Canadian Journal of Cardiology 30 (2014) 96e101
Clinical Research
The Effect of Intravenous Vitamin C Infusion on Periprocedural Myocardial Injury for Patients Undergoing Elective Percutaneous Coronary Intervention Zhi Jian Wang, MD, Wen Kun Hu, MD, Yu Yang Liu, MD, Dong Mei Shi, MD, Wan Jun Cheng, MD, Yong He Guo, MD, Qing Yang, MD, Ying Xin Zhao, MD, and Yu Jie Zhou, MD, PhD Department of Cardiology, Anzhen Hospital, Capital Medical University, Beijing, China
See editorial by Gebhard and Tardif, pages 3-5 of this issue. ABSTRACT
RESUM E
Background: This small study has determined the effect of vitamin C on myocardial reperfusion in patients undergoing elective percutaneous coronary intervention (PCI). This study was to explore whether antioxidant vitamin C infusion before the procedure is able to affect the incidence of periprocedural myocardial injury (PMI) in patients undergoing PCI. Methods: In this prospective single-centre randomized study, 532 patients were randomized into 2 groups: the vitamin C group, which received a 3-g vitamin C infusion within 6 hours before PCI, and a control group, which received normal saline. The primary end point was the troponin Iedefined PMI, and the second end point was the creatine kinase (CK)-MBedefined PMI. Separate analyses using both end points were performed. PMI was defined as an elevation of cardiac biomarker values (CK-MB or troponin I) > 5 times the upper limit of normal (ULN), alone or associated with chest pain or ST-segment or Twave changes.
tude à petite e chelle a de termine l’effet de la Introduction : Cette e vitamine C lors de reperfusion myocardique chez les patients subissant e (ICP) e lective. Cette e tude une intervention coronarienne percutane avait pour but d’examiner si la perfusion de vitamine C (antioxydant) sion avant une intervention est capable de modifier l’incidence d’une le riope ratoire (PMI : periprocedural myocardial injury) myocardique pe chez les patients subissant une ICP. thodes : Dans cette e tude ale atoire unicentrique prospective, 532 Me taient re partis au hasard en 2 groupes : le groupe de patients e vitamine C, qui recevait une perfusion de 3 g de vitamine C dans les 6 ce dant l’ICP, et un groupe te moin, qui recevait le solute heures pre tait la PMI physiologique salin. Le critère de jugement principal e finie par la troponine I, et le second critère de jugement e tait la PMI de finie par la cre atine-kinase (CK)-MB. Des analyses distinctes utilisant de taient re alise es. La PMI e tait de finie les deux critères de jugement e le vation des valeurs du biomarqueur cardiaque (CK-MB comme une e
Periprocedural myocardial injury (PMI), which presents with cardiac biomarker elevation, is common and occurs in up to 5% to 30% of patients after otherwise successful elective percutaneous coronary intervention (PCI).1-3 Although the clinical significance of PMI has been questioned by several analyses,4-6 multiple studies have shown that PMI is associated with increased mortality with a graded risk related to the extent of creatine kinase-MB (CK-MB) or cardiac troponin elevation.7-12 In some studies, even a minor elevation of cardiac biomarker was found to be related to a significantly increased
risk of late mortality.10-12 Many mechanisms, such as distal embolization, side branch occlusion, coronary dissection, and disruption of collateral flow, may account for the occurrence of PMI. Increased oxidative stress has been proposed to potentially contribute to the pathogenesis of PMI. An elevation of F2isoprostane, a stable end product of lipid peroxidation, has been found in coronary or systemic venous blood samples after PCI but not after diagnostic angiography.13 Vitamin C, also known as ascorbic acid, is a water-soluble antioxidant molecule that scavenges reactive oxygen and nitrogen species and inhibits oxidative damage to important biological macromolecules, including DNA, proteins, and lipids. Recently, a prospective single-centre randomized study involving 56 patients has shown that intravenous infusion of vitamin C before a procedure was associated with improved myocardial reperfusion in patients undergoing PCI.14 However, the impact of vitamin C on PMI has not been
Received for publication June 25, 2013. Accepted August 9, 2013. Corresponding author: Dr Ying Xin Zhao, Department of Cardiology, Anzhen Hospital, Capital Medical University, Anzhen Avenue #2, Chaoyang District, Beijing, 100029, China. Tel.: 86-010-64556489; fax: 86-01064442234. E-mail: [email protected] See page 100 for disclosure information.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.08.018
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Results: After PCI, the incidence of PMI was reduced, whether defined by troponin or by CK-MB, compared with the control group (troponin I, 10.9% vs 18.4%; P ¼ 0.016; CK-MB, 4.2% vs 8.6%; P ¼ 0.035). Logistic multivariate analysis showed that preprocedure use of vitamin C is an independent predictor of PMI either defined by troponin I (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.33-0.97; P ¼ 0.037) or by CK-MB (OR, 0.37; 95% CI, 0.14-0.99; P ¼ 0.048). Conclusions: In patients undergoing elective PCI, preprocedure intravenous treatment with vitamin C is associated with less myocardial injury.
rieure de la normale (LSN), seul ou troponine I) > 5 fois la limite supe à la douleur thoracique, au segment ST ou aux modificaou associe tions de l’onde T. sultats : Après l’ICP, l’incidence de la PMI e tait re duite, soit de finie Re moin par la troponine ou par la CK-MB, comparativement au groupe te (troponine I, 10,9 % vs 18,4 %; P ¼ 0,016; CK-MB, 4,2 % vs 8,6 %; P ¼ e montrait que l’utilisation de la 0,035). L’analyse logistique multivarie riode pre ope ratoire est un pre dicteur inde pendant de vitamine C en pe finie par la troponine I (ratio d’incidence approche [RIA], 0,56; la PMI de intervalle de confiance [IC] à 95 %, 0,33-0,97; P¼ 0,037) ou par la CKMB (RIA, 0,37; IC à 95 %, 0,14-0,99; P ¼ 0,048). lective, le traiteConclusions : Chez les patients subissant une ICP e ope ratoire entraîne moins de ment intraveineux à la vitamine C en pre sion myocardique. le
clearly investigated in a large population. Thus, we designed a prospective randomized controlled trial to assess whether preprocedural infusion of vitamin C is effective for prevention of PMI in patients undergoing elective PCI.
troponin I. Serum levels of 8-hydroxy-2-deoxyguanosine (8OHdG), a blood marker of oxidative stress, were also measured, by enzyme-linked immunosorbent assay, in the last 30 patients (15 patients in each study arm) at baseline and 6 hours after the procedure.
Methods
PCI procedure
Patient population
All eligible patients underwent angiography first. The treatment strategies, including PCI, medication, or bypass surgery, were at the discretion of the operators. All the operators were blinded to the randomization of the study. Only patients undergoing PCI finally were enrolled in the present analysis. All PCI procedures followed the current practice guidelines.16 Weight-adjusted intraprocedural unfractionated heparin (with a goal-activated clotting time of 250-300 seconds) was administered during the procedure and was routinely discontinued at the end of the procedure. A loading dose of 300 to 600 mg clopidogrel was given to all patients at least 6 hours before PCI, followed by a maintenance dose of 75 mg daily for at least 12 months unless severe bleeding complications appeared. In addition, all patients were administered loading doses of 300 mg aspirin the day of the procedure and continued with 100 mg daily indefinitely.
This was a prospective, single-centre, randomized placebocontrolled study. From June 2010 to December 2010, patients scheduled for elective PCI for de novo lesions in native coronary arteries were enrolled. Exclusion criteria included acute ST-segment elevation or noneST-segment elevation myocardial infarction with an elevated baseline CKMB or troponin value, cardiogenic shock, severe congenital or valvular heart disease that required surgical treatment, previous history of vitamin C allergy, previous coronary stent implantation or coronary artery bypass graft, and chronic kidney disease with an estimated glomerular filtration rate < 30 mL/min. The study design was reviewed and approved by our institutional research ethics committee, and all patients gave written informed consent. Study design All eligible patients were randomly assigned to vitamin C treatment 2 to 6 hours before procedures (3 g of vitamin C diluted in 250 mL of isotonic saline infused at 2.5 mL/min) or to placebo treatment (isotonic saline infused at 2.5 mL/ min). Randomization was performed by a 1:1 ratio using computer-generated random numbers (Fig. 1). To access the effect of vitamin C infusion on the incidence of PMI, blood samples were collected in the study patients before and 6 and 24 hours after PCI to measure CK-MB and troponin I using a radioimmunoassay analyzer. Additional measurements were performed in case of postprocedural symptoms suggestive of myocardial ischemia. The upper limit of normal (ULN) was defined as the 99th percentile of the normal population with a total imprecision of < 10%, according to the European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Heart Federation universal definition.15 Normal limits were < 6.3 ng/mL for CK-MB and < 0.04 ng/mL for
End points and definitions The primary end point was the troponin Iedefined PMI, and the second end point was the CK-MBedefined PMI. Separate analyses using both end points were performed. PMI was defined as an elevation of cardiac biomarker values (CK-MB or troponin I) > 5 times ULN alone or associated with chest pain or ST-segment or T-wave changes. Statistical analysis According to previous studies, we assumed a 12% incidence of primary end point events in control patients and a 50% reduction in patients who received vitamin C treatment; a total sample size of 482 patients (241 in each group) would provide 80% power to detect differences with an alpha level of .05. Data are presented as mean standard deviation for normally distributed continuous variables and were compared using 2-sample independent or paired t tests as appropriate.
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Figure 1. Flow chart of patient enrollment. CABG, coronary artery bypass grafting; CK-MB, creatine kinase-MB; c-TNI, cardiac troponin I; eGFR, estimated glomerular filtration rate; PCI, percutaneous coronary intervention.
Categorical variables are presented as frequencies and percentages. Differences in baseline characteristics between patients with and without depression were compared with c2 tests or exact tests if expected cell frequencies were small. The troponin I and CK-MB data were skewed; therefore, these values are presented as the median with the interquartile range. The Mann-Whitney U test was used to analyze the difference between the medians in both groups. Independent predictors of end points were identified using binary logistic regression. The candidate variables entered in the model included age (continuous), sex, smoking status, history of previous myocardial infarction, left ventricular ejection fraction, diagnosis of diabetes mellitus, hypertension, hypercholesterolemia, chronic kidney disease (estimated glomerular filtration rate < 60 mL/min), concomitant medication, multivessel disease, and the occurrence of major angiographic complications. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. All statistical analyses were 2tailed. A value of P < 0.05 was considered statistically significant. Analysis was performed with SPSS software, version 16.0 for Windows (SPSS, Inc, Chicago, IL).
Results Baseline characteristics A total of 645 patients fulfilling the inclusion criteria were initially evaluated; 31 patients were excluded because of exclusion criteria or refusal to participate. Of 614 patients evaluated for randomization, another 82 patients were excluded
after angiography. Finally 532 patients undergoing PCI were enrolled in this study, 265 of whom were randomized to vitamin C treatment and the other 267 to placebo treatment. The baseline demographic and clinical characteristics of patients according to randomization at the infusion treatmentdincluding age, sex, risk factor distribution, and concomitant medication treatmentddid not differ between the groups (Supplemental Table S1). As shown in Supplemental Table S2, the baseline angiographic characteristics were also very similar between the 2 groups. Angiographic success was reached in 100% of cases in both groups. Major angiographic complications during the procedure occurred in 11 patients (4.2%) in the vitamin C group and 12 patients (4.5%) in the control group (P ¼ 0.85) (Supplemental Table S3). The effect of vitamin C on PMI After the procedure, the incidence of PMI, defined as elevation of troponin I values > 5 times the ULN, was significantly decreased by vitamin C infusion (10.9% vs 18.4%, P ¼ 0.016). The CK-MBedefined PMI was also significantly reduced by vitamin C treatment compared with the control group (4.2% vs 8.6%; P ¼ 0.035). Troponin I elevation > 3 times the ULN occurred in 20.1% of the vitamin C group and in 28.8% of the control group (P ¼ 0.020). CK-MB elevation > 3 times the ULN occurred in 6.8% of the vitamin C group and in 12.7% of the control group (P ¼ 0.021). The proportion of patients with elevation greater than the ULN of troponin I and CK-MB were both lower in the vitamin C group than in the control group but without statistical significance (CK-MB, 17.7% vs 24.0%;
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Table 1. Baseline and post-PCI troponin I and CK-MB values Variables Troponin I (ng/mL) Baseline Median Interquartile range After PCI Median Interquartile range CK-MB (ng/mL) Baseline Median Interquartile range After PCI Median Interquartile range
Vitamin C group (n ¼ 265)
Control group (n ¼ 267)
0.02 0.02-0.03
0.02 0.02-0.03
0.03 0.03-0.06
0.04 0.02-1.12
4.3 3.6-5.1
4.4 3.1-6.0
4.9 4.1-5.7
6.1 4.4-6.4
P value 0.214 0.017
0.104 < 0.001
CK-MB, creatine kinase-MB; PCI, percutaneous coronary intervention.
procedure was significantly lower in the vitamin C group than in the control group (2.4 1.0 ng/mL vs 4.1 1.1 ng/mL; P < 0.001) (Fig. 3).
Figure 2. Percentages of patients in vitamin C group and control group defined by a range of biomarker ratios for creatine kinase-MB (A) and troponin I (B). ULN, upper limit of normal.
P ¼ 0.077; troponin I, 25.3% vs 32.6%; P ¼ 0.063) (Fig. 2). Compared with the control group, prophylactic vitamin C treatment also led to significantly lower elevations of troponin I and CK-MB levels after PCI (troponin I: median, 0.03 ng/ mL; interquartile range, 0.03-0.06 vs 0.04 ng/mL, interquartile range, 0.02-1.12; P ¼ 0.017; CK-MB: median 4.9 ng/mL, interquartile range, 4.1-5.7 vs 6.1 ng/mL; interquartile range, 4.4-6.4; P < 0.001) (Table 1). The influence of clinical, angiographic, and procedural variables on CK-MB and troponin I elevation > 5 times the ULN after stenting was evaluated with a multivariable binary logistic regression analysis. Vitamin C infusion before the procedure is an independent predictor of PMI defined by either troponin I (OR, 0.56; 95% CI, 0.33-0.97; P ¼ 0.037) or CK-MB (OR, 0.37; 95% CI, 0.14-0.99; P ¼ 0.048) (Table 2). The effect of vitamin C on oxidative stress At baseline, there was no difference in serum values of 8OHdG between the2 groups (vitamin C group, 3.6 1.2 ng/mL vs control group, 3.8 1.2 ng/mL; P ¼ 0.580). After the procedure, the serum level of 8-OHdG was significantly decreased by vitamin C infusion (P ¼ 0.011) but not by placebo (P ¼ 0.528). The serum value of 8-OHdG after the
Discussion This prospective randomized study showed that vitamin C infusion before PCI was associated with a lower incidence of PMI, defined as elevation of troponin I or CK-MB values > 5 times the ULN. The cardioprotective effect of vitamin C may result from the inhibition of oxidative stress. PCI has been reported to be associated with increased oxidative stress.13,14,17-22 Most previous studies on oxidative stress have focused on primary PCI in patients with acute ST-segment elevation myocardial infarction,17,18 indicating that oxidative stress associated with PCI owes more to ischemia reperfusion injury. However, several recent studies found that elective PCI also induced increased oxidative stress. Isoprostane F2alphaIII and isoprostane F2alpha-VI, both stable end products of oxygen free radicalemediated lipid peroxidation, were found to be markedly increased in coronary sinus blood samples after elective PCI,13 suggesting that PCI induces increased F2-isoprostane formation in the local coronary system. More recently, plasma levels of other markers of oxidative stress, such as ischemia-modified albumin, 8-OHdG, and 8-isoprostaglandin F2alpha, have also been reported to be elevated after elective PCI.14,19 Although the association of oxidative stress after PCI and cardiovascular outcomes has not been clearly proved, a significant positive correlation between serum creatine phosphokinase levels and some oxidative stress markers was found, indicating a potential correlation between Table 2. Independent predictors of PCI-related myocardial infarction defined by CK-MB or troponin I Independent predictors CK-MB > 5 ULN Vitamin C infusion Major angiographic complications Troponin I > 5 ULN Vitamin C infusion Major angiographic complications Diabetes
Odds ratio (95% CI)
P value
0.37 (0.14-0.99) 10.6 (10.0-28.6)
0.048 < 0.001
0.56 (0.33-0.97) 6.7 (2.8-16.3) 1.7 (1.0-2.8)
0.037 < 0.001 0.039
CK-MB, creatine kinase-MB; CI, confidence interval; PCI, percutaneous coronary intervention; ULN, upper limit of normal.
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Figure 3. Changes of serum level of 8-hydroxy-2-deoxyguanosine before and after percutaneous coronary intervention in vitamin C group (A) and control group (B).
oxidative stress and the severity of myocardial injury (MI).20 Elevated circulating F2-isoprostanes in young healthy adults have also been associated with markers of inflammation and endothelial dysfunction, which are both proposed to contribute to mechanisms of PCI-related MI.21 Vitamin C, also known as ascorbic acid, is a potent watersoluble natural antioxidant that quenches reactive oxygen species and inhibits reactive oxygen speciesemediated nitric oxide inactivation. In addition, vitamin C can regenerate other antioxidants, acting as a coantioxidant. Multiple studies have shown that vitamin C is effective not only in attenuating postPCI oxidative stress but also in improving clinical outcomes.14,17,23-28 Spargias et al found that prophylactic oral administration of 3 g of vitamin C before a procedure and 2 g after a procedure had a protective effect against contrastmediated nephropathy when compared with placebo in 231 patients with an elevated serum creatinine level who were undergoing angiography or PCI.23 Preprocedure oral vitamin C was also found to reduce the incidence of post-PCI restenosis when compared with a control group in a preliminary study.24 A more recent randomized controlled study including 56 patients showed that a 1-g vitamin C infusion before a procedure vs placebo was associated with a lower plasma level of 8-OHdG and 8-iso-prostaglandin F2alpha and improved microcirculatory reperfusion defined as thrombolysis in myocardial infarction frame count and thrombolysis in myocardial infarction perfusion grade in patients undergoing elective PCI.14 However, the small sample size of this study makes it impossible to detect the effect of vitamin C on the incidence of PMI. Our data extended these previous findings by demonstrating that a 3-g vitamin C infusion before PCI was associated with a lower incidence of PMI, defined as elevation of troponin I or CK-MB values > 5 times the ULN. Although limitation of such myocardial injury has been proved to be beneficial to the patient, the effect of vitamin C on longterm clinical outcomes should be confirmed by further investigations.
The mechanism for the cardioprotective effect of vitamin C has not been clearly defined. A potential role of oxidative stress has been suggested by the fact that vitamin C infusion blunted the increase of levels of plasma 8-OHdG, a product of hydroxyl radical/deoxyribonucleic acid interaction. However, a cause-effect relationship cannot be established by our study. There are several limitations of this study. The study was not blinded. Optimal dose, time of onset, and duration of vitamin C use before PCI were not identified. The vitamin C treatment protocols used in this study were arbitrary. Blood samples for postprocedure CK-MB or troponin I measurements were drawn 6 and 24 hours after PCI. Thus, we might have missed the opportunity to identify additional events if more serial blood samples had been assessed. We measured the plasma 8-OHdG level for only the last 30 patients, which made the correlation analysis between the antioxidants and myocardial injury unfeasible. Therefore, as we mentioned earlier, a cause-effect relationship between a cardioprotective effect of vitamin C and its antioxidant effect cannot be established by our study. Furthermore, no clinical follow-up was required after hospital discharge. Therefore, further studies are necessary to investigate the effect of vitamin C on the long-term clinical prognosis in this setting. In summary, the results of this prospective randomized study show that prophylactic infusion of vitamin Cda safe, well-tolerated, and inexpensive antioxidantdappears to decrease myocardial injury associated with elective PCI. The underlying mechanisms and clinical prognosis of this cardioprotective effect need to be investigated by further studies. Disclosures The authors have no conflicts of interest to disclose. References 1. Califf RM, Abdelmeguid AE, Kunitz RE, et al. Myonecrosis after revascularization procedures. J Am Coll Cardiol 1998;31:241-51.
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2. Abdelemeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation 1996;94:1528-36.
of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44-122.
3. Pervaiz MH, Sood P, Sudhir K, et al. Periprocedural myocardial infarction in a randomized trial of everolimus-eluting and Paclitaxel-eluting coronary stents: frequency and impact on mortality according to historic versus universal definitions. Circ Cardiovasc Interv 2012;5: 150-6.
17. Reilly MP, Delanty N, Roy L, et al. Increased formation of the isoprostanes IPF2alpha-I and 8-epi-prostaglandin F2alpha in acute coronary angioplasty: evidence for oxidant stress during coronary reperfusion in humans. Circulation 1997;96:3314-20.
4. Prasad A, Gersh BJ, Bertrand ME, et al. Prognostic significance of periprocedural versus spontaneously occurring myocardial infarction after percutaneous coronary intervention in patients with acute coronary syndromes: an analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol 2009;54: 477-86. 5. Fuchs S, Kornowski R, Mehran R, et al. Prognostic value of cardiac troponin-I levels following catheter-based coronary interventions. Am J Cardiol 2000;85:1077-82. 6. Jeremias A, Baim DS, Ho KK, et al. Differential mortality risk of postprocedural creatine kinase-MB elevation following successful versus unsuccessful stent procedures. J Am Coll Cardiol 2004;44:1210-4. 7. Lindsey JB, Kennedy KF, Stolker JM, et al. Prognostic implications of creatine kinase-MB elevation after percutaneous coronary intervention: results from the Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) registry. Circ Cardiovasc Interv 2011;4:474-80. 8. Akkerhuis KM, Alexander JH, Tardiff BE, et al. Minor myocardial damage and prognosis: are spontaneous and percutaneous coronary intervention-related events different? Circulation 2002;105:554-6.
18. Kaminski K, Bonda T, Wojtkowska I, et al. Oxidative stress and antioxidative defense parameters early after reperfusion therapy for acute myocardial infarction. Acute Card Care 2008;10:121-6. 19. Pignatelli P, Tanzilli G, Carnevale R, et al. Ascorbic acid infusion blunts CD40L upregulation in patients undergoing coronary stent. Cardiovasc Ther 2011;29:385-94. 20. Farah R, Shurtz-Swirski R, Bolotin Y, Brezins M. Oxidative stress and inflammation due to peripheral polymorphonuclear leukocytes after coronary angiography vs percutaneous coronary intervention. Minerva Cardioangiol 2008;56:189-95. 21. Hozawa A, Jacobs DR Jr, Steffes MW, et al. Relationships of circulating carotenoid concentrations with several markers of inflammation, oxidative stress, and endothelial dysfunction: the Coronary Artery Risk Development in Young Adults (CARDIA)/Young Adult Longitudinal Trends in Antioxidants (YALTA) study. Clin Chem 2007;53:447-55. 22. Sinha MK, Gaze DC, Tippins JR, Collinson PO, Kaski JC. Ischemia modified albumin is a sensitive marker of myocardial ischemia after percutaneous coronary intervention. Circulation 2003;107:2403-5.
9. Novack V, Pencina M, Cohen DJ, et al. Troponin criteria for myocardial infarction after percutaneous coronary intervention. Arch Intern Med 2012;172:502-8.
23. Spargias K, Alexopoulos E, Kyrzopoulos S, et al. Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation 2004;110: 2837-42.
10. Kong TQ, Davidson CJ, Meyers SN, et al. Prognostic implication of creatine kinase elevation following elective coronary artery interventions. JAMA 1997;277:461-6.
24. Tomoda H, Yoshitake M, Morimoto K, Aoki N. Possible prevention of postangioplasty restenosis by ascorbic acid. Am J Cardiol 1996;78: 1284-6.
11. Ioannidis JP, Karvouni E, Katritsis DG. Mortality risk conferred by small elevations of creatine kinase-MB isoenzyme after percutaneous coronary intervention. J Am Coll Cardiol 2003;42:1406-11.
25. Albabtain MA, Almasood A, Alshurafah H, Alamri H, Tamim H. Efficacy of ascorbic acid, N-acetylcysteine, or combination of both on top of saline hydration versus saline hydration alone on prevention of contrastInduced nephropathy: a prospective randomized study. J Interv Cardiol 2013;26:90-6.
12. Prasad A, Singh M, Lerman A, et al. Isolated elevation in troponin T after percutaneous coronary intervention is associated with higher long-term mortality. J Am Coll Cardiol 2006;48:1765-70. 13. Iuliano L, Praticò D, Greco C, et al. Angioplasty increases coronary sinus F2-isoprostane formation: evidence for in vivo oxidative stress during PTCA. J Am Coll Cardiol 2001;37:76-80. 14. Basili S, Tanzilli G, Mangieri E, et al. Intravenous ascorbic acid infusion improves myocardial perfusion grade during elective percutaneous coronary intervention: relationship with oxidative stress markers. JACC Cardiovasc Interv 2010;3:221-9. 15. Thygesen K, Alpert JS, Jaffe AS, et al; Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Eur Heart J 2012;33: 2551-67. 16. American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College
26. Zhou L, Chen H. Prevention of contrast-induced nephropathy with ascorbic acid. Intern Med 2012;51:531-5. 27. Jo SH, Koo BK, Park JS, et al. N-acetylcysteine versus AScorbic acid for preventing contrast-Induced nephropathy in patients with renal insufficiency undergoing coronary angiography NASPI studyda prospective randomized controlled trial. Am Heart J 2009;157:576-83. 28. Boscheri A, Weinbrenner C, Botzek B, et al. Failure of ascorbic acid to prevent contrast-media induced nephropathy in patients with renal dysfunction. Clin Nephrol 2007;68:279-86.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2013.08.018.
Clinical Research
The Effect of Intravenous Vitamin C Infusion on Periprocedural Myocardial Injury for Patients Undergoing Elective Percutaneous Coronary Intervention Zhi Jian Wang, MD, Wen Kun Hu, MD, Yu Yang Liu, MD, Dong Mei Shi, MD, Wan Jun Cheng, MD, Yong He Guo, MD, Qing Yang, MD, Ying Xin Zhao, MD, and Yu Jie Zhou, MD, PhD Department of Cardiology, Anzhen Hospital, Capital Medical University, Beijing, China
See editorial by Gebhard and Tardif, pages 3-5 of this issue. ABSTRACT
RESUM E
Background: This small study has determined the effect of vitamin C on myocardial reperfusion in patients undergoing elective percutaneous coronary intervention (PCI). This study was to explore whether antioxidant vitamin C infusion before the procedure is able to affect the incidence of periprocedural myocardial injury (PMI) in patients undergoing PCI. Methods: In this prospective single-centre randomized study, 532 patients were randomized into 2 groups: the vitamin C group, which received a 3-g vitamin C infusion within 6 hours before PCI, and a control group, which received normal saline. The primary end point was the troponin Iedefined PMI, and the second end point was the creatine kinase (CK)-MBedefined PMI. Separate analyses using both end points were performed. PMI was defined as an elevation of cardiac biomarker values (CK-MB or troponin I) > 5 times the upper limit of normal (ULN), alone or associated with chest pain or ST-segment or Twave changes.
tude à petite e chelle a de termine l’effet de la Introduction : Cette e vitamine C lors de reperfusion myocardique chez les patients subissant e (ICP) e lective. Cette e tude une intervention coronarienne percutane avait pour but d’examiner si la perfusion de vitamine C (antioxydant) sion avant une intervention est capable de modifier l’incidence d’une le riope ratoire (PMI : periprocedural myocardial injury) myocardique pe chez les patients subissant une ICP. thodes : Dans cette e tude ale atoire unicentrique prospective, 532 Me taient re partis au hasard en 2 groupes : le groupe de patients e vitamine C, qui recevait une perfusion de 3 g de vitamine C dans les 6 ce dant l’ICP, et un groupe te moin, qui recevait le solute heures pre tait la PMI physiologique salin. Le critère de jugement principal e finie par la troponine I, et le second critère de jugement e tait la PMI de finie par la cre atine-kinase (CK)-MB. Des analyses distinctes utilisant de taient re alise es. La PMI e tait de finie les deux critères de jugement e le vation des valeurs du biomarqueur cardiaque (CK-MB comme une e
Periprocedural myocardial injury (PMI), which presents with cardiac biomarker elevation, is common and occurs in up to 5% to 30% of patients after otherwise successful elective percutaneous coronary intervention (PCI).1-3 Although the clinical significance of PMI has been questioned by several analyses,4-6 multiple studies have shown that PMI is associated with increased mortality with a graded risk related to the extent of creatine kinase-MB (CK-MB) or cardiac troponin elevation.7-12 In some studies, even a minor elevation of cardiac biomarker was found to be related to a significantly increased
risk of late mortality.10-12 Many mechanisms, such as distal embolization, side branch occlusion, coronary dissection, and disruption of collateral flow, may account for the occurrence of PMI. Increased oxidative stress has been proposed to potentially contribute to the pathogenesis of PMI. An elevation of F2isoprostane, a stable end product of lipid peroxidation, has been found in coronary or systemic venous blood samples after PCI but not after diagnostic angiography.13 Vitamin C, also known as ascorbic acid, is a water-soluble antioxidant molecule that scavenges reactive oxygen and nitrogen species and inhibits oxidative damage to important biological macromolecules, including DNA, proteins, and lipids. Recently, a prospective single-centre randomized study involving 56 patients has shown that intravenous infusion of vitamin C before a procedure was associated with improved myocardial reperfusion in patients undergoing PCI.14 However, the impact of vitamin C on PMI has not been
Received for publication June 25, 2013. Accepted August 9, 2013. Corresponding author: Dr Ying Xin Zhao, Department of Cardiology, Anzhen Hospital, Capital Medical University, Anzhen Avenue #2, Chaoyang District, Beijing, 100029, China. Tel.: 86-010-64556489; fax: 86-01064442234. E-mail: [email protected] See page 100 for disclosure information.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.08.018
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Results: After PCI, the incidence of PMI was reduced, whether defined by troponin or by CK-MB, compared with the control group (troponin I, 10.9% vs 18.4%; P ¼ 0.016; CK-MB, 4.2% vs 8.6%; P ¼ 0.035). Logistic multivariate analysis showed that preprocedure use of vitamin C is an independent predictor of PMI either defined by troponin I (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.33-0.97; P ¼ 0.037) or by CK-MB (OR, 0.37; 95% CI, 0.14-0.99; P ¼ 0.048). Conclusions: In patients undergoing elective PCI, preprocedure intravenous treatment with vitamin C is associated with less myocardial injury.
rieure de la normale (LSN), seul ou troponine I) > 5 fois la limite supe à la douleur thoracique, au segment ST ou aux modificaou associe tions de l’onde T. sultats : Après l’ICP, l’incidence de la PMI e tait re duite, soit de finie Re moin par la troponine ou par la CK-MB, comparativement au groupe te (troponine I, 10,9 % vs 18,4 %; P ¼ 0,016; CK-MB, 4,2 % vs 8,6 %; P ¼ e montrait que l’utilisation de la 0,035). L’analyse logistique multivarie riode pre ope ratoire est un pre dicteur inde pendant de vitamine C en pe finie par la troponine I (ratio d’incidence approche [RIA], 0,56; la PMI de intervalle de confiance [IC] à 95 %, 0,33-0,97; P¼ 0,037) ou par la CKMB (RIA, 0,37; IC à 95 %, 0,14-0,99; P ¼ 0,048). lective, le traiteConclusions : Chez les patients subissant une ICP e ope ratoire entraîne moins de ment intraveineux à la vitamine C en pre sion myocardique. le
clearly investigated in a large population. Thus, we designed a prospective randomized controlled trial to assess whether preprocedural infusion of vitamin C is effective for prevention of PMI in patients undergoing elective PCI.
troponin I. Serum levels of 8-hydroxy-2-deoxyguanosine (8OHdG), a blood marker of oxidative stress, were also measured, by enzyme-linked immunosorbent assay, in the last 30 patients (15 patients in each study arm) at baseline and 6 hours after the procedure.
Methods
PCI procedure
Patient population
All eligible patients underwent angiography first. The treatment strategies, including PCI, medication, or bypass surgery, were at the discretion of the operators. All the operators were blinded to the randomization of the study. Only patients undergoing PCI finally were enrolled in the present analysis. All PCI procedures followed the current practice guidelines.16 Weight-adjusted intraprocedural unfractionated heparin (with a goal-activated clotting time of 250-300 seconds) was administered during the procedure and was routinely discontinued at the end of the procedure. A loading dose of 300 to 600 mg clopidogrel was given to all patients at least 6 hours before PCI, followed by a maintenance dose of 75 mg daily for at least 12 months unless severe bleeding complications appeared. In addition, all patients were administered loading doses of 300 mg aspirin the day of the procedure and continued with 100 mg daily indefinitely.
This was a prospective, single-centre, randomized placebocontrolled study. From June 2010 to December 2010, patients scheduled for elective PCI for de novo lesions in native coronary arteries were enrolled. Exclusion criteria included acute ST-segment elevation or noneST-segment elevation myocardial infarction with an elevated baseline CKMB or troponin value, cardiogenic shock, severe congenital or valvular heart disease that required surgical treatment, previous history of vitamin C allergy, previous coronary stent implantation or coronary artery bypass graft, and chronic kidney disease with an estimated glomerular filtration rate < 30 mL/min. The study design was reviewed and approved by our institutional research ethics committee, and all patients gave written informed consent. Study design All eligible patients were randomly assigned to vitamin C treatment 2 to 6 hours before procedures (3 g of vitamin C diluted in 250 mL of isotonic saline infused at 2.5 mL/min) or to placebo treatment (isotonic saline infused at 2.5 mL/ min). Randomization was performed by a 1:1 ratio using computer-generated random numbers (Fig. 1). To access the effect of vitamin C infusion on the incidence of PMI, blood samples were collected in the study patients before and 6 and 24 hours after PCI to measure CK-MB and troponin I using a radioimmunoassay analyzer. Additional measurements were performed in case of postprocedural symptoms suggestive of myocardial ischemia. The upper limit of normal (ULN) was defined as the 99th percentile of the normal population with a total imprecision of < 10%, according to the European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Heart Federation universal definition.15 Normal limits were < 6.3 ng/mL for CK-MB and < 0.04 ng/mL for
End points and definitions The primary end point was the troponin Iedefined PMI, and the second end point was the CK-MBedefined PMI. Separate analyses using both end points were performed. PMI was defined as an elevation of cardiac biomarker values (CK-MB or troponin I) > 5 times ULN alone or associated with chest pain or ST-segment or T-wave changes. Statistical analysis According to previous studies, we assumed a 12% incidence of primary end point events in control patients and a 50% reduction in patients who received vitamin C treatment; a total sample size of 482 patients (241 in each group) would provide 80% power to detect differences with an alpha level of .05. Data are presented as mean standard deviation for normally distributed continuous variables and were compared using 2-sample independent or paired t tests as appropriate.
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Figure 1. Flow chart of patient enrollment. CABG, coronary artery bypass grafting; CK-MB, creatine kinase-MB; c-TNI, cardiac troponin I; eGFR, estimated glomerular filtration rate; PCI, percutaneous coronary intervention.
Categorical variables are presented as frequencies and percentages. Differences in baseline characteristics between patients with and without depression were compared with c2 tests or exact tests if expected cell frequencies were small. The troponin I and CK-MB data were skewed; therefore, these values are presented as the median with the interquartile range. The Mann-Whitney U test was used to analyze the difference between the medians in both groups. Independent predictors of end points were identified using binary logistic regression. The candidate variables entered in the model included age (continuous), sex, smoking status, history of previous myocardial infarction, left ventricular ejection fraction, diagnosis of diabetes mellitus, hypertension, hypercholesterolemia, chronic kidney disease (estimated glomerular filtration rate < 60 mL/min), concomitant medication, multivessel disease, and the occurrence of major angiographic complications. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. All statistical analyses were 2tailed. A value of P < 0.05 was considered statistically significant. Analysis was performed with SPSS software, version 16.0 for Windows (SPSS, Inc, Chicago, IL).
Results Baseline characteristics A total of 645 patients fulfilling the inclusion criteria were initially evaluated; 31 patients were excluded because of exclusion criteria or refusal to participate. Of 614 patients evaluated for randomization, another 82 patients were excluded
after angiography. Finally 532 patients undergoing PCI were enrolled in this study, 265 of whom were randomized to vitamin C treatment and the other 267 to placebo treatment. The baseline demographic and clinical characteristics of patients according to randomization at the infusion treatmentdincluding age, sex, risk factor distribution, and concomitant medication treatmentddid not differ between the groups (Supplemental Table S1). As shown in Supplemental Table S2, the baseline angiographic characteristics were also very similar between the 2 groups. Angiographic success was reached in 100% of cases in both groups. Major angiographic complications during the procedure occurred in 11 patients (4.2%) in the vitamin C group and 12 patients (4.5%) in the control group (P ¼ 0.85) (Supplemental Table S3). The effect of vitamin C on PMI After the procedure, the incidence of PMI, defined as elevation of troponin I values > 5 times the ULN, was significantly decreased by vitamin C infusion (10.9% vs 18.4%, P ¼ 0.016). The CK-MBedefined PMI was also significantly reduced by vitamin C treatment compared with the control group (4.2% vs 8.6%; P ¼ 0.035). Troponin I elevation > 3 times the ULN occurred in 20.1% of the vitamin C group and in 28.8% of the control group (P ¼ 0.020). CK-MB elevation > 3 times the ULN occurred in 6.8% of the vitamin C group and in 12.7% of the control group (P ¼ 0.021). The proportion of patients with elevation greater than the ULN of troponin I and CK-MB were both lower in the vitamin C group than in the control group but without statistical significance (CK-MB, 17.7% vs 24.0%;
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Table 1. Baseline and post-PCI troponin I and CK-MB values Variables Troponin I (ng/mL) Baseline Median Interquartile range After PCI Median Interquartile range CK-MB (ng/mL) Baseline Median Interquartile range After PCI Median Interquartile range
Vitamin C group (n ¼ 265)
Control group (n ¼ 267)
0.02 0.02-0.03
0.02 0.02-0.03
0.03 0.03-0.06
0.04 0.02-1.12
4.3 3.6-5.1
4.4 3.1-6.0
4.9 4.1-5.7
6.1 4.4-6.4
P value 0.214 0.017
0.104 < 0.001
CK-MB, creatine kinase-MB; PCI, percutaneous coronary intervention.
procedure was significantly lower in the vitamin C group than in the control group (2.4 1.0 ng/mL vs 4.1 1.1 ng/mL; P < 0.001) (Fig. 3).
Figure 2. Percentages of patients in vitamin C group and control group defined by a range of biomarker ratios for creatine kinase-MB (A) and troponin I (B). ULN, upper limit of normal.
P ¼ 0.077; troponin I, 25.3% vs 32.6%; P ¼ 0.063) (Fig. 2). Compared with the control group, prophylactic vitamin C treatment also led to significantly lower elevations of troponin I and CK-MB levels after PCI (troponin I: median, 0.03 ng/ mL; interquartile range, 0.03-0.06 vs 0.04 ng/mL, interquartile range, 0.02-1.12; P ¼ 0.017; CK-MB: median 4.9 ng/mL, interquartile range, 4.1-5.7 vs 6.1 ng/mL; interquartile range, 4.4-6.4; P < 0.001) (Table 1). The influence of clinical, angiographic, and procedural variables on CK-MB and troponin I elevation > 5 times the ULN after stenting was evaluated with a multivariable binary logistic regression analysis. Vitamin C infusion before the procedure is an independent predictor of PMI defined by either troponin I (OR, 0.56; 95% CI, 0.33-0.97; P ¼ 0.037) or CK-MB (OR, 0.37; 95% CI, 0.14-0.99; P ¼ 0.048) (Table 2). The effect of vitamin C on oxidative stress At baseline, there was no difference in serum values of 8OHdG between the2 groups (vitamin C group, 3.6 1.2 ng/mL vs control group, 3.8 1.2 ng/mL; P ¼ 0.580). After the procedure, the serum level of 8-OHdG was significantly decreased by vitamin C infusion (P ¼ 0.011) but not by placebo (P ¼ 0.528). The serum value of 8-OHdG after the
Discussion This prospective randomized study showed that vitamin C infusion before PCI was associated with a lower incidence of PMI, defined as elevation of troponin I or CK-MB values > 5 times the ULN. The cardioprotective effect of vitamin C may result from the inhibition of oxidative stress. PCI has been reported to be associated with increased oxidative stress.13,14,17-22 Most previous studies on oxidative stress have focused on primary PCI in patients with acute ST-segment elevation myocardial infarction,17,18 indicating that oxidative stress associated with PCI owes more to ischemia reperfusion injury. However, several recent studies found that elective PCI also induced increased oxidative stress. Isoprostane F2alphaIII and isoprostane F2alpha-VI, both stable end products of oxygen free radicalemediated lipid peroxidation, were found to be markedly increased in coronary sinus blood samples after elective PCI,13 suggesting that PCI induces increased F2-isoprostane formation in the local coronary system. More recently, plasma levels of other markers of oxidative stress, such as ischemia-modified albumin, 8-OHdG, and 8-isoprostaglandin F2alpha, have also been reported to be elevated after elective PCI.14,19 Although the association of oxidative stress after PCI and cardiovascular outcomes has not been clearly proved, a significant positive correlation between serum creatine phosphokinase levels and some oxidative stress markers was found, indicating a potential correlation between Table 2. Independent predictors of PCI-related myocardial infarction defined by CK-MB or troponin I Independent predictors CK-MB > 5 ULN Vitamin C infusion Major angiographic complications Troponin I > 5 ULN Vitamin C infusion Major angiographic complications Diabetes
Odds ratio (95% CI)
P value
0.37 (0.14-0.99) 10.6 (10.0-28.6)
0.048 < 0.001
0.56 (0.33-0.97) 6.7 (2.8-16.3) 1.7 (1.0-2.8)
0.037 < 0.001 0.039
CK-MB, creatine kinase-MB; CI, confidence interval; PCI, percutaneous coronary intervention; ULN, upper limit of normal.
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Figure 3. Changes of serum level of 8-hydroxy-2-deoxyguanosine before and after percutaneous coronary intervention in vitamin C group (A) and control group (B).
oxidative stress and the severity of myocardial injury (MI).20 Elevated circulating F2-isoprostanes in young healthy adults have also been associated with markers of inflammation and endothelial dysfunction, which are both proposed to contribute to mechanisms of PCI-related MI.21 Vitamin C, also known as ascorbic acid, is a potent watersoluble natural antioxidant that quenches reactive oxygen species and inhibits reactive oxygen speciesemediated nitric oxide inactivation. In addition, vitamin C can regenerate other antioxidants, acting as a coantioxidant. Multiple studies have shown that vitamin C is effective not only in attenuating postPCI oxidative stress but also in improving clinical outcomes.14,17,23-28 Spargias et al found that prophylactic oral administration of 3 g of vitamin C before a procedure and 2 g after a procedure had a protective effect against contrastmediated nephropathy when compared with placebo in 231 patients with an elevated serum creatinine level who were undergoing angiography or PCI.23 Preprocedure oral vitamin C was also found to reduce the incidence of post-PCI restenosis when compared with a control group in a preliminary study.24 A more recent randomized controlled study including 56 patients showed that a 1-g vitamin C infusion before a procedure vs placebo was associated with a lower plasma level of 8-OHdG and 8-iso-prostaglandin F2alpha and improved microcirculatory reperfusion defined as thrombolysis in myocardial infarction frame count and thrombolysis in myocardial infarction perfusion grade in patients undergoing elective PCI.14 However, the small sample size of this study makes it impossible to detect the effect of vitamin C on the incidence of PMI. Our data extended these previous findings by demonstrating that a 3-g vitamin C infusion before PCI was associated with a lower incidence of PMI, defined as elevation of troponin I or CK-MB values > 5 times the ULN. Although limitation of such myocardial injury has been proved to be beneficial to the patient, the effect of vitamin C on longterm clinical outcomes should be confirmed by further investigations.
The mechanism for the cardioprotective effect of vitamin C has not been clearly defined. A potential role of oxidative stress has been suggested by the fact that vitamin C infusion blunted the increase of levels of plasma 8-OHdG, a product of hydroxyl radical/deoxyribonucleic acid interaction. However, a cause-effect relationship cannot be established by our study. There are several limitations of this study. The study was not blinded. Optimal dose, time of onset, and duration of vitamin C use before PCI were not identified. The vitamin C treatment protocols used in this study were arbitrary. Blood samples for postprocedure CK-MB or troponin I measurements were drawn 6 and 24 hours after PCI. Thus, we might have missed the opportunity to identify additional events if more serial blood samples had been assessed. We measured the plasma 8-OHdG level for only the last 30 patients, which made the correlation analysis between the antioxidants and myocardial injury unfeasible. Therefore, as we mentioned earlier, a cause-effect relationship between a cardioprotective effect of vitamin C and its antioxidant effect cannot be established by our study. Furthermore, no clinical follow-up was required after hospital discharge. Therefore, further studies are necessary to investigate the effect of vitamin C on the long-term clinical prognosis in this setting. In summary, the results of this prospective randomized study show that prophylactic infusion of vitamin Cda safe, well-tolerated, and inexpensive antioxidantdappears to decrease myocardial injury associated with elective PCI. The underlying mechanisms and clinical prognosis of this cardioprotective effect need to be investigated by further studies. Disclosures The authors have no conflicts of interest to disclose. References 1. Califf RM, Abdelmeguid AE, Kunitz RE, et al. Myonecrosis after revascularization procedures. J Am Coll Cardiol 1998;31:241-51.
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2. Abdelemeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation 1996;94:1528-36.
of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44-122.
3. Pervaiz MH, Sood P, Sudhir K, et al. Periprocedural myocardial infarction in a randomized trial of everolimus-eluting and Paclitaxel-eluting coronary stents: frequency and impact on mortality according to historic versus universal definitions. Circ Cardiovasc Interv 2012;5: 150-6.
17. Reilly MP, Delanty N, Roy L, et al. Increased formation of the isoprostanes IPF2alpha-I and 8-epi-prostaglandin F2alpha in acute coronary angioplasty: evidence for oxidant stress during coronary reperfusion in humans. Circulation 1997;96:3314-20.
4. Prasad A, Gersh BJ, Bertrand ME, et al. Prognostic significance of periprocedural versus spontaneously occurring myocardial infarction after percutaneous coronary intervention in patients with acute coronary syndromes: an analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol 2009;54: 477-86. 5. Fuchs S, Kornowski R, Mehran R, et al. Prognostic value of cardiac troponin-I levels following catheter-based coronary interventions. Am J Cardiol 2000;85:1077-82. 6. Jeremias A, Baim DS, Ho KK, et al. Differential mortality risk of postprocedural creatine kinase-MB elevation following successful versus unsuccessful stent procedures. J Am Coll Cardiol 2004;44:1210-4. 7. Lindsey JB, Kennedy KF, Stolker JM, et al. Prognostic implications of creatine kinase-MB elevation after percutaneous coronary intervention: results from the Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) registry. Circ Cardiovasc Interv 2011;4:474-80. 8. Akkerhuis KM, Alexander JH, Tardiff BE, et al. Minor myocardial damage and prognosis: are spontaneous and percutaneous coronary intervention-related events different? Circulation 2002;105:554-6.
18. Kaminski K, Bonda T, Wojtkowska I, et al. Oxidative stress and antioxidative defense parameters early after reperfusion therapy for acute myocardial infarction. Acute Card Care 2008;10:121-6. 19. Pignatelli P, Tanzilli G, Carnevale R, et al. Ascorbic acid infusion blunts CD40L upregulation in patients undergoing coronary stent. Cardiovasc Ther 2011;29:385-94. 20. Farah R, Shurtz-Swirski R, Bolotin Y, Brezins M. Oxidative stress and inflammation due to peripheral polymorphonuclear leukocytes after coronary angiography vs percutaneous coronary intervention. Minerva Cardioangiol 2008;56:189-95. 21. Hozawa A, Jacobs DR Jr, Steffes MW, et al. Relationships of circulating carotenoid concentrations with several markers of inflammation, oxidative stress, and endothelial dysfunction: the Coronary Artery Risk Development in Young Adults (CARDIA)/Young Adult Longitudinal Trends in Antioxidants (YALTA) study. Clin Chem 2007;53:447-55. 22. Sinha MK, Gaze DC, Tippins JR, Collinson PO, Kaski JC. Ischemia modified albumin is a sensitive marker of myocardial ischemia after percutaneous coronary intervention. Circulation 2003;107:2403-5.
9. Novack V, Pencina M, Cohen DJ, et al. Troponin criteria for myocardial infarction after percutaneous coronary intervention. Arch Intern Med 2012;172:502-8.
23. Spargias K, Alexopoulos E, Kyrzopoulos S, et al. Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation 2004;110: 2837-42.
10. Kong TQ, Davidson CJ, Meyers SN, et al. Prognostic implication of creatine kinase elevation following elective coronary artery interventions. JAMA 1997;277:461-6.
24. Tomoda H, Yoshitake M, Morimoto K, Aoki N. Possible prevention of postangioplasty restenosis by ascorbic acid. Am J Cardiol 1996;78: 1284-6.
11. Ioannidis JP, Karvouni E, Katritsis DG. Mortality risk conferred by small elevations of creatine kinase-MB isoenzyme after percutaneous coronary intervention. J Am Coll Cardiol 2003;42:1406-11.
25. Albabtain MA, Almasood A, Alshurafah H, Alamri H, Tamim H. Efficacy of ascorbic acid, N-acetylcysteine, or combination of both on top of saline hydration versus saline hydration alone on prevention of contrastInduced nephropathy: a prospective randomized study. J Interv Cardiol 2013;26:90-6.
12. Prasad A, Singh M, Lerman A, et al. Isolated elevation in troponin T after percutaneous coronary intervention is associated with higher long-term mortality. J Am Coll Cardiol 2006;48:1765-70. 13. Iuliano L, Praticò D, Greco C, et al. Angioplasty increases coronary sinus F2-isoprostane formation: evidence for in vivo oxidative stress during PTCA. J Am Coll Cardiol 2001;37:76-80. 14. Basili S, Tanzilli G, Mangieri E, et al. Intravenous ascorbic acid infusion improves myocardial perfusion grade during elective percutaneous coronary intervention: relationship with oxidative stress markers. JACC Cardiovasc Interv 2010;3:221-9. 15. Thygesen K, Alpert JS, Jaffe AS, et al; Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Eur Heart J 2012;33: 2551-67. 16. American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College
26. Zhou L, Chen H. Prevention of contrast-induced nephropathy with ascorbic acid. Intern Med 2012;51:531-5. 27. Jo SH, Koo BK, Park JS, et al. N-acetylcysteine versus AScorbic acid for preventing contrast-Induced nephropathy in patients with renal insufficiency undergoing coronary angiography NASPI studyda prospective randomized controlled trial. Am Heart J 2009;157:576-83. 28. Boscheri A, Weinbrenner C, Botzek B, et al. Failure of ascorbic acid to prevent contrast-media induced nephropathy in patients with renal dysfunction. Clin Nephrol 2007;68:279-86.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2013.08.018.
