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Letters

Intravenous Hydration(With or WithoutRosuvastatin) ShouldRemain the Cornerstoneof the Prevention ofContrast-Induced AcuteKidney Injury in PatientsWith Diabetes andChronic Kidney Disease

In a recent randomized, controlled, multicenter trial,Han et al. (1) showed that rosuvastatin, comparedwith “standard of care,” significantly reduced therisk of contrast-induced acute kidney injury (AKI) indiabetic patients with chronic kidney diseaseundergoing an intra-arterial contrast mediuminjection. On the basis of Figure 3, the authors claimthat rosuvastatin was consistently effective amongvarious subgroups. We disagree. No effect (p ¼ 0.89)was observed in approximately 43% of patientsgiven intravenous hydration (the standard of care,not given consistently in this study, in contrast tothe authors’ claim). Thus, we conclude thatrosuvastatin may at best prevent contrast-inducedAKI in some patients not given intravenoushydration. The latter will remain the cornerstoneof the prevention of contrast-induced AKI, assummarized by the Class I Level of Evidence: A in therecent Kidney Disease: Improving Global Outcomesguidelines (KDIGO) (2).

Nicolas Cecere, MDMichel Jadoul, MD*Laura Labriola, MD

*NephrologyCliniques Universitaires Saint-LucUniversité catholique de LouvainAvenue Hippocrate 10Brussels B1200BelgiumE-mail: laura.labriola@uclouvain.behttp://dx.doi.org/10.1016/j.jacc.2014.02.614

R EF E RENCE S

1. Han Y, Zhu G, Han L, et al. Short term rosuvastatin therapy for preventionof contrast-induced acute kidney injury in patients with diabetes and chronickidney disease. J Am Coll Cardiol 2014;63:62–70.

2. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney InjuryWork Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. KidneyInt 2012;2 Suppl:1–138.

REPLY: Intravenous Hydration (With or

Without Rosuvastatin) Should Remain the

Cornerstone of the Prevention of Contrast-

Induced Acute Kidney Injury in Patients With

Diabetes and Chronic Kidney Disease

We thank Dr. Cecere and colleagues for their interestin and comments on our study (1). They raise a veryimportant question of whether rosuvastatin wasconsistently effective among various subgroups,especially the subgroup of patients with or withoutintravenous hydration.

We agree that intravenous hydration is an impor-tant factor that should be well controlled in a studyin either the design or analysis phase. Unfortunately,no special consideration (e.g., stratified randomiza-tion) was given in the design phase back in 2008when this preventing strategy was not yet wellestablished in the guidelines (2). Therefore, hydrationwas administered at the discretion of individualinvestigators according to their daily practice.

Is hydration a confounding factor to our conclusion?Looking at our data, first in Table 1 (1), we observedthat hydration therapy was well balanced across 2arms, probably as a result of our large sample size(44.9% and 42.8% in the rosuvastatin and controlgroups, respectively), which reassured us a bit thathydration therapy is unlikely to confound our overallconclusion that rosuvastatin can significantly reducethe risk of contrast-induced acute kidney injury(CI-AKI) in patients with diabetes mellitus (DM) andchronic kidney disease (CKD) undergoing arterialcontrast medium injection. This was furtherexamined and confirmed in a multivariate analysisas shown in Table 4 (2) that hydration was not anindependent predictor of CI-AKI (odds ratio: 0.83,95% confidence interval: 0.53 to 1.31, p ¼ 0.43), andmost importantly, in a test of treatment by hydrationinteraction (p > 0.05, data not shown).

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Dr. Cecere and colleagues also point out that noeffect (p ¼ 0.89) was observed in approximately43% of patients given intravenous hydration. Thatis probably not valid, and is too early a conclusion,because subgroup analysis was usually underpow-ered. A nonsignificant result does not mean no effect.We think a more appropriate way is to have aninteraction test, and as mentioned in the precedingtext, the test assured us that rosuvastatin was con-sistently effective among patients with or withouthydration.

We admit that the point estimate of the rosuvas-tatin effect observed in patients with hydration wasless significant. Whether rosuvastatin can provide anadd-on effect in pure hydration patients needsfurther investigation. We also admit that hydrationremains the cornerstone of the prevention of CI-AKIbased on accumulated evidence in recent years.

In summary, we think our conclusion of “rosuvas-tatin significantly reduced the risk of CI-AKI in pa-tients with DM and CKD undergoing arterial contrastmedium injection” remains valid in a population withhydration or without hydration as a whole.

*Yaling Han, MD, PhD

*Department of CardiologyShenyang Northern Hospital83 Wenhua RoadShenyangChinaE-mail: hanyl169@gmail.comhttp://dx.doi.org/10.1016/j.jacc.2014.04.039

RE F E RENCE S

1. Han Y, Zhu G, Han L, et al. Short-term rosuvastatin therapy for preventionof contrast-induced acute kidney injury in patients with diabetes and chronickidney disease. J Am Coll Cardiol 2014;63:62–70.

2. King SB 3rd, Smith SC Jr., Hirshfeld JW Jr., et al. 2007 focused updateof the ACC/AHA/SCAI 2005 guideline update for percutaneous coronaryintervention: a report of the American College of Cardiology/American HeartAssociation Task Force on Practice guidelines. J Am Coll Cardiol 2008;51:172–209.

The Importance ofGenotype VariationBeyond DifferentAntiplatelet Therapy inNonresponder Patients

We read with great interest the recently publishedpaper on prasugrel or high-dose clopidogrel for highplatelet reactivity (HPR) in the Journal (1). Using the

Multiplate analyzer (Roche Diagnostics, Mannheim,Germany), the authors described how in patientswith acute coronary syndrome (ACS), with HPR,switching therapy from clopidogrel to prasugrelreduces thrombotic and bleeding events to a levelsimilar to those without HPR compared with high-dose clopidogrel.

As is known, the therapeutic effectiveness of clo-pidogrel is conditional upon its variability in its an-tiplatelet effect, which is influenced by numerousfactors both genotypic (e.g., specific mutations incytochrome P450 CYP2C19) and phenotypic (e.g.,patient presentation with ACS). It has been de-monstrated unequivocally that genotype testing formutations in the clopidogrel metabolic pathwaycan identify patients who are poor respondersand are at higher risk for subsequent ischemic events(2). Either increasing the dose of clopidogrel orsubstitution of other more potent agents notaffected by the CYP2C19 pathway in patients withthese mutations can lower platelet reactivity (PR)(3,4). Encouraged by these results, we also analyzedthe superior efficacy of prasugrel to reduce thePR compared with a double dose of clopidogrel,and the correlation with genotype assessment. Weshowed the importance of CYP2C19*2 genotyping(5), describing the superiority of prasugrel over adouble clopidogrel dose in patients carrying theCYP2C19*2 loss-of-function allele, while observinga similar efficacy of the 2 treatments in noncarriersof the CYP2C19*2 loss-of-function allele. PR wassignificantly lower (p ¼ 0.045) for prasugrel incarriers, whereas no differences were observed innoncarriers (p ¼ 0.575), but no one remained a poorresponder to prasugrel (p ¼ 0.003), whereas, despitea double clopidogrel dose, carriers always showedHPR.

It would be interesting to know the genotypingassay results of the all-comer patients enrolled in the2 arms of this nonrandomized study to show theincidence of the CYP2C19*2 loss-of-function allele. Infact, the presence of this genotype variation couldinfluence the superiority of prasugrel showed byAradi et al. (1) over a high dose of clopidogrel. In ouropinion, this is a central characteristic for anonrandomized study to obtain 2 more similarpopulations to reach their aim and to evaluate theclinical and pharmacodynamic impact of using ADP–P2Y12 receptor inhibitors.

Finally, considering the high number of ST-segment elevation myocardial infarctions in thisstudy, some concerns could arise about the clopi-dogrel utilization even if with a double dose andindependently from PR responsiveness; in this