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Acetylcysteine in the Prevention of Contrast-Induced Nephropathy

Acetylcysteine in the Prevention of Contrast-Induced Nephropathy During the past 5 years, 19 randomized controlled trials, 4 prospective nonrandomized studies, and 11 meta-analyses that explored the role of acetylcysteine for prevention of contrast-induced nephropathy have been published. Herein, we summarize this literature and demonstrate that these 34 empirical studies have not yet conclusively resolved this research question. We use the evidence on acetylcysteine as a case study of how research evidence accumulates and consider whether an alternative approach to investigating the question of acetylcysteine's efficacy could have resulted in a more definitive conclusion. We consider the broader lessons learned from this acetylcysteine case study for the medical and research communities and propose specific steps that could be taken to improve the future coordination of research activity to ultimately yield more meaningful and definitive evidence on important clinical questions.We are drowning in information, but starved for knowledgeJohn Nesbitt, Megatrends, 1987The remarkable proliferation of peer-reviewed publications that explore the role of acetylcysteine for prevention of contrast-induced nephropathy (CIN) in the past 5 years is an interesting case study on the evolution of medical knowledge. Since the first clinical trial was published in 2000,another 18 randomized controlled trials (RCTs),4 prospective nonrandomized studies,and 11 meta-analyseshave appeared. Although 5 of the RCTs found statistically significant benefits and 9 concluded that acetylcysteine was beneficial, 13 RCTs reported results that were not statistically significant and 10 concluded that acetylcysteine was not beneficial (Table 1). Likewise, meta-analyses have also yielded conflicting messages, with 7 concluding that acetylcysteine is beneficial and 4 concluding that the data remain inconclusive (Table 2).Table 1. Publication History and Summary of Findings for RCTs on the Efficacy of Acetylcysteine for Prevention of Contrast-Induced NephropathyRCT*PopulationQuality ScoreConcealed Allocation DescribedAcetylcysteine ProtocolHydration ProtocolPrimary OutcomeAcetylcysteine Event Rate, No. (%)Control Event Rate, No. (%)Summary RR (95% CI)†Tepel et al(n = 83)Elective CT2Unclear600 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>44.2-&mgr;mol/L SCr increase at 48 h1/41 (2)9/42 (21)0.11 (0.02-0.86)Diaz-Sandoval et al(n = 54)Elective angiography4Unclear600 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 2-12 h pre and 12 h post>44.2-&mgr;mol/L or 25% SCr increase at 48 h2/25 (8)13/29 (45)0.18 (0.04-0.72)Briguori et al(n = 183)Elective angiography1Unclear600 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>25% SCr increase at 48 h or dialysis6/92 (7)10/91 (11)0.59 (0.23-1.57)Vallero et al(n = 100)Angiography2Unclear600 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 1-2 h pre and 24 h post>44.2-&mgr;mol/L or 33% SCr increase at 48 h4/47 (9)4/53 (8)1.1 (0.3-4.3)Shyu et al(n = 121)Elective angiography3Unclear400 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>44.2-&mgr;mol/L SCr increase at 48 h2/60 (3)15/61 (25)0.13 (0.08-0.2)Allaqaband et al(n = 85)Angiography3Unclear600 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>44.2-&mgr;mol/L SCr increase at 48 h8/45 (18)6/40 (15)1.2 (0.47-3.3)Durham et al(n = 83)Angiography5Adequate1200 mg orally 1 h pre and 3 h post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>44.2-&mgr;mol/L SCr increase at 48 h10/38 (26)9/41 (22)1.2 (0.55-2.6)Kay et al(n = 200)Elective angiography5Adequate600 mg orally twice daily 4 times (3 pre)0.9% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre and 6 h post>25% SCr increase at 48 h4/102 (4)12/98 (12)0.32 (0.11-0.96)Baker et al(n = 80)Angiography2Unclear150 mg/kg intravenously 30 min pre and 50 mg/kg intravenous infusion 4 h postControl 0.9% isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>25% SCr increase at 48 or 96 h2/41 (5)8/39 (21)0.28 (0.08-0.98)MacNeill et al(n = 43)Elective angiography4Unclear600 mg orally 5 times (2 pre)Inpatient: 0.45% isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre; outpatient: 0.45% isotonic sodium chloride solution, 2 mL/kg hourly 4 h pre and 12 h post>25% SCr increase at 72 h1/21 (5)7/22 (32)0.15 (0.02-1.1)&numsp;   RCT*PopulationQuality ScoreConcealed Allocation DescribedAcetylcysteine ProtocolHydration ProtocolPrimary OutcomeAcetylcysteine Event Rate, No. (%)Control Event Rate, No. (%)Summary RR (95% CI)†Efrati et al(n = 49)Elective angiography4Unclear1000 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>25% SCr increase at 24 or 96 h0/24 (0)2/25 (8)NAOldemeyer et al(n = 96)Elective angiography4Unclear1500 mg twice daily 4 times (1 pre)0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>44.2-&mgr;mol/L or 25% SCr increase at 48 h4/49 (8)3/47 (6)1.28 (0.30-5.4)Kefer et al(n = 104)Angiography4Unclear1200 mg intravenously 12 h pre and immediately postDextrose 5%, 20 mL/h 12 h pre and 24 h post>44.2-&mgr;mol/L SCr increase at 24 h2/53 (8)3/51 (6)0.64 (0.1-3.7)Goldenberg et al(n = 80)Angiography5Adequate600 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>44.2-&mgr;mol/L SCr increase at 48 h4/41 (10)3/39 (8)1.30 (0.27-6.2)‡Fung et al(n = 91)Elective angiography4Adequate400 mg orally 3 times daily pre/post0.9% Isotonic sodium chloride solution, 100 mL/h 12 h pre/post>44.2-&mgr;mol/L or 25% decrease in GFR8/46 (17)6/45 (13)1.3 (0.5-3.5)Ochoa et al(n = 80)Angiography3Adequate1000 mg orally 1 h pre and 4 h post0.9% Isotonic sodium chloride solution, ≥1500 mL>44.2-&mgr;mol/L or 25% SCr increase at 48 h3/36 (8)11/44 (25)0.33 (0.1-1.1)Webb et al(n = 487)Angiography3Adequate500 mg intravenously pre0.9% Isotonic sodium chloride solution, 200 mL pre and 1.5 mL/kg hourly for 6 h post>5-mL/min decrease in GFR (or>44.2-&mgr;mol/L SCr increase at 48 h)51/220 (23) (16/200 [7.3])47/227 (21) (13/227 [5.7])1.1 (0.8-1.6)Miner et al(n = 171)Angiography4Unclear2000 mg orally 2-3 times pre0.45% Isotonic sodium chloride solution, 75 mL/h for 24 h>25% SCr increase at 48-72 h9/89 (10)18/82 (22)0.37 (0.14-0.93)Rashid et al(n = 94)Elective angiography4Unclear1000 mg intravenously pre/post0.9% Isotonic sodium chloride solution, 500 mL pre/post>44.2-&mgr;mol/L or 25% SCr increase at 48 h3/46 (6.5)3/48 (6.3)1.0 (0.2-4.9) Abbreviations: CI, confidence interval; CT, computed tomography; GFR, glomerular filtration rate; NA, not applicable; pre, preoperatively; post, postoperatively; RCT, randomized controlled trial; RR, relative risk; SCr, serum creatinine.  Conventional unit conversion factor: To convert SCr to milligrams per deciliter, divide by 88.4. *All trials were single center except the ones by Baker et al(multicenter, 3 sites) and Webb et al(multicenter, 2 sites). †Pooled RR estimate calculated from available data for selected studies. ‡Pooled estimate is odds ratio.Table 2. Publication History and Summary of Findings for Meta-analyses on the Efficacy of Acetylcysteine for Prevention of Contrast-Induced NephropathySourceClinical ScopeStudies Included*No. of Trials IncludedNo. of Patients IncludedHeterogeneity (PValue)Pooled Estimate (95% CI)Author ConclusionsBirck et alCT or angiographyA7805Present (P = .02)RR, 0.44 (0.22-0.88)Treatment beneficialIsenbarger et alCT or angiographyA7805Present (P = .01)OR, 0.37 (0.16-0.84)Treatment beneficialAlonso et alCT or angiographyA, B8885Not reportedRR, 0.41 (0.22-0.79)Treatment beneficialKshirsagar et alCT or angiographyA, B161538Present (P<.001)Not reportedInconclusivePannu et alCT or angiographyA, B, D151776Present (P = .02)RR, 0.65 (0.43-1.0)InconclusiveGuru and FremesCT or angiographyA, C111213Present (P = .01)OR, 0.46 (0.32-0.66)Treatment beneficialBagshaw and GhaliAngiographyA141261Present (P = .03)OR, 0.54 (0.32-0.91)InconclusiveMisra et alAngiographyA5643Present (P = .05)RR, 0.30 (0.11-0.82)Treatment beneficialNallamothu et alCT or angiographyA, D202195Present (P = .01)RR, 0.73 (0.52-1.0)InconclusiveLiu et alCT or angiographyA, B91028Present (P = .03)RR, 0.43 (0.24-0.75)Treatment beneficialDuong et alCT or angiographyA, C141584Present (P = .01)RR, 0.57 (0.37-0.84)Treatment beneficial Abbreviations: CI, confidence interval; CT, computed tomography; OR, odds ratio; RR, relative risk. *Source(s) of data for meta-analyses: A indicates published articles describing randomized controlled trials; B, published abstracts describing randomized controlled trials; C, published articles describing nonrandomized clinical trials; and D, unpublished data.WHY SO MANY RCTs?Generally, the design, planning, and completion of RCTs represent a substantial undertaking that demands considerable resources. However, several aspects of acetylcysteine and the target condition (CIN) may have contributed to the rapid proliferation of RCTs on this topic. Notably, radiocontrast use is frequent, CIN is relatively common and potentially preventable, and acetylcysteine has established familiarity with clinicians, is inexpensive, and poses relatively little risk to patients. Also, the primary outcome in these trials (change in serum creatinine level) is easy to measure and requires limited patient follow-up. Finally, the stimuli provided to trialists by virtue of the first trial on this topicbeing published in a major front-line journal and reporting a large treatment effect (but with wide confidence intervals) should not be discounted.It is conceivable that the relative ease of conducting these studies encouraged less experienced groups to perform clinical trials, a notion perhaps supported by the predominance of small single-center studies. However, many of the acetylcysteine trials were well done and scored highly on a widely accepted scale assessing RCT quality(Table 1).WHY SO MANY META-ANALYSES?The appearance of several trials in such a short period also seems to have created a scenario that appealed to many as a subject for meta-analysis, particularly given the divergent results across trials. A common misperception, however, is that meta-analyses can serve as a tool for simply resolving contradictory data. In fact, pooling of data to arrive at a summary estimate for treatment efficacy should generally be avoided in situations where the trials exhibit significant statistical and/or clinical heterogeneity.This is not to say that meta-regression cannot be used as a tool to explore the reasons for discordant data and develop hypotheses, but meta-analysis to generate a pooled estimate should not be seen as a means to resolve discordant data.Statistical heterogeneity is present when the variation in results across individual studies is beyond that expected from chance alone.When present, quantitative pooling may lead to erroneous conclusions.Interestingly, the pooled efficacy estimates for acetylcysteine across meta-analyses published to date are generally similar, but the disparate interpretations arise from differences in how the meta-analysts deal with the issue of heterogeneity. The 7 meta-analyses that concluded that acetylcysteine was beneficial largely overlooked the issue of heterogeneity,whereas the 4 that highlighted the presence of heterogeneity concluded that the data were still inconclusive.Clinical heterogeneity, meanwhile, is judged by examining the patient populations, eligibility criteria, intervention protocols, cointerventions, and primary outcomes in a group of trials. Table 1confirms considerable clinical heterogeneity across the trials of acetylcysteine, and the disparate conclusions from the meta-analyses published to date may partially relate to different study inclusion criteria (published RCTs only vs inclusion of unpublished data, abstracts, and/or nonrandomized studies)or inclusion of different patient populations and procedures (ie, 2 meta-analyses focused only on arterial angiography). Additionally, earlier meta-analyses are more likely to be influenced by time-lag bias,since small clinical trials are more likely to be published early if they find large benefits and clinical trials that report fewer benefits (even if they include more outcome events) are less likely to be published or tend to be published later(Table 2).Thus, given the clinical trial data published to date, meta-analysis cannot resolve the uncertainty engendered by 19 small RCTs with heterogeneous results for a surrogate outcome (change in serum creatinine level rather than “harder” end points, such as need for dialysis or mortality). In fact, for a trial to detect a meaningful reduction in risk for a clinically important outcome such as need for dialysis even in a high-risk cohort (for example, with a baseline risk of dialysis approaching 7%), researchers would need to enroll more than 1800 patients.Ultimately, a much larger trial with high methodologic quality that involves multiple centers to achieve sufficient power to study clinically meaningful outcomes is needed to definitively resolve whether acetylcysteine prevents CIN.COMMENTDespite the proliferation of acetylcysteine studies, we still do not know whether acetylcysteine is efficacious for the prevention of CIN. This raises the question of whether the medical community would have been better served by an alternative approach to the investigation of acetylcysteine for CIN.A first observation is that the research performed to date on acetylcysteine has occurred without any obvious coordination of activity across research groups. This lack of coordination amounts to a missed opportunity; if the authors of the published trials had initially collaborated on a large multicenter trial like that described herein, more definitive evidence could have been produced.Encouragingly, new initiatives exist that may enhance the coordination of research activity in the future. These initiatives include searchable registries that can inform researchers of ongoing trials in specific clinical areas and therefore potentially reduce duplication and enhance the coordination of research activity; for example, see the National Library of Medicine (ClinicalTrials.gov), Veteran Affairs Cooperative Studies Program (www.vacsp.gov), the Cochrane Central Register of Controlled Trials (www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/HOME), and the Current Controlled Trials (www.controlled-trials.com/mrct) Web sites.These clinical trial registry initiatives will assume greater importance now that the International Committee of Medical Journal Editors (ICMJE) has drawn attention to the importance of comprehensive clinical trial registries and imposed a new policy of mandatory registration of all clinical trials. Registration of all trials may also help address the issue of selective reporting in the medical literature.A second observation is that early studies frequently score lower on scales that assess methodologic quality than later, larger, and more definitive studies (Table 1). This finding indicates either that the early studies were less well done or that their reporting was suboptimal. Either way, valuable new initiatives are contributing positively to the quality of reporting of research (and perhaps, by extension, to the actual conduct of research). These include the Consolidated Standards for Reporting Trials,Standards for Reporting of Diagnostic Accuracy,Meta-analysis of Observational Studies in Epidemiology,and Quality of Reporting of Meta-analysis.An important consideration is that existing university advancement schemes for academic promotion may serve as somewhat of a disincentive to multicenter collaboration. By and large, investigators still receive greater academic recognition for being the primary investigators of small trials conducted within their institution than they do for being a site investigator in a large multicenter trial where someone else is the primary investigator.Yet another consideration of relevance to acetylcysteine is that the drug is no longer patent protected. As a result, there is relatively little incentive for industry sponsorship of a large multicenter trial. In such circumstances, small single-center studies are perhaps more likely to be conducted.A PROPOSAL FOR CHANGEThe preceding discussion identifies several areas in which specific changes or interventions could conceivably improve the coordination and conduct of clinical research. First, although the endorsement of mandatory registration of trials as a prerequisite for publication by the ICMJE is necessary, this will not in and of itself be sufficient to improve the coordination of research activity. The registration of clinical trials also needs to be explicitly endorsed by agencies that fund research so that researchers considering new clinical trials actually use the information recorded in trial registries. One potential approach involves mandatory prompting by funding bodies. In such a scenario, a funding agency such as the National Institutes of Health could require researchers to query clinical trial registries before submission of their grant to demonstrate that there are no ongoing trials similar to the one being proposed. If a similar trial exists, the researchers could then be required to either (1) demonstrate how their proposed clinical trial provides added value or differs from the trial already registered (for instance, early in the research process, small RCTs often provide important information on issues such as study feasibility or event rates) or (2) consider whether trial collaboration is feasible (and whether funding agencies will partner with other agencies to facilitate trial collaboration and expansion). This is important to consider given that some funding agencies specify a ceiling for individual grant funding and prohibit cofunding.Second, funding agencies could dictate that a meta-analysis or systematic review of prior studies be routinely presented in the background and rationale of funding applications rather than the current norm of narrative review. Once the literature has been summarized systematically, researchers and reviewers can then make better informed decisions on the need for another trial on a specific treatment. In some instances, it will be clear that existing trials consistently and homogeneously suggest benefit of a treatment without any evidence of publication bias or methodologic concerns. In other cases, it will become apparent that a more definitive trial is needed, as seems to be the case for acetylcysteine.Such policies could be implemented relatively easily for mainstream funding agencies, such as the National Institutes of Health in the United States and the Canadian Institutes of Health Research in Canada. It may be more challenging to enforce such policies for other research funding, such as investigator-initiated grants from the pharmaceutical industry, charitable foundations, or regional and institutional funding bodies. With endorsement and assistance by the academic community, however, the same high standards used for peer review by national funding agencies (and by some of the larger charitable foundations such as the American Heart Association and the Heart and Stroke Foundation of Canada) could be encouraged for smaller funding bodies. Moreover, academic institutions could be encouraged to more strategically use local funding sources to explicitly avoid support of nondefinitive, single-center trials. For instance, rather than providing small amounts to support a small single-center study, institutional funds could be given to a local researcher to support the staging of a planning meeting for a larger multicenter trial.To address the issue of academic recognition for various types of research activity, we propose that the academic community, and specifically university appointment and promotion committees and peer review committees, be encouraged to more explicitly recognize the role of site investigators on multicenter trials. Clinical investigators themselves, of course, need to be encouraged to participate indefinitive multicenter trials on the basis of their eventual important contributions to medical knowledge and patient care, even if current academic merit schemes fail to appropriately reward such contributions.To encourage such participation in trials, we also advocate that the accepted formatting on curriculum vitae be revised to more appropriately reflect the considerable work and responsibility associated with the site investigator role. For example, instead of the traditional reference format for a clinical trial such as the Heart Outcomes Prevention Evaluation (HOPE) Trial(eg, The HOPE Investigators. N Engl J Med.2000;342:145-153), we propose an alternative form that perhaps better represents the contribution of site investigators (eg, [investigator name], site investigator for [center], for the HOPE Investigators. N Engl J Med.2000;342:145-153).THE WAY FORWARD: DIALOGUE TOWARD CONSENSUSThe preceding proposals represent preliminary ideas. Funding agencies, industry, academia, and the ICMJE should now consider the issues and proposals presented herein and engage in dialogue toward specific solutions. Ultimately, such dialogue could convert disorganized and redundant research activity, such as that seen with acetylcysteine, into more coordinated research efforts that are likely to yield more meaningful and definitive research evidence.Correspondence:William A. Ghali, MD, MPH, Faculty of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta, Canada T2N 4N1 (wghali@ucalgary.ca).Accepted for Publication:August 8, 2005.Financial Disclosure:None.Funding/Support:Dr Bagshaw is supported by a Canada Graduate Scholarship Masters Award from the Canadian Institutes for Health Research (Ottawa, Ontario) and by a clinical fellowship from the Alberta Heritage Foundation for Medical Research (Edmonton). Dr McAlister is supported by a Health Scholar Award from the Alberta Heritage Foundation for Medical Research and the Canadian Institutes of Health Research. Dr Manns is supported by the Canadian Institutes of Health Research. 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Acetylcysteine in the Prevention of Contrast-Induced Nephropathy

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American Medical Association
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Copyright 2006 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
ISSN
2168-6106
eISSN
2168-6114
DOI
10.1001/archinte.166.2.161
pmid
16432083
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Abstract

During the past 5 years, 19 randomized controlled trials, 4 prospective nonrandomized studies, and 11 meta-analyses that explored the role of acetylcysteine for prevention of contrast-induced nephropathy have been published. Herein, we summarize this literature and demonstrate that these 34 empirical studies have not yet conclusively resolved this research question. We use the evidence on acetylcysteine as a case study of how research evidence accumulates and consider whether an alternative approach to investigating the question of acetylcysteine's efficacy could have resulted in a more definitive conclusion. We consider the broader lessons learned from this acetylcysteine case study for the medical and research communities and propose specific steps that could be taken to improve the future coordination of research activity to ultimately yield more meaningful and definitive evidence on important clinical questions.We are drowning in information, but starved for knowledgeJohn Nesbitt, Megatrends, 1987The remarkable proliferation of peer-reviewed publications that explore the role of acetylcysteine for prevention of contrast-induced nephropathy (CIN) in the past 5 years is an interesting case study on the evolution of medical knowledge. Since the first clinical trial was published in 2000,another 18 randomized controlled trials (RCTs),4 prospective nonrandomized studies,and 11 meta-analyseshave appeared. Although 5 of the RCTs found statistically significant benefits and 9 concluded that acetylcysteine was beneficial, 13 RCTs reported results that were not statistically significant and 10 concluded that acetylcysteine was not beneficial (Table 1). Likewise, meta-analyses have also yielded conflicting messages, with 7 concluding that acetylcysteine is beneficial and 4 concluding that the data remain inconclusive (Table 2).Table 1. Publication History and Summary of Findings for RCTs on the Efficacy of Acetylcysteine for Prevention of Contrast-Induced NephropathyRCT*PopulationQuality ScoreConcealed Allocation DescribedAcetylcysteine ProtocolHydration ProtocolPrimary OutcomeAcetylcysteine Event Rate, No. (%)Control Event Rate, No. (%)Summary RR (95% CI)†Tepel et al(n = 83)Elective CT2Unclear600 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>44.2-&mgr;mol/L SCr increase at 48 h1/41 (2)9/42 (21)0.11 (0.02-0.86)Diaz-Sandoval et al(n = 54)Elective angiography4Unclear600 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 2-12 h pre and 12 h post>44.2-&mgr;mol/L or 25% SCr increase at 48 h2/25 (8)13/29 (45)0.18 (0.04-0.72)Briguori et al(n = 183)Elective angiography1Unclear600 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>25% SCr increase at 48 h or dialysis6/92 (7)10/91 (11)0.59 (0.23-1.57)Vallero et al(n = 100)Angiography2Unclear600 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 1-2 h pre and 24 h post>44.2-&mgr;mol/L or 33% SCr increase at 48 h4/47 (9)4/53 (8)1.1 (0.3-4.3)Shyu et al(n = 121)Elective angiography3Unclear400 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>44.2-&mgr;mol/L SCr increase at 48 h2/60 (3)15/61 (25)0.13 (0.08-0.2)Allaqaband et al(n = 85)Angiography3Unclear600 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>44.2-&mgr;mol/L SCr increase at 48 h8/45 (18)6/40 (15)1.2 (0.47-3.3)Durham et al(n = 83)Angiography5Adequate1200 mg orally 1 h pre and 3 h post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>44.2-&mgr;mol/L SCr increase at 48 h10/38 (26)9/41 (22)1.2 (0.55-2.6)Kay et al(n = 200)Elective angiography5Adequate600 mg orally twice daily 4 times (3 pre)0.9% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre and 6 h post>25% SCr increase at 48 h4/102 (4)12/98 (12)0.32 (0.11-0.96)Baker et al(n = 80)Angiography2Unclear150 mg/kg intravenously 30 min pre and 50 mg/kg intravenous infusion 4 h postControl 0.9% isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>25% SCr increase at 48 or 96 h2/41 (5)8/39 (21)0.28 (0.08-0.98)MacNeill et al(n = 43)Elective angiography4Unclear600 mg orally 5 times (2 pre)Inpatient: 0.45% isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre; outpatient: 0.45% isotonic sodium chloride solution, 2 mL/kg hourly 4 h pre and 12 h post>25% SCr increase at 72 h1/21 (5)7/22 (32)0.15 (0.02-1.1)&numsp;   RCT*PopulationQuality ScoreConcealed Allocation DescribedAcetylcysteine ProtocolHydration ProtocolPrimary OutcomeAcetylcysteine Event Rate, No. (%)Control Event Rate, No. (%)Summary RR (95% CI)†Efrati et al(n = 49)Elective angiography4Unclear1000 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>25% SCr increase at 24 or 96 h0/24 (0)2/25 (8)NAOldemeyer et al(n = 96)Elective angiography4Unclear1500 mg twice daily 4 times (1 pre)0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>44.2-&mgr;mol/L or 25% SCr increase at 48 h4/49 (8)3/47 (6)1.28 (0.30-5.4)Kefer et al(n = 104)Angiography4Unclear1200 mg intravenously 12 h pre and immediately postDextrose 5%, 20 mL/h 12 h pre and 24 h post>44.2-&mgr;mol/L SCr increase at 24 h2/53 (8)3/51 (6)0.64 (0.1-3.7)Goldenberg et al(n = 80)Angiography5Adequate600 mg orally twice daily pre/post0.45% Isotonic sodium chloride solution, 1 mL/kg hourly 12 h pre/post>44.2-&mgr;mol/L SCr increase at 48 h4/41 (10)3/39 (8)1.30 (0.27-6.2)‡Fung et al(n = 91)Elective angiography4Adequate400 mg orally 3 times daily pre/post0.9% Isotonic sodium chloride solution, 100 mL/h 12 h pre/post>44.2-&mgr;mol/L or 25% decrease in GFR8/46 (17)6/45 (13)1.3 (0.5-3.5)Ochoa et al(n = 80)Angiography3Adequate1000 mg orally 1 h pre and 4 h post0.9% Isotonic sodium chloride solution, ≥1500 mL>44.2-&mgr;mol/L or 25% SCr increase at 48 h3/36 (8)11/44 (25)0.33 (0.1-1.1)Webb et al(n = 487)Angiography3Adequate500 mg intravenously pre0.9% Isotonic sodium chloride solution, 200 mL pre and 1.5 mL/kg hourly for 6 h post>5-mL/min decrease in GFR (or>44.2-&mgr;mol/L SCr increase at 48 h)51/220 (23) (16/200 [7.3])47/227 (21) (13/227 [5.7])1.1 (0.8-1.6)Miner et al(n = 171)Angiography4Unclear2000 mg orally 2-3 times pre0.45% Isotonic sodium chloride solution, 75 mL/h for 24 h>25% SCr increase at 48-72 h9/89 (10)18/82 (22)0.37 (0.14-0.93)Rashid et al(n = 94)Elective angiography4Unclear1000 mg intravenously pre/post0.9% Isotonic sodium chloride solution, 500 mL pre/post>44.2-&mgr;mol/L or 25% SCr increase at 48 h3/46 (6.5)3/48 (6.3)1.0 (0.2-4.9) Abbreviations: CI, confidence interval; CT, computed tomography; GFR, glomerular filtration rate; NA, not applicable; pre, preoperatively; post, postoperatively; RCT, randomized controlled trial; RR, relative risk; SCr, serum creatinine.  Conventional unit conversion factor: To convert SCr to milligrams per deciliter, divide by 88.4. *All trials were single center except the ones by Baker et al(multicenter, 3 sites) and Webb et al(multicenter, 2 sites). †Pooled RR estimate calculated from available data for selected studies. ‡Pooled estimate is odds ratio.Table 2. Publication History and Summary of Findings for Meta-analyses on the Efficacy of Acetylcysteine for Prevention of Contrast-Induced NephropathySourceClinical ScopeStudies Included*No. of Trials IncludedNo. of Patients IncludedHeterogeneity (PValue)Pooled Estimate (95% CI)Author ConclusionsBirck et alCT or angiographyA7805Present (P = .02)RR, 0.44 (0.22-0.88)Treatment beneficialIsenbarger et alCT or angiographyA7805Present (P = .01)OR, 0.37 (0.16-0.84)Treatment beneficialAlonso et alCT or angiographyA, B8885Not reportedRR, 0.41 (0.22-0.79)Treatment beneficialKshirsagar et alCT or angiographyA, B161538Present (P<.001)Not reportedInconclusivePannu et alCT or angiographyA, B, D151776Present (P = .02)RR, 0.65 (0.43-1.0)InconclusiveGuru and FremesCT or angiographyA, C111213Present (P = .01)OR, 0.46 (0.32-0.66)Treatment beneficialBagshaw and GhaliAngiographyA141261Present (P = .03)OR, 0.54 (0.32-0.91)InconclusiveMisra et alAngiographyA5643Present (P = .05)RR, 0.30 (0.11-0.82)Treatment beneficialNallamothu et alCT or angiographyA, D202195Present (P = .01)RR, 0.73 (0.52-1.0)InconclusiveLiu et alCT or angiographyA, B91028Present (P = .03)RR, 0.43 (0.24-0.75)Treatment beneficialDuong et alCT or angiographyA, C141584Present (P = .01)RR, 0.57 (0.37-0.84)Treatment beneficial Abbreviations: CI, confidence interval; CT, computed tomography; OR, odds ratio; RR, relative risk. *Source(s) of data for meta-analyses: A indicates published articles describing randomized controlled trials; B, published abstracts describing randomized controlled trials; C, published articles describing nonrandomized clinical trials; and D, unpublished data.WHY SO MANY RCTs?Generally, the design, planning, and completion of RCTs represent a substantial undertaking that demands considerable resources. However, several aspects of acetylcysteine and the target condition (CIN) may have contributed to the rapid proliferation of RCTs on this topic. Notably, radiocontrast use is frequent, CIN is relatively common and potentially preventable, and acetylcysteine has established familiarity with clinicians, is inexpensive, and poses relatively little risk to patients. Also, the primary outcome in these trials (change in serum creatinine level) is easy to measure and requires limited patient follow-up. Finally, the stimuli provided to trialists by virtue of the first trial on this topicbeing published in a major front-line journal and reporting a large treatment effect (but with wide confidence intervals) should not be discounted.It is conceivable that the relative ease of conducting these studies encouraged less experienced groups to perform clinical trials, a notion perhaps supported by the predominance of small single-center studies. However, many of the acetylcysteine trials were well done and scored highly on a widely accepted scale assessing RCT quality(Table 1).WHY SO MANY META-ANALYSES?The appearance of several trials in such a short period also seems to have created a scenario that appealed to many as a subject for meta-analysis, particularly given the divergent results across trials. A common misperception, however, is that meta-analyses can serve as a tool for simply resolving contradictory data. In fact, pooling of data to arrive at a summary estimate for treatment efficacy should generally be avoided in situations where the trials exhibit significant statistical and/or clinical heterogeneity.This is not to say that meta-regression cannot be used as a tool to explore the reasons for discordant data and develop hypotheses, but meta-analysis to generate a pooled estimate should not be seen as a means to resolve discordant data.Statistical heterogeneity is present when the variation in results across individual studies is beyond that expected from chance alone.When present, quantitative pooling may lead to erroneous conclusions.Interestingly, the pooled efficacy estimates for acetylcysteine across meta-analyses published to date are generally similar, but the disparate interpretations arise from differences in how the meta-analysts deal with the issue of heterogeneity. The 7 meta-analyses that concluded that acetylcysteine was beneficial largely overlooked the issue of heterogeneity,whereas the 4 that highlighted the presence of heterogeneity concluded that the data were still inconclusive.Clinical heterogeneity, meanwhile, is judged by examining the patient populations, eligibility criteria, intervention protocols, cointerventions, and primary outcomes in a group of trials. Table 1confirms considerable clinical heterogeneity across the trials of acetylcysteine, and the disparate conclusions from the meta-analyses published to date may partially relate to different study inclusion criteria (published RCTs only vs inclusion of unpublished data, abstracts, and/or nonrandomized studies)or inclusion of different patient populations and procedures (ie, 2 meta-analyses focused only on arterial angiography). Additionally, earlier meta-analyses are more likely to be influenced by time-lag bias,since small clinical trials are more likely to be published early if they find large benefits and clinical trials that report fewer benefits (even if they include more outcome events) are less likely to be published or tend to be published later(Table 2).Thus, given the clinical trial data published to date, meta-analysis cannot resolve the uncertainty engendered by 19 small RCTs with heterogeneous results for a surrogate outcome (change in serum creatinine level rather than “harder” end points, such as need for dialysis or mortality). In fact, for a trial to detect a meaningful reduction in risk for a clinically important outcome such as need for dialysis even in a high-risk cohort (for example, with a baseline risk of dialysis approaching 7%), researchers would need to enroll more than 1800 patients.Ultimately, a much larger trial with high methodologic quality that involves multiple centers to achieve sufficient power to study clinically meaningful outcomes is needed to definitively resolve whether acetylcysteine prevents CIN.COMMENTDespite the proliferation of acetylcysteine studies, we still do not know whether acetylcysteine is efficacious for the prevention of CIN. This raises the question of whether the medical community would have been better served by an alternative approach to the investigation of acetylcysteine for CIN.A first observation is that the research performed to date on acetylcysteine has occurred without any obvious coordination of activity across research groups. This lack of coordination amounts to a missed opportunity; if the authors of the published trials had initially collaborated on a large multicenter trial like that described herein, more definitive evidence could have been produced.Encouragingly, new initiatives exist that may enhance the coordination of research activity in the future. These initiatives include searchable registries that can inform researchers of ongoing trials in specific clinical areas and therefore potentially reduce duplication and enhance the coordination of research activity; for example, see the National Library of Medicine (ClinicalTrials.gov), Veteran Affairs Cooperative Studies Program (www.vacsp.gov), the Cochrane Central Register of Controlled Trials (www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/HOME), and the Current Controlled Trials (www.controlled-trials.com/mrct) Web sites.These clinical trial registry initiatives will assume greater importance now that the International Committee of Medical Journal Editors (ICMJE) has drawn attention to the importance of comprehensive clinical trial registries and imposed a new policy of mandatory registration of all clinical trials. Registration of all trials may also help address the issue of selective reporting in the medical literature.A second observation is that early studies frequently score lower on scales that assess methodologic quality than later, larger, and more definitive studies (Table 1). This finding indicates either that the early studies were less well done or that their reporting was suboptimal. Either way, valuable new initiatives are contributing positively to the quality of reporting of research (and perhaps, by extension, to the actual conduct of research). These include the Consolidated Standards for Reporting Trials,Standards for Reporting of Diagnostic Accuracy,Meta-analysis of Observational Studies in Epidemiology,and Quality of Reporting of Meta-analysis.An important consideration is that existing university advancement schemes for academic promotion may serve as somewhat of a disincentive to multicenter collaboration. By and large, investigators still receive greater academic recognition for being the primary investigators of small trials conducted within their institution than they do for being a site investigator in a large multicenter trial where someone else is the primary investigator.Yet another consideration of relevance to acetylcysteine is that the drug is no longer patent protected. As a result, there is relatively little incentive for industry sponsorship of a large multicenter trial. In such circumstances, small single-center studies are perhaps more likely to be conducted.A PROPOSAL FOR CHANGEThe preceding discussion identifies several areas in which specific changes or interventions could conceivably improve the coordination and conduct of clinical research. First, although the endorsement of mandatory registration of trials as a prerequisite for publication by the ICMJE is necessary, this will not in and of itself be sufficient to improve the coordination of research activity. The registration of clinical trials also needs to be explicitly endorsed by agencies that fund research so that researchers considering new clinical trials actually use the information recorded in trial registries. One potential approach involves mandatory prompting by funding bodies. In such a scenario, a funding agency such as the National Institutes of Health could require researchers to query clinical trial registries before submission of their grant to demonstrate that there are no ongoing trials similar to the one being proposed. If a similar trial exists, the researchers could then be required to either (1) demonstrate how their proposed clinical trial provides added value or differs from the trial already registered (for instance, early in the research process, small RCTs often provide important information on issues such as study feasibility or event rates) or (2) consider whether trial collaboration is feasible (and whether funding agencies will partner with other agencies to facilitate trial collaboration and expansion). This is important to consider given that some funding agencies specify a ceiling for individual grant funding and prohibit cofunding.Second, funding agencies could dictate that a meta-analysis or systematic review of prior studies be routinely presented in the background and rationale of funding applications rather than the current norm of narrative review. Once the literature has been summarized systematically, researchers and reviewers can then make better informed decisions on the need for another trial on a specific treatment. In some instances, it will be clear that existing trials consistently and homogeneously suggest benefit of a treatment without any evidence of publication bias or methodologic concerns. In other cases, it will become apparent that a more definitive trial is needed, as seems to be the case for acetylcysteine.Such policies could be implemented relatively easily for mainstream funding agencies, such as the National Institutes of Health in the United States and the Canadian Institutes of Health Research in Canada. It may be more challenging to enforce such policies for other research funding, such as investigator-initiated grants from the pharmaceutical industry, charitable foundations, or regional and institutional funding bodies. With endorsement and assistance by the academic community, however, the same high standards used for peer review by national funding agencies (and by some of the larger charitable foundations such as the American Heart Association and the Heart and Stroke Foundation of Canada) could be encouraged for smaller funding bodies. Moreover, academic institutions could be encouraged to more strategically use local funding sources to explicitly avoid support of nondefinitive, single-center trials. For instance, rather than providing small amounts to support a small single-center study, institutional funds could be given to a local researcher to support the staging of a planning meeting for a larger multicenter trial.To address the issue of academic recognition for various types of research activity, we propose that the academic community, and specifically university appointment and promotion committees and peer review committees, be encouraged to more explicitly recognize the role of site investigators on multicenter trials. Clinical investigators themselves, of course, need to be encouraged to participate indefinitive multicenter trials on the basis of their eventual important contributions to medical knowledge and patient care, even if current academic merit schemes fail to appropriately reward such contributions.To encourage such participation in trials, we also advocate that the accepted formatting on curriculum vitae be revised to more appropriately reflect the considerable work and responsibility associated with the site investigator role. For example, instead of the traditional reference format for a clinical trial such as the Heart Outcomes Prevention Evaluation (HOPE) Trial(eg, The HOPE Investigators. N Engl J Med.2000;342:145-153), we propose an alternative form that perhaps better represents the contribution of site investigators (eg, [investigator name], site investigator for [center], for the HOPE Investigators. N Engl J Med.2000;342:145-153).THE WAY FORWARD: DIALOGUE TOWARD CONSENSUSThe preceding proposals represent preliminary ideas. Funding agencies, industry, academia, and the ICMJE should now consider the issues and proposals presented herein and engage in dialogue toward specific solutions. Ultimately, such dialogue could convert disorganized and redundant research activity, such as that seen with acetylcysteine, into more coordinated research efforts that are likely to yield more meaningful and definitive research evidence.Correspondence:William A. Ghali, MD, MPH, Faculty of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta, Canada T2N 4N1 (wghali@ucalgary.ca).Accepted for Publication:August 8, 2005.Financial Disclosure:None.Funding/Support:Dr Bagshaw is supported by a Canada Graduate Scholarship Masters Award from the Canadian Institutes for Health Research (Ottawa, Ontario) and by a clinical fellowship from the Alberta Heritage Foundation for Medical Research (Edmonton). Dr McAlister is supported by a Health Scholar Award from the Alberta Heritage Foundation for Medical Research and the Canadian Institutes of Health Research. Dr Manns is supported by the Canadian Institutes of Health Research. 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Journal

JAMA Internal Medicine – American Medical Association

Published: Jan 23, 2006

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