives This study sought to investigate whether the beneficial impact of high-dose rosuvastatin against contrast-induced acute kidney injury (CI-AKI) in acute coronary syndrome (ACS) patients varied in relation to baseline high-sensitivity C-reactive protein (hs-CRP) levels.
Background High-dose rosuvastatin administered on admission has been shown to prevent CI-AKI and improve short- and mid-term clinical outcome in ACS patients.
Methods All 504 statin-naïve ACS patients enrolled in the PRATO-ACS (Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Acute Kidney Injury and Myocardial Damage in ACS Patients) study were stratified into baseline hs-CRP tertiles: <2.7 mg/l, ≥2.7 to <7.5 mg/l, and ≥7.5 mg/l. The primary endpoint was CI-AKI occurrence (creatinine ≥0.5 mg/dl or ≥25% above baseline within 72 h). Logistic regression models were used to evaluate the relationship between hs-CRP levels and effects of rosuvastatin.
Results Patients with higher baseline hs-CRP values presented a significantly higher incidence of CI-AKI (5.4%, 8.7%, and 18.3% in the first, second, and third tertiles, respectively; p = 0.0001). The beneficial effect of rosuvastatin was markedly significant in the third hs-CRP tertile (odds ratio: 0.20; 95% confidence interval: 0.07 to 0.54; p = 0.002). Statin-treated patients in the third tertile presented a significantly lower rate of adverse events at 30 days (7.2% vs. 17.4%, p = 0.043) with a trend toward better outcome at 6 months (6.02% vs. 13.04%, p = 0.12).
Conclusions High-dose rosuvastatin administered on admission appears to exert more effective kidney protection in ACS subjects with higher baseline hs-CRP levels resulting in better short- and mid-term clinical outcome. (Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Nephropathy and Myocardial Damage in Patients With Acute Coronary Syndrome Undergoing Coronary Intervention [PRATO-ACS]; NCT01185938)
Increased systemic inflammation evidenced by elevated C-reactive protein (CRP) levels is associated with higher risk of cardiovascular events (1–3). There is a growing body of evidence that the benefit of statin therapy may also be related to the drug anti-inflammatory effects (4–6). Patients with higher CRP levels treated with statins show substantially greater reduction of cardiovascular events than those without signs of inflammation, even in cases of low-density lipoprotein cholesterol levels (6).
Elevated CRP levels are also associated with endothelial injury and impaired vasodilation, which may lead to acute renal damage and progressive loss of kidney function (7). Systemic inflammation could render the kidneys more vulnerable to local inflammatory processes elicited by iodinated contrast medium reabsorption following angiographic procedures, favoring development of contrast-induced acute kidney injury (CI-AKI) (8–10). Recent randomized studies have evidenced the beneficial effects of statins against CI-AKI especially in high-risk patients such as those with diabetes or acute coronary syndrome (ACS) who present evident signs of inflammation (10–16).
The continued evidence of the beneficial effects of statins in these patients and the presumed importance of inflammation in the pathogenesis of acute renal damage encouraged us to focus on the possible specific relationship between statin treatment and baseline CRP levels in our PRATO-ACS (Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Acute Kidney Injury and Myocardial Damage in ACS Patients) study patients. The PRATO-ACS randomized study has shown that in addition to standard preventive measures (intravenous hydration, use of low- or iso-osmolar contrast media and reduced dosages of contrast agents) early high-dose rosuvastatin administration reduces CI-AKI occurrence and improves short- and mid-term clinical outcome in statin-naïve patients with ACS without ST-segment elevation (NSTE) selected for early invasive strategy (15).
The design and main results of the PRATO-ACS study have been previously described (15). Briefly, 543 statin-naïve patients with NSTE-ACS scheduled for early invasive strategy were enrolled in the trial immediately on admission. Exclusion criteria were as follows: long-term lipid-lowering therapy at the time of the index ACS; high-risk features warranting emergency coronary angiography (within 2 h); acute renal failure or end-stage renal failure requiring dialysis or serum creatinine ≥3 mg/dl; severe comorbidities that precluded early invasive strategy; contraindications to statin treatment; contrast media administration within the last 10 days; pregnancy; or refusal of consent. Eligible patients were randomly assigned to receive high-dose rosuvastatin (statin group) or no statin treatment (control group). After randomization, 39 patients were excluded from the final analysis for the following reasons: 17 had not undergone angiography, and 22 did not complete creatinine determination. Thus, a total of 504 patients were analyzed, 252 per group.
At the time of randomization, patients in the statin group were administered 40 mg of rosuvastatin followed by 20 mg/day (time of statin administration: 10 PM); the control group did not receive statin treatment. At discharge, statin group patients continued treatment with 20 mg/day rosuvastatin (10 mg/day for patients with estimated glomerular filtration rate <30 ml/min/m2) whereas control subjects received 40 mg/day atorvastatin.
Serum creatinine was measured at baseline (always before hydration) and at 24, 48, and 72 h after contrast media administration; a further measurement was performed at 30 days in all CI-AKI cases. High-sensitivity C-reactive protein (hs-CRP) was measured on admission (always before randomization) with an immunoturbodimetric assay (Unicel DxC Clinical Systems 800, Beckman Coulter Inc., Brea, California); the working range of the assay was 0.0 to 5.0 mg/l. Total and differential white blood cell counts were obtained with a Coulter LH 750 Analyzer (Beckman Coulter Inc., Brea, California). All tests, even after discharge, were done in our hospital laboratory with consistent methodology.
The primary endpoint of the PRATO-ACS study was CI-AKI defined as an increase in serum creatinine of ≥0.5 mg/dl or ≥25% over the baseline value within 72 h after contrast agent administration. Additional endpoints were as follows: CI-AKI defined by other criteria; CI-AKI occurrence in pre-specified risk subgroups; adverse cardiovascular and renal events at 30 days including acute renal failure requiring dialysis, persistent renal damage, all-cause mortality, myocardial infarction, or stroke; and all-cause mortality or nonfatal myocardial infarction rate at 6 months (15).
The protocol was approved by the hospital ethics committee and all patients gave written informed consent.
Categorical variables were summarized as percentages and continuous variables as mean ± SD or median with interquartile range. The differences between categorical variables were investigated by chi-squared or Fisher exact tests. Parametric unpaired Student t test (with Satterthwaite correction for degrees of freedom when necessary) or the analogous nonparametric test (Wilcoxon-Mann-Whitney test = U) was applied to evaluate differences for continuous variables between the statin and the control groups.
Spearman correlation coefficient was used to measure the relationship between hs-CRP and various clinical and laboratory variables.
Patients were stratified into 3 groups according to tertiles of baseline hs-CRP: <2.7 mg/l; ≥2.7 to <7.5 mg/l; and ≥7.5 mg/l. Baseline characteristics of the 3 groups were compared using chi-square analysis for categorical variables and parametric or nonparametric analysis of variance (Kruskal-Wallis test) for continuous variables. Multiplicity issues resulting from the pairwise comparisons with respect to the highest tertile (≥7.5 mg/l) were solved applying the Bonferroni corrections (yielding a significance threshold of 0.025).
Rates of CI-AKI were compared between tertiles using chi-square analysis. The multivariate logistic analysis performed to evaluate the association between statin treatment and CI-AKI occurrence included various potential prognostic and confounding factors such as sex, age, diabetes, hypertension, low-density lipoprotein cholesterol level, creatinine clearance at baseline, left ventricular ejection fraction, contrast volume, CI-AKI risk score, and baseline hs-CRP. Baseline hs-CRP was entered into the models as either a continuous or categorical variable, using the 3 tertiles described. The association between treatment and CI-AKI was expressed as odds ratio (OR) and 95% confidence interval (CI).
An interaction term for statin treatment and baseline hs-CRP levels was also introduced into the multivariate models to examine the possible role as effect modifier. All probability values were 2-tailed and a p value of <0.05 was considered significant. All the analyses were carried out using STATA software (version 12, StataCorp LP, College Station, Texas).
Table 1 shows baseline clinical, biochemical, and angiographic parameters in the statin and control groups. There were no significant differences between the 2 groups regarding baseline hs-CRP values and other clinical and biochemical inflammation-related factors, including, for example, body mass index, glycemia, hemoglobin, creatinine clearance, leukocytes. Other parameters investigated are reported in a previous paper (15).
Overall, 55 patients (10.9%) developed CI-AKI after angiographic procedure: 17 (6.7%) in the statin group and 38 (15.1%) in the control group with a crude odds ratio of 0.41 (95% CI: 0.22 to 0.74; p = 0.003) (15). Adjusting the original logistic model for baseline hs-CRP (continuous variable), this OR remains highly significant (adjusted odds ratio [ORadj]: 0.41, 95% CI: 0.22 to 0.77; p = 0.005), showing that rosuvastatin pre-treatment exerted a significant protective effect against CI-AKI occurrence independent of baseline hs-CRP. This favorable effect was consistently confirmed even using nonprimary endpoint CI-AKI criteria (Table 2). No significant statistical interaction between treatment allocation and baseline levels of hs-CRP was observed (p = 0.25).
Effect of statin pre-treatment on CI-AKI by baseline hs-CRP tertiles
Table 3 shows the clinical and biochemical parameters in patients stratified into tertiles of baseline hs-CRP levels. Patients in the highest hs-CRP tertile were generally older, more apt to have diabetes, and had lower ejection fraction and estimated creatinine clearance. These higher hs-CRP values on admission signal higher risk of CI-AKI and adverse clinical events.
Baseline hs-CRP values were slightly but significantly correlated with various parameters that reflect comorbidities and presentation acuity (Table 3).
Overall, there was a progressive increase in CI-AKI rates from the lowest to the highest hs-CRP tertile (p for trend = 0.0001) (Figure 1A). Patients in the control group presented an impressive increase in CI-AKI occurrence from the first to the third hs-CRP tertile (p for trend <0.0001) (Figure 1B). The tertiles of statin-treated patients, instead, do not evidence significant differences in trend (p = 0.65).
After adjustment for hs-CRP (categorical variable) and other confounders, the relationship between statin treatment and CI-AKI development remained markedly significant only in the third tertile (ORadj: 0.20, 95% CI: 0.07 to 0.54; p = 0.002) (Figure 2). Moreover, statin treatment showed the greatest effect in the third baseline hs-CRP tertile for all the pre-specified risk categories of patients (Figure 3).
Effect of statin pre-treatment on clinical outcome by baseline hs-CRP tertiles
The incidence of cumulative adverse cardiovascular and renal events at 30 days was markedly higher in patients in the third tertile (p for trend <0.0001) (Figure 4A). Compared with control subjects, statin-treated patients in the third tertile presented a significantly lower rate of such events (7.2% vs. 17.4%, p = 0.043) (Figure 4B). Follow-up at 6 months showed continued higher rates of adverse events in patients with higher baseline hs-CRP (third tertile) (Figure 5A) but with a positive trend toward lower rates of death or myocardial infarction in statin-treated patients (6.02% vs. 13.04%, p = 0.12) (Figure 5B).
The present analysis of the PRATO-ACS data, in particular CRP levels, shows a close relationship between baseline hs-CRP levels and CI-AKI occurrence in patients with ACS subjected to early invasive strategy. The magnitude of CI-AKI reduction attributable to rosuvastatin pre-treatment was substantially greater in patients with higher baseline hs-CRP than in patients with lower levels. The clinical benefits are evidenced by lower rates of adverse cardiovascular and renal events that are especially notable in patients with higher baseline hs-CRP levels.
In the last few decades, research has demonstrated the important role of inflammation in ACS; it not only promotes the development of atheroma, but also contributes decisively to precipitating subsequent acute thrombotic complications (3). Moreover, elevated circulating markers of inflammation, in particular CRP, predict an unfavorable clinical course, independent of the severity of atherosclerosis (1) or the levels of traditional risk factors (17,18).
Systemic inflammation is also associated with impaired renal function (7); it can predict worsening of renal function in both patients with manifest chronic kidney disease (7) and patients with subclinical renal disease (19). In this very vulnerable population, CRP is a relevant prognostic indicator of adverse cardiovascular events (20).
CI-AKI is a multifactorial process but, in particular, various inflammation-related factors, including endothelial dysfunction, oxidative stress, and renal vasoconstriction, can actively influence its development (9,21). Moreover, systemic inflammation could render the kidneys more vulnerable to local inflammatory processes elicited by iodinated contrast medium reabsorption following angiographic procedures, favoring development of CI-AKI (8–10).
Recent clinical studies indicate that there is a significant independent association between pre-procedural CRP levels and CI-AKI occurrence in both stable coronary artery disease patients submitted to elective percutaneous coronary intervention (PCI) (22) and ST-segment elevation myocardial infarction patients submitted to primary PCI (23). We note that these studies showed a significant association between pre-procedural CRP and clinical outcome notwithstanding the different clinical settings.
The present analysis of the PRATO-ACS study confirms the relationship between baseline hs-CRP levels and CI-AKI development even in NSTE-ACS patients subjected to early invasive strategy and shows a close link between baseline hs-CRP levels and prognosis. The present study shows that baseline hs-CRP (correlated with pre-existing comorbidities, extent of myocardial damage, and other inflammatory markers) helps identify patients with particularly high clinical risk–those very patients who presented phenotypes associated with higher risk of CI-AKI development.
Effect of statin pre-treatment
In stable coronary artery disease and ACS patients, the reduction of risk for cardiovascular events attributable to statin therapy is substantially greater among patients with high levels of inflammation (6,24,25). A number of randomized clinical trials and registry settings have indicated that the apparent cardiovascular and renoprotective effects of statin treatment are probably mediated by its anti-inflammatory properties (6,19). In fact, the anti-inflammatory action of statins is well documented both in vitro (26) and in vivo (27). In patients with ACS, statin administration led to significantly lower CRP levels after PCI (11,12,28) and lower CRP levels at follow-up resulting in evidently better clinical outcome (29).
The beneficial effects against CI-AKI occurrence exerted by statin pre-treatment (loading) in statin-naïve patients with ACS (11,12,14,15) could well be related to the acute non-lipid-mediated properties of statins, including their anti-inflammatory mechanisms. The results of the present in-depth analysis show an incrementally beneficial effect of statin pre-treatment in patients with very high baseline CRP levels, thus further supporting this hypothesis.
Even short-term statin treatment may reduce susceptibility to CI-AKI given its anti-inflammatory effects, both systemic and on the kidneys in particular. In fact, statin treatment increases tubular proteinuria in a dose-dependent manner, potentially leading to lower levels of peri-tubular inflammation (30,31). The diminished levels of inflammation render the tubular cells less vulnerable to the direct toxic effects of contrast medium.
In the PRATO-ACS study, high-dose rosuvastatin treatment administered on admission was associated with a significantly lower rate of 30-day adverse cardiovascular and renal events and a continued positive trend at 6 months. The present study also shows that those patients with higher markers of inflammation are more subject to adverse events, and it is these very patients who benefit most from statin pre-treatment.
Patients with NSTE-ACS are a particularly high-risk group: they require aggressive medical management, including early high-dose statin therapy. Statin benefits are evident independent of baseline hs-CRP in all risk categories, but this study shows that the higher the baseline hs-CRP levels, the higher the CI-AKI and adverse event rates, and the higher the benefits of on-admission statin administration. Whether or not these benefits are due to the anti-inflammatory properties of rosuvastatin cannot be established on the basis of this study, but our findings represent a further reason in favor of early use of high-dose statin therapy and assessment of hs-CRP in ACS patients.
hs-CRP was measured only on admission. We did not repeat this measurement, and therefore, we do not know whether hs-CRP levels were lowered by the statin before contrast medium administration or subsequently.
High-dose rosuvastatin therapy administered on admission reduced CI-AKI occurrence and improved short- and mid-term clinical outcome in statin-naïve patients with NSTE-ACS, who were subjected to early invasive strategy with particularly remarkable effects in patients with higher baseline hs-CRP levels.
The study was supported by the Centro Cardiopatici Toscani. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndrome
- confidence interval
- contrast-induced acute kidney injury
- C-reactive protein
- high-sensitivity C-reactive protein
- non–ST-segment elevation
- odds ratio
- adjusted odds ratio
- percutaneous coronary intervention
- Received March 14, 2014.
- Revision received June 3, 2014.
- Accepted June 18, 2014.
- American College of Cardiology Foundation
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