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Meta-analysis: Effectiveness of Drugs for Preventing Contrast-Induced Nephropathy FREE

Aine M. Kelly, MD, MS; Ben Dwamena, MD; Paul Cronin, MD, MS; Steven J. Bernstein, MD, MPH; and Ruth C. Carlos, MD, MS
[+] Article and Author Information

From the University of Michigan and Veteran Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan.


Grant Support: Funded in part by the National Institutes of Health and the National Cancer Institute (grant 1 K07 CA108664 01A1) and the General Electric–Association of University Radiologists Radiology Research Academic Fellowship.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Aine M. Kelly, MD, MS, Department of Radiology, Division of Cardiothoracic Radiology, University of Michigan Hospitals, B1 132K Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109; e-mail, ainekell@med.umich.edu.

Current Author Addresses: Drs. Kelly and Cronin: Department of Radiology, Division of Cardiothoracic Imaging, University of Michigan, 1500 East Medical Center, Ann Arbor, MI 48109.

Dr. Dwamena: Division of Nuclear Medicine, University of Michigan, 1500 East Medical Center, Ann Arbor, MI 48109.

Dr. Bernstein: Department of Internal Medicine, University of Michigan, 1500 East Medical Center, Ann Arbor, MI 48109.

Dr. Carlos: Department of Radiology, Division of Magnetic Resonance Imaging, University of Michigan, 1500 East Medical Center, Ann Arbor, MI 48109.


Ann Intern Med. 2008;148(4):284-294. doi:10.7326/0003-4819-148-4-200802190-00007
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Background: N-Acetylcysteine, theophylline, and other agents have shown inconsistent results in reducing contrast-induced nephropathy.

Purpose: To determine the effect of these agents on preventing nephropathy.

Data Sources: Relevant randomized, controlled trials were identified by computerized searches in MEDLINE (from 1966 through 3 November 2006), EMBASE (1980 through November 2006), PubMed, Web of Knowledge (Current Contents Connect, Web of Science, BIOSIS Previews, and ISI Proceedings for the latest 5 years), and the Cochrane Library databases (up to November 2006). Databases were searched for studies in English, Spanish, French, Italian, and German.

Study Selection: Randomized, controlled trials that administered N-acetylcysteine, theophylline, fenoldopam, dopamine, iloprost, statin, furosemide, or mannitol to a treatment group; used intravenous iodinated contrast; defined contrast-induced nephropathy explicitly; and reported sufficient data to construct a 2 × 2 table of the primary effect measure.

Data Extraction: Abstracted information included patient characteristics, type of contrast media and dose, periprocedural hydration, definition of contrast-induced nephropathy, and prophylactic agent dose and route.

Data Synthesis: In the 41 studies included, N-acetylcysteine (relative risk, 0.62 [95% CI, 0.44 to 0.88]) and theophylline (relative risk, 0.49 [CI, 0.23 to 1.06]) reduced the risk for contrast-induced nephropathy more than saline alone, whereas furosemide increased it (relative risk, 3.27 [CI, 1.48 to 7.26]). The remaining agents did not significantly affect risk. Significant subgroup heterogeneity was present only for N-acetylcysteine. No publication bias was discerned.

Limitations: All trials evaluated the surrogate end point of contrast-induced nephropathy as the primary outcome. The lack of a statistically significant renoprotective effect of theophylline may result from insufficient data or study heterogeneity. True study quality remains uncertain.

Conclusion: N-Acetylcysteine is more renoprotective than hydration alone. Theophylline may also reduce risk for contrast-induced nephropathy, although the detected association was not significant. Our data support the administration of N-acetylcysteine prophylaxis, particularly in high-risk patients, given its low cost, availability, and few side effects.

Editors' Notes
Context

  • Contrast-induced nephropathy is a common cause of acute renal failure in hospitalized patients. Clinicians use a variety of contrast agents to reduce the risk for contrast-induced nephropathy, including N-acetylcysteine, theophylline, fenoldopam, dopamine, furosemide, mannitol, and bicarbonate.

Contribution

  • Although all of the agents included in this analysis reduced the risk for contrast-induced nephropathy, this meta-analysis of 33 trials involving 3622 patients found the strongest evidence for the effectiveness of N-acetylcysteine, mannitol, and theophylline when compared with periprocedural hydration alone.

Caution

  • Available studies examined laboratory end points (such as an increase in serum creatinine levels) rather than clinical end points (such as dialysis or death).

—The Editors

Contrast-induced nephropathy, defined as an increase in serum creatinine greater than 25% or 44.2 µmol/L (>0.5 mg/dL) within 3 days of intravascular contrast administration in the absence of an alternative cause, is the third most common cause of new acute renal failure in hospitalized patients (12). Contrast-induced nephropathy develops in 0% to 10% of patients with normal renal function (3). However, the incidence may be as high as 25% in patients with preexisting renal impairment or certain risk factors, such as diabetes, congestive heart failure, advanced age, and concurrent administration of nephrotoxic drugs (3). Large doses of intravenous contrast and use of high-osmolar contrast agents in patients with renal impairment also increase the risk for contrast-induced nephropathy (46). High-osmolar contrast agents are more rarely used now. The risk difference between iso-osmolar agents, such as iodixanol, and low-osmolar agents, such as iopamidol, ioxaglate, or iohexol, is less clear (79). Most episodes of contrast-induced nephropathy are not detected clinically because patients are asymptomatic. However, contrast-induced nephropathy may increase the risk for renal failure and is associated with dialysis, prolonged hospital stay, increased health care costs, potentially irreversible reduction in renal function, and death (10).

Use of preprocedural fluids and low-osmolar or iso-osmolar contrast agents has been shown to decrease the risk for contrast-induced nephropathy (1113). These measures suffice for many patients; however, the risk is reduced but not eliminated in some patients—even when iso-osmolar contrast is used (1415). Other studies have evaluated the use of N-acetylcysteine, theophylline, fenoldopam, and other agents as preventive strategies in contrast-induced nephropathy; the results have been heterogeneous and are difficult to compare across the different treatment strategies. Given the widespread use of iodinated intravascular contrast agents, an improved understanding of the potential value of these agents has important patient safety and cost implications.

We conducted a meta-analysis of the literature to quantify the effects of individual strategies on the prevention of contrast-induced nephropathy and to facilitate comparison of preventive effects across strategies.

Study Search Strategy

We performed a computerized search by using standard meta-analytic techniques (16) to identify relevant articles in MEDLINE (from 1966 through 3 November 2006), EMBASE (1980 through November 2006), PubMed, Web of Knowledge (Current Contents Connect, Web of Science, BIOSIS Previews, and ISI Proceedings for the latest 5 years), and the Cochrane Library databases. For the MEDLINE search, we used the following combination of keywords: [renal failure or kidney failure to include all subheadings] and [contrast media or iopamidol or iodine or ioxaglic acid or iodine compounds or iohexol or urography or drug hyper sensitivity or tomography, X ray computed or diatrizoate] and [hydration or fluid therapy or water or dehydration or skin or nutritional support or body water] and [clinical trial or randomized controlled trial] and [prospective trial or prospective studies or clinical trials] and [adult or middle aged or aged] and [N-Acetylcysteine or acetylcysteine] or [theophylline] or [mannitol] or [dopamine] or [fenoldopam] or [bicarbonate]. For the PubMed, Cochrane Library Database, and Web of Knowledge searches, we used the search words renal failure, contrast medium, hydration, randomized controlled trial, N acetyl cysteine, Theophylline, Mannitol, Fenoldopam, Dopamine and Bicarbonate. We included English-, French-, German-, Spanish- and Italian-language studies and clinical trials and excluded review articles and nonhuman studies. We combined this strategy with a manual search of reference lists from identified articles.

Study Selection

We included a study if 1 of the treatment groups received N-acetylcysteine, theophylline, fenoldopam, iloprost, statin, dopamine, trimetazidine, bicarbonate, ascorbic acid, furosemide, or mannitol. Criteria for inclusion were randomized, controlled trials that compared treatment with control; used intravenous iodinated contrast; explicitly defined contrast-induced nephropathy; and sufficiently reported data to construct a 2 × 2 table and calculate the primary effect measure (relative risk reduction). Where data were missing, we contacted the original authors for the relevant information.

Data Extraction

One reviewer examined the abstracts to determine whether the study met the inclusion and exclusion criteria. Two reviewers separately abstracted complete articles according to a standardized form for studies meeting criteria. Abstracted information included patient characteristics (mean age, proportion of men and patients with diabetes mellitus or hypertension, and mean baseline creatinine level), type of radiologic or cardiologic imaging, inclusion and exclusion criteria, type of contrast media and dose used, periprocedural hydration, specific definition of contrast-induced nephropathy, prophylactic agent dose and route, and serum creatinine level at baseline and at 48 hours after contrast injection.

Analysis of Renoprotective Agents

The primary outcome was the development of contrast-induced nephropathy, defined as an absolute increase in baseline serum creatinine greater than 44.2 µmol/L (>0.5 mg/dL) or a relative increase greater than 25% at 48 hours after contrast injection. For trials missing this datum, we contacted the original authors to get the number of patients with this outcome. We calculated individual study relative risks and 95% CIs before aggregation. Subsequently, we obtained overall and subgroup summary risk ratios by random-effects modeling of the binary data from the multiple 2 × 2 tables. We used the method of DerSimonian and Laird (17), with the estimate of heterogeneity taken from the inverse variance fixed-effect model. We used the metan module in Stata, version 9.0 (Stata, College Station, Texas), to perform data synthesis.

We performed subgroup evaluation of each therapeutic regimen. In studies comparing 2 dosage regimens of the same intervention with a single control group (1820), we considered the same-study dosage groups as representing a single intervention to avoid double-counting of shared control observations. When we identified only 1 study that examined a given therapy, we assigned that study to a group termed “other” and pooled data from all such studies together. This group included 1 study each on the use of iloprost; trimetazidine; mannitol; bicarbonate; ascorbic acid; and combinations of furosemide, dopamine, and mannitol and furosemide and dopamine. We used relative risk ratios to estimate the treatment effects.

Assessment of Methodological Quality

Criteria for quality assessment included concealment of allocation, similarity of both groups at baseline regarding prognostic indicators, eligibility criteria, blinding of patient, blinding of care provider, blinding of outcome assessor, point estimates and measures of variability for the primary outcome measure, and inclusion of an intention-to-treat analysis (21). Any disagreements in abstracted data between the reviewers were adjudicated by a third reviewer. We explored potential heterogeneity in estimates of treatment efficacy attributable to each quality criterion by using meta-regression.

Assessment of Heterogeneity

We used Forest plots to visualize the extent of heterogeneity among studies. We also examined I2, a standard test for heterogeneity that measures the degree of inconsistency across studies. I2 values, which range from 0% to 100%, describe the proportion of variation in treatment effect estimates that is due to genuine variation rather than sampling error (22). A value of 0% indicates no observed heterogeneity. Higgins and colleagues (22) suggest describing I2 values of 25%, 50%, and 75% as low, moderate, and high, respectively. We obtained the group-specific and overall I2 as standard output of the metan program.

We performed an Egger precision-weighted linear regression test as a statistical test of funnel plot asymmetry and publication bias (23).

All statistical analyses were performed with Stata.

Study Identification

Our initial search yielded 619 citations and references. We excluded 531 studies on the basis of our criteria, including nonclinical trials; trials not conducted on humans; trials not reported in English, French, German, Spanish, or Italian; trials reporting only nonnephropathy outcomes; and trials using nonclinical outcome measures, leaving 88 studies that met the inclusion criteria (Figure 1). We reviewed abstracts from the 88 articles and excluded an additional 23 trials, including nonrandomized clinical trials; trials not conducted on humans; trials not reported in English, French, German, Spanish, or Italian; trials reporting only nonnephropathy outcomes; and trials that used nonclinical outcome measures, leaving 65 studies for full publication review. The full articles were then reviewed, and a further 24 studies were excluded for reasons similar to those just mentioned. After the final screening, 41 randomized clinical trials met our inclusion criteria (1820, 2459), involving 6379 patients who had elective radiographic procedures involving contrast agents.

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Figure 1.
Trial identification, inclusion, and exclusion.
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Study Characteristics

The trials were published between 1994 and 2006, and the Table shows their characteristics. Fifteen trials were performed in the United States (9, 20, 2425, 3032, 34, 44, 4849, 5152, 5859), and 26 trials were performed elsewhere (1819, 2629, 33, 3543, 4547, 50, 5357, 59). Thirty-four trials evaluated patients with impaired renal function (9, 1920, 2429, 3246, 4852, 5659), defined as serum creatinine levels greater than 106.1 to 132.6 µmol/L (>1.2 to 1.5 mg/dL). We had insufficient data to separately evaluate patients with normal renal function. Only 3 trials evaluated patients with normal and impaired renal function, and 2 trials evaluated only patients with normal renal function (3031, 47, 5354). One trial evaluated patients having computed tomography (58); the rest evaluated patients having cardiac catheterization. The average age of the study patients was greater than 65 years in all but 8 studies (9, 18, 29, 37, 4041, 45, 48), and all studies included patients with diabetes. Dosing regimens for each trial are detailed in the Table. The outcome measure of contrast-induced nephropathy was reported in all studies. Changes in serum creatinine levels were reported at 48 hours in most trials (9, 1820, 2447, 4959), although we used outcomes reported at 72 hours for 1 trial (48).

Analysis of Renoprotective Agents

Of the evaluated agents, N-acetylcysteine significantly decreased the risk for contrast-induced nephropathy compared with saline alone (relative risk, 0.62 [95% CI, 0.44 to 0.88]) (Figure 2). Although seemingly renoprotective, the effects of theophylline on nephropathy prevention were not significant (relative risk, 0.49 [CI, 0.23 to 1.06]). In the heterogeneous group of treatments for which only a single study was identified (labeled “other”), only ascorbic acid (relative risk, 0.46 [CI, 0.23 to 0.90]) and bicarbonate (relative risk, 0.12 [CI, 0.02 to 0.95]) significantly reduced contrast-induced nephropathy. Furosemide (relative risk, 3.27 [CI, 1.48 to 7.26]) increased the risk for contrast-induced nephropathy.

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Figure 2.
Forest plot describing relative risk for contrast-induced nephropathy, by treatment agent.

The intervention and control columns show the number of events among the total number of participants randomly assigned to the group for each study. We estimated heterogeneity within subgroups by using the I2 statistic.

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Assessment of Methodological Quality

The Appendix Table presents the quality characteristics of each study. Most studies included patients with similar baseline characteristics (94%) or specific inclusion characteristics (90%). Most also presented variance estimates of treatment effects (59%) or blinding of patients to treatment (51%). Fewer than half of the studies reported concealment of allocation (47%) or blinding of care providers to treatment (43%). Few studies noted outcome evaluation by individuals blinded to treatment assignment (6%) or an intention-to-treat design (8%). In exploratory analysis, only the quality characteristic of explicitly stating specific inclusion criteria (P = 0.007) independently contributed to heterogeneity across study efficacies.

Table Jump PlaceholderAppendix Table.  Summary of Study Quality Characteristics
Assessment of Within-Group Heterogeneity and Publication Bias

Treatment effect estimates within the N-acetylcysteine group showed moderate heterogeneity (I2 = 55%; P < 0.001). As expected, we found a moderate to high level of heterogeneity among the pooled studies that each examined a different therapy (labeled “other”) (I2 = 61%; P = 0.024). No other groups demonstrated significant within-group heterogeneity (Figure 2). No significant publication bias was discerned (bias coefficient, −0.55; P = 0.20).

In our meta-analysis of 41 randomized trials, we found that preprocedural treatment with N-acetylcysteine effectively reduced the risk for contrast-induced nephropathy. Theophylline also produced larger risk reductions than previously mentioned; however, the effects of this agent were not significant. Not all agents analyzed had beneficial effects—fenoldopam; furosemide; mannitol; and the combination of furosemide, dopamine, and mannitol had odds ratios greater than 1. Our findings for N-acetylcysteine support previous studies (6063). To date, no meta-analyses have studied preprocedural dopamine or statins for the prevention of contrast-induced nephropathy. Our findings for theophylline support previous studies that showed a risk reduction (64). However, the effects of theophylline were not statistically significant in our study. In contrast, Ix and colleagues (64) found borderline statistical significance when they limited their analysis to studies using concomitant intravenous fluids or contrast volumes greater than 100 mL and no statistical significance when their analysis was limited to studies of only coronary angiography patients or where the theophylline was given within 1 hour of the procedure. Bagshaw and Ghali (65), however, did not find a statistically significant effect, similar to our findings.

N-Acetylcysteine is extremely inexpensive at 23 cents for a 500-mg tablet (price as of 17 January 2007 at http://www.shopping.com), is readily available, and is easily administered. Side effects and drug interactions are very rare with continued use and are highly unlikely to result from the limited use for renal protection. Therefore, although no formal cost-effective analysis has been performed to date, these findings support the use of N-acetylcysteine in selected at-risk patients.

Hydration and iso-osmolar or low-osmolar contrast agents, such as iodixanol, are all associated with a decreased incidence of contrast-induced nephropathy in patients with renal impairment (creatinine clearance <1 mL/s [<60 mL/min]) (44). In a recent meta-analysis, McCullough and colleagues (15) found that although low-osmolar contrast agents reduced the risk for contrast-induced nephropathy by two thirds, they did not totally eliminate the risk. Thus, protective agents must still be considered for patients with severe renal impairment who are to receive large volumes of contrast agents.

Our meta-analysis has several limitations. All included trials evaluated the surrogate end point of contrast-induced nephropathy as the primary outcome. Contrast-induced nephropathy was defined as an increase in serum creatinine of more than 44.2 μmol/L (>0.5 mg/dL) or 25% from baseline values, which represents a minor deterioration in renal function in patients with chronic renal failure. Even in high-risk patients, contrast-induced nephropathy is almost always transient and only rarely requires dialysis. Only the trial by Kay and colleagues (46) examined length of hospital stay as an end point and found a significant reduction in length of stay among patients given N-acetylcysteine. Despite the reported association of contrast-induced nephropathy with impaired outcomes, no trial has examined clinical end points, such as dialysis dependency or in-hospital morbidity and mortality. The clinical relevance of the renoprotective effects of N-acetylcysteine, dopamine, and other agents is therefore debatable, whereas periprocedural hydration is of proven benefit (66). In addition, it is possible that we did not detect a significant effect for theophylline because of study heterogeneity or insufficient data.

Because we primarily identified and used published studies, our results are weighted on the findings of published trials. The exclusion of unpublished data is generally associated with an overestimate of the true effect in meta-analysis (67). The single most common reason for inability to publish a trial is the lack of statistical significance, although some have suggested that the quality of unpublished data is not comparable to that accepted by peer-reviewed journals (68). In addition, many of the included studies did not have high quality scores, and many did not specify that they met the quality criteria, with the true quality remaining uncertain.

Strengths of our study include the comprehensive search strategy and the careful statistical methods used. We identified 41 trials with a total of 6379 patients and evaluated multiple therapeutic agents within 1 analysis framework, allowing side-by-side comparison of the efficacies across agents.

Our meta-analysis shows that N-acetylcysteine is the most effective agent for preventing contrast-induced nephropathy in patients with chronic renal insufficiency. Whether this risk reduction translates into a benefit in clinical outcomes remains to be proven. The reported association of contrast-induced nephropathy with increased morbidity, mortality, and hospital stay might justify the use of N-acetylcysteine as a routine intervention for prophylaxis of contrast-induced nephropathy, given that N-acetylcysteine is readily available and inexpensive and has a favorable side effect profile.

The results of this meta-analysis should be evaluated in head-to-head empirical studies of active agents to identify the most efficacious regimen for preventing contrast-induced nephropathy. However, our findings indicate that the use of such oral agents as N-acetylcysteine is reasonable in high-risk patients who are to receive large or repeated volumes of contrast agents. We believe that the lack of significant side effects and the low cost justifies use of these agents while empirical data on clinical outcomes mature.

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Goldenberg I, Shechter M, Matetzky S, Jonas M, Adam M, Pres H. et al.  Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy following coronary angiography. A randomized controlled trial and review of the current literature. Eur Heart J. 2004; 25:212-8. PubMed
 
Gomes VO, Poli de Figueredo CE, Caramori P, Lasevitch R, Bodanese LC, Araújo A. et al.  N-acetylcysteine does not prevent contrast induced nephropathy after cardiac catheterisation with an ionic low osmolality contrast medium: a multicentre clinical trial. Heart. 2005; 91:774-8. PubMed
 
Gulel O, Keles T, Eraslan H, Aydogdu S, Diker E, Ulusoy V.  Prophylactic acetylcysteine usage for prevention of contrast nephropathy after coronary angiography. J Cardiovasc Pharmacol. 2005; 46:464-7. PubMed
 
Huber W, Ilgmann K, Page M, Hennig M, Schweigart U, Jeschke B. et al.  Effect of theophylline on contrast material-nephropathy in patients with chronic renal insufficiency: controlled, randomized, double-blinded study. Radiology. 2002; 223:772-9. PubMed
 
Huber W, Schipek C, Ilgmann K, Page M, Hennig M, Wacker A. et al.  Effectiveness of theophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficiency. Am J Cardiol. 2003; 91:1157-62. PubMed
 
Jo SH, Koo BK, Youn TJ, Hahn JY, Kim YS, Kang HJ.  Prevention of contrast induced nephropathy by short term statin in patients with renal insufficiency undergoing coronary angiography: a randomized controlled trial [Abstract]. In: TCT 2005. Abstracts of the 17th Annual Transcatheter Cardiovascular Therapeutics Symposium, October 17-21, 2005, Washington DC, USA. Am J Cardiol. 2005;96:1H-213H. [PMID: 16252422]
 
Kapoor A, Kumar S, Gulati S, Gambhir S, Sethi RS, Sinha N.  The role of theophylline in contrast-induced nephropathy: a case-control study. Nephrol Dial Transplant. 2002; 17:1936-41. PubMed
 
Kay J, Chow WH, Chan TM, Lo SK, Kwok OH, Yip A. et al.  Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. JAMA. 2003; 289:553-8. PubMed
 
Kefer JM, Hanet CE, Boitte S, Wilmotte L, De Kock M.  Acetylcysteine, coronary procedure and prevention of contrast-induced worsening of renal function: which benefit for which patient? Acta Cardiol. 2003; 58:555-60. PubMed
 
MacNeill BD, Harding SA, Bazari H, Patton KK, Colon-Hernadez P, DeJoseph D. et al.  Prophylaxis of contrast-induced nephropathy in patients undergoing coronary angiography. Catheter Cardiovasc Interv. 2003; 60:458-61. PubMed
 
Merten GJ, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ. et al.  Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004; 291:2328-34. PubMed
 
Namgung J, Doh JH, Lee SY, Lee WR.  Effect of N acetylcysteine in the prevention of contrast induced nephropathy after coronary angiography [Abstract]. In: Abstracts of the 10th Annual Interventional Vascular Therapeutics Angioplasty Summit-Transcatheter Cardiovascular Therapeutics Asia Pacific Symposium. April 28-30, 2005, Seoul, Korea. Am J Cardiol. 2005;95:1A-83A. [PMID: 15889504].
 
Ochoa A, Pellizzon G, Addala S, Grines C, Isayenko Y, Boura J. et al.  Abbreviated dosing of N-acetylcysteine prevents contrast-induced nephropathy after elective and urgent coronary angiography and intervention. J Interv Cardiol. 2004; 17:159-65. PubMed
 
Oldemeyer JB, Biddle WP, Wurdeman RL, Mooss AN, Cichowski E, Hilleman DE.  Acetylcysteine in the prevention of contrast-induced nephropathy after coronary angiography. Am Heart J. 2003; 146:23. PubMed
 
Rashid ST, Salman M, Myint F, Baker DM, Agarwal S, Sweny P. et al.  Prevention of contrast-induced nephropathy in vascular patients undergoing angiography: a randomized controlled trial of intravenous N-acetylcysteine. J Vasc Surg. 2004; 40:1136-41. PubMed
 
Sandhu C, Belli AM, Oliveira DB.  The role of N-acetylcysteine in the prevention of contrast-induced nephrotoxicity. Cardiovasc Intervent Radiol. 2006; 29:344-7. PubMed
 
Shyu KG, Cheng JJ, Kuan P.  Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol. 2002; 40:1383-8. PubMed
 
Sinha SK, Berry WA, Bueti J, Junaid A, Fine A, Krahn J.  The prevention of radiocontrast-induced nephropathy trial (print): a prospective, double-blind, randomized, controlled trial of iso-osmolar versus low-osmolar radiocontrast in combination with N-acetylcysteine versus placebo [Abstract]. Presented at the American Heart Association Scientific Sessions, New Orleans, Louisiana, 7-10 November 2004. Accessed athttp://www.abstractsonline.com/arch/RecordPrintView.aspx?LookupKey=12345&RecordID=717on 19 December 2007.
 
Stone GW, McCullough PA, Tumlin JA, Lepor NE, Madyoon H, Murray P, et al. CONTRAST Investigators.  Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial. JAMA. 2003; 290:2284-91. PubMed
 
Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W.  Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med. 2000; 343:180-4. PubMed
 
Spargias K, Alexopoulos E, Kyrzopoulos S, Iokovis P, Iacovis P, Greenwood DC. et al.  Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation. 2004; 110:2837-42. PubMed
 
Webb JG, Pate GE, Humphries KH, Buller CE, Shalansky S, Al Shamari A. et al.  A randomized controlled trial of intravenous N-acetylcysteine for the prevention of contrast-induced nephropathy after cardiac catheterization: lack of effect. Am Heart J. 2004; 148:422-9. PubMed
 
Alonso A, Lau J, Jaber BL, Weintraub A, Sarnak MJ.  Prevention of radiocontrast nephropathy with N-acetylcysteine in patients with chronic kidney disease: a meta-analysis of randomized, controlled trials. Am J Kidney Dis. 2004; 43:1-9. PubMed
 
Birck R, Krzossok S, Markowetz F, Schnülle P, van der Woude FJ, Braun C.  Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet. 2003; 362:598-603. PubMed
 
Liu R, Nair D, Ix J, Moore DH, Bent S.  N-acetylcysteine for the prevention of contrast-induced nephropathy. A systematic review and meta-analysis. J Gen Intern Med. 2005; 20:193-200. PubMed
 
Ix JH, McCulloch CE, Chertow GM.  Theophylline for the prevention of radiocontrast nephropathy: a meta-analysis. Nephrol Dial Transplant. 2004; 19:2747-53. PubMed
 
Bagshaw SM, Ghali WA.  Theophylline for prevention of contrast-induced nephropathy: a systematic review and meta-analysis. Arch Intern Med. 2005; 165:1087-93. PubMed
 
Trivedi HS, Moore H, Nasr S, Aggarwal K, Agrawal A, Goel P. et al.  A randomized prospective trial to assess the role of saline hydration on the development of contrast nephrotoxicity. Nephron Clin Pract. 2003; 93:C29-34. PubMed
 
McAuley L, Pham B, Tugwell P, Moher D.  Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses? Lancet. 2000; 356:1228-31. PubMed
 
Cook DJ, Guyatt GH, Ryan G, Clifton J, Buckingham L, Willan A. et al.  Should unpublished data be included in meta-analyses? Current convictions and controversies. JAMA. 1993; 269:2749-53. PubMed
 

Figures

Grahic Jump Location
Figure 1.
Trial identification, inclusion, and exclusion.
Grahic Jump Location
Grahic Jump Location
Figure 2.
Forest plot describing relative risk for contrast-induced nephropathy, by treatment agent.

The intervention and control columns show the number of events among the total number of participants randomly assigned to the group for each study. We estimated heterogeneity within subgroups by using the I2 statistic.

Grahic Jump Location

Tables

Table Jump PlaceholderAppendix Table.  Summary of Study Quality Characteristics

Audio

Audio Summary

Other Audio Options: Download MP3

References

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Abizaid AS, Clark CE, Mintz GS, Dosa S, Popma JJ, Pichard AD. et al.  Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with preexisting renal insufficiency. Am J Cardiol. 1999; 83:260-3, A5. PubMed
 
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Azmus AD, Gottschall C, Manica A, Manica J, Duro K, Frey M. et al.  Effectiveness of acetylcysteine in prevention of contrast nephropathy. J Invasive Cardiol. 2005; 17:80-4. PubMed
 
Baker CS, Wragg A, Kumar S, De Palma R, Baker LR, Knight CJ.  A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study. J Am Coll Cardiol. 2003; 41:2114-8. PubMed
 
Balderramo DC, Verdu MB, Ramacciotti CF, Cremona LS, Lemos PA, Orías M. et al.  Renoprotective effect of high periprocedural doses of oral N-acetylcysteine in patients scheduled to undergo a same-day angiography. Rev Fac Cien Med Univ Nac Cordoba. 2004; 61:13-9. PubMed
 
Briguori C, Manganelli F, Scarpato P, Elia PP, Golia B, Riviezzo G. et al.  Acetylcysteine and contrast agent-associated nephrotoxicity. J Am Coll Cardiol. 2002; 40:298-303. PubMed
 
Coyle LC, Rodriguez A, Jeschke RE, Simon-Lee A, Abbott KC, Taylor AJ.  Acetylcysteine In Diabetes (AID): a randomized study of acetylcysteine for the prevention of contrast nephropathy in diabetics. Am Heart J. 2006; 151:1032.e9-12. PubMed
 
Diez T, Bagilet D, Ramos M, Jolly H, Diab M, Marcucci R. et al.  [Evaluation of two methods to avoid the nephropathy associated with radiologic contrast]. Medicina (B Aires). 1999; 59:55-8. PubMed
 
Diaz-Sandoval LJ, Kosowsky BD, Losordo DW.  Acetylcysteine to prevent angiography-related renal tissue injury (the APART trial). Am J Cardiol. 2002; 89:356-8. PubMed
 
Drager LF, Andrade L, Barros de Toledo JF, Laurindo FR, Machado César LA, Seguro AC.  Renal effects of N-acetylcysteine in patients at risk for contrast nephropathy: decrease in oxidant stress-mediated renal tubular injury. Nephrol Dial Transplant. 2004; 19:1803-7. PubMed
 
Durham JD, Caputo C, Dokko J, Zaharakis T, Pahlavan M, Keltz J. et al.  A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. Kidney Int. 2002; 62:2202-7. PubMed
 
Dussol B, Morange S, Loundoun A, Auquier P, Berland Y.  A randomized trial of saline hydration to prevent contrast nephropathy in chronic renal failure patients. Nephrol Dial Transplant. 2006; 21:2120-6. PubMed
 
El Mahmoud R, Le Feuvre C, Le Quan Sang KH, Helft G, Beygui F, Batisse JP. et al.  [Absence of nephro-protective effect of acetylcysteine in patients with chronic renal failure investigated by coronary angiography]. Arch Mal Coeur Vaiss. 2003; 96:1157-61. PubMed
 
Erley CM, Duda SH, Rehfuss D, Scholtes B, Bock J, Müller C. et al.  Prevention of radiocontrast-media-induced nephropathy in patients with pre-existing renal insufficiency by hydration in combination with the adenosine antagonist theophylline. Nephrol Dial Transplant. 1999; 14:1146-9. PubMed
 
Fung JW, Szeto CC, Chan WW, Kum LC, Chan AK, Wong JT. et al.  Effect of N-acetylcysteine for prevention of contrast nephropathy in patients with moderate to severe renal insufficiency: a randomized trial. Am J Kidney Dis. 2004; 43:801-8. PubMed
 
Goldenberg I, Shechter M, Matetzky S, Jonas M, Adam M, Pres H. et al.  Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy following coronary angiography. A randomized controlled trial and review of the current literature. Eur Heart J. 2004; 25:212-8. PubMed
 
Gomes VO, Poli de Figueredo CE, Caramori P, Lasevitch R, Bodanese LC, Araújo A. et al.  N-acetylcysteine does not prevent contrast induced nephropathy after cardiac catheterisation with an ionic low osmolality contrast medium: a multicentre clinical trial. Heart. 2005; 91:774-8. PubMed
 
Gulel O, Keles T, Eraslan H, Aydogdu S, Diker E, Ulusoy V.  Prophylactic acetylcysteine usage for prevention of contrast nephropathy after coronary angiography. J Cardiovasc Pharmacol. 2005; 46:464-7. PubMed
 
Huber W, Ilgmann K, Page M, Hennig M, Schweigart U, Jeschke B. et al.  Effect of theophylline on contrast material-nephropathy in patients with chronic renal insufficiency: controlled, randomized, double-blinded study. Radiology. 2002; 223:772-9. PubMed
 
Huber W, Schipek C, Ilgmann K, Page M, Hennig M, Wacker A. et al.  Effectiveness of theophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficiency. Am J Cardiol. 2003; 91:1157-62. PubMed
 
Jo SH, Koo BK, Youn TJ, Hahn JY, Kim YS, Kang HJ.  Prevention of contrast induced nephropathy by short term statin in patients with renal insufficiency undergoing coronary angiography: a randomized controlled trial [Abstract]. In: TCT 2005. Abstracts of the 17th Annual Transcatheter Cardiovascular Therapeutics Symposium, October 17-21, 2005, Washington DC, USA. Am J Cardiol. 2005;96:1H-213H. [PMID: 16252422]
 
Kapoor A, Kumar S, Gulati S, Gambhir S, Sethi RS, Sinha N.  The role of theophylline in contrast-induced nephropathy: a case-control study. Nephrol Dial Transplant. 2002; 17:1936-41. PubMed
 
Kay J, Chow WH, Chan TM, Lo SK, Kwok OH, Yip A. et al.  Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. JAMA. 2003; 289:553-8. PubMed
 
Kefer JM, Hanet CE, Boitte S, Wilmotte L, De Kock M.  Acetylcysteine, coronary procedure and prevention of contrast-induced worsening of renal function: which benefit for which patient? Acta Cardiol. 2003; 58:555-60. PubMed
 
MacNeill BD, Harding SA, Bazari H, Patton KK, Colon-Hernadez P, DeJoseph D. et al.  Prophylaxis of contrast-induced nephropathy in patients undergoing coronary angiography. Catheter Cardiovasc Interv. 2003; 60:458-61. PubMed
 
Merten GJ, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ. et al.  Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004; 291:2328-34. PubMed
 
Namgung J, Doh JH, Lee SY, Lee WR.  Effect of N acetylcysteine in the prevention of contrast induced nephropathy after coronary angiography [Abstract]. In: Abstracts of the 10th Annual Interventional Vascular Therapeutics Angioplasty Summit-Transcatheter Cardiovascular Therapeutics Asia Pacific Symposium. April 28-30, 2005, Seoul, Korea. Am J Cardiol. 2005;95:1A-83A. [PMID: 15889504].
 
Ochoa A, Pellizzon G, Addala S, Grines C, Isayenko Y, Boura J. et al.  Abbreviated dosing of N-acetylcysteine prevents contrast-induced nephropathy after elective and urgent coronary angiography and intervention. J Interv Cardiol. 2004; 17:159-65. PubMed
 
Oldemeyer JB, Biddle WP, Wurdeman RL, Mooss AN, Cichowski E, Hilleman DE.  Acetylcysteine in the prevention of contrast-induced nephropathy after coronary angiography. Am Heart J. 2003; 146:23. PubMed
 
Rashid ST, Salman M, Myint F, Baker DM, Agarwal S, Sweny P. et al.  Prevention of contrast-induced nephropathy in vascular patients undergoing angiography: a randomized controlled trial of intravenous N-acetylcysteine. J Vasc Surg. 2004; 40:1136-41. PubMed
 
Sandhu C, Belli AM, Oliveira DB.  The role of N-acetylcysteine in the prevention of contrast-induced nephrotoxicity. Cardiovasc Intervent Radiol. 2006; 29:344-7. PubMed
 
Shyu KG, Cheng JJ, Kuan P.  Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol. 2002; 40:1383-8. PubMed
 
Sinha SK, Berry WA, Bueti J, Junaid A, Fine A, Krahn J.  The prevention of radiocontrast-induced nephropathy trial (print): a prospective, double-blind, randomized, controlled trial of iso-osmolar versus low-osmolar radiocontrast in combination with N-acetylcysteine versus placebo [Abstract]. Presented at the American Heart Association Scientific Sessions, New Orleans, Louisiana, 7-10 November 2004. Accessed athttp://www.abstractsonline.com/arch/RecordPrintView.aspx?LookupKey=12345&RecordID=717on 19 December 2007.
 
Stone GW, McCullough PA, Tumlin JA, Lepor NE, Madyoon H, Murray P, et al. CONTRAST Investigators.  Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial. JAMA. 2003; 290:2284-91. PubMed
 
Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W.  Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med. 2000; 343:180-4. PubMed
 
Spargias K, Alexopoulos E, Kyrzopoulos S, Iokovis P, Iacovis P, Greenwood DC. et al.  Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation. 2004; 110:2837-42. PubMed
 
Webb JG, Pate GE, Humphries KH, Buller CE, Shalansky S, Al Shamari A. et al.  A randomized controlled trial of intravenous N-acetylcysteine for the prevention of contrast-induced nephropathy after cardiac catheterization: lack of effect. Am Heart J. 2004; 148:422-9. PubMed
 
Alonso A, Lau J, Jaber BL, Weintraub A, Sarnak MJ.  Prevention of radiocontrast nephropathy with N-acetylcysteine in patients with chronic kidney disease: a meta-analysis of randomized, controlled trials. Am J Kidney Dis. 2004; 43:1-9. PubMed
 
Birck R, Krzossok S, Markowetz F, Schnülle P, van der Woude FJ, Braun C.  Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet. 2003; 362:598-603. PubMed
 
Liu R, Nair D, Ix J, Moore DH, Bent S.  N-acetylcysteine for the prevention of contrast-induced nephropathy. A systematic review and meta-analysis. J Gen Intern Med. 2005; 20:193-200. PubMed
 
Ix JH, McCulloch CE, Chertow GM.  Theophylline for the prevention of radiocontrast nephropathy: a meta-analysis. Nephrol Dial Transplant. 2004; 19:2747-53. PubMed
 
Bagshaw SM, Ghali WA.  Theophylline for prevention of contrast-induced nephropathy: a systematic review and meta-analysis. Arch Intern Med. 2005; 165:1087-93. PubMed
 
Trivedi HS, Moore H, Nasr S, Aggarwal K, Agrawal A, Goel P. et al.  A randomized prospective trial to assess the role of saline hydration on the development of contrast nephrotoxicity. Nephron Clin Pract. 2003; 93:C29-34. PubMed
 
McAuley L, Pham B, Tugwell P, Moher D.  Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses? Lancet. 2000; 356:1228-31. PubMed
 
Cook DJ, Guyatt GH, Ryan G, Clifton J, Buckingham L, Willan A. et al.  Should unpublished data be included in meta-analyses? Current convictions and controversies. JAMA. 1993; 269:2749-53. PubMed
 

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Precision in language
Posted on February 18, 2008
Laurence B. Gardner
Miller School of Medicine, University of Miami
Conflict of Interest: None Declared

To the Editor,

The article by Kelley and colleagues suggesting a beneficial effect of N-acetyl-cysteine in the prevention of contrast nephropathy is interesting and helpful. The use of the term, "hydration", however is both misleading and inaccurate. Hydration, according to Steadman's medical dictionary (http://www.stedmans.com/section.cfm/45) refers to the ingestion or administration of water and water alone.

The confusion between the state of hydration and the state of extra cellular fluid volume adequacy is one shared by students and clinicians alike and made less clear by the casual use of "hydration" (or even worse "dehydration") when refering to states of volume expansion or volume depletion.

I write to suggest that precision in the use of language would make a good article even better.

Laurence B. Gardner, M.D.

Conflict of Interest:

None declared

A LARGE-SCALE RANDOMIZED CONTROLLED TRIAL WITH N-ACETYLCYSTEINE IS URGENTLY NEEDED
Posted on February 25, 2008
Otavio Berwanger
Research-Institute Cardiac Hospital (HCor)
Conflict of Interest: None Declared

I would like to congratulate Kelly and co-workers for a well conducted systematic review and meta-analysis (comprehensive search strategy, critical appraisal of included studies, duplicate data extraction and adequate meta-analysis model). On the other hand, I disagree with the authors conclusions that: "the use of N-acetylcysteine is reasonable in high-risk patients who are to receive large or repeated volumes of contrast agents". Although N-acetylcysteine represents an inexpensive, potentially safe, and wide available intervention, the evidence that N-acetylcysteine reduces contrast-induced nephropathy (a surrogate outcome) comes from trials with heterogeneous results, the majority of which of low-methodological quality according to the authors critical appraisal. Moreover, the impact of N-acetylcysteine on patient- important outcomes such as all-cause mortality, doubling of serum creatinine, and need for dialysis is uncertain. The current available N- acetylcysteine evidence is encouraging, but too unreliable to allow definitive conclusions. Thus, a well-designed large-scale placebo controlled randomized trial evaluating clinical outcomes is urgently needed before implementing this intervention in clinical practice.

Conflict of Interest:

None declared

Utilization pattern of N-acetylcysteine
Posted on March 10, 2008
Sagar U Nigwekar
Rochester General Hospital and University of Rochester, Rochester, NY
Conflict of Interest: None Declared

To the Editor, We read with interest the detailed systematic review of agents to prevent contrast nephropathy by Kelly and colleagues (1). Their analysis rightly supports the administration of N-acetylcysteine for high-risk patients. However, how N-acetylcysteine is actually prescribed in clinical practice is not well described. To characterize the utilization pattern of N- acetylcysteine, we retrospectively reviewed the data in patients undergoing elective percutaneous coronary intervention at two institutes. Our analysis consisted of 515 non-dialysis dependent adult patients. We abstracted information on following variables- age, baseline hematocrit, baseline serum creatinine and estimated glomerular filtration rate (eGFR), New York Heart Association class III/IV congestive heart failure (CHF), periprocedural blood pressure, intra-aortic balloon pump (IABP) requirement, diabetes mellitus, and volume of necessary contrast medium. As per the prediction model by Mehran (2), we calculated contrast nephropathy risk score for each patient and then stratified the population as follows- risk score < or = to 5 (group I) which corresponds to the risks of contrast nephropathy (defined as an increase of 25% or 0.5 mg/dl in pre-procedure serum creatinine at 48 hour after the procedure) and dialysis of 7.5% and 0.04% respectively, risk score 6 to10 (group II) corresponding to the risks of contrast nephropathy and dialysis of 14.0% and 0.12% respectively, risk score 11 to 15 (group III) corresponding to the risks of contrast nephropathy and dialysis of 26.1% and 1.09% respectively, and risk score > or equal to 16 (group IV) corresponding to the risks of contrast nephropathy and dialysis of 57.3% and 12.6% respectively. In our sample population, group I consisted of 206 patients, group II had179 patients, group III 102 patients and group IV had 28 patients. N-acetylcysteine was administered in 13.1%, 24.6%, 26.5%, and 35.7% of patients in groups I, II, III and IV respectively (p<0.01). Thus, although the utilization of N-acetylcysteine was more in high-risk patients compared to low-risk patients, we found that clinicians prescribed N-acetylcysteine in a significant number of low-risk patients. N-acetylcysteine is typically administered at least 12 hours in advance of contrast exposure and insistence on such protocol has a potential to delay procedures. Such delay may not be justified in low-risk patients since there is no evidence to support its use in low-risk patients. Meta- analysis by Kelly et al will help clinicians understand the current evidence in the literature about agents to prevent contrast-induced nephropathy and improve the utilization pattern of N-acetylcysteine.

References: 1. Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC. Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med. 2008 Feb 19;148(4):284-94. 2. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol. 2004 Oct 6;44(7):1393-9.

Conflict of Interest:

None declared

Meta-analysis: Effectiveness of drugs for preventing contrast-induced nephropathy
Posted on March 14, 2008
Giuseppe Ferrante
Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
Conflict of Interest: None Declared

We read with interest the article by Kelly et al. (1) in which the authors assessed the effectiveness of several drugs, including N- Acetylcysteine and theophylline, in preventing contrast induced nephropathy (CIN) by means of meta-analysis. A total of 41 studies were assessed and the authors conclude that the administration of N-acetylcysteine is the most effective agent for preventing CIN (1). The authors should be commended in undertaking such a comprehensive review of the literature. Several issues, however, particularly with the methodology adopted in the meta-analysis need to be considered before the results are accepted as truly representative of "˜real world' practice. The treatment effect estimates from the selected 41 articles were not combined into a single summary pooled estimate, thus it is not known which effect the use of a renoprotective agent has on the occurence of CIN. Moreover the overall heterogeneity has not been reported. Instead, only subgroup summary estimates are presented as risk ratios, with subgroups according to the specific renoprotective agent, without any comparison of the estimates of treatment effect between subgroups as recommended (2). If the aim was to make a comparison between different agents, the lack of head of head direct comparisons should then have prompted "˜an indirect comparison meta-analysis' with a common comparator (3,4). In the simplest case of an indirect comparison between two treatments, each directly compared to placebo (common comparator), the use of an appropriate test on interaction is mandatory (2) to provide the statistical evidence of a qualitative and/or quantitative interaction between subgroups. Thus, the present work cannot conclude if N-Acetylcysteine has a different effect on CIN compared to theophilline. Another factor that may have provided even greater insights is the evaluation of the possible sources of heterogeneity in the subgroup of N- Acetylcysteine, including dosage, timing and duration of its administration. This may have been performed, by means of metaregression analysis. Finally the authors did not state in the methods the level of statistical significance, and which test of heterogeneity they used to derive the p value reported in Figure 2. The finding of a p =0.14 in the theophilline subgroup cannot rule out the presence of clinical heterogeneity, as the standard Cochran's Q test has a poor power (5), and also I2=39.7 % is not negligible.

References

1.Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC. Meta- analysis: effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med. 2008;148:284-294.

2.Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ 2003;326:219.

3.Bucher HC, Guyatt GH, Griffith LE,Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 1997;50:683-691.

4.Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003;326:472.

5.Fleiss JL. The design and analysis of clinical experiments. New York, NY: John Wiley & Sons, 1986:100-102.

Conflict of Interest:

None declared

N-Acetylcysteine for Contrast-induced Nephrotoxicity: Persistent Concerns about Safety and Efficacy
Posted on March 19, 2008
Robert L. Danner
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD
Conflict of Interest: None Declared

To the Editor

A recent meta-analysis of treatments to prevent contrast-induced nephrotoxicity (CIN) by Kelly et al. concluded that N-acetylcysteine (NAC) was renoprotective; prophylaxis was recommended "particularly in high risk patients, given its low cost, availability, and few side effects (1)." At least 13 other meta-analyses have examined this issue and 6 of these, including one performed by us (2), reached different conclusions.

Like Kelly et al. (1), we found significant unexplained heterogeneity among 22 published trials (2). This heterogeneity and most of the apparent benefit of NAC was attributable to four small, relatively early trials (open circles in Fig. 1; circles weighted by trial size). In these overly influential trials, NAC administration not only prevented CIN, but also tended to decrease creatinine below baseline (p = 0.07). As noted by Kelly et al. and the Editor, NAC trials have been limited by the lack of clinically relevant endpoints; until recently the primary outcome has been creatinine change (1). Importantly, Hoffman et al found that NAC did not affect plasma cystatin C, a less confounded measure of renal function, even while decreasing creatinine (3). Moreover, protection against contrast-induced nephrotoxicity by NAC, based on change in creatinine, has not been confirmed using simultaneous measurements of cystatin C (4); therefore effects of NAC on creatinine may not reflect true benefit in regards to the glomerular filtration rate. Examining a more clinically relevant outcome across 22 trials (2), we found that only 13 patients received dialysis, 5 control and 8 NAC-treated (p = 0.42); this result does not suggest a meaningful therapeutic effect.

In addition to the doubtful claim of NAC efficacy, unreferenced statements of proven safety also warrant comment. Clinical trials for the prevention of CIN have largely employed small oral doses of NAC in stable outpatient populations. However, critically ill patients with shock and ARDS are also at high-risk for CIN and some physicians advocate the use of intravenous doses of NAC in these settings. When prospectively studied in acetaminophen poisoning, intravenous NAC produced anaphylactoid reactions in up to 48% of subjects (5). While most of these reactions were mild, at least one fatality has been reported in a patient with asthma (6). Other investigators have reported potentially harmful effects of NAC in septic shock (7, 8) and a trial of oxothiazolidine-4-carboxylic acid (a cysteine pro-drug) in ARDS (9) was stopped early due to excess mortality in the treatment arm (29.7% versus 15.8%, p = 0.014).

We conclude that the efficacy of NAC for preventing CIN remains unproven. Future studies should not use change in serum creatinine as the primary endpoint. In critically ill patients at risk for CIN, the efficacy and safety of NAC has not been established.

Denise A. Gonzales MD Presbyterian Hospital, Albuquerque, NM

Robert A. Star MD Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

Steven J. Kern BS, Charles Natanson MD, and Robert L. Danner MD Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD

1. Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC. Meta- analysis: Effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med. 2008; 148:284-94.

2. Gonzales DA, Norsworthy KJ, Kern SJ, Banks S, Sieving PC, Star RA, et al. A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity. BMC Medicine 2007; 5:32.

3. Hoffman U, Fischereder M, Kruger B, Drobnik W, Krämer BK. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol. 2004; 15:407-10.

4. Poletti P-A, Saudan P, Platon QA, Mermillod B, Seutter A-M, Vermeulen B, et al. IV N-Acetylcysteine and emergency CT: Use of serum creatinine and cystatin C as markers for radiocontrast nephrotoxicity. Am J Radiol. 2007; 188:687-92.

5. Lynch RM, Robertson R. Anaphylactoid reactions to intravenous N- acetylcysteine: a prospective case controlled study. Accident and Emergency Nursing 2008; 12:10-15.

6. Appelboam AV, Dargan PI, Knighton J. Fatal anaphylactoid reaction to N-acetylcysteine: caution in patients with asthma. Emerg Med. 2002; 19:594-5.

7. Molnár Z, Shearer E, Lowe D. N-Acetylcysteine treatment to prevent the progression of multisystem organ failure: A prospective, randomized, placebo-controlled study. Crit Care Med. 1999; 27:1100-04.

8. Peake SL, Moran JL, Leppard PI. N-acetyl-L-cysteine depresses cardiac performance in patients with septic shock. Crit Care Med. 1996; 24:1302-10.

9. Morris PE, Papadakos P, Russell JA, Wunderkink R, Schuster DP, Truwit JD, et al. A double-blind placebo-controlled study to evaluate the safety and efficacy of L-2-oxothiazolidine-4-carbosylic acid in the treatment of patients with acute respiratory distress syndrome. Crit Care Med. 2008; 36: [epub ahead of print].

Conflict of Interest:

None declared

Effectiveness of drugs for preventing contrast-induced nephropathy
Posted on March 19, 2008
Hariprasad S. Trivedi
Medical College of Wisconsin
Conflict of Interest: None Declared

To The Editor:

While efforts by Kelly et al for their exhaustive meta-analysis (1) are laudable I have some comments.

Firstly, readers would welcome clarification of the number of studies involving N-acetylcysteine that were finally included. There is a discrepancy in the number of N-acetylcysteine studies in Figure 1 and those listed in the Table and Forest plot. It would be helpful to understand why four studies were excluded after deemed to have satisfied criteria. Secondly, the paper cited as a study involving furosemide and mannitol (Table) is a review relating to selection of contrast media (2). The actual mannitol and furosemide study was published elsewhere (3). Such errors in referencing tend to perpetuate.

Further, the significant heterogeneity with respect to N- acetylcysteine effect merits comment. Some statistical authorities suggest that if there is substantial heterogeneity a summary effect should not be derived (4), a point that at least merits discussion. The random-effects model does not necessarily eliminate the problem of heterogeneity (5). Particularly, if there is significant proportion of studies that differ in treatment effect and direction (see study Forest plot) combining them could lead to misleading conclusions (5). Thus, consistent with prior meta -analyses, the effect of N-acetylcysteine remains uncertain and to conclude otherwise is incorrect.

Further, I want to draw attention to the editors' note. The paper presents no evidence of the benefit of theophylline. The analysis itself, which includes one aminophylline trial (Abizaid et al. Am J Cardiol 1999:83:260-263), did not reach statistical significance. Upon closer examination, two included studies were published from the same institute and had similar methodology (Huber et al. Radiology 2002;223:772-779 & Huber et al. Am J Cardiol 2003;91:1157-62). There are differences, such as the first paper was not restricted to subjects undergoing coronary angiography but had 54 such subjects. The second paper solely included subjects undergoing coronary angiography. It is possible the second paper included 54 subjects also included in the first study. If so, inclusion of both could bias results in favor of theophylline. Lastly, the editorial comment regarding the benefit of mannitol merits correction. The authors presented only one mannitol study, which had shown that mannitol was harmful as compared to half-normal saline (3).

I applaud the authors and the editors for making the point that change in creatinine is a surrogate laboratory outcome. It is of greater importance to show the benefit of preventative interventions on clinical outcomes such as mortality regarding which there are scant data.

References:

1)Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC. Meta- analysis: Effectiveness of Drugs for Preventing Contrast-Induced Nephropathy. Ann Intern Med 2008;148:284-294.

2)Solomon R, Briguori C, Biguori C, Bettmann M. Selection of contrast media. Kidney Int Suppl. 2006:S39-45.

3)Solomon R, Werner C, Mann D, D'Elia J, Silva Pl. Effects of saline, mannitol, and furosemide on acute decreases in renal function caused by radiocontrast agents. N Engl J Med 1994;331:1416-1420.

4)Hulley SB, Cummings SR, Browner WS, Grady D, Hearst N, Newman TB. Designing Clinical Research, 2nd edition. Philadelphia, PA: Lippincott, Williams, and Wilkins; 2001.

5)Deeks JJ, Higgins, JPT, Altman DG, editors. Analysing and presenting results. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005]; Section 8. http://www.cochrane.org/resources/handbook/hbook.htm (last accessed 19 March 2008)

Conflict of Interest:

None declared

THE PRIMACY OF ACCURATE DISEASE MARKERS
Posted on March 30, 2008
Charles J. Diskin
Auburn Univeristy
Conflict of Interest: None Declared

While I admire Dr. Kelly's meta-analysis that advocates the superior protection of N-acetylcysteine (NAC) in radiocontrast induced nephropathy (CIN),1 her efforts may have only merely once again proven the importance of understanding the strengths and limitations of your disease marker before embarking on any statistical analysis. Unfortunately serum creatinine was chosen as her surrogate marker for glomerular filtration rate (GFR). Serum creatinine has long been known to be a poor marker of GFR.2 When serum values are less than 1.0 mg/dl (88 micromol/L), the Jaffe reaction overestimated true creatinine by as much as 90%,3 but in clearance studies, that error is often counterbalanced by tubular secretion unrelated to GFR. Anything that interferes with the tenuous balance of creatinine secretion and overestimation of noncreatinine chromogens will result in major miscalculations of estimated GFR (eGFR).4 Many drugs have been long known to interfere with that relationship. Trimethoprim,5 cimetidine6 or fenofibrate7 interfere with tubular secretion while dopamine and dobutamine interfere with the with the Jaffe reaction and the measurement of creatinine.8 In one recent study of fifty healthy volunteers, NAC administered orally at a dose of 600 mg every 12 h, for a total of four doses resulted in a significant decrease in the mean serum creatinine concentration (P < 0.05) and a significant increase in the eGFR (P < 0.02) without any change in cystatin C concentrations.9 That study has led many to conclude that NAC merely interferes with the measurement of serum creatinine without any real effect on kidney function. That may explain why NAC administration not only prevented CIN, but also tended to decrease creatinine below baseline in some studies. While others have disagreed 10 with those findings, further studies will be needed to determine the effect of NAC on the laboratory measurement of creatinine. Until then, meta-analyses of studies using isolated serum creatinines as a surrogate of GFR are pointless.

REFERENCES

1. Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC. Meta- analysis: effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med. 2008 Feb 19;148(4):284-94. 2. Carrie BJ, Golbetz HV, Michaels AS and Myers BD. Creatinine: an inadequate filtration marker in glomerular disease. Am J Med 1980;69:177- 182. 3. Chasson AL, Grady HJ, Stanley MA. Determination of creatinine by means of automatic chemical analysis. Tech Bull Regist Med Technol. 1960 Dec; 30:207-12. 4. Diskin CJ. Creatinine and glomerular filtration rate: evolution of an accommodation. Ann Clin Biochem. 2007 Jan;44(Pt 1):16-9. 5. Berglund F, Killander J, Pompeius R. Effect of trimethoprim- sulfamethoxazole on the renal excretion of creatinine in man. J Urol. 1975 Dec;114(6):802-8. 6. Burgess E, Blair A, Krichman K, Cutler RE. Inhibition of renal creatinine secretion by cimetidine in humans. Ren Physiol. 1982;5(1):27- 30. 7. Hottelart C, El Esper N, Rose F, Achard JM, Fournier A. Fenofibrate increases creatininemia by increasing metabolic production of creatinine. Nephron. 2002;92(3):536-41. 8. Daly TM, Kempe KC, Scott MG. Bouncing Creatinine levels. N Engl J Med 1996;334:1749-1750. 9. Hoffmann U, Fischereder M, Kruger B, et al. The value of N-acetyl- cysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol (2004) 15:407"“410 10. Haase M, Haase-Fielitz A, Ratnaike S, Reade MC, Bagshaw SM, Morgera S, Dragun D, Bellomo R. N-Acetylcysteine does not artifactually lower plasma creatinine concentration. Nephrol Dial Transplant. 2008 Jan 17;epublished ahead of print

Conflict of Interest:

None declared

Use of Non-FDA Approved N-acetylcysteine
Posted on April 14, 2008
Justin Keeler
Sparrow Hospital
Conflict of Interest: None Declared

In the meta-analysis by Kelly et. al., they investigate the use of N- acetylcysteine (NAC) for preventing contrast-induced nephropathy (CIN) and demonstrate a significant reduction in relative risk associated with the use of this agent.1 The article explains that NAC is inexpensive, readily available, easily administered, associated with few adverse events in long -term use, and may therefore be cost-effective in appropriate patients. The Internet website Shopping.com (http://www.shopping.com/) was cited for pricing and formulation data of NAC.

It is important to note that prescription-only NAC is available as either an inhalation solution or an injectable product. The inhalation solution is commonly used off-label as an oral solution in acetaminophen overdose. NAC also is available without prescription as oral and are considered a dietary supplement, which are not mandated to comply with U.S. Pharmacopeia (USP) drug manufacturing standards. The American Society of Health-System Pharmacists (ASHP) published a statement on the use of dietary supplements and advocates appropriate caution in their use.2

Federal regulations affecting dietary supplements and prescription medications differ. Dietary supplement manufacturers may voluntarily adhere to USP standards or may belong to a trade group and voluntarily follow their own devised current good manufacturing practices (cGMP's). Variability among the safety, quality, identity, potency, and purity (SQuIPP) criteria of the dietary supplemental formulation of NAC is assumed to exist, yet the degree of variability remains unknown due to the observed manufacturer's non-submission to independent testing. No adherence to USP standards was observed among the NAC brands available at Shopping.com at the time of composition of this article (04/04/08).

The available inhalation formulation of NAC is relatively inexpensive, and may not threaten the cost-effectiveness of NAC use for CIN prophylaxis. The price of one NAC 500-mg tablet was cited as 23 cents in the article. The institutional cost of the inhalation-formulated NAC 500 mg to a hospital may approximate 30 cents. Ingestion of the inhalation solution may be less palatable than oral tablets due to the inherent sulfurous smell and taste of NAC. However, the integrity and purity of the USP-compliant NAC solution is ensured. Several studies have investigated the dilution, flavoring, and stability of NAC solution to improve patient acceptance of its taste and smell.4,5

Patient health concerns are paramount in the selection of a dietary supplement to satisfy a therapeutic need. Given the current state of dietary supplement regulation in the U.S, we recommend using FDA-approved formulations to achieve best patient care practices.

References: 1. Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC. Meta-analysis: Effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med. 2008 Feb 19;148:284-94.

2. Kroll DJ. ASHP statement on the use of dietary supplements. Am J Health Syst Pharm. 2004 Aug 15;61(16):1707-11.

3. Crouch BI, Caravati EM, Dandoy C. Effect of dilution with beverages on the smell and taste of oral acetylcysteine. Am J Health-Syst Pharm. 2007;64:1965-8.

4. Siden R, Johnson CE. Stability of flavored formulation of acetylcysteine for oral administration. Am J Health-Syst Pharm. 2008;65:558-61.

Conflict of Interest:

None declared

N-acetylcysteine in Clinical Studies
Posted on April 23, 2008
Brian M. Gilfix
McGill University Health Centre
Conflict of Interest: None Declared

I read with interest the study of Kelly et al (Ann Intern Med 2008;148:284-294) on the use of N-acetylcysteine (NAC) as a renal protective agent to prevent contrast-induced nephropathy. The authors comment that significant subgroup heterogeneity was present only for NAC. Besides the obvious causes of differences in dose, timing of dose, and route of administration, I would suggest that there is another potential contributor. The pill forms of NAC used appear to have been obtained "over -the-counter" and, thus, not subject to FDA or Health Canada oversight as least in terms of NAC content, availability, or stability of the these oral preparations. Differences in the potency of the various NAC preparations may have produced some of the variability in the results. At best only 5 of the 26 studies cited used a form of NAC (liquid either p.o. or IV) subject to regulatory approval. In contrast, pharmaceutical companies produced the other medications studied.

The use of NAC in this fashion is, in fact, an "off-label" use of this medication. From personal experience, extramural funding agencies and ethics boards require approval by Health Canada in Canada and, I presume, the FDA in the US, of any medication used off "“label. For approval, Health Canada further requires stability and analytical data on any product not already having a DIN number which none of the pill forms of NAC have. Obtaining the necessary information from manufacturers of these pill forms can prove very difficult, if not impossible. Investigators planning the off-label use of a known medication or use of "over-the-counter" preparation must be cognizant of these facts both to obtain resources for such studies and to obtain reliable and consistent results.

Conflict of Interest:

None declared

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