Aine M. Kelly, MD, MS; Ben Dwamena, MD; Paul Cronin, MD, MS; Steven J. Bernstein, MD, MPH; Ruth C. Carlos, MD, MS
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, firstname.lastname@example.org.
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.
N-Acetylcysteine, theophylline, and other agents have shown inconsistent results in reducing contrast-induced nephropathy.
To determine the effect of these agents on preventing nephropathy.
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.
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.
Abstracted information included patient characteristics, type of contrast media and dose, periprocedural hydration, definition of contrast-induced nephropathy, and prophylactic agent dose and route.
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.
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.
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.
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.
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.
Available studies examined laboratory end points (such as an increase in serum creatinine levels) rather than clinical end points (such as dialysis or death).
Trial identification, inclusion, and exclusion.
Table. Study Characteristics
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.
Appendix Table. Summary of Study Quality Characteristics
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Laurence B. Gardner
Miller School of Medicine, University of Miami
February 18, 2008
Precision in language
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.
Research-Institute Cardiac Hospital (HCor)
February 25, 2008
A LARGE-SCALE RANDOMIZED CONTROLLED TRIAL WITH N-ACETYLCYSTEINE IS URGENTLY NEEDED
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.
Sagar U Nigwekar
Rochester General Hospital and University of Rochester, Rochester, NY
March 10, 2008
Utilization pattern of N-acetylcysteine
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.
Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
March 14, 2008
Meta-analysis: Effectiveness of drugs for preventing contrast-induced nephropathy
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.
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.
Robert L. Danner
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD
March 19, 2008
N-Acetylcysteine for Contrast-induced Nephrotoxicity: Persistent Concerns about Safety and Efficacy
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, KrÃ¤mer 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. MolnÃ¡r 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].
Hariprasad S. Trivedi
Medical College of Wisconsin
Effectiveness of drugs for preventing contrast-induced nephropathy
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.
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)
Charles J. Diskin
March 30, 2008
THE PRIMACY OF ACCURATE DISEASE MARKERS
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.
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
April 14, 2008
Use of Non-FDA Approved N-acetylcysteine
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.
Brian M. Gilfix
McGill University Health Centre
April 23, 2008
N-acetylcysteine in Clinical Studies
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.
Aine M. Kelly, Ben Dwamena, Paul Cronin, Steven J. Bernstein, Ruth C. Carlos. Meta-analysis: Effectiveness of Drugs for Preventing Contrast-Induced Nephropathy. Ann Intern Med. 2008;148:284–294. doi: 10.7326/0003-4819-148-4-200802190-00007
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